02 Linfoma Cutaneos

NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®)
Primary Cutaneous
Lymphomas
Version 2.2024 — May 6, 2024
NCCN.org
NCCN Guidelines for Patients® available at www.nccn.org/patients
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Version 2.2024, 05/06/24 © 2024 National Comprehensive Cancer Network® (NCCN®), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN.
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NCCN Guidelines Version 2.2024 NCCN Guidelines Index

Table of Contents
Primary Cutaneous Lymphomas Discussion
*Steven M. Horwitz, MD/Chair † Þ Bradley M. Haverkos, MD, MPH, MS † *Sima Rozati, MD, PhD ϖ
Memorial Sloan Kettering Cancer Center University of Colorado Cancer Center The Sidney Kimmel Comprehensive
*Stephen Ansell, MD, PhD/Vice-Chair ‡ Francisco Hernandez-Ilizaliturri, MD † Cancer Center at Johns Hopkins
Mayo Clinic Comprehensive Cancer Center Roswell Park Comprehensive Cancer Center Jonathan Said, MD ≠
Weiyun Z. Ai, MD, PhD † ‡ Richard T. Hoppe, MD § UCLA Jonsson Comprehensive Cancer Center
UCSF Helen Diller Family Stanford Cancer Institute Aaron Shaver, MD, PhD ≠
Comprehensive Cancer Center Eric Jacobsen, MD † Vanderbilt-Ingram Cancer Center
Jeffrey Barnes, MD, PhD † Dana-Farber/Brigham and Lauren Shea, MD ‡
Mass General Cancer Center Women's Cancer Center O'Neal Comprehensive Cancer Center at UAB
Stefan K. Barta, MD, MRCP, MS † ‡ Deepa Jagadeesh, MD, MPH † ‡ *Michi M. Shinohara, MD ϖ ≠
Abramson Cancer Center Case Comprehensive Cancer Center/ Fred Hutchinson Cancer Center
at the University of Pennsylvania University Hospitals Seidman Cancer Center and
Cleveland Clinic Taussig Cancer Institute Lubomir Sokol, MD, PhD † ‡ Þ
Jonathan Brammer, MD ‡ Moffitt Cancer Center
The Ohio State University Comprehensive Allison Jones, MD ϖ
Cancer Center - James Cancer Hospital St. Jude Children's Research Hospital/ Matthew Stephany, MD ϖ
and Solove Research Institute The University of Tennessee Health Science Center Fred & Pamela Buffett Cancer Center
Mark W. Clemens, MD ʘ *Youn H. Kim, MD ϖ † Susan Thornton ¥
The University of Texas Stanford Cancer Institute Patient Advocate
MD Anderson Cancer Center Kiran Kumar, MD, MBA § Carlos Torres-Cabala, MD ≠
Utpal P. Davé, MD ‡ UT Southwestern Simmons The University of Texas
Indiana University Melvin and Bren Simon Comprehensive Cancer Center MD Anderson Cancer Center
Comprehensive Cancer Center *Neha Mehta-Shah, MD, MSCI † ‡ Ryan Wilcox, MD, PhD † ‡
Ahmet Dogan, MD, PhD ≠ Siteman Cancer Center at Barnes- University of Michigan
Memorial Sloan Kettering Cancer Center Jewish Hospital and Washington Rogel Cancer Center
University School of Medicine Peggy Wu, MD, MPH ϖ
Francine Foss, MD † ‡ ξ
Yale Cancer Center/Smilow Cancer Hospital Elise A. Olsen, MD ϖ † UC Davis Comprehensive Cancer Center
Duke Cancer Institute Jasmine Zain, MD † ‡
Zachary Frosch, MD, MSHP ‡
Fox Chase Cancer Center Saurabh A. Rajguru, MD † ‡ City of Hope National Medical Center
University of Wisconsin
Aaron M. Goodman, MD ‡ ξ Carbone Cancer Center
UC San Diego Moores Cancer Center NCCN
Peter Riedell, MD ‡ Mary Dwyer, MS
Joan Guitart, MD ≠ ϖ The UChicago Medicine Hema Sundar, PhD
Robert H. Lurie Comprehensive Cancer Comprehensive Cancer Center
Center of Northwestern University ξ Bone marrow transplantation ≠ Pathology
ϖ Dermatology ¥ Patient advocacy
Ahmad Halwani, MD ‡ Continue ‡ Hematology/Hematology ʘ Plastic surgery
Huntsman Cancer Institute
oncology § Radiotherapy/Radiation oncology
at the University of Utah Þ Internal medicine * Discussion Section Writing
NCCN Guidelines Panel Disclosures † Medical oncology Committee Member

Table of Contents
NCCN Primary Cutaneous Lymphomas Panel Members

Summary of the Guidelines Updates Clinical Trials: NCCN believes that
the best management for any patient
Primary Cutaneous B-Cell Lymphomas Primary Cutaneous CD30+ T-Cell with cancer is in a clinical trial.
• Principles of Primary Cutaneous B-Cell Lymphomas Lymphoproliferative Disorders Participation in clinical trials is
(CUTB/INTRO) • Principles of Primary Cutaneous CD30+ especially encouraged.
• Diagnosis and Workup (CUTB-1) T-Cell Lymphoproliferative Disorders Find an NCCN Member Institution:
• Primary Cutaneous Marginal Zone Lymphoma (CUTB-2) (PCTLD/INTRO-1) https://www.nccn.org/home/member-
• Primary Cutaneous Follicle Center Lymphoma (CUTB-2) • Diagnosis (PCTLD-1) institutions.
• TNM Classification of Cutaneous Lymphoma other than • Workup (PCTLD-2)
MF/SS (CUTB-A) • Primary Cutaneous ALCL (PCTLD-4) NCCN Categories of Evidence and
• Treatment References (CUTB-B) • Lymphomatoid Papulosis (PCTLD-5) Consensus: All recommendations
Mycosis Fungoides/Sézary Syndrome (MF/SS) • Therapy References (PCTLD-A) are category 2A unless otherwise
• Principles for Mycosis Fungoides/Sézary Syndrome specified.
(MFSS/INTRO-1) Principles of Radiation Therapy (PCLYM-A)
See NCCN Categories of Evidence
• General Principles (MFSS/INTRO-2) Principles of Molecular Analysis in Primary and Consensus.
• Diagnosis (MFSS-1) Cutaneous Lymphomas (PCLYM-B)
• Workup (MFSS-2) NCCN Categories of Preference:
• TNMB Classification and Staging (MFSS-3) Supportive Care for Patients With Cutaneous All recommendations are considered
• Clinical Staging (MFSS-4) Lymphomas (PCLYM-C) appropriate.
• Stage IA (Limited Skin Involvement Alone, <10% BSA)
(MFSS-6) Use of Immunophenotyping/Genetic Testing See NCCN Categories of
• Stage IB (Skin Only Disease with ≥10% BSA) - Stage IIA in Differential Diagnosis of Mature B-Cell and Preference.
(MFSS-7) NK/T-Cell Neoplasms (See NCCN Guidelines
• Stage IIB (Tumor Stage Disease) (MFSS-8) for B-Cell Lymphomas - NHODG-A)
• Stage III (Erythrodermic Disease) (MFSS-10)
• Stage IV (MFSS-11) For Primary Cutaneous Diffuse Large B-Cell
• Large Cell Transformation (LCT) (MFSS-12) Lymphoma, Leg Type (See NCCN Guidelines
• Suggested Treatment Regimens (MFSS-A) for B-Cell Lymphomas - DLBCL)
• Supportive Care (MFSS-B)
Classification (ST-1)
Abbreviations (ABBR-1)
The NCCN Guidelines® are a statement of evidence and consensus of the authors regarding their views of currently accepted approaches to
treatment. Any clinician seeking to apply or consult the NCCN Guidelines is expected to use independent medical judgment in the context of individual
clinical circumstances to determine any patient’s care or treatment. The National Comprehensive Cancer Network® (NCCN®) makes no representations
or warranties of any kind regarding their content, use or application and disclaims any responsibility for their application or use in any way. The NCCN
Guidelines are copyrighted by National Comprehensive Cancer Network®. All rights reserved. The NCCN Guidelines and the illustrations herein may not
be reproduced in any form without the express written permission of NCCN. ©2024.

Table of Contents
Terminologies in all NCCN Guidelines are being actively modified to advance the goals of equity, inclusion, and representation.
Updates in Version 2.2024 of the NCCN Guidelines for Primary Cutaneous Lymphomas from Version 1.2024 include:
MS-1
• Discussion section updated to reflect changes in the algorithm.
Global changes
• References updated throughout the guideline.
Primary Cutaneous B-Cell Lymphomas
CUTB/INTRO-1
• Overview & Definition
2nd subtype modified: Primary cutaneous marginal zone lymphoma (PCMZL)(WHO)/Primary cutaneous marginal zone lymphoproliferative disorder (ICC)
• Diagnosis
PCMZL, 2nd bullet, 1st sub-bullet modified: Immunophenotype – cells are negative for CD10 and BCL6, but are often positive for BCL2, CD20, CD79a.
PCDLBCL, leg type, 2nd bullet modified: Gene expression profiling: PCDLBCL, leg type has been demonstrated to be always most commonly activated B-cell (ABC)
subtype.
CUTB-1
• Diagnosis
Essential
◊ 1st bullet added: Biopsy of suspicious skin sites, Multiple biopsies may be necessary to capture the pathologic variability of disease at diagnosis
◊ 3rd bullet modified: Adequate biopsy (by punch, incisional, excisional) of all types of clinical lesions present will aid in final diagnosis
Useful in certain circumstances,
◊ 1st bullet, 2nd sub-bullet modified: Assessment of IgM, IgD, IgA, IgG, IgE, and FOXP1
◊ 4th bullet modified: If adequate biopsy material is available, flow cytometry or molecular analysis to detect IgH gene rearrangement studies can be useful in
determining B-cell clonality
CUTB-A (1 of 2)
• Footnote removed: Patients with both erythroderma and tumors may be designated as T4(T3). The BSA of 80% is used to define erythroderma in MF/SS at study
entry, but any decrease in BSA during the study does not affect the entry classification.
Mycosis Fungoides/Sézary Syndrome

MFSS-1
• Diagnosis
Essential, 2nd bullet modified: Review of a sufficient number of slides with adequate material to perform a comprehensive work-up as described below and/or at least
one paraffin block representative of the tumor lesion should be done by a pathologist...
MFSS-2
• Workup
Useful in certain circumstances, 2nd bullet modified: ...Rebiopsy if consult material is nondiagnostic. Rebiopsy if pathological findings are non-diagnostic and/or
discordant with the clinical presentation.
MFSS-3
• Description added: Changes or confirmation of staging are noted in bold in table above and in further description below. Options for characterizing clonality further by
designation as A (clone negative or equivocal) and B (clone positive and identical to skin) are presented. If a clone in LN or viscera is detected but different from that
identified in the skin, another concurrent lymphoproliferative process should be considered. Continued
UPDATES

Table of Contents
MFSS-3A
• Footnote x modified by adding: Patients with lymphopenia (defined as <1000 absolute lymphocytes) may potentially have an underestimation of aberrant lymphocyte
burden if assessed only by the absolute number and not also by the percentage of immunophenotypically abnormal lymphocytes.
MFSS-4
• IVB (Visceral disease), M(visceral) cell modified: M1A or M1B
• Footnote y reference updated: Olsen E, et al. Blood 2007;110:1713-1722 Olsen EA, et al. Blood 2022;140:419-437.
MFSS-7
• Stage IIB, Treatment and response assessment
Inadequate response, option modified: Retreat with primary treatment or treat as high skin disease burden (see below)
MFSS-8
• Stage IIB, Treatment and response assessment
CR/PR, relapse options modified:
◊ T1–2 with limited tumor lesions See Table 1 or See Table 2)
◊ T3 with limited tumor lesions
Inadequate response, option modified: Persistent T1–T3 with limited tumor lesions (also for MFSS-9)
MFSS-A (2 of 12)
• Treatment Considerations
2nd option modified: Cumulative dose of UV, in particular PUVA, which carries a higher risk than NBUVB, is associated with increased risk of UV-associated skin
neoplasms...
7th option modified: Topical mechlorethamine has no significant systemic absorption, and can be used alone or in combination with other skin directed therapies, in
particular topical steroids. Topical mechlorethamine use, in particular gel preparation, can be complicated by dermatitis, and can result in skin irritation when used
on face and intertriginous body areas. Consider initiating at less than daily use to determine tolerability. Slowly increase the application of topical mechlorethamine
to once daily five times per week. Initiating at less than daily use can be useful to determine tolerability and topical steroids can be considered as needed to alleviate
skin reactions from topical mechlorethamine gel. If used with phototherapy, topical mechlorethamine gel should be applied after exposure to UVL.
MFSS-A (3 of 12)
• Treatment Considerations
5th option modified: In stage IA, ECP is primarily reserved for the uncommon stage IA patients rare patient with stage IA MF with low level blood involvement (B1).
MFSS-A (5 of 12)
• Limited Tumor Disease
2nd bullet modified: Systemic therapy ± local RT ± skin-directed therapy
MFSS-A (9 of 12)
• Footnote b modified: Interferon alfa (2a and 2b) and peginterferon alfa-2b have been discontinued. Peginterferon alfa-2a may be substituted for other interferon
preparations (Schiller M, et al. J Eur Acad Dermatol Venerol 2017;31:1841-1847). Peginterferon alfa-2a is the only interferon available for clinical use in the US and
it may be substituted for other interferon preparations.(Schiller M, et al. J Eur Acad Dermatol Venerol 2017;31:1841-1847; Patsatsi A, et al. J Eur Acad Dermatol
Venereol 2022;36:e291-e293; Osman S, et al. Dermatologic Therapy 2023;2023:7171937).
Continued
UPDATES

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Primary Cutaneous CD30+ T-Cell Lymphoproliferative Disorders

PCTLD-1
• Diagnosis, essential
3rd bullet modified: Complete skin examination for evidence of MF for any sign of benign or malignant skin lesions
4th bullet,
◊ 1st sub-bullet added: Multiple biopsies may be necessary to capture the pathologic variability of disease at diagnosis
◊ 2nd sub-bullet modified: Adequate biopsy (by punch, incisional, or excisional) of all types of clinical lesions present will aid in final diagnosis
Principles of Radiation Therapy

PCLYM-A 1 of 3
• General principles
2nd bullet modified: Treatment External beam radiation therapy (EBRT) with photons, electrons, or low-energy x-rays may all be appropriate, depending on clinical
circumstances.
PCLYM-A 2 of 3
• General dose guidelines
PCMZL and PCFCL,1st bullet modified: Optimal initial management for solitary/regional disease is with 24–30 Gy external beam radiation therapy (EBRT).
Alternatively, lower doses (eg, 4 Gy) may be used initially, with supplemental RT (4-20 Gy) for inadequate response or subsequent local failure.
MF/SS
◊ 1st bullet modified: Treatment of individual patches, plaques or tumors
– 1st sub-bullet modified: Optimal management for individual plaque and tumor lesions is with EBRT, 8–12 Gy given with palliative intent (usually as combined
modality therapy; 8 Gy may be given in 1–2 fractions). Even lower doses (4 Gy) may achieve a similar response, but these may be less durable.
– 2nd sub-bullet modified: For unilesional MF at initial presentation, 24–30 Gy.
◊ TSEBT
– 2nd bullet modified: The dose range is 12–36 Gy, generally 4–6 Gy per week. The common dose is ~12 Gy, generally 4–6 Gy per week. Higher doses (24-36
Gy) have been used for more advanced or refractory disease. The advantages of a lower total dose includes fewer short-term complications and better ability to
retreat for relapsed disease
Supportive Care
PCLYM-C
• Monoclonal Antibody (mAb) Therapy and Viral Reactivation, bullet removed: Anti-CD20 Antibody Therapy - See NCCN Guidelines for B-Cell Lymphomas
UPDATES

Table of Contents
Primary Cutaneous B-Cell Lymphomas Discussion
Overview & Definition PRINCIPLES FOR PRIMARY CUTANEOUS B-CELL LYMPHOMAS (PCBCL)
Three subtypes of PCBCL:
1. Primary cutaneous follicle center lymphoma (PCFCL)
• Most common subtype of PCBCL (57%),1,2 located primarily in the scalp, face, forehead, and trunk, usually with indolent course and
excellent prognosis (5-year overall survival [OS] rate is >95%).
• Typically presents as solitary, firm, and pink to violaceous papules, nodules, plaques, or tumors. Multifocal skin lesions are seen in 15%
of cases.1,2 Ulceration is rare.
• Dissemination to extracutaneous sites is extremely uncommon; cutaneous recurrences occur near the initial site in approximately 30%
of cases.
2. Primary cutaneous marginal zone lymphoma (PCMZL) (WHO5)/Primary cutaneous marginal zone lymphoproliferative disorder (ICC)
• Second most common subtype of PCBCL (24%–31%)1 with distribution primarily on the trunk, upper extremities, and head. Typically
presents as solitary or multiple erythematous to violaceous papules, small nodules, plaques, or tumors with indolent course and
excellent prognosis (5-year survival rate is 99%).
• Relapses in the skin occur in 50% of patients.
3. Primary cutaneous diffuse large B-cell lymphoma (PCDLBCL, leg type)
• The rarest subtype of PCBCL (11%–19%), constituting 4% of all primary cutaneous lymphomas. It is distributed mostly to the leg, but
not uncommonly (10%–15%) can be found in other sites.1
• Typical clinical presentation is red to bluish plaques or tumors located on one or both legs that can ulcerate.
• It is usually aggressive and associated with a poor prognosis (high frequency of extracutaneous relapses) (5-year OS rate is 50%).2,3
• Multiple skin lesions, inactivation of CDKN2A, and MYD88 L265P associated with inferior prognosis.
Diagnosis
• PCFCL: punch biopsy/incision/excision of skin lesion preferred to shave biopsy
Immunophenotype – cells express CD20, CD79a, and BCL6; surface Ig is negative. CD10 can be negative in cases with diffuse growth
pattern. BCL2 is usually negative, or minimally expressed.
When CD10 and BCL2 are strongly expressed, or BCL2 is rearranged, consider a nodal follicular lymphoma (FL) with secondary skin involvement.
Germinal (or follicle) center phenotype with large cells in a skin lesion is consistent with PCFCL with a diffuse population of large cells
(PCFCL-LC) and should not be considered as DLBCL.
• PCMZL: punch biopsy/incision/excision of skin lesion preferred to shave biopsy
Immunophenotype – cells are negative for CD10 and BCL6, but are often positive for BCL2, CD20, and CD79a. IgG4 can be expressed in
about a third of cases.
Can be divided into 2 groups with different prognosis based on the immunoglobulin heavy chain IgH gene rearrangement: 1) CXCR3-
negative and Ig class-switched subtype (IgG, IgA, and IgE), characterized by nodular infiltrates of plasma cells; and 2) a less common
subtype that is CXCR3-positive and IgM positive (non class-switched), which may have extracutaneous extension.4-7 IgG class-switched
subtype is a clonal chronic lymphoproliferative disorder (LPD), with indolent course.7,8
• PCDLBCL, leg type: punch biopsy/incision/excision of skin lesion preferred to shave biopsy
Immunophenotype – cells express CD20, CD79a, monotypic immunoglobulins, BCL2 (strong), IRF/MUM1, FOXP1, and MYC. CD10 staining
is usually negative.
Gene expression profiling: PCDLBCL, leg type has been demonstrated to be most commonly activated B-cell (ABC) subtype. Germinal
center B-cell (GCB) subtype should be considered PCFCL, even if large cells are present.9,10
Fluorescence in situ hybridization (FISH): frequently shows translocations of MYC, BCL6, and IGH genes.
Note: All recommendations are category 2A unless otherwise indicated. Continued
Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.
CUTB/INTRO-1

Table of Contents
PRINCIPLES FOR PRIMARY CUTANEOUS B-CELL LYMPHOMAS (PCBCL)

General Principles
• PCFCL, PCMZL: If the pathology or clinical presentation is not typical, complete staging with chest/abdominal/pelvic CT and/or FDG-PET/
CT scan to rule out systemic involvement. Low-dose localized radiation therapy (RT), topical or intralesional steroids, or observation are
excellent treatment options.
• PCDLBCL, leg type: Complete staging with FDG-PET/CT scan. Treat with chemoimmunotherapy and localized RT. (See NCCN Guidelines for
B-Cell Lymphomas - DLBCL)
1 Willemze R, Cerroni L, Kempf W, et al. The 2018 update of the WHO-EORTC classification for primary cutaneous lymphomas. Blood 2019;133:1703-1714.
2 Zinzani PL, Quaglino P, Pimpinelli N, et al. Prognostic factors in primary cutaneous B-cell lymphoma: the Italian Study Group for Cutaneous Lymphomas. J Clin Oncol
2006;24:1376-1382.
3 Felcht M, Klemke CD, Nicolay JP, et al. Primary cutaneous diffuse large B-cell lymphoma, NOS and leg type: Clinical, morphologic and prognostic differences. J Dtsch
Dermatol Ges 2019;17:275-285.
4 van Maldegem F, van Dijk R, Wormhoudt TA, et al. The majority of cutaneous marginal zone B-cell lymphomas expresses class-switched immunoglobulins and
develops in a T-helper type 2 inflammatory environment. Blood 2008;112:3355-3361.
5 Edinger JT, Kant JA, Swerdlow SH. Cutaneous marginal zone lymphomas have distinctive features and include 2 subsets. Am J Surg Pathol 2010;34:1830-1841.
6 Kogame T, Takegami T, Sakai TR, et al. Immunohistochemical analysis of class-switched subtype of primary cutaneous marginal zone lymphoma in terms of inducible
skin-associated lymphoid tissue. J Eur Acad Dermatol Venereol. 2019;33:e401-e403.
7 Carlsen ED, Swerdlow SH, Cook JR, Gibson SE. Class-switched primary cutaneous marginal zone lymphomas are frequently IgG4-positive and have features distinct
from IgM-positive cases. Am J Surg Pathol 2019;43:1403-1412.
8 Gibson SE, Swerdlow SH. How I diagnose primary cutaneous marginal zone lymphoma. Am J Clin Pathol 2020;154:428-449.
9 Hoefnagel JJ, Dijkman R, Basso K, et al. Distinct types of primary cutaneous large B-cell lymphoma identified by gene expression profiling. Blood 2005;105:3671-3678.
10 Menguy S, Beylot-Barry M, Parrens M, et al. Primary cutaneous large B-cell lymphomas: relevance of the 2017 World Health Organization classification:
clinicopathological and molecular analyses of 64 cases. Histopathology 2019;74:1067-1080.
Note: All recommendations are category 2A unless otherwise indicated.

CUTB/INTRO-2

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DIAGNOSISa WORKUPc
ESSENTIAL:
• Biopsy of suspicious skin sites
Multiple biopsies may be necessary to capture the
pathologic variability of disease at diagnosis ESSENTIALd:
• Review of a sufficient number of slides with adequate
material to perform a comprehensive workup as described • History and physical exam, including complete
below and/or at least one paraffin block representative of skin exam
the tumor should be done by a pathologist with expertise • CBC with differential PCMZL (CUTB-2)
in the diagnosis of PCBCL. Rebiopsy if pathological • Comprehensive metabolic panel
findings are non-diagnostic and/or discordant with the • Lactate dehydrogenase (LDH)
clinical presentation • Chest/abdominal/pelvic CT with contrast
• Adequate biopsy (by punch, incisional, excisional) of all
types of clinical lesions present will aid in final diagnosis and/or FDG-PET/CT scan (may be omitted if
• Adequate immunophenotyping to establish diagnosisb clinically indicated)
Immunohistochemistry (IHC) panel may include: CD20, • Pregnancy testing in patients of childbearing
PCFCL (CUTB-2)
CD3, CD10, BCL2, BCL6, IRF4/MUM1 potential (if chemotherapy or RT planned)
USEFUL IN CERTAIN CIRCUMSTANCES:
• Additional immunohistochemical studies to establish
lymphoma subtype USEFUL IN CERTAIN CIRCUMSTANCES:
IHC panel may include: Ki-67, CD5, CD43, CD21, CD23, • Bone marrow biopsye
cyclin D1, kappa/lambda (IHC or ISH) • Peripheral blood flow cytometry, if complete PC-DLBCL, Leg
Assessment of IgM, IgD, and FOXP1 expression (to blood count (CBC) demonstrates lymphocytosis Type (See NCCN
further help in distinguishing PC-DLBCL, leg type from • SPEP/quantitative immunoglobulins for PCMZL Guidelines for B-Cell
PCFCL) • HIV testing Lymphomas - DLBCL)
• EBER-ISH
• Cytogenetics (FISH and karyotype): t(14;18) if systemic FL • Hepatitis B and C testingf
is suspected • Discuss fertility preservationg
• If adequate biopsy material is available, flow cytometry or
molecular analysis to detect IgH gene rearrangement can d Rule out drug-induced cutaneous lymphoid hyperplasia.
be useful in determining B-cell clonality e Often reserved for patients with unexplained cytopenias or if there is clinical
a For non-cutaneous extranodal B-cell lymphomas, see Extranodal MZL of Nongastric suspicion of other subtypes (eg, PC-DLBCL, leg type).
Sites in the NCCN Guidelines for B-Cell Lymphomas. A germinal (or follicle) f Hepatitis B testing is indicated because of the risk of reactivation with
center phenotype and large cells in a skin lesion is not equivalent to DLBCL but is immunotherapy + chemotherapy. See monoclonal antibody and viral reactivation
consistent with primary cutaneous germinal/follicle center lymphoma. in the NCCN Guidelines B-Cell Lymphomas. Tests include hepatitis B surface
b Use of Immunophenotyping/Genetic Testing in Differential Diagnosis of Mature antigen and core antibody for a patient with no risk factors. For patients with risk
B-Cell and NK/T-Cell Neoplasms (See NCCN Guidelines for B-Cell Lymphomas). factors or previous history of hepatitis B, add e-antigen. If positive, check viral
c A multidisciplinary team approach involving hematology/oncology, dermatology, load and consult with a gastroenterologist.
pathology (with expertise in cutaneous lymphoma), and radiation oncology is often g Fertility preservation options include: sperm banking, semen cryopreservation,
optimal for the management of patients with PCBCL. in vitro fertilization (IVF), or ovarian tissue or oocyte cryopreservation.

CUTB-1

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PRIMARY CUTANEOUS MARGINAL ZONE LYMPHOMA OR FOLLICLE CENTER LYMPHOMAh

STAGEi INITIAL THERAPYj RESPONSE/ADDITIONAL THERAPY PCFCL, manage
as Follicular
Lymphoma in the
Regional NCCN Guidelines
Local ISRT (preferred)k for B-Cell
Relapsed or Lymphomas
Responseh Observe progressive Generalized disease (FOLL-4)
In selected cases:
diseaseh (extracutaneous or
Observation l
disease) PCMZL, manage
or
Solitary/regional, as Nodal
Excisionm
T1–2 Generalized Marginal Zone
or
disease (skin Lymphoma in the
Skin-directed NCCN Guidelines
therapiesn Generalized disease only)
Refractory for B-Cell
or (skin only), T3
diseaseh (CUTB-3)
Lymphomas
Intralesional steroids (NODE-2)
Generalized disease
Generalized (skin only), T3
disease (skin only), CUTB-3 (CUTB-3)
T3
For PCFCL, manage as Follicular Lymphoma
in the NCCN Guidelines for B-Cell Lymphomas
(FOLL-4)
Extracutaneous or
disease For PCMZL, manage as Nodal Marginal Zone
Lymphoma in the NCCN Guidelines for B-Cell
Lymphomas (NODE-2)
h Additional imaging studies during the course of treatment are not needed. FDG-PET/CT or C/A/P CT with contrast at the end of treatment may be needed to assess
response or if there is clinical suspicion of progressive disease.
i TNM Classification of Cutaneous Lymphoma other than MF/SS (CUTB-A).
j Treatment References (CUTB-B).
k Local ISRT is the preferred initial treatment, but not necessarily the preferred treatment for relapse. See Principles of Radiation Therapy (PCLYM-A).
l When RT or surgical treatment is neither feasible nor desired.
m Small lesions may be excised with minimal non-disfiguring surgery.
n There are case reports showing efficacy of skin-directed therapies, which include topical steroids, imiquimod, nitrogen mustard, and bexarotene (useful in pediatric
patients).

CUTB-2

Table of Contents
PRIMARY CUTANEOUS MARGINAL ZONE LYMPHOMA OR FOLLICLE CENTER LYMPHOMAh

STAGEi INITIAL THERAPYj RESPONSE/ADDITIONAL THERAPY
PCFCL, manage
Generalized disease as Follicular
(skin only) Lymphoma in the
Observationo Relapsed or NCCN Guidelines
or for B-Cell
Responseh Observe progressive Lymphomas
Skin-directed therapiesn diseaseh
or (FOLL-4)
Generalized disease or
Local ISRTk (extracutaneous
Generalized disease PCMZL, manage
or disease)
(skin only), T3 as Nodal
Intralesional steroids
or Marginal Zone
Rituximabp,q Refractory Alternate regimen not Lymphoma in the
or diseaseh used for initial therapy NCCN Guidelines
Other systemic therapyr for B-Cell
Lymphomas
(NODE-2)
h Additional imaging studies during the course of treatment are not needed. FDG-
PET/CT or C/A/P CT with contrast at the end of treatment may be needed to p See monoclonal antibody and viral reactivation in the NCCN Guidelines for B-Cell
assess response or if there is clinical suspicion of progressive disease. Lymphomas.
i TNM Classification of Cutaneous Lymphoma other than MF/SS (CUTB-A). q Rituximab and hyaluronidase human injection for subcutaneous use may be
j Treatment References (CUTB-B). substituted for rituximab after patients have received the first full dose of rituximab
k Local ISRT is the preferred initial treatment, but not necessarily the preferred by intravenous infusion. This substitution cannot be made for rituximab used
treatment for relapse. See Principles of Radiation Therapy (PCLYM-A). in combination with ibritumomab tiuxetan. An FDA-approved biosimilar is an
n There are case reports showing efficacy of skin-directed therapies, which include appropriate substitute for rituximab.
topical steroids, imiquimod, nitrogen mustard, and bexarotene (useful in pediatric r In rare circumstances for very extensive or refractory disease, other combination
patients). chemoimmunotherapy regimens listed in NCCN Guidelines for B-Cell
o Considered appropriate in asymptomatic patients. Lymphomas, FOLL-B can be used.

CUTB-3

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TNM CLASSIFICATION OF CUTANEOUS LYMPHOMA OTHER THAN MF/SSa,b

TNM Size/location of lesions
T
T0* Absence of clinically suspicious lesions
T1 T1A Solitary lesion <5 cm diameter
Solitary lesion
T1B Solitary ≥5 cm diameter
T2 T2A All disease encompassing in a <15-cm-diameter circular area
Multiple lesions limited to 1 body
T2B All disease encompassing a 15 to <30 cm diameter circular area
region or 2 contiguous body regionsb
T2C All disease encompassing a ≥30 cm diameter circular area
T3 T3A Multiple lesions involving 2 noncontiguous body regionsb
Generalized skin involvement
T3B Multiple lesions involving ≥3 body regionsb
N
N0 No clinical or pathologic LN involvement
N1 Involvement of 1 peripheral LN regionc that drains an area of current or prior skin involvement: biopsy positive for lymphoma
N2 Involvement of >2 peripheral LN regionsc or involvement of any LN region that does not drain an area of current or prior skin
involvement: biopsy positive for lymphoma
N3 Involvement of central lymph nodes: biopsy positive for lymphoma
NX Clinically abnormal peripheral or central LN but no pathologic determination. Other surrogate means of determining involvement
may be determined by Tri-Society consensus
M
M0 No visceral involvement
M1 Visceral involvement
MX Visceral involvement is neither confirmed nor refuted by available pathologic or imaging assessment
a This work was originally published in Blood. Olsen EA, Whittaker S, Willemze R, et al. Primary cutaneous lymphoma: recommendations for clinical trial design and
staging update from the ISCL, USCLC, and EORTC. Blood 2022;140:419-437. © The American Society of Hematology.
b For definition of body regions, see Body Regions for the Designation of T (Skin Involvement) Category (CUTB-A 2 of 2).
c Definition of lymph node regions is consistent with the Ann Arbor system: Peripheral sites: antecubital, cervical, supraclavicular, axillary, inguinal-femoral, and
popliteal. Central sites: mediastinal, pulmonary hilar, paraaortic, and iliac.

CUTB-A
Version 2.2024, 05/06/24 © 2024 National Comprehensive Cancer Network (NCCN ), All rights reserved. NCCN Guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN.
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BODY REGIONS FOR THE DESIGNATION OF T (SKIN INVOLVEMENT) CATEGORYa,d,e
a This work was originally published in Blood. Olsen EA, Whittaker S, Willemze R, et al. Primary cutaneous lymphoma: recommendations for clinical trial design and
d Left and right extremities are assessed as separate body regions. The designation of these body regions is based on regional lymph node drainage patterns.
e Definition of body regions: Head and neck (HN), inferior borders = clavicles anterior and T1 spinous process posterior; left upper arm (LUA), superior border = glenohumeral
joint (exclusive of axilla), inferior border = ulnar/radial/humeral (elbow) joint; left lower arm and hand (LLAH), superior border = ulnar/radial/humeral (elbow) joint; right upper
arm (RUA), superior border = glenohumeral joint (exclusive of axilla), inferior border = ulnar/radial/humeral (elbow) joint; right lower arm and hand (RLAH), superior border
= ulnar/radial/humeral (elbow) joint; chest (C), superior border = superior border clavicles, inferior border = inferior margin rib cage, lateral borders = midaxillary lines and
glenohumeral joints (inclusive of axilla); abdomen/genital (AG), superior border = inferior margin rib cage, inferior border = inguinal folds and anterior perineum; upper back
(UB), superior border = T1 spinous process, inferior border = inferior margin rib cage, lateral borders = midaxillary lines; lower back/buttocks (LBB), superior border = inferior
margin rib cage, inferior border = inferior gluteal fold and anterior perineum (inclusive of perineum), lateral borders = midaxillary lines; left upper leg (LUL), superior border =
inguinal fold and gluteal folds, inferior border = midpatella anterior and mid–popliteal fossa posterior; left lower leg and foot (LLLF), superior border = midpatella anterior and
mid–popliteal fossa posterior; right upper leg (RUL), superior border = inguinal fold and gluteal folds, inferior border = midpatella anterior and mid–popliteal fossa posterior;
right lower leg and foot (RLLF), superior border = midpatella anterior, and mid–popliteal fossa posterior.

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TREATMENT REFERENCES
Skin-directed therapies Chemotherapy/Chemoimmuotherapy
Topical/intralesional corticosteroids Bekkenk MW, Vermeer MH, Geerts ML, et al. Treatment of multifocal primary
Bekkenk MW, Vermeer MH, Geerts ML, et al. Treatment of multifocal primary cutaneous B-cell lymphoma: a clinical follow-up study of 29 patients. J Clin Oncol
cutaneous B-cell lymphoma: a clinical follow-up study of 29 patients. J Clin Oncol 1999;17:2471-2478.
1999;17:2471-2478. Brice P, Cazals D, Mounier N, et al. Primary cutaneous large-cell lymphoma:
Perry A, Vincent BJ, Parker SR. Intralesional corticosteroid therapy for primary analysis of 49 patients included in the LNH87 prospective trial of
cutaneous B-cell lymphoma. Br J Dermatol 2010;163:223-225. polychemotherapy for high-grade lymphomas. Groupe d'Etude des Lymphomes
de l'Adulte. Leukemia 1998;12:213-219.
Topical nitrogen mustard Hoefnagel JJ, Vermeer MH, Jansen PM, et al. Primary cutaneous marginal zone
Bachmeyer C, Orlandini V, Aractingi S. Topical mechlorethamine and clobetasol B-cell lymphoma: Clinical and therapeutic features in 50 cases. Arch Dermatol
in multifocal primary cutaneous marginal zone-B cell lymphoma. B J Dermatol 2005;141:1139-1145.
2006;154:1207-1209. Grange F, Beylot-Barry M, Courville P, et al. Primary cutaneous diffuse large B-cell
lymphoma, leg type: clinicopathologic features and prognostic analysis in 60
Topical bexarotene cases. Arch Dermatol 2007;143:1144-1150.
Trent JT, Romanelli P, Kerdel FA. Topical targretin and intralesional interferon alfa Grange F, Joly P, Barbe C, et al. Improvement of survival in patients with primary
for cutaneous lymphoma of the scalp. Arch Dermatol 2002;138:1421-1423. cutaneous diffuse large B-cell lymphoma, leg type, in France. JAMA Dermatol
2014;150:535-541.
Topical imiquimod Rijlaarsdam JU, Toonstra J, Meijer OW, et al. Treatment of primary cutaneous
Coors EA, Schuler G, Von Den Driesch P. Topical imiquimod as treatment for B-cell lymphomas of follicle center cell origin: A clinical follow-up study of
different kinds of cutaneous lymphoma. Eur J Dermatol 2006;16:391-393. 55 patients treated with radiotherapy or polychemotherapy. J Clin Oncol
Stavrakoglou A, Brown VL, Coutts I. Successful treatment of primary cutaneous 1996;14:549-555.
follicle centre lymphoma with topical 5% imiquimod. Br J Dermatol 2007;157:620- Senff NJ, Noordijk EM, Kim YH, et al. European Organization for Research
622. and Treatment of Cancer and International Society for Cutaneous Lymphoma
consensus recommendations for the management of cutaneous B-cell
Rituximab lymphomas. Blood 2008;112:1600-1609.
Morales AV, Advani R, Horwitz SM, et al. Indolent primary cutaneous B-cell Vermeer MH, Geelen FA, van Haselen CW, et al. Primary cutaneous large B-cell
lymphoma: experience using systemic rituximab. J Am Acad Dermatol lymphomas of the legs. A distinct type of cutaneous B-cell lymphoma with an
2008;59:953-957. intermediate prognosis. Dutch Cutaneous Lymphoma Working Group. Arch
Heinzerling LM, Urbanek M, Funk JO, et al. Reduction of tumor burden and Dermatol 1996;132:1304-1308.
stabilization of disease by systemic therapy with anti-CD20 antibody (rituximab) Palliative low-dose RT
in patients with primary cutaneous B-cell lymphoma. Cancer 2000;89:1835-1844. Neelis KJ, Schimmel EC, Vermeer MH, et al. Low-dose palliative radiotherapy for
Valencak J, Weihsengruber F, Rappersberger K, et al. Rituximab monotherapy for cutaneous B- and T-cell lymphomas. Int J Radiat Oncol Biol Phys 2009;74:154-
primary cutaneous B-cell lymphoma: Response and follow-up in 16 patients. Ann 158.
Oncol 2009;20:326-330.
Senff NJ, Noordijk EM, Kim YH, et al. European Organization for Research
and Treatment of Cancer and International Society for Cutaneous Lymphoma
consensus recommendations for the management of cutaneous B-cell
lymphomas. Blood 2008;112:1600-1609.
Heinzerling L, Dummer R, Kempf W, et al. Intralesional therapy with anti-CD20
monoclonal antibody rituximab in primary cutaneous B-cell lymphoma. Arch
Dermatol 2000;136:374-378.

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Mycosis Fungoides/Sezary Syndrome Discussion
PRINCIPLES FOR MYCOSIS FUNGOIDES/SÉZARY SYNDROME (MF/SS)

Definition
• Mycosis fungoides (MF)
MF is the most common cutaneous T-cell lymphoma (CTCL) and many clinicopathologic variants of MF have been described.1,2
Most patients with MF exhibit an indolent clinical course with intermittent, stable, or slow progression of the lesions.
Extracutaneous involvement may be seen in advanced stages, with involvement of lymph nodes, blood, or less commonly other organs.1,2
• Sézary syndrome (SS)
SS represents the leukemic variant of CTCL and is closely related to MF but has unique characteristics. SS is rare, accounting for less than
5% of cutaneous lymphomas and predominantly affects older individuals.
SS is characterized by the presence of atypical T cells (Sézary cells) in skin causing diffuse erythema (erythroderma) and significant blood
involvement with abnormal T cells (>1000 abnormal cells/uL) defined as Sézary cells by cytopathologic assessment or flow cytometry
(abnormal subsets including but not limited to CD4+CD7- or CD4+CD26- cells; TRBC1 may contribute in detecting clonality and is especially
useful in cases where CD7 or CD26 are not lost).3
SS is thought to arise from thymic memory T cells, while skin resident effector memory T cells are the cells of origin of MF. This supports the
contention that SS is a process distinct from MF.4 Cases presenting clinically as an overlap of these two conditions exist.
Diagnosis
• The histopathologic findings of MF, even in cases showing classic features, need to be correlated with clinical presentation in order to reach a
definitive diagnosis.5
• Patch lesions are often difficult for conclusive diagnosis; thus, in some instances multiple skin biopsies may be necessary for diagnosis.
Stopping skin-directed therapy for 2–3 weeks or longer to individual lesions before obtaining a skin biopsy is advisable and may aid in
diagnosis.1,2
• Awareness of specific clinicopathologic variants may aid in accurate diagnosis:
Lesions may be hyper- or hypopigmented.
Folliculotropic MF (FMF) may present as folliculocentric papules or nodules or areas of alopecia in any hair-bearing area of the body. A skin
biopsy reaching the deep dermis may be required to assess adnexal structures.
Unilesional, pagetoid reticulosis and CD8+ MF variants tend to be associated with an indolent course.
Granulomatous slack skin is rare and presents with redundant skin resembling cutis laxa on flexural areas.
• By IHC, the tumor cells are usually CD3+, CD4+, and CD8-, although CD8+ variants are not uncommon. In selected cases, additional IHC
markers and molecular studies to evaluate clonal TCR gene rearrangements are necessary for diagnosis.
• Large-cell transformation (LCT) of MF is defined histologically as greater than 25% of the tumor cells displaying large size. CD30 expression
may be seen but is not included in the definition of LCT.6
• The histopathologic findings of SS in skin are generally similar to, but may be more subtle than those seen in MF. Correlation with clinical and
laboratory findings in blood is essential for a definitive diagnosis.
General Principles on MFSS/INTRO-2

References on MFSS/INTRO-A

MFSS/INTRO-1

Table of Contents
PRINCIPLES FOR MYCOSIS FUNGOIDES/SÉZARY SYNDROME (MFSS)

General Principles
• Multidisciplinary team approach (hematology/oncology, dermatology, pathology, and radiation oncology) with expertise in CTCL is often
optimal for the management of patients with MF/SS, particularly those with advanced disease.
• Given the rarity of the disease, it is preferred that treatment or consultation occur at centers with expertise in the management of CTCL.
• Evaluation of skin and/or nodal biopsies by a pathologist with expertise in CTCL at a referral center is recommended.
• Folliculotropism and LCT are histologic features that can occur irrespective of stage.
• Recent studies have reported that FMF presents with two distinct patterns of clinicopathologic features with different prognostic
implications (early stage and advanced stage); in a subgroup of patients with early skin-limited disease, FMF has an indolent disease course
and a favorable prognosis.7,8,9 Early-stage cutaneous disease is associated with significantly higher disease-specific survival compared
to advanced-stage cutaneous disease. Treatment may require skin-directed therapy that reaches the subcutaneous tissue (eg, psoralen
plus ultraviolet A [PUVA], involved-site RT [ISRT]) or the addition of systemic therapy as used for stages I–IIB in patients with disease not
responding to skin-directed therapy alone.
• The incidence of LCT is strongly dependent on the disease stage at diagnosis.10,11 LCT often but not always corresponds to a more
aggressive growth rate requiring systemic therapies (MFSS-12).
• Goals of therapy should be individualized but often include:
Attain adequate response in order to reduce and control symptoms and minimize risk of progression.
Most treatments for MF/SS do not result in durable remissions off of treatment.
Therapies with lower side-effect profiles and an absence of cumulative toxicity are often given in an ongoing or maintenance fashion to
improve and maintain disease control and quality of life.
Other than allogeneic hematopoietic cell transplant (HCT), therapies are not given with curative intent.
• Generally, skin-directed therapies and systemic therapy regimens that can be tolerated for longer durations of therapy with lower rates of
cumulative toxicity, less immunosuppression, and/or higher efficacy are used in earlier lines of therapy.
• In patients requiring chemotherapy, single agents are preferred over combination chemotherapy, due to the higher toxicity profiles
associated with multi-agent regimens and the short-lived responses seen with time-limited combination chemotherapy.
• Responses can vary between the different compartments (ie, skin, blood, lymph nodes). Often decisions to continue or switch therapy are on
a clinical basis.
• Disease relapse after discontinuation of therapy may respond to re-treatment with previous therapy.
• Partial responses with suboptimal quality of life should be treated with other or additional primary treatment options.
• Use of supportive care measures to minimize risk of skin infections and treat pruritus is an important part of disease and symptom control
(MFSS-B).
References on MFSS/INTRO-A

MFSS/INTRO-2

Table of Contents
PRINCIPLES FOR MYCOSIS FUNGOIDES/SÉZARY SYNDROME (MFSS)

1 Alaggio R, Amador C, Anagnostopoulos I, et al. The 5th edition of the World Health Organization Classification of Haematolymphoid Tumours: Lymphoid Neoplasms.
Leukemia 2022;36:1720-1748.
2 Campo E, Jaffe ES, Cook JR, et al. The International Consensus Classification of Mature Lymphoid Neoplasms: a report from the Clinical Advisory Committee. Blood
2022;140:1229-1253.
3 Olsen E, Whittaker S, Kim YH, et al. Clinical end points and response criteria in mycosis fungoides and Sézary syndrome: a consensus statement of the International
Society for Cutaneous Lymphomas, the United States Cutaneous Lymphoma Consortium, and the Cutaneous Lymphoma Task Force of the European Organisation
for Research and Treatment of Cancer. J Clin Oncol 2011;29:2598-2607.
4 Campbell JJ, Clark RA, Watanabe R, Kupper TS. Sezary syndrome and mycosis fungoides arise from distinct T-cell subsets: a biologic rationale for their distinct
clinical behaviors. Blood 2010;116:767-771.
5 Pimpinelli N, Olsen EA, Santucci M, et al. Defining early mycosis fungoides. J Am Acad Dermatol 2005;53:1053-1063.
6 Talpur R, Sui D, Gangar P, et al. Retrospective Analysis of Prognostic Factors in 187 Cases of Transformed Mycosis Fungoides. Clin Lymphoma Myeloma Leuk
2016;16:49-56.
7 Hodak E, Amitay-Laish I, Atzmony L, et al. New insights into folliculotropic mycosis fungoides (FMF): A single-center experience. J Am Acad Dermatol 2016;75:347-
355.
8 van Santen S, Roach RE, van Doorn R, et al. Clinical staging and prognostic factors in folliculotropic mycosis fungoides. JAMA Dermatol 2016;152:992-1000.
9 van Santen S, van Doorn R, Neelis KJ, et al. Recommendations for treatment in folliculotropic mycosis fungoides: report of the Dutch Cutaneous Lymphoma Group.
Br J Dermatol 2017;177:223-228.
10 Vergier B, de Muret A, Beylot-Barry M, et al. Transformation of mycosis fungoides: clinicopathological and prognostic features of 45 cases. French Study Group of
Cutaneious Lymphomas. Blood 2000;95:2212-2218.
11 Arulogun SO, Prince HM, Ng J, et al. Long-term outcomes of patients with advanced-stage cutaneous T-cell lymphoma and large cell transformation. Blood
2008;112:3082-3087.

MFSS/INTRO-A

Table of Contents
DIAGNOSISa
ESSENTIAL:
• Biopsy of suspicious skin sites
Multiple biopsies may be necessary to capture the pathologic variability of disease at diagnosis
• Review of a sufficient number of slides with adequate material to perform a comprehensive workup as described
below and/or at least one paraffin block representative of the lesion should be done by a pathologist with expertise
in the diagnosis of CTCLs. Rebiopsy if pathological findings are non-diagnostic and/or discordant with the clinical
presentationb
• IHC panel of skin biopsy may includec,d,e:
CD2, CD3, CD4, CD5, CD7, CD8, CD20, CD30
• Molecular analysis to detect clonal T-cell receptor (TCR) gene rearrangements or other assessment Workup
of clonalitya,f
(MFSS-2)
• Assessment of peripheral blood for Sézary cells (in extensive skin disease where skin biopsy is not diagnostic in extensive
patch or erythrodermic skin disease and/or strongly suggestive but not diagnostic of advanced-stage disease) including:
Flow cytometry and molecular analysis to assess and quantitate an expanded T-cell population with aberrant
phenotype.a,g See MFSS-3 for specifics.
Sézary cell preparation is less useful than flow cytometry due to the subjective nature of the process.
• IHC panel of skin biopsy may includeb,c:
CD25, CD56, TIA1, granzyme B, TCRß, TCRẟ; CCR4,h CXCL13, inducible T-cell co-stimulator (ICOS), and programmed
cell death protein 1 (PD-1)
• Assessment of HTLV-1/2i by serology or other methods is encouraged as results can impact therapy.
a Principles f Clonal TCR gene rearrangements alone are not sufficient for diagnosis, as these can also
of Molecular Analysis in Primary Cutaneous Lymphomas
(PCLYM-B). be seen in patients with non-malignant conditions. Results should be interpreted in the
b Presence of LCT or areas of folliculotropism may have important context of overall presentation. See Principles of Molecular Analysis in Primary Cutaneous
implications for selection of therapy and outcome and should be included Lymphomas (PCLYM-B).
g Flow cytometry panel may include CD3, CD4, CD7, CD8, CD26, CD45, to assess for
in pathology reports.
c Pimpinelli N, et al. Clinically suspicious and histologically non-diagnostic expanded CD4+ cells with increased CD4/CD8 ratio or with abnormal immunophenotype,
cases. J Am Acad Dermatol 2005;53:1053-1063. including loss of CD7 or CD26. TRBC1 may contribute in detecting clonality and is
d Use of Immunophenotyping/Genetic Testing in Differential Diagnosis especially useful in cases where CD7 or CD26 are not lost.
h The loss of CCR4 expression and emergence of CCR4 genomic alterations might be
of Mature B-Cell and NK/T-Cell Neoplasms (see NCCN Guidelines for
B-Cell Lymphomas). associated with resistance to mogamulizumab (Beygi S, et al. Blood 2022;139:3732-3736).
e Typical immunophenotype: CD2+, CD3+, CD5+, CD7-, CD4+, CD8- i See map for prevalence of HTLV-1/2 by geographic region. HTLV-1 has been described in
(rarely CD8+), CD30-/+ cytotoxic granule proteins negative. patients in non-endemic areas.

MFSS-1

Table of Contents
WORKUP
ESSENTIAL:
• History and complete physical examination:
Complete skin examination: assessment of % body surface area (BSA) (palm plus all 5 digits ≈1% BSA) and type of skin
lesion (ie, patch/plaque, tumor, erythroderma)
Palpation of peripheral lymph node regions
Palpation for organomegaly/masses
• Laboratory studies:j
CBC with differential and determination of absolute lymphocyte count
Flow cytometric studies to assess and quantitate an expanded T-cell population with aberrant phenotype (optional for
T1k) (MFSS-3)
◊ Recommended for any patient with T2–4 skin classification, any suspected extracutaneous disease including
adenopathy For TNMB
Clonal TCR gene rearrangement in peripheral blood lymphocytes if blood involvement suspecteda Classification,
Comprehensive metabolic panel see MFSS-3
LDH and
• Imaging studies: For Clinical
Chest/abdomen/pelvis (C/A/P) CT with contrast or integrated whole body FDG-PET/CTl for T3 or T4 (arms/legs included Staging of MF
when disease assessment of entire body is needed) and SS, see
MFSS-4
• Bone marrow biopsy in patients with unexplained hematologic abnormality
• Biopsy of enlarged lymph nodes or suspected extracutaneous sites. Excisional or adequate core needle biopsy is
preferred. An fine-needle aspiration (FNA) biopsy alone is not sufficient for the initial diagnosis of lymphoma. Rebiopsy if
pathological findings are nondiagnostic and/or discordant with the clinical presentation.
• Rebiopsy skin if suspicious of LCT or FMF and not previously confirmed pathologically or aggressive clinical behavior
• C/A/P CT with contrast or integrated whole body FDG-PET/CTl for ≥T2b or LCT or FMF, or with palpable adenopathy or
abnormal laboratory studies; consider for T2a (patch disease with ≥10% BSA) or otherwise clinically indicatedm
• Neck CT with contrast if whole body FDG-PET/CT not done
• Pregnancy testing in patients of childbearing potential if contemplating treatments that are contraindicated in pregnancyn
• Discuss fertility preservationo
a Principles of Molecular Analysis in Primary Cutaneous Lymphomas

(PCLYM-B). m New significant adenopathy on clinical exam, abnormal laboratory results concerning
j Sézary syndrome (B2) is as defined on MFSS-3. of lymphoma, or accelerated skin disease.
k See Discussion for when Sézary flow cytometric study is appropriate in T1 n Many skin-directed and systemic therapies are contraindicated or of unknown safety in
disease. pregnancy. Refer to full prescribing information for individual drugs.
l Patients with cutaneous lymphomas have extranodal disease, which may be o Fertility preservation options include: sperm banking, semen cryopreservation, IVF, or
inadequately imaged by CT. PET scan may be preferred in these instances. ovarian tissue or oocyte cryopreservation.

MFSS-2

Table of Contents
Changes or confirmation of staging are noted in bold in table below and in further description on MFSS-3A. Options for characterizing clonality further by designation as A (clone negative or equivocal) and B (clone
positive and identical to skin) are presented. If a clone in LN or viscera is detected but different from that identified in the skin, another concurrent lymphoproliferative process should be considered.
TNMB TNMB Classification and Staging of Mycosis Fungoides and Sézary Syndromep,q,r,s,t,v Clinical Staging of MF and SS (MFSS-4)
Skin (T) u
T0 Absence of clinically suspicious lesions
T1 T1A Patch only lesions

Patches, plaques, or papules <10% BSA
T1B Plaque/papule ± patch lesions
T2 T2A Patch only

Patches, plaques, or papules ≥10% BSA
T2B Plaque ± patch
T3 One or more tumors ≥1 cm in diameter
T4 Confluence of erythema covering ≥80% BSAv
Node N0 No clinically abnormal LN; no biopsy necessary
(N)w Dutch Criteria for Lymph Nodes on MFSS-5
N1A Pathology Dutch grade 1 or NCI LN 0-2: clone negative or equivocal
N1
N1B Pathology Dutch grade 1 or NCI LN 0-2: clone positive and identical to skin NCI Lymph Node Classification on MFSS-5
N2A Dutch grade 2, NCI LN3: clone negative or equivocal
N2
N2B Dutch grade 2, NCI LN3: clone positive and identical to skin
N3A Dutch grade 3-4, NCI LN4: clone negative or equivocal
N 3w
N3B Dutch grade 3-4, NCI LN4: clone positive and identical to skin
Clinically abnormal peripheral or central lymph node but no pathologic determination of representative LN. Other surrogate means of determining involvement may be
NX
determined by Tri-Society consensus
Visceral M0 No visceral involvement
(M)
BM only Clone positive and identical to skin
M1a
involvement Clone negative or indeterminate
Non-BM Clone positive and identical to skin
M1b visceral
involvement Clone negative or indeterminate
MX Visceral involvement is neither confirmed nor refuted by available pathologic or imaging assessment
Blood B0A Clone negative or equivocal
(B)x B0 Absence of significant blood involvement
B0B Clone positive and identical to skin
B1A Clone negative or equivocal
B1 Low blood tumor burden
B2A Clone negative or equivocal
B2 High blood tumor burden
BXA Clone negative or equivocal
BX Unable to quantify blood involvement according to agreed upon guidelines
BXB Clone positive and identical to skin
Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged. Footnotes on MFSS-3A
MFSS-3

Table of Contents
FOOTNOTES
p This work was originally published in Blood. Olsen EA, Whittaker S, Willemze R, et al. Primary cutaneous lymphoma: recommendations for clinical trial design and
q Sézary syndrome is defined by B2 blood involvement and a clonal rearrangement of TCR in the blood (clones should be relevant to clone in the skin).
r Patch = Any size skin lesion without significant elevation or induration. Presence/absence of hypo- or hyperpigmentation, scale, crusting, and/or poikiloderma should be
noted.
s Plaque = Any size skin lesion that is elevated or indurated. Presence or absence of scale, crusting, and/or poikiloderma should be noted. Histologic features such as
folliculotropism or LCT (≥25% large cells), CD30+ or CD30-, and clinical features such as ulceration are important to document.
t Tumor = at least one ≥1 cm diameter solid or nodular lesion with evidence of depth and/or vertical growth. Note total number of lesions, total volume of lesions, largest
size lesion, and region of body involved. Also note if histologic evidence of LCT has occurred. Phenotyping for CD30 is encouraged.
u T is used for clinical trials in order to track clearance of lesions in the skin compartment. No patient with PCL at time of diagnosis should be T .
0 0
v Patients with both erythroderma and tumors may be designated as T (T ). The BSA of 80% is used to define erythroderma in MF/SS at study entry, but any decrease in
4 3
BSA during the study does not affect the entry classification.
w Abnormal LNs are those now >1.5 cm longest diameter (LDi) according to the Lugano classification and confirmed by imaging. The pathological findings of a
representative abnormal LN may apply to all abnormal lymph nodes.
x Blood staging for MF/SS is defined currently as B = 250/µL of CD4+/CD26- or CD4+/CD7- cells, B = does not meet criteria for B or B , and B = ≥1000/µL of CD4+/
0 1 0 2 2
CD26- or CD4+/CD7- cells or other aberrant population of lymphocytes identified by flow cytometry. It is expected that patients with high blood tumor burden (B2) will
have a clone in the blood that is identical to that in the skin. Nonidentical T-cell clones are often detected in peripheral blood with increasing age and are of unknown
clinical significance. Patients with lymphopenia (defined as <1000 absolute lymphocytes) may potentially have an underestimation of aberrant lymphocyte burden if
assessed only by the absolute number and not also by the percentage of immunophenotypically abnormal lymphocytes.

MFSS-3A

Table of Contents
CLINICAL STAGING OF MF AND SSy
Clinical Stagez T (Skin) N (Node) M (Visceral) B (Blood Involvement) Guidelines Page
T1
IA (Patches, papules, and/or plaques
(Limited skin involvement) N0 M0 B0 or B1 MFSS-6
covering <10% body surface area
[BSA])
IB T2
(Skin only disease) (Patches, papules, and/or plaques N0 M0 B0 or B1 MFSS-7
covering ≥10% BSA)
IIA T1–2 N1–2 M0 B0 or B1 MFSS-7
IIB T3
(Tumor stage disease) (One or more tumors [≥1 cm in N0–2 M0 B0 or B1 MFSS-8
diameter])
IIIA T4 N0–2 M0 B0 MFSS-10
(Erythrodermic disease) (Confluence of erythema ≥80% BSA)
IIIB T4 N0–2 M0 B1 MFSS-10

(Erythrodermic disease) (Confluence of erythema ≥80% BSA)
IVA1 (Sézary syndrome) T1–4 N0–2 M0 B2 MFSS-11
IVA2 (Sézary syndrome or T1–4 N3 M0 B0 or B1 or B2 MFSS-11

Non-Sézary)
IVB (Visceral disease) T1–4 N0–3 M1A or M1B B0 or B1 or B2 MFSS-11
Large-cell transformation (LCT)aa MFSS-12
y Olsen EA, et al. Blood 2022;140:419-437.

z Folliculotropism is a histologic feature that can occur irrespective of stage. Histologic evidence of FMF is associated with higher risk of disease progression. In selected
cases or inadequate response, consider primary treatment for stage IIB (tumor stage disease).
aa LCT is a histologic feature that can occur irrespective of clinical stage. LCT often but not always corresponds to a more aggressive growth rate requiring systemic therapies.
TNMB Classification on
Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged. MFSS-3
MFSS-4

Table of Contents
LYMPH NODE CLASSIFICATION IN MF AND SS

NCI-VA Lymph Node Classification
LN0: no atypical lymphocytes
LN1: occasional and isolated atypical lymphocytes (not arranged in clusters)
LN2: many atypical lymphocytes or in 3–6 cell clusters
LN3: aggregates of atypical lymphocytes; nodal architecture preserved
LN4: partial/complete effacement of nodal architecture by atypical lymphocytes or frankly neoplastic cells
Clendenning WE, Rappaport HW. Report of the Committee on Pathology of Cutaneous T Cell Lymphomas.
Cancer Treat Rep 1979;63:719-724.
Dutch Criteria for Lymph Nodes

Grade 1: Dermatopathic lymphadenopathy
Grade 2: Early involvement by mycosis fungoides (presence of cerebriform nuclei >7.5 micrometers)
Grade 3: Partial effacement of lymph node architecture; many atypical cerebriform mononuclear cells
Grade 4: Complete effacement of lymph node architecture
Scheffer E, Meijer CJLM, van Vloten WA. Dermatopathic lymphadenopathy and lymph node
involvement in mycosis fungoides. Cancer 1980;45:137-148.

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STAGEbb TREATMENT AND RESPONSE ASSESSMENT

(MFSS-3 and
MFSS-4)
Complete Relapse with T1 skin disease

response/
partial
response Relapse with
(CR/PR)ee > stage IA disease
Stage IA Treatment based on clinical
Table 1: Stage IA MF stage. See MFSS-4 for
(limited skin
(Limited Skin Involvement appropriate clinical stage
involvement alone,
Alone; <10% BSA) Progression to > stage
<10% BSA)cc,dd
IA on skin-directed
therapies
Inadequate or Manage as Stage IB–IIA MF
response Refractory disease (MFSS-7)
to multiple previous or
therapies Consider RT if not
or previously usedff
Persistent T1 skin or
disease Clinical trial
bb Principles for Mycosis Fungoides/Sézary Syndrome (MFSS/INTRO-1) and General Considerations for the Treatment of Patients with MF and SS (MFSS-A 1 of 12).
cc In rare cases of confirmed unilesional MF, RT has been shown to provide long-term remission.
dd Rebiopsy if LCT is suspected; if histologic evidence of LCT, see MFSS-12.
ee Patients with disease achieving a clinical benefit and/or those with disease responding to primary treatment should be considered for maintenance or tapering of
regimens to optimize response duration.
ff Principles
of Radiation Therapy (PCLYM-A).

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STAGEbb TREATMENT AND RESPONSE ASSESSMENTgg

(MFSS-3 and
MFSS-4) Relapse with low skin
disease burden
Lower skin CR/PRee Relapse with high skin disease burden (see below)
disease Table 2: Stage IB MF (Skin Treatment based on
burden (eg, Only Disease with ≥10% clinical stage. See
predominantly BSA) – Stage IIA MF Progression to > stage IB–IIA
MFSS-4 for appropriate
patch disease) Inadequate clinical stage
response
Retreat with primary treatment or treat as high skin
Stage IB (skin disease burden (see below)
only disease
with ≥10% BSA) Relapse with T1–T2 disease
- Stage IIAdd
CR/PRee
Treatment based on
Higher skin Relapse with > stage IB–IIA disease clinical stage. See
disease
Table 2: Stage IB MF (Skin MFSS-4 for appropriate
burden (eg, Progression to > stage IB–IIA
Only Disease with ≥10% clinical stage
predominantly or
BSA) – Stage IIA MF
plaque Clinical trial
disease) or
Refractory disease to multiple TSEBTff (if not previously
Inadequate used)
response previous therapies
or
or Manage as Stage IIB
- Generalized Tumor
Persistent T1–T2 skin disease Lesions (MFSS-9)
ff Principles of Radiation Therapy (PCLYM-A).
gg Imaging (with modalities used in workup) indicated when suspicious of clinical extracutaneous disease.

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(MFSS-3 and
MFSS-4)
Relapse
• T1–2 with limited tumor lesions
(Table 1 or Table 2)
CR/PRee • T3 with limited tumor lesions
Relapse with > stage

Treatment based on
Limited tumor Table 3: Stage IIB MF (Tumor IIB disease
clinical stage. See
lesions Stage Disease)
Progression > stage IIB MFSS-4 for appropriate
disease clinical stage
or
Inadequate Refractory disease Manage as Stage IIB
Stage IIB to multiple previous - Generalized Tumor
(tumor stage response
therapies Lesions (MFSS-9)
disease)dd or
Persistent T1–T3 with
limited tumor lesions
Generalized
MFSS-9
tumor lesions

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(MFSS-3 and
MFSS-4)
Relapse:
• T1–2 (Table 1 or Table 2)
• T3
CR/PRee
Relapse with > stage IIB Treatment based on
Stage IIB Generalized Table 3: Stage IIB MF disease clinical stage. See
(tumor stage tumor (Tumor Stage Disease) MFSS-4 for appropriate
disease)dd lesions Progression > stage IIB clinical stage
disease Table 6 - Suggested
or regimens for MF with Large-
Inadequate Refractory disease Cell Transformation (LCT) or
response to multiple previous Table 7 - Relapsed/Refractory
therapies Disease Requiring Systemic
or Therapy
Persistent T1–T3 with or
generalized tumor lesions Clinical trial
or
Consider allogeneic HCThh
dd Rebiopsy if LCT is suspected, if histologic evidence of LCT, see MFSS-12.
hh Allogeneic HCT is associated with better outcomes in patients with disease responding to primary treatment prior to transplant. See Discussion for further details.

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(MFSS-3 and
MFSS-4)
Relapse
CR/PRee
Relapse with > stage III

Stage III Table 4: Stage III MF MFSS-11
(erythrodermic (Erythrodermic Disease) Progression with
disease)dd
> stage III
or Clinical trial
Inadequate or
response Table 6 - Suggested Regimens for
Refractory disease
to multiple MF with Large-Cell Transformation
previous therapies (LCT) or Table 7 - Relapsed/Refractory
Disease Requiring Systemic Therapy
or or
Consider allogeneic HCThh as
Persistent disease appropriate

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STAGEbb TREATMENT AND RESPONSE ASSESSMENTii

(MFSS-3 and
MFSS-4)
Clinical trial
or
Sézary CR/PRee Relapse Table 7: Suggested
syndrome Regimens for Relapsed/
(stage Table 5: Sézary Syndrome Persistent disease Refractory Disease Requiring
(Stage IVA1 or IVA2) or Systemic Therapy
IVA1 or Inadequate
IVA2) Refractory disease or
response Consider allogeneic HCThh
to multiple previous
therapies as appropriate
Retreat with
Stage IVdd primary treatment
or
Repeat CR/PRee Relapse Clinical trial
Non-Sézary imaging or
(stage IVA2) Table 6: Suggested with Consider allogeneic HCThh
or Regimens for Non- modalities as appropriate
Visceral Sézary (stage IVA2) or used in Refractory Clinical trial
(stage IVB) Visceral/solid Organ workup disease to or
disease (stage IVB) Disease (frequency multiple Table 7: Suggested
Inadequate previous
(solid organ) as clinically response Regimens for Relapsed/
indicated)ii therapies Refractory Disease Requiring
or Systemic Therapy
Persistent or
disease Consider allogeneic HCThh
as appropriate
bb Principlesfor Mycosis Fungoides/Sézary Syndrome (MFSS/INTRO-1) and

General Considerations for the Treatment of Patients with MF and SS (MFSS-A
1 of 12). hh Allogeneic HCT is associated with better outcomes in patients with disease
dd Rebiopsy if LCT is suspected; if histologic evidence of LCT, see MFSS-12. responding to primary treatment prior to transplant. See Discussion for further details.
ee Patients with disease achieving a clinical benefit and/or those with disease ii If disease in lymph nodes and/or viscera or suspicious of disease progression,
responding to primary treatment should be considered for maintenance or imaging (with modalities used in workup) as clinically indicated based on distribution
tapering of regimens to optimize response duration. of disease.

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(MFSS-3 and
MFSS-4) • Table 6 - Suggested Regimens
for MF with Large-Cell
CR/PRee Relapse Transformation (LCT) or Table
Consider RTff to lesions 7 - Relapsed/Refractory Disease
with LCTee Requiring Systemic Therapy
Limited
and Refractory disease and concurrent management of
cutaneous
Concurrent management to multiple previous co-existing disease based on
lesions with LCT Inadequate
of co-existing disease therapies clinical stage (MFSS-4)
based on clinical stage response or • Consider allogeneic HCThh as
Persistent disease appropriate
• Clinical trial
LCT
Retreat with
primary treatment
or
Repeat Clinical trial
imaging CR/PRee Relapse or
Generalized with Consider allogeneic HCThh
Table 6 - Suggested as appropriate
cutaneous or modalities
Regimens for MF Refractory
extracutaneous used in Clinical trial
with Large-Cell disease to
lesions with workup or
Transformation (LCT) multiple
LCT (frequency Table 7 - Suggested Regimens
Inadequate previous
as clinically for Relapsed/Refractory Disease
response therapies
indicated) Requiring Systemic Therapy
or
or
Persistent Consider allogeneic HCThh as
disease appropriate
ff Principles of Radiation Therapy (PCLYM-A).

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GENERAL CONSIDERATIONS FOR THE TREATMENT OF PATIENTS WITH MF AND SS

• Generally, skin-directed therapies and systemic therapy regimens that can often be tolerated for longer durations of therapy with lower rates
of cumulative toxicity, less immunosuppression, and/or higher efficacy are used in earlier lines of therapy before moving on to treatment
options that carry a higher risk of cumulative toxicity and/or immunosuppression.
• Therapies with lower side effect profiles and an absence of cumulative toxicity are often given in an ongoing or maintenance fashion to
improve and maintain disease control and quality of life.
• Systemic therapy is often combined with skin-directed therapy to maximize clinical responses in the skin compartment and to provide
additive efficacy without cumulative toxicities.
• Bexarotene, brentuximab vedotin, mogamulizumab, vorinostat, and romidepsin are approved by the U.S. Food and Drug Administration
(FDA) for the treatment of MF and SS. Other systemic therapies such as interferons (alfa and gamma), methotrexate, and other retinoids
(acitretin and isotretinoin) also offer clinical benefit but have only been evaluated in small studies.
• The optimal treatment for any patient at any given time is often individualized based on symptoms of disease, route of administration,
toxicities, and overall goals of therapy.
• Use of supportive care measures to minimize risk of skin infections and treat pruritus is an important part of disease and symptom control
(MFSS-B).

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SUGGESTED REGIMENS: SKIN-DIRECTED THERAPIES

SKIN-LIMITED/LOCAL TREATMENT CONSIDERATIONS
(FOR LIMITED/LOCALIZED SKIN INVOLVEMENT)
• Local radiation (involved-site radiation therapy [ISRT]) 1. Skin-directed therapies can be used alone or in combination with other skin-directed therapies.
8–12 Gy; 24–30 Gy for unilesional presentation 2. Cumulative dose of UV, in particular PUVA, which carries a higher risk than NBUVB, is
• Phototherapy associated with increased risk of UV-associated skin neoplasms; thus, phototherapy
UVB or narrowband UVB (NB-UVB) use should be balanced against these risks in patients with a history of extensive
• Topical corticosteroids squamoproliferative skin neoplasms or basal cell carcinomas or who have had melanoma.
• Topical imiquimod 3. TSEBT, and in certain cases PUVA or UVA1 may be considered for widespread thicker plaques
• Topical mechlorethamine (nitrogen mustard) or tumors.
• Topical retinoids (bexarotene, tazarotene) 4. Low-dose local RT (8–12 Gy) is given with palliative intent (usually as combined modality
• Topical carmustine (category 2B) therapy). Some Member Institutions are exploring the use of lower dose options (eg, 4 Gy).
Up to 8 Gy can be given in a single fraction, although lower dose per fraction (3–5 Gy) may be
preferred depending on skin condition, irradiation volume, and prior RT. For rare initial unilesional
Useful in Certain Circumstances presentations, RT (24–30 Gy) is given as monotherapy with curative intent.
• Topical calcineurin inhibitor (pimecrolimus) 5. Optimal use of topical steroids is often dependent on lesion type and location of disease. This
SKIN-GENERALIZED is best done in consultation with a dermatologist or physician with experience in the use of
(FOR GENERALIZED SKIN INVOLVEMENT) topical steroids. In general, high-potency steroids may be less well-tolerated intertriginous
body areas or other areas such as the face. Potency of steroid and extent/duration of skin
• Phototherapy treated can result in systemic absorption and/or skin atrophy.
UVB or NB-UVB 6. Topical imiquimod can be considered (often in consultation with a dermatologist or physician
PUVA with experience in its safety and use) for areas with few patches/plaques/small tumors that are
UVA1 (if available) recalcitrant to treatment or on sun-damaged skin such as forearms, scalp, and face.
• Topical corticosteroids 7. Topical mechlorethamine has no significant systemic absorption, and can be used alone
• Topical mechlorethamine (nitrogen mustard) or in combination with other skin directed therapies, in particular topical steroids. Topical
• Total skin electron beam therapy (TSEBT) (12–36 Gy) app mechlorethamine use, in particular gel preparation, can be complicated by dermatitis, and can
result in skin irritation when used on face and intertriginous body areas. Initiating at less than
daily use can be useful to determine tolerability and topical steroids can be considered as
needed to alleviate skin reactions from topical mechlorethamine gel. If used with phototherapy,
topical mechlorethamine gel should be applied after exposure to UVL.
8. Topical retinoids can cause skin irritation including redness, peeling, and dermatitis when used
on face and intertriginous body areas.
9. Topical calcineurin inhibitors can be considered for perioral and periorbital affected areas of
skin as a steroid-sparing treatment.
10. It is common practice to follow TSEBT with systemic therapies to maintain response. There
is limited safety data for the use of TSEBT in combination with systemic retinoids, histone
deacetylase (HDAC) inhibitors (such as vorinostat or romidepsin), or mogamulizumab, or
combining phototherapy with vorinostat or romidepsin.

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TABLE 1: STAGE IA MF (Limited skin involvement alone; <10% BSA) - MFSS-6a,b
TREATMENT CONSIDERATIONS
SUGGESTED REGIMENS
(SEE ALSO GENERAL CONSIDERATIONS ON MFSS-A [1 of 12])
• Skin-directed therapies (alone or in combination with other skin-
directed therapies) [See Skin-Limited/Local (for limited/localized skin1. Stage IA MF most often can be treated with skin-directed therapies
involvement, MFSS-A 2 of 12)] (alone or in combination with other skin-directed therapies).
OR 2. In patients with histologic evidence of FMF, skin disease may be less
• Skin-directed therapy (Skin-Limited/Local) in combination with responsive to topical therapies.
systemic therapy (in selected cases) 3. Systemic therapies (single agents or combination therapies) should be
reserved for patients with blood involvement or for whom skin-directed
therapies do not provide sufficient disease control or who have disease
Preferred Regimens (alphabetical order) that is not amenable to skin-directed therapy (eg, in regions where topical
• Systemic therapy + skin-directed therapy (limited/local or generalized therapies are difficult to apply regularly).
including phototherapy as indicated for stage of disease)
Bexarotene 4. Alternative retinoids (acitretin or isotretinoin) could be considered in
b place of bexarotene.
Interferon alfa
Methotrexate 5. In stage IA, ECP is primarily reserved for the rare patient with stage IA
MF with low level blood involvement (B1).
Useful in Certain Circumstances (alphabetical order) 6. Patients with disease achieving a clinical benefit and/or those with
• Systemic therapy + skin-directed therapy (limited/local or generalized disease responding to primary treatment should be considered for
including phototherapy as indicated for stage of disease) maintenance or tapering of regimens to optimize response duration.
Acitretin
Extracorporeal photopheresis (ECP)
Interferon gamma-1b
Isotretinoin
Footnotes on
Note: All recommendations are category 2A unless otherwise indicated. MFSS-A 9 of 12
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TABLE 2: STAGE IB MF (Skin only disease with ≥10% BSA) – STAGE IIA MF - MFSS-7a,b,c
SUGGESTED REGIMENS
• Skin-directed therapies (alone or in combination with other skin- 1. Stage IB–IIA MF can be treated with skin-directed therapies (alone or in
directed therapies) combination with other skin-directed therapies).
Lower skin disease burden (eg, predominantly patch disease):
Limited patches/plaques: Skin-directed therapy can be considered as
Skin-Limited/Local (for limited/localized skin involvement) monotherapy.
Higher skin disease burden (eg, predominantly plaque disease): Extensive skin involvement: Phototherapy may be given alone or in
Skin-Generalized (for generalized skin involvement) combination with other skin-directed therapies. TSEBT maybe given alone or
OR in combination with topical corticosteroids.
• Systemic therapy + skin-directed therapy (limited/local or 2. In patients with histologic evidence of FMF, skin disease may be less
generalized including phototherapy as indicated for stage of responsive to topical therapies.
disease) 3. Systemic therapies (single agents or combination therapies) should be
Preferred Regimens (alphabetical order) considered for patients with extensive skin involvement, higher skin disease
• Bexarotene burden, predominantly plaque disease, blood involvement, and/or inadequate
• Brentuximab vedotin response to skin-directed therapy.
• Interferon alfab 4. In the randomized ALCANZA trial (Prince HM, et al. Lancet 2017;390:555-
• Methotrexate 566), brentuximab vedotin was more effective than methotrexate or
bexarotene in patients with previously treated MF (≥ stage IB). Patients with
• Mogamulizumab SS were excluded from the ALCANZA trial.
• Romidepsin
5. In the randomized MAVORIC trial (Kim YH, et al. Lancet Oncol 2018;19:1192-
• Vorinostat 1204), mogamulizumab was more effective than vorinostat in patients with
previously treated MF (≥ stage IB) and SS. Responses were higher in patients
Useful in Certain Circumstances (alphabetical order) with blood involvement (stage III or stage IV disease) than those with stage
• Acitretin IIB or stage IB/IIA disease. Patients with MF-LCT were excluded from the
• Alemtuzumab (category 2B) MAVORIC trial.
• Gemcitabine (category 2B) 6. Alternative retinoids (acitretin or isotretinoin) could be considered in place of
• ECP bexarotene.
• Interferon gamma-1b 7. In stage IB/IIA, ECP is primarily reserved for patients with low-level blood
• Isotretinoin involvement (B1).
• Liposomal doxorubicin (category 2B) 8. There is limited safety data for the use of TSEBT in combination with
• Pembrolizumab (category 2B) systemic retinoids, HDAC inhibitors (such as vorinostat or romidepsin), or
• Pralatrexate (category 2B) mogamulizumab, or combining phototherapy with vorinostat or romidepsin.
9. Patients with disease achieving a clinical benefit and/or those with disease
responding to treatment should be considered for maintenance or tapering of
Footnotes on
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TABLE 3: STAGE IIB MF (Tumor stage disease)a,b,c

LIMITED TUMOR DISEASE GENERALIZED TUMOR DISEASE (SEE ALSO GENERAL CONSIDERATIONS ON
MFSS-A [1 of 12])
• Local RT and/or skin-directed therapy • TSEBT 1. RT is preferred for limited tumor lesions. Topical therapies
alone are often inadequate for tumor stage disease.
OR OR
2. In patients with histologic evidence of FMF, skin disease
• Systemic therapy + skin-directed therapy (limited/ may be less responsive to topical therapies.
• Systemic therapy ± local RT ± skin-directed local or generalized including phototherapy as
therapy (limited/ local or generalized 3. Adjuvant systemic biologic therapy may be considered
indicated for stage of disease) after TSEBT for generalized tumor lesions to improve
including phototherapy as indicated for stage
OR response duration.
of disease)
4. In the randomized ALCANZA trial (Prince HM, et al.
• Combination therapies
Preferred Regimens (alphabetical order) Lancet 2017;390:555-566), brentuximab vedotin was
• Bexarotene more effective than methotrexate or bexarotene in
Preferred Regimens (alphabetical order) patients with previously treated MF (≥ stage IB). Patients
• Brentuximab vedotin • Single agents Liposomal doxorubicin with SS were excluded from the ALCANZA trial.
• Interferon alfab Bexarotene Methotrexate 5. In the randomized MAVORIC trial (Kim YH, et al. Lancet
• Methotrexate Brentuximab vedotin
• Mogamulizumab
Mogamulizumab Oncol 2018;19:1192-1204), mogamulizumab was more
Gemcitabine
• Romidepsin b Pralatrexate effective than vorinostat in patients with previously
Interferon alfa Romidepsin treated MF (≥ stage IB) and SS. Responses were higher
• Combination therapy in patients with blood involvement (stage III or stage IV
Other Recommended Regimen Retinoid + interferon alfab disease) than those with stage IIB or stage IB/IIA disease.
• Vorinostat Patients with MF-LCT were excluded from the MAVORIC
• Pembrolizumab (category 2B) Other Recommended Regimens trial.
• Pembrolizumab 6. Alternative retinoids (acitretin or isotretinoin) could be
Useful in Certain Circumstances (alphabetical • Vorinostat considered in place of bexarotene.
order)
• Acitretin 7. ECP may be more appropriate as systemic therapy in
Useful in Certain Circumstances (alphabetical order)
• ECP patients with some blood involvement (B1 or B2).
• Single agents
• Interferon gamma-1b Acitretin 8. There is limited safety data for the use of TSEBT in
• Isotretinoin combination with systemic retinoids, HDAC inhibitors
ECP (such as vorinostat or romidepsin), or mogamulizumab, or
Interferon gamma-1b combining phototherapy with vorinostat or romidepsin.
Isotretinoin
9. Patients with disease achieving a clinical benefit and/
• Combination therapy or those with disease responding to treatment should be
ECP + interferon alfab or retinoid considered for maintenance or tapering of regimens to
ECP + interferon alfab + retinoid optimize response duration.
Footnotes on
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TABLE 4: STAGE III MF (Erythrodermic disease) - MFSS-10a,b,c,d

SUGGESTED REGIMENS
• Systemic therapy + skin-directed therapy (limited/local or 1. In the randomized ALCANZA trial (Miles Prince H, et al. Lancet
generalized including phototherapy as indicated for stage of 2017;390:555-566), brentuximab vedotin was more effective than
disease) methotrexate or bexarotene in patients with previously treated MF (≥ stage
IB). Patients with SS were excluded from the ALCANZA trial.
Preferred Regimens (alphabetical order) 2. In the randomized MAVORIC trial (Kim YH, et al. Lancet Oncol
• Single agents 2018;19:1192-1204), mogamulizumab was more effective than vorinostat in
Bexarotene patients with previously treated MF (≥ stage IB) and SS. Responses were
Brentuximab vedotin higher in patients with blood involvement (stage III or stage IV disease)
ECP than those with stage IIB or stage IB/IIA disease. Patients with MF-LCT
Interferon alfab were excluded from the MAVORIC trial.
Methotrexate 3. Alternative retinoids (acitretin or isotretinoin) could be considered in place
Mogamulizumab of bexarotene.
Romidepsin 4. ECP may be more appropriate as systemic therapy in patients with some
• Combination therapy blood involvement (B1 or B2).
ECP + interferon alfab or retinoid
5. Phototherapy and TSEBT may be associated with increased toxicity in
ECP + interferon alfab + retinoid
patients with erythroderma and modification is dose/schedule may be
Retinoid + interferon alfab
considered.
Other Recommended Regimens 6. There is limited safety data for the use of TSEBT in combination with
• Vorinostat systemic retinoids, HDAC inhibitors (such as vorinostat or romidepsin), or
mogamulizumab, or combining phototherapy with vorinostat or romidepsin.
Useful in Certain Circumstances (alphabetical order) 7. Patients with disease achieving a clinical benefit and/or those with disease
• Single agents responding to treatment should be considered for maintenance or tapering
Acitretin of regimens to optimize response duration.
Alemtuzumab 8. Patients with erythrodermic disease are at increased risk for secondary
Gemcitabine infection with skin pathogens and systemic antibiotic therapy should be
Interferon gamma-1b considered. See MFSS-B.
Isotretinoin
Liposomal doxorubicin
Pembrolizumab
Pralatrexate
• Skin-directed therapy
Phototherapy
TSEBT (category 2B)
Footnotes on
Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged. MFSS-A 9 of 12
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TABLE 5: SÉZARY SYNDROME (Stage IVA1 or IVA2) - MFSS-11a,b,c,d

SUGGESTED REGIMENS TREATMENT CONSIDERATIONS
Low-Intermediate Burden High Burden (SEE ALSO GENERAL CONSIDERATIONS ON
(eg, ASC <5 K/mm3) (eg, ASC >5 K/mm3) MFSS-A [1 of 12])
• Systemic therapy + skin-directed therapy (limited/local • Systemic therapy + skin-directed therapy (limited/ 1. In the randomized ALCANZA trial (Miles Prince
or generalized including phototherapy as indicated for local or generalized including phototherapy as H, et al. Lancet 2017;390:555-566), brentuximab
stage of disease) indicated for stage of disease) vedotin was more effective than methotrexate or
bexarotene in patients with previously treated MF
Preferred Regimens (alphabetical order) Preferred Regimens (alphabetical order) (≥ stage IB). Patients with SS were excluded from
• Single agents • Single agents the ALCANZA trial.
Bexarotene Mogamulizumab 2. In the randomized MAVORIC trial (Kim YH,
ECP Romidepsin et al. Lancet Oncol 2018;19:1192-1204),
Interferon alfab • Combination therapy mogamulizumab was more effective than vorinostat
Methotrexate ECP + interferon alfab or retinoid in patients with previously treated MF (≥ stage IB)
and SS. Responses were higher in patients with
Mogamulizumab ECP + interferon alfab + retinoids
blood involvement (stage III or stage IV disease)
Romidepsin Retinoid + interferon alfab than those with stage IIB or stage IB/IIA disease.
Vorinostat Patients with MF-LCT were excluded from the
• Combination therapy Other Recommended Regimens MAVORIC trial.
ECP + interferon alfab or retinoid (alphabetical order)
3. Alternative retinoids (acitretin or isotretinoin) could
ECP + interferon alfab + retinoids • Alemtuzumab be considered in place of bexarotene.
Retinoid + interferon alfab • Bexarotene
• Brentuximab vedotin 4. There is limited safety data for the use of TSEBT
in combination with systemic retinoids, HDAC
Other Recommended Regimens (alphabetical order) • ECP inhibitors (such as vorinostat or romidepsin), or
• Alemtuzumab • Gemcitabine mogamulizumab, or combining phototherapy with
• Brentuximab vedotin • Interferon alfab vorinostat or romidepsin.
• Gemcitabine • Liposomal doxorubicin 5. Patients with disease achieving a clinical benefit
• Liposomal doxorubicin • Methotrexate and/or those with disease responding to treatment
• Pembrolizumab • Pembrolizumab should be considered for maintenance or tapering
• Pralatrexate • Pralatrexate of regimens to optimize response duration.
• Vorinostat
Useful in Certain Circumstances (alphabetical order)
• Acitretin Useful in Certain Circumstances (alphabetical
• Interferon gamma-1b order)
• Isotretinoin • Acitretin
• Interferon gamma-1b
• Isotretinoin
Footnotes on
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TABLE 6: STAGE IV MF (Non-Sézary/Visceral organ disease) AND MF WITH LARGE CELL TRANSFORMATION (MF-LCT)c,d,e
SUGGESTED REGIMENS
Non-Sézary (stage IVA2) or Visceral/Solid (SEE ALSO GENERAL CONSIDERATIONS ON MFSS-A [1 of 12])
MF-LCT (MFSS-12)
Organ (stage IVB) Disease (MFSS-11)
• Systemic therapy ± RT for local control • TSEBT 1. In the MAVORIC trial (Kim YH, et al. Lancet Oncol
OR 2018;19:1192-1204), mogamulizumab was more effective
Preferred Regimens (alphabetical order) • Systemic therapy + skin directed than vorinostat in patients with previously treated MF and SS.
• Brentuximab vedotin therapy Response rates were higher in the blood compartment than in
• Gemcitabine lymph nodes or viscera. Patients with MF-LCT were excluded
• Liposomal doxorubicin Preferred Regimens (alphabetical from the MAVORIC trial.
• Pralatrexate order) 2. There is limited safety data for the use of TSEBT in combination
• Romidepsin • Brentuximab vedotin with systemic retinoids, HDAC inhibitors (such as vorinostat or
romidepsin), or mogamulizumab, or combining phototherapy
• Gemcitabine with vorinostat or romidepsin.
Other Recommended Regimens • Liposomal doxorubicin
• Mogamulizumab • Pralatrexate 3. In patients requiring chemotherapy, single agents are
• Multiagent chemotherapy regimens (See • Romidepsin preferred over combination chemotherapy, due to the higher
NCCN Guidelines for T-Cell Lymphomas toxicity profiles associated with multi-agent regimens and
• Multiagent chemotherapy regimens the short-lived responses seen with time-limited combination
- PTCL-B 3 of 8 for regimens listed for (See NCCN Guidelines for T-Cell chemotherapy.
PTCL- NOS) Lymphomas -PTCL-B 3 of 8 for
regimens listed for PTCL-NOS) 4. Multiagent chemotherapy regimens are generally reserved for
patients with relapsed/refractory or extracutaneous disease.
Most patients are treated with multiple single-agent systemic
Other Recommended Regimens therapies before receiving multiagent chemotherapy.
• Pembrolizumab
TABLE 7: RELAPSED OR REFRACTORY DISEASE TO MULTIPLE PRIOR THERAPIES
SUGGESTED REGIMENS
Useful in Certain Circumstances (alphabetical order by category)
• Alemtuzumab
• Chlorambucil
• Cyclophosphamide
• Etoposide
• Pembrolizumab
• Pentostatin
• Temozolomide for central nervous system (CNS) involvement at some NCCN Member Institutions
• Bortezomib (category 2B)
• Multiagent chemotherapy regimens (See NCCN Guidelines for T-Cell Lymphomas - PTCL-B 3 of 8 for regimens listed for PTCL-NOS)
Footnotes on
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FOOTNOTES
a Laboratory studies for triglycerides, and thyroid function tests (with free thyroxine T4) are recommended for patients receiving bexarotene.
b Peginterferon alfa-2a is the only alpha interferon available for clinical use in the United States and it may be substituted for other alpha interferon
preparations (Schiller
M, et al. J Eur Acad Dermatol Venerol 2017;31:1841-1847; Patsatsi A, et al. J Eur Acad Dermatol Venereol 2022;36:e291-e293; Osman S, et al. Dermatologic Therapy
2023;2023:7171937).
c In the ALCANZA trial, brentuximab vedotin was associated with superior clinical outcome in patients with previously treated CD30+ MF (CD30 positivity was defined as
CD30 expression in ≥10% of total lymphoid cells). In other clinical studies, clinical responses with brentuximab vedotin have been reported across all CD30 expression
levels including negligible CD30 expression.
d Rapid progression has been reported in patients, who are positive for human t-lymphotropic virus (HTLV), receiving pembrolizumab. Disease flare is seen in some
patients (especially in erythrodermic skin/Sézary patients) and should be distinguished from disease progression (Khodadoust MS, et al. J Clin Oncol 2020:38:20-28).
e Lower doses of alemtuzumab administered subcutaneously have shown lower incidence of infectious complications. While alemtuzumab is no longer commercially
available, it may be obtained for clinical use. Recommend CMV monitoring or prophylaxis (see PCLYM-C).

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SUGGESTED TREATMENT REGIMENS

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Skin-Directed Therapies Topical calcineurin inhibitor (pimecrolimus)
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Tazarotene gel
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Deeths MJ, Chapman JT, Dellavalle RP, et al. Treatment of patch and plaque stage mycosis Morris S, Scarisbrick J, Frew J, et al. The results of low-dose total skin electron beam radiation therapy
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Specht L, Dabaja B, Illidge T, et al. Modern radiation therapy for primary cutaneous lymphomas: field and
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Continued
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Bortezomib intravenous pegylated liposomal doxorubicin monochemotherapy in patients with stage IIB, IVA, or IVB
Zinzani PL, Musuraca G, Tani M, et al. Phase II trial of proteasome inhibitor bortezomib in patients with advanced mycosis fungoides: final results from EORTC 21012. J Clin Oncol 2012;30:4091-4097.
relapsed or refractory cutaneous T-cell lymphoma. J Clin Oncol 2007;25:4293-4297. Weiner D, Ly A, Talluru S, et al. Efficacy of single‑agent chemotherapy with pegylated liposomal
Brentuximab vedotin doxorubicin or gemcitabine in a diverse cohort of patients with recalcitrant cutaneous T‑cell lymphoma.
Kim YH, Tavallaee M, Sundram U, et al. Phase II investigator-initiated study of brentuximab vedotin Br J Dermatol 2024;190:436‑438.
in mycosis fungoides and Sezary syndrome with variable CD30 expression level: A multi-institution Falkenhain‑Lopez D, Fulgencio‑Barbarin J, Puerta‑Pena M, et al. Single‑centre experience of using
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Prince HM, Kim YH, Horwitz SM, et al. Brentuximab vedotin or physician's choice in CD30-positive 2022;186:363‑365.
cutaneous T-cell lymphoma (ALCANZA): an international, open-label, randomised, phase 3, Methotrexate
multicentre trial. Lancet 2017;390:555-566. Zackheim HS, Kashani-Sabet M, Hwang ST. Low-dose methotrexate to treat erythrodermic cutaneous
Extracorporeal photopheresis (ECP) T-cell lymphoma: results in twenty-nine patients. J Am Acad Dermatol 1996;34:626-631.
Talpur R, Demierre MF, Geskin L, et al. Multicenter photopheresis intervention trial in early-stage Zackheim HS, Kashani-Sabet M, McMillan A. Low-dose methotrexate to treat mycosis fungoides: a
mycosis fungoides. Clin Lymphoma Myeloma Leuk 2011;11:219-227. retrospective study in 69 patients. J Am Acad Dermatol 2003;49:873-878.
Knobler R, Duvic M, Querfeld C, et al. Long-term follow-up and survival of cutaneous T-cell lymphoma Mogamulizumab
patients treated with extracorporeal photopheresis. Photodermatol Photoimmunol Photomed Kim YH, Bagot M, Pinter-Brown L, et al. Mogamulizumab versus vorinostat in previously treated
2012;28:250-257. cutaneous T-cell lymphoma (MAVORIC): An international, open-label, randomised, controlled phase 3
Atilla E, Atilla PA, Bozdag SC, et al. Extracorporeal photochemotherapy in mycosis fungoides. Transfus trial. Lancet Oncol 2018;19:1192-1204.
Clin Biol 2017;24:454-457. Pembrolizumab
Gao C, McCormack C, van der Weyden C, et al. Prolonged survival with the early use of a novel Khodadoust MS, Rook AH, Porcu P, et al. Pembrolizumab in relapsed and refractory mycosis fungoides
and Sezary syndrome: A multicenter phase II study. J Clin Oncol 2020;38:20-28.
extracorporeal photopheresis regimen in patients with Sezary syndrome. Blood 2019;134:1346-1350.
Pentostatin
Gemcitabine
Cummings FJ, Kim K, Neiman RS, et al. Phase II trial of pentostatin in refractory lymphomas and
Duvic M, Talpur R, Wen S, et al. Phase II evaluation of gemcitabine monotherapy for cutaneous T-cell
cutaneous T-cell disease. J Clin Oncol 1991;9:565-571.
lymphoma. Clin Lymphoma Myeloma 2006;7:51-58.
Greiner D, Olsen EA, Petroni G. Pentostatin (2'-deoxycoformycin) in the treatment of cutaneous T-cell
Marchi E, Alinari L, Tani M, et al. Gemcitabine as frontline treatment for cutaneous T-cell lymphoma:
lymphoma. J Am Acad Dermatol 1997;36:950-955.
phase II study of 32 patients. Cancer 2005;104:2437-2441.
Tsimberidou AM, Giles F, Duvic M, et al. Phase II study of pentostatin in advanced T-cell lymphoid
Zinzani PL, Baliva G, Magagnoli M, et al. Gemcitabine treatment in pretreated cutaneous T-cell
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lymphoma: experience in 44 patients. J Clin Oncol 2000;18:2603-2606.
Pralatrexate
Zinzani PL, Venturini F, Stefoni V, et al. Gemcitabine as single agent in pretreated T-cell lymphoma
Horwitz SM, Kim YH, Foss F, et al. Identification of an active, well-tolerated dose of pralatrexate in
patients: evaluation of the long-term outcome. Ann Oncol 2010;21:860-863.
patients with relapsed or refractory cutaneous T-cell lymphoma. Blood 2012;119:4115-4122.
Awar O, Duvic M. Treatment of transformed mycosis fungoides with intermittent low-dose gemcitabine.
Foss F, Horwitz SM, Coiffier B, et al. Pralatrexate is an effective treatment for relapsed or refractory
Oncology 2007;73:130-135.
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Myeloma Leuk 2012;12:238-243.
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Systemic Therapies (continued) Systemic + systemic
Romidepsin Straus DJ, Duvic M, Kuzel T, et al. Results of a phase II trial of oral bexarotene (Targretin) combined with
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romidepsin as monotherapy for patients with cutaneous T-cell lymphoma. J Clin Oncol 2009;27:5410-5417. Talpur R, Ward S, Apisarnthanarax N, et al. Optimizing bexarotene therapy for cutaneous T-cell
Whittaker SJ, Demierre MF, Kim EJ, et al. Final results from a multicenter, international, pivotal study of
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romidepsin in refractory cutaneous T-cell lymphoma. J Clin Oncol 2010;28:4485-4491.
Retinoids Suchin KR, Cucchiara AJ, Gottleib SL, et al. Treatment of cutaneous T-cell lymphoma with combined
Zhang C, Duvic M. Treatment of cutaneous T-cell lymphoma with retinoids. Dermatol Ther 2006;19:264-271. immunomodulatory therapy: a 14-year experience at a single institution. Arch Dermatol 2002;138:1054-
Duvic M, Martin AG, Kim Y, et al. Phase 2 and 3 clinical trial of oral bexarotene (Targretin capsules) for the 1060.
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593. immunomodulatory therapies: prognostic markers of response. Arch Dermatol 2011;147:1410-1415.
Duvic M, Hymes K, Heald P, et al. Bexarotene is effective and safe for treatment of refractory advanced-
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Temozolomide Allogeneic HCT
Tani M, Fina M, Alinari L, et al. Phase II trial of temozolomide in patients with pretreated cutaneous T-cellde Masson A, Beylot-Barry M, Bouaziz JD, et al. Allogeneic stem cell transplantation for advanced
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SUPPORTIVE CARE FOR PATIENTS WITH MF/SS

Collaboration with dermatologist for supportive care is essential.
Pruritus Infections
• Assessment • Active or suspected infections
Pruritus should be assessed Cutaneous viral infections
Correlation between sites of disease and localization of pruritus ◊ High risk for skin dissemination of localized viral infections
may be useful in tailoring therapy herpes simplex virus (HSV)/varicella zoster virus (VZV).
For severe or persistent pruritus despite therapeutic response ◊ HSV prophylaxis with acyclovir or equivalent should be
considered for patients with frequent recurrence of HSV
other potential causes for pruritus should be investigated infection.
Erythroderma:
• Treatment ◊ Swab of skin, nares, or other areas for cultures of
Co-management with a dermatologist with expertise in skin care Staphylococcus aureus infection or colonization
and CTCL ◊ Intranasal mupirocin for S. aureus carriers
Optimized skin-directed and systemic therapy for MF/SS ◊ Oral dicloxacillin or cephalexin
Mild, unscented soaps for bathing are gentle and optimal to ◊ Sulfamethoxazole/trimethoprim, doxycycline, minocycline,
prevent skin dryness or clindamycin if suspected methicillin-resistant
Moisturizers/emollients staphylococcus aureus (MRSA)
Topical steroid application (appropriate strength for body ◊ Vancomycin if no improvement or documented bacteremia
region) ± occlusion1 ◊ Bleach baths [1/2 cup of regular strength bleach (5%–6%) in
full tub of water] or for limited areas, soaks (1 tsp of bleach
Topical over-the-counter preparations
in 1 gallon of water). Bleach baths should be taken for 5 to 10
Systemic agents minutes two to three times a week maximum followed by tap
◊ First-line water to rinse off the bleach water. Moisturizer should be put
– H1 antihistamines; single agent or combination of on immediately following the bleach bath or soak.
antihistamines from different classes2 Ulcerated and necrotic tumors:
– Gabapentin3,4 ◊ Infection or colonization with Gram-negative rods should be
– Pregabalin considered in addition to the more common gram-positive
◊ Second-line organisms.
– Aprepitant5-8 ◊ Ulcer will not heal unless disease is treated. Consider local
– Mirtazapine4 RT if feasible.
– Selective serotonin reuptake inhibitors (SSRIs)9 • Prophylaxis
◊ Third-line Optimize skin barrier protection with moisturizing of skin
Consider mupirocin to the nares for S. aureus carriers
– Naltrexone10 Diluted bleach baths or soaks (if limited area) as noted above
– Systemic steroids Minimize use of central lines when possible
For patients receiving alemtuzumab, see PCLYM-C
Note: All recommendations are category 2A unless otherwise indicated. References

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SUPPORTIVE CARE FOR PATIENTS WITH MF/SS

REFERENCES
1 Yosipovitch G, Szolar C, Hui XY, Maibach H. High-potency topical corticosteroid rapidly decrease histamine-induced itch but not thermal sensation and pain in
human beings. J Am Acad Dermatol 1996;35:118-120.
2 Eschler D, Klein PA. An evidence-based review of the efficacy of topical antihistamines in the relief of pruritus. J Drugs Dermatol 2010;9:992-997.
3 Matsuda KM, Sharma D, Schonfeld AR, Kwatra SG. Gabapentin and pregabalin for the treatment of chronic pruritus. J Am Acad Dermatol 2016;75:619-625.
4 Demierre MF, Taverna J. Mirtazapine and gabapentin for reducing pruritus in cutaneous T-cell lymphoma. Am Acad Dermatol 2006;55:543-544.
5 Jiménez Gallo D, Albarrán Planelles C, Linares Barrios M, et al. Treatment of pruritus in early-stage hypopigmented mycosis fungoides with aprepitant. Dermatol
Ther 2014;27:178-182.
6 Duval A, Dubertret L. Aprepitant as an antipruritic agent? N Engl J Med 2009;361:1415-1416.
7 Booken N, Heck M, Nicolay JP, et al. Oral apepritant in the therapy of refractory pruritus in erythrodermic cutaneous T-cell lymphoma. Br J Dermatol 2011;164:665-
667.
8 Ladizinski B, Bazakas A, Olsen EA. Aprepitant: A novel neurokinin-1 receptor/substance P antagonist as antipruritic therapy in cutaneous T-cell lymphoma. J Am
Acad Dermatol 2012;67:e198-e199.
9 Ständer S, Böckenholt B, Schürmeyer-Horst F, et al. Treatment of chronic pruritus with the selective serotonin re-uptake inhibitors paroxetine and fluvoxamine:
results of an open-labelled, two-arm proof-of-concept study. Acta Derm Venereol 2009;89:45-51.
10 Brune A, Metze D, Luger T, Ständer S. Antipruritic therapy with the oral opioid receptor antagonist naltrexone. Open, non-placebo controlled administration in 133
patients. Hautarzt 2004;55:1130-1136.

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Primary Cutaneous CD30+ T-Cell Lymphoproliferative Disorders Discussion
PRINCIPLES OF PRIMARY CUTANEOUS CD30+ T-CELL LYMPHOPROLIFERATIVE DISORDERS (LPD)

Overview & Definition
• Primary cutaneous CD30+ T-cell LPDs represent a spectrum • Primary cutaneous ALCL (PC-ALCL)
that includes primary cutaneous anaplastic large cell lymphoma Represents about 8% of cutaneous lymphoma cases.a
(ALCL), lymphomatoid papulosis (LyP), and “borderline” cases Unlike systemic ALCL, PC-ALCL typically follows an indolent
a,b,c course and although cutaneous relapses are common, an excellent
with overlapping clinical and histopathologic features.
prognosis is usually maintained.d,e
• Clinical correlation with histopathologic features is essential for Histologically characterized by diffuse, cohesive sheets of large
establishing the diagnosis of primary cutaneous CD30+ T-cell CD30-positive (in >75%) cells with anaplastic, pleomorphic, or
LPDs; diagnosis cannot be made based on pathology review alone. immunoblastic appearance.a
Differential Diagnosis Clinical features typically include solitary or localized nodules or
• It is critical to distinguish CD30+ T-cell LPDs from other processes tumors (often ulcerated); multifocal lesions occur in about 20%
of cases. Extracutaneous disease occurs in about 10% of cases,
involving skin that may express CD30:
usually involving regional lymph nodes.a Patches and plaques may
Systemic T-cell lymphomas (eg, ALCL, adult T-cell leukemia/ also be present and some degree of spontaneous remittance in
lymphoma [ATLL], peripheral T-cell lymphoma [PTCL]); lesions may also be seen.
Other CD30+ cutaneous lymphomas such as MF, especially MF
with LCT • Lymphomatoid papulosis (LyP)
Benign disorders such as lymphomatoid drug reactions, LyP is included under the classification system for lymphomas
arthropod bites, viral infections, and others. (WHO-EORTC) but may be best classified as an LPD as it is a
• Lymphomatoid drug reactions have been linked with certain drugs frequently spontaneously regressing process.a
(eg, amlodipine, carbamazepine, cefuroxime, valsartan) and may be LyP has been reported to be associated with other lymphomas
associated with CD30+ atypical large cells in histology. such as MF, PC-ALCL, systemic ALCL, or Hodgkin lymphoma.f,g
• MF and primary cutaneous CD30+ T-cell LPD can coexist in the Lyp is histologically heterogeneous with large atypical anaplastic,
same patient. immunoblastic, or Hodgkin-like cells in a marked inflammatory
backgrounda; several histologic subtypes can be defined based on
evolution of skin lesions.f
Lyp clinical features are characterized by chronic, recurrent,
spontaneously regressing papulonodular (grouped or generalized)
skin lesions.a,f
d Benner MF, Willemze R. Arch Dermatol 2009;145:1399-1404.

e Woo DK, et al. Arch Dermatol 2009;145:667-674.
a Alaggio R, et al. Leukemia 2022;36:1720-1748; Campo E, et al. Blood f Kempf W, et al. Blood 2011;118:4024-4035.
2022;140:1229-1253. See Classification (ST-1). g Due to overlapping immunophenotype and morphology, need to use caution to not
b Vergier B, et al. Am J Surg Pathol 1998;22:1192-1202. diagnose CD30+ T-cell in lymph nodes as HL (Eberle FC, et al. Am J Surg Pathol
c Liu HL, et al. J Am Acad Dermatol 2003;49:1049-1058. 2012;36:716-725).
Diagnosis on
Note: All recommendations are category 2A unless otherwise indicated. PCTLD-1
PCTLD/INTRO-1

Table of Contents
DIAGNOSISa
ESSENTIAL:
• Clinical presentation: see Overview and Definition (PCTLD/INTRO-1)
• Clinical pathologic correlation is essential
• Complete skin examination for any sign of benign or malignant skin lesions Workup
Cutaneous ALCL
• Biopsy of suspicious skin sites (PCTLD-2)
Multiple biopsies may be necessary to capture the pathologic variability of
disease at diagnosis
\Review of a sufficient number of slides with adequate material to perform a
comprehensive workup as described below and/or at least one paraffin block
representative of the tumor should be done by a pathologist with expertise in
the diagnosis of CTCLs. Rebiopsy if pathological findings are non-diagnostic
Workup
and/or discordant with the clinical presentation LyPg (PCTLD-3)
Adequate biopsy (by punch, incisional, or excisional) of all types of clinical
lesions present will aid in final diagnosis
• Adequate immunophenotyping to establish diagnosisb,c on skin biopsy:
IHC panel may include: CD3, CD4, CD8, CD20, CD30, CD56, ALKd

• On skin biopsy, expanded IHC panel may include: CD2, CD5, CD7, CD25, TIA1, Mycosis Fungoides
granzyme B, perforin, IRF4/MUM1, EMA, TCRꞵ, TCRδ CD30+ transformed MF
(MFSS-1)
• EBER-ISH
• Molecular analysis to detect clonal TCR gene rearrangements or other
assessment of clonalitya,e
• FISH: ALK and DUSP22 gene rearrangementsa
• Excisional or incisional biopsy of suspicious lymph nodes
• Assessment of HTLV-1/2 serologyf is encouraged as results can impact therapy
a Principles of Molecular Analysis in Primary Cutaneous Lymphomas (PCLYM-B).

b Use of Immunophenotyping/Genetic Testing in Differential Diagnosis of Mature B-Cell and NK/T-Cell Neoplasms (See NCCN Guidelines for B-Cell Lymphomas).
c Typical immunophenotype: CD30+ (>75% cells), CD4+ variable loss of CD2/CD5/CD3, CD8+ (<5%) cytotoxic granule proteins positive.
d ALK positivity and t(2;5) translocation is typically absent in PC-ALCL and LyP.
e Clonal TCR gene rearrangements alone are not sufficient for diagnosis, as these can also be seen in patients with non-malignant conditions. Results should be
interpreted in the context of overall presentation. See Principles of Molecular Analysis in T-Cell Lymphomas (TCLYM-A).
f See map for prevalence of HTLV-1/2 by geographic region. HTLV-1 has been described in patients in non-endemic areas.
g LyP is not considered a malignant disorder; however, there is an association with other lymphoid malignancy (MF or PC-ALCL). Staging studies are done in LyP only if
there is suspicion of systemic involvement by an associated lymphoma.

PCTLD-1

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WORKUP
ESSENTIAL:
• History and complete physical examination including complete skin
examinationh; palpation of peripheral lymph node regions;
liver or spleen enlargement
• CBC with differential PC-ALCL
• Comprehensive metabolic panel
• LDH PCTLD-4
• C/A/P CT with contrast or integrated whole body FDG-PET/CT (arms/legs
included when disease assessment of entire body is needed)i Cutaneous
Cutaneous • Biopsy suspicious nodesj,k,l: Biopsy of enlarged lymph nodes or suspected ALCL with
ALCL extracutaneous sites. Excisional or adequate core needle biopsy is regional node
preferred. An FNA biopsy alone is not sufficient for the initial diagnosis of
lymphoma. Rebiopsy if consult material is nondiagnostic.
See NCCN
USEFUL IN CERTAIN CIRCUMSTANCES Guidelines for
• Bone marrow aspiration and biopsy (optional for solitary cutaneous ALCL Systemic ALCL T-Cell Lymphomas -
or cutaneous ALCL without extracutaneous involvement on imaging) Peripheral T-Cell
• Pregnancy testing in patients of childbearing potential if contemplating (PTCL-1)
treatments that are contraindicated in pregnancym
• Discuss fertility preservationn
k Consider
systemic ALCL, regional lymph node involvement with PC-ALCL, or
h Monitoring the size and number of lesions will assist with response assessment. lymph node involvement with transformed MF.
i Patients with T-cell lymphomas often have extranodal disease, which may be l Consider PC-ALCL if in draining lymph nodes only.
inadequately imaged by CT. FDG-PET scan may be preferred in these instances. m Many skin-directed and systemic therapies are contraindicated or are of
j Due to overlapping immunophenotype and morphology, need to use caution to avoid unknown safety in pregnancy. Refer to individual drug information.
diagnosing CD30+ T-cell in lymph nodes as HL (Eberle FC, et al. Am J Surg Pathol n Fertility preservation options include: sperm banking, semen cryopreservation,
2012;36:716-725). IVF, or ovarian tissue or oocyte cryopreservation.

PCTLD-2

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WORKUP
ESSENTIAL:
• History and complete physical examination including complete skin examinationh; palpation
of peripheral lymph node regions; liver or spleen enlargement
• CBC with differential
• Comprehensive metabolic panel
• LDH
LyP g USEFUL IN CERTAIN CIRCUMSTANCES: PCTLD-5

• Pregnancy testing in patients of childbearing potential if contemplating treatments that are
contraindicated in pregnancym
• Discuss fertility preservationn
• C/A/P CT with contrast or integrated whole body FDG-PET/CT (arms/legs included when
disease assessment of entire body is needed)g,i,o (not done for typical LyP)
• Neck CT with contrast if whole body FDG-PET/CT not done (not done for typical LyP)
• Bone marrow aspiration and biopsy (not done for typical LyP) g,o
g LyP is not considered a malignant disorder; however, there is an association with other lymphoid malignancy (MF or PC-ALCL). Staging studies are done in LyP only if
there is suspicion of systemic involvement by an associated lymphoma.
h Monitoring the size and number of lesions will assist with response assessment.
i Patients with T-cell lymphomas often have extranodal disease, which may be inadequately imaged by CT. FDG-PET scan may be preferred in these instances.
m Many skin-directed and systemic therapies are contraindicated or are of unknown safety in pregnancy. Refer to individual drug information.
n Fertility preservation options include: sperm banking, semen cryopreservation, IVF, or ovarian tissue or oocyte cryopreservation.
o Only done to exclude an associated lymphoma.

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SUBTYPE EXTENT OF PRIMARY FOLLOW-UPy RELAPSED/REFRACTORY

DISEASE TREATMENTr DISEASE
• Retreat with initial treatment
Observe for
Solitary or ISRTs Responsez if disease confined to skin
recurrence
grouped or • For multifocal lesions or
lesions Surgical excisiont ± ISRTs No response/ extracutaneous involvement,
See Multifocal
refractory lesions below see multifocal lesions below
PC- disease
ALCLp Preferred regimen
• Brentuximab vedotinu Observe for
Responsez
Other recommended regimens ± recurrence
skin-directed therapies (MFSS-A)
Multifocal • Methotrexate (≤50 mg weekly)
lesions • Systemic retinoidsv • Clinical trial
• Pralatrexate • Retreat with same regimen
• Observation, if asymptomatic No response/ (unless refractory or
• Interferonw (category 3) refractory disease intolerant)
Preferred regimens • Alternative regimen not used
• Brentuximab vedotinu ± ISRTs for primary treatment
• ISRTs,w in selected cases • Systemic Therapies for
Cutaneous ALCL with Other recommended regimens Observe for
• Brentuximab vedotinu + Responsez Large-Cell Transformation
regional nodeq (N1) (See recurrence
(LCT) (Table 6 - Suggested
CHP (cyclophosphamide,
CUTB-A for N definition) doxorubicin, and prednisone) Regimens for MF with LCT)
(excludes systemic ALCL) • Methotrexate ± ISRTs,x No response/
• Pralatrexate ± ISRTs,x refractory disease
• CHOP or CHOEP ± ISRTs,x in
selected cases
p Regression of lesions may occur in up to 44% of cases.
q Biopsy-proven lymphoma in lymph node. x ISRT to include lymph node(s) ± primary skin lesions.
r Therapy References (PCTLD-A). y Mycosis fungoides can develop over time; continue to
s Principles of Radiation Therapy (PCLYM-A). conduct thorough skin exam
t Small lesions may be excised with minimal non-disfiguring surgery. during follow-up.
z Patients with a clinical benefit and/or those with disease responding to primary
u Supportive Care for Patients with Cutaneous Lymphomas (PCLYM-C).
v Limited data from case reports (eg, bexarotene). treatment should be considered for maintenance or tapering of regimens to optimize
w Peginterferon alfa-2a is the only interferon available for clinical use in the response duration. Relapsed disease often responds well to the same treatment.
Partial response should be treated with other primary treatment options not received
US and it may be substituted for other interferon preparations (Schiller M, et before to improve response before moving onto treatment for refractory disease.
al. J Eur Acad Dermatol Venerol 2017;31:1841-1847; Patsatsi A, et al. J Eur Patients with disease relapse or persistent disease after initial primary treatment may
Acad Dermatol Venereol 2022;36:e291-e293; Osman S, et al. Dermatologic be candidates for clinical trials.
Therapy 2023;2023:7171937).
PCTLD-4

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SUBTYPE EXTENT OF PRIMARY TREATMENTr FOLLOW-UPcc RELAPSED/REFRACTORY DISEASE

DISEASE
Continue current
Observation Responsez
management
Limited lesions, (preferred)
asymptomatic or
Topical steroids
Alternative regimen not used for
primary treatment
Topical steroids No response/refractory or
or disease Other regimens
Limited lesions,
Phototherapyaa or
symptomatic
or Clinical trial
LyP Observation
Clinical trial
Observation (preferred for or
asymptomatic) Observe Observation
or Responsez for or
Methotrexate (10–35 mg weeklybb) recurrence Retreat with primary
or treatment or treat Refractory
Phototherapyaa with alternative disease
Extensive lesions or regimen not
Systemic retinoidsv used for primary
or No response/
treatment
Topical steroids refractory disease
or
Topical mechlorethamine Clinical trial
(nitrogen mustard) or Clinical trial
Alternative regimen or
r Therapy References (PCTLD-A). not used for primary Refractory Brentuximab
u Supportive Care for Patients with Cutaneous Lymphomas (PCLYM-C). treatment disease vedotinu
v Limited data from case reports (eg, bexarotene).
z Patients with a clinical benefit and/or those with disease responding to primary
treatment should be considered for maintenance or tapering of regimens to optimize
response duration. Relapsed disease often responds well to the same treatment. Partial response should be treated with the other primary treatment options not
received before to improve response before moving onto treatment for refractory disease. Patients with disease relapse or persistent disease after initial primary
treatment may be candidates for clinical trials.
aa NB-UVB is generally preferred over PUVA.
bb Kempf W, et al. Blood 2011;118:4024-4035.
cc Life-long follow-up is warranted due to high risk for second lymphoid malignancies; continue to conduct thorough skin exam during follow-up.

PCTLD-5

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THERAPY REFERENCES
Skin-Directed Therapies Systemic Therapies
Topical steroids Brentuximab vedotin
Paul MA, Krowchuk DP, Hitchcock MG, Jorizzo JL. Lymphomatoid papulosis: Prince HM, Kim YH, Horwitz SM, et al. Brentuximab vedotin or physician's choice in CD30-positive
successful weekly pulse superpotent topical corticosteroid therapy in three cutaneous T-cell lymphoma (ALCANZA): an international, open-label, randomised, phase 3,
pediatric patients. Pediatr Dermatol 1996;13:501-506. multicentre trial. Lancet 2017;390:555-566.
Phototherapy Duvic M, Tetzlaff MT, Gangar P, et al. Results of a phase II trial of brentuximab vedotin for CD30+
Wantzin GL, Thomsen K. PUVA-treatment in lymphomatoid papulosis. Br J cutaneous T-cell lymphoma and lymphomatoid papulosis. J Clin Oncol 2015;33:3759-3765.
Dermatol 1982;107:687-690. Lewis DJ, Talpur R, Huen AO, et al. Brentuximab Vedotin for Patients With Refractory Lymphomatoid
Topical nitrogen mustard Papulosis: An Analysis of Phase 2 Results. JAMA Dermatol 2017;153:1302-1306.
Vonderheid EC, Tan ET, Kantor AF, et al. Long-term efficacy, curative potential, Brentuximab vedotin + CHP (cyclophosphamide, doxorubicin, and prednisone)
and carcinogenicity of topical mechloethamine chemotherapy in cutaneous T cell Horwitz S, O'Connor OA, Pro B, et al. Brentuximab vedotin with chemotherapy for CD30-positive
lymphoma. J Am Acad Dermatol 1989;20:416-428. peripheral T-cell lymphoma (ECHELON-2): a global, double-blind, randomised, phase 3 trial. Lancet
Radiation therapy 2019;393:229-240.
Million L, Yi EJ, Wu F, et al. Radiation therapy for primary cutaneous anaplastic Interferons
large cell lymphoma: An International Lymphoma Radiation Oncology Group Proctor SJ, Jackson GH, Lennard AL, Marks J. Lymphotoid papulosis: response to treatment with
Multi-institutional Experience. Int J Radiat Oncol Biol Phys 2016;95:1454-1459. recombinant interferon alfa-2b. J Clin Oncol 1992;10:170.
Specht L, Dabaja B, Illidge T, et al. Modern radiation therapy for primary Schmuth M, Topar G, Illersperger B, et al. Therapeutic use of interferon-alpha for lymphomatoid
cutaneous lymphomas: field and dose guidelines from the International papulosis. Cancer 2000;89:1603-1610.
Lymphoma Radiation Oncology Group. Int J Radiat Oncol Biol Phys 2015;92:32- Methotrexate
39. Everett MA. Treatment of lymphomatoid papulosis with methotrexate. Br J Dermatol 1984;111:631.
Smith GL, Duvic M, Yehia ZA, et al. Effectiveness of low-dose radiation for primary Vonderheid EC, Sajjadian A, Kaden ME. Methotrexate is effective for lymphomatoid papulosis and
cutaneous anaplastic large cell lymphoma. Adv Radiat Oncol 2017;2:363-369. other primary cutaneous CD30+ lymphoproliferative disorders. J Am Acad Dermatol 1996;34:470-481.
Fujita H, Nagatani T, Miyazawa M, et al. Primary cutaneous anaplastic large cell lymphoma
successfully treated with low-dose methotrexate. Eur J Dermatol 2008;18:360-361.
Pralatrexate
Horwitz SM, Kim YH, Foss F, et al. Identification of an active, well-tolerated dose of pralatrexate in
patients with relapsed or refractory cutaneous T-cell lymphoma. Blood 2012;119:4115-4122.
Systemic retinoids
Nakamura S, Hashimoto Y, Nishi K, et al. Primary cutaneous CD30+ lymphoproliferative disorder
successfully treated with etretinate. Eur J Dermatol 2012;22:709-710.
Krathen RA, Ward S, Duvic M. Bexarotene is a new treatment option for lymphomatoid papulosis.
Dermatology 2003;206:142-147.
Wyss M, Dummer R, Dommann SN, et al. Lymphomatoid papulosis--treatment with recombinant
interferon alfa-2a and etretinate. Dermatology 1995;190:288-291.
Sheehy JM, Catherwood M, Pettengell R, Morris TCC. Sustained response of primary cutaneous
CD30+ anaplastic large cell lymphoma to bexarotene and photopheresis. Leuk Lymphoma
2009;50:1389-1391.

PCTLD-A

Table of Contents
PRINCIPLES OF RADIATION THERAPYa

General Principles
• The general intent of RT is to treat the evident skin disease with adequate margin both circumferentially and in depth.
• External beam radiation therapy (EBRT) with photons, electrons, or low-energy x-rays may all be appropriate, depending on clinical
circumstances.
Target Volumes
• ISRT for cutaneous lesions:
ISRT is recommended as the appropriate field for treating primary cutaneous lymphomas.
Planning to define the clinical target volume (CTV) may often only require a careful physical exam. However, when the depth of disease is
not evident or when disease extends around curved surfaces, treatment planning may be facilitated by ultrasound imaging or CT-based
simulation and planning. Incorporating other modern imaging like PET and MRI may enhance treatment volume determination in some
cases.
ISRT targets the site of skin involvement. The volume encompasses the clinically evident disease with adequate margins.
The visible or palpable disease defines the gross tumor volume (GTV) and provides the basis for determining the CTV. If using CT-based
planning, delineating tumor boundary with wire for CT simulation will guide treatment volumes. Concerns for questionable subclinical
disease and uncertainties in original imaging accuracy or localization will lead to expansion of the CTV and are determined individually
using clinical judgment but generally include a margin of 1–2 cm both circumferentially and in depth. The CTV need not be expanded into
intact bone.
The planning target volume (PTV) is an additional expansion of the CTV that accounts only for setup variations (see ICRU definitions).
The treatment plan is designed using conventional or 3-D conformal techniques using clinical treatment planning considerations of
coverage and dose reductions for organs at risk (OARs).
• ISRT for nodal disease:
Principles of Radiation Therapy for T-Cell Lymphomas (Target Volumes: ISRT for nodal disease).
Principles of Radiation Therapy for B-Cell Lymphomas (Target Volumes: ISRT for nodal disease).
• Radiation Dose Constraints – Recommendations for normal tissue dose constraints can be found in the Principles of
Radiation Therapy NCCN Guidelines for Hodgkin Lymphoma
a References on PCLYM-A 3 of 3.
Continued
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PRINCIPLES OF RADIATION THERAPYa

General Dose Guidelines: (RT in conventional fraction sizes)
• PCMZL and PCFCL:
Optimal initial management for solitary/regional disease is with 24–30 Gy EBRT. Alternatively, lower doses (eg, 4 Gy) may be used initially,
with supplemental RT (4–20 Gy) for inadequate response or subsequent local relapse.
◊ Surface margins beyond area of clinically evident disease will vary depending on lesion size and body site and must take into account
dosimetry of the beam being used. Surface margins of 1.0–1.5 cm are generally adequate.
◊ Margins in depth should include the volume at risk for involvement.
◊ Generally, treatment with 6–9 MeV electrons (with surface bolus) provides an adequate depth of treatment. Alternatively, low-energy
x-rays (~100 Kv) may be used.
◊ Doses as low as 4 Gy are used occasionally, but data are limited regarding response and duration.
RT for relapsed disease: 4 Gy EBRT may be adequate.
• MF/SS
Treatment of individual patches, plaques, or tumors
◊ Optimal management for individual plaque and tumor lesions is with EBRT, 8–12 Gy given with palliative intent (usually as combined
modality therapy; 8 Gy may be given in 1–2 fractions). Even lower doses (4 Gy) may achieve a similar response, but it may be less durable.
◊ For unilesional MF at initial presentation, the definitive RT dose is 24–30 Gy.
◊ Surface margins beyond area of clinically evident disease will vary depending on lesion size and body site and must take into account
dosimetry of the beam being used. Surface margins of 1.0–1.5 cm are generally adequate.
◊ Margins in depth should include the volume at risk for involvement.
◊ Generally, treatment with 6–9 MeV electrons (with surface bolus) provides an adequate depth of treatment. Alternatively, low-energy
x-rays (~100 Kv) may be used.
◊ For certain body surfaces, higher energy photon fields and opposed-field treatment (with bolus) may be required.
TSEBT
◊ A variety of techniques may be utilized to cover the entire cutaneous surface. Patients are generally treated in the standing position on
a rotating platform or with multiple body positions to ensure total skin coverage.
◊ The common dose is ~12 Gy, generally 4–6 Gy per week. Higher doses (24–36 Gy) have been used for more extensive or refractory
disease. The advantages of a lower dose includes fewer short-term complications and better ability to retreat for relapsed disease
◊ “Shadowed” areas may need to be supplemented with individual electron fields.
◊ Individual tumors may be boosted with doses of 4–12 Gy.
◊ For patients with recalcitrant sites after generalized skin treatment, additional local treatment may be needed.
• PC-ALCL:
RT for curative treatment: 24–30 Gy
Doses as low as 6 Gy are used at some Member Institutions, but data are limited regarding response and duration.
Palliative RT: 2 Gy x 2 or 4 Gy x 1
a References on PCLYM-A 3 of 3.

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PRINCIPLES OF RADIATION THERAPY

REFERENCES
Akhtari M, Reddy JP, Pinnix CC, et al. Primary cutaneous B-cell lymphoma (non-leg type) has excellent outcomes even after very low dose radiation as single-modality
therapy. Leuk Lymphoma 2016;57:34-38.
Goyal A, Carter JB, Pashtan I, et al. Very low-dose versus standard dose radiation therapy for indolent primary cutaneous B-cell lymphomas: A retrospective study. J
Am Acad Dermatol 2018;78:408-410.
Hoppe RT, Harrison C, Tavallaee M, et al. Low-dose total skin electron beam therapy as an effective modality to reduce disease burden in patients with mycosis
fungoides: results of a pooled analysis from 3 phase-II clinical trials. J Am Acad Dermatol 2015;72:286-292.
Million L, Yi EJ, Wu F, et al. Radiation therapy for primary cutaneous anaplastic large cell lymphoma: An International Lymphoma Radiation Oncology Group Multi-
institutional Experience. Int J Radiat Oncol Biol Phys 2016;95:1454-1459.
Neelis KJ, Schimmel EC, Vermeer MH, et al. Low-dose palliative radiotherapy for cutaneous B- and T-cell lymphomas. Int J Radiat Oncol Biol Phys 2009;74:154-158.
Patel AM, West L, Atluri PS, et al. Optimizing Palliative Focal Radiation Therapy Dose in Cutaneous T-Cell Lymphoma: How Low Can You Go? Pract Radiat Oncol
2023;13:e192-e199.
Smith GL, Duvic M, Yehia ZA, et al. Effectiveness of low-dose radiation for primary cutaneous anaplastic large cell lymphoma. Adv Radiat Oncol 2017;2:363-369.
Specht L, Dabaja B, Illidge T, et al. Modern radiation therapy for primary cutaneous lymphomas: field and dose guidelines from the International Lymphoma Radiation
Oncology Group. Int J Radiat Oncol Biol Phys 2015;92:32-39.
Thomas TO, Agrawal P, Guitart J, et al. Outcome of patients treated with a single-fraction dose of palliative radiation for cutaneous T-cell lymphoma. Int J Radiat Oncol
Biol Phys 2013;85:747-753.

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PRINCIPLES OF MOLECULAR ANALYSIS IN PRIMARY CUTANEOUS LYMPHOMASa

• Genetic testing, including high-throughput sequencing (HTS), array-based comparative genomic hybridization (CGH), next-generation
sequencing (NGS), karyotype, or FISH to detect somatic mutations or genetic abnormalities are often informative and in some cases essential
for an accurate and precise diagnostic and prognostic assessment of primary cutaneous lymphomas (PCL).
T-Cell Antigen Receptor (TCR) Gene Rearrangements
• TCR gene rearrangement testing is recommended to support a diagnosis of PCL.
• Diseases:
MF/SS; primary cutaneous CD30+ T-cell LPDs
• Description:
TCR gene rearrangement is indicative of T-cell clonal expansion. The test targets the gamma and/or beta TCR genes using PCR methods
with capillary or gel electrophoresis detection methods. Alternatively, HTS methods are increasingly utilized. HTS methods are more
sensitive, precise, and capable of providing a unique sequence of the T-cell clone, which allows for comparison and confirmation of
disease evolution and monitoring during remission. Clonal T-cell expansions can also be detected using V beta families in blood or tissue
with flow cytometry methods.
• Diagnostic value:
Clonal TCR gene rearrangements without cytologic histopathologic and immunophenotypic evidence of abnormal T-cell population does
not constitute a diagnosis of T-cell lymphoma since it can be identified in patients with non-malignant conditions. Conversely, a negative
result does not exclude the diagnosis of T-cell lymphoma, which occasionally may fail TCR amplification. Nonetheless, it often provides
essential information and increased precision for many of these complex diagnoses.
• Prognostic value:
Identification of clonal TCR gene rearrangement has no definitive established prognostic value; however, it could be helpful when used to
determine clinical staging or assess relapsed or residual disease.
DUSP22-IRF4 Gene Rearrangement
• Testing for DUSP22 (dual-specificity phosphatase 22) rearrangement is considered useful under certain circumstances for the diagnosis of
primary cutaneous CD30+ T-cell LPDs.
• Diseases:
Primary cutaneous CD30+ T-cell LPDs
• Description:
DUSP22 is a tyrosine/threonine/serine phosphatase that may function as a tumor suppressor gene. DUSP22 inactivation contributes to
the development of PTCLs.
• Detection:
FISH using probes to DUPS22-IRF4 gene region at 6p25.3
• Diagnostic value:
DUSP22 rearrangement has been described in patients with PC-ALCL and LyP but is not associated with prognostic significance.
a See References on PCLYM-B 2 of 2.

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PRINCIPLES OF MOLECULAR ANALYSIS IN CUTANEOUS LYMPHOMAS

REFERENCES
Chiarle R, Voena C, Ambrogio C, et al. The anaplastic lymphoma kinase in the pathogenesis of cancer. Nat Rev Cancer 2008;8:11-23.
De Schouwer PJ, Dyer MJ, Brito-Babapulle VB, et al. T-cell prolymphocytic leukaemia: antigen receptor gene rearrangement and a novel mode of MTCP1-B1
activation. Br J Haematol 2000;110:831-838.
Hu Z, Medeiros LJ, Fang L, et al. Prognostic significance of cytogenetic abnormalities in T-cell prolymphocytic leukemia. Am J Hematol 2017;92:441-447.
Karai LJ, Kadin ME, Hsi ED, et al. Chromosomal rearrangements of 6p25.3 define a new subtype of lymphomatoid papulosis. Am J Surg Pathol 2013;37:1173-1181.
Morris SW, Kirstein MN, Valentine MB, et al. Fusion of a kinase gene, ALK, to a nucleolar protein gene, NPM, in non-Hodgkin’s Lymphoma. Science 1994;263:1281-
1284.
Odejide O, Weigert O, Lane AA, et al. A targeted mutational landscape of angioimmunoblastic T-cell lymphoma. Blood 2014;123:1293-1296.
Onaindia A, Montes-Moreno S, Rodriguez-Pinilla SM, et al. Primary cutaneous anaplastic large cell lymphomas with 6p25.3 rearrangement exhibit particular
histological features. Histopathology 2015;66:846-855.
Pedersen MB, Hamilton-Dutoit SJ, Bendix K, et al. DUSP22 and TP63 rearrangements predict outcome of ALK-negative anaplastic large cell lymphoma: a Danish
cohort study. Blood 2017;130:554-557.
Wada DA, Law ME, Hsi ED, et al. Specificity of IRF4 translocations for primary cutaneous anaplastic large cell lymphoma: a multicenter study of 204 skin biopsies.
Mod Pathol 2011;24:596-605.

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SUPPORTIVE CARE FOR PATIENTS WITH CUTANEOUS LYMPHOMAS

For other immunosuppressive situations, see NCCN Guidelines for Prevention and Treatment of Cancer-Related Infections.
Monoclonal Antibody (mAb) Therapy and Viral Reactivation
• Brentuximab vedotin (anti-CD30 antibody-drug conjugate)
Progressive multifocal leukoencephalopathy (PML):
◊ Caused by reactivation of the John Cunningham (JC) virus and is usually fatal.
◊ Diagnosis made by PCR of cerebrospinal fluid (CSF) and in some cases brain biopsy.
◊ Clinical indications may include changes in behavior such as confusion, dizziness or loss of balance, difficulty talking or walking, and
vision problems.
◊ No known effective treatment.
• Alemtuzumab (anti-CD52 mAb)
Cytomegalovirus (CMV) reactivation:
◊ CMV viremia should be measured by quantitative PCR at least every 2 to 3 weeks
◊ The current recommendations for the appropriate management is controversial; some clinicians use ganciclovir (PO or IV) preemptively
if viremia is present, others only if viral load is rising.
Antiinfective prophylaxis
◊ HSV prophylaxis with acyclovir or equivalent.
◊ Pneumocystis jirovecii pneumonia (PJP) prophylaxis with sulfamethoxazole/trimethoprim or equivalent.
◊ Consider antifungal prophylaxis.
◊ Consultation with an infectious disease expert may be necessary. See NCCN Guidelines for Prevention and Treatment of Cancer-Related
Infections.
Adverse Events Associated with Mogamulizumab
• Graft-Versus-Host Disease (GVHD): A retrospective study showed a particularly high risk of developing GVHD in patients proceeding to
allogeneic HCT within 50 days of mogamulizumab.a
• Mogamulizumab-associated rash (MAR): Mogamulizumab has been associated with a drug eruption (termed as MAR) that can clinically mimic
CTCL. Skin biopsy is recommended to distinguish progression of disease versus drug eruption.b,c
Pralatrexate-Induced Mucositisd,e,f
• Vitamin B12 (cyanocobalamin) at a dose of 1000 mcg intramuscular to be started no more than 10 weeks prior to starting therapy with
pralatrexate and then every 8 to 10 weeks.
• Oral folic acid 1 to 1.25 mg daily to be started within 10 days of starting therapy and continuing for 30 days after the last dose of pralatrexate.
• Consider use of oral leucovorin 25 mg three times daily for two consecutive days (total of 6 doses), starting 24 hours after each dose of
pralatrexate.
a Fuji S, et al. J Clin Oncol 2016;34:3426-3433. d Mould DR, et al. Clin Pharmacol Ther 2009;86:190-196.
b Chen L, et al. JAMA Dermatol 2019;155:968-971. e Shustov AR, et al. Blood 2018;132:2910.
c Hirotsu KE, et al. JAMA Dermatol 2021;157:700-707. f Koch E, et al. Leuk Lymphoma 2013;54:2448-2451.

PCLYM-C

Table of Contents
Classification
Table 1: Classification of Cutaneous B-Cell Lymphomas
WHO Classification of Hematolymphoid

WHO-EORTC classification for The International Consensus Classification
Tumors: Lymphoid Neoplasms (5th edition,
Primary Cutaneous Lymphomas (2018) (ICC) of Mature Lymphoid Neoplasms (2022)
2022)
Cutaneous B-Cell Lymphomas Mature B-cell Neoplasms Mature B-cell Neoplasms
Primary cutaneous marginal zone Marginal zone lymphoma
Primary cutaneous marginal zone lymphoma
lymphoproliferative disorder • Primary cutaneous marginal zone lymphoma
Cutaneous follicle center lymphoma
Primary cutaneous follicle center lymphoma Primary cutaneous follicle center lymphoma
• Primary cutaneous follicle center lymphoma
Primary cutaneous DLBCL, leg type Primary cutaneous DLBCL, leg type Large B-cell lymphomas
• Primary cutaneous DLBCL, leg type
Intravascular large B-cell lymphoma Intravascular large B-cell lymphoma • Intravascular large B-cell lymphoma
Lymphoid proliferations and lymphomas
associated with immune deficiency and
EBV+ mucocutaneous ulcer (provisional) EBV-positive mucocutaneous ulcer
dysregulation
• EBV-positive mucocutaneous ulcer
Table 2: Classification of Cutaneous

T-Cell Lymphomas (ST-2)
With permission, Alaggio R, Amador C, Anagnostopoulos I, et al. The 5th edition of the World Health Organization Classification of
Haematolymphoid Tumours: Lymphoid Neoplasms. Leukemia 2022;36:1720-1748.
Willemze R, Cerroni L, Kempf W, et al. The 2018 update of the WHO-EORTC classification for primary cutaneous lymphomas. Blood
2019;133:1703-1714.
The International Consensus Classification of Mature Lymphoid Neoplasms: A Report from the Clinical Advisory Committee. Blood 2022;140:1229-
1253.
ST-1

Table of Contents
Classification
Table 2: Classification of Cutaneous T-Cell Lymphomas
WHO Classification of Hematolymphoid
WHO-EORTC classification for The International Consensus Classification
Tumors: Lymphoid Neoplasms (5th edition,
Primary Cutaneous Lymphomas (2018) (ICC) of Mature Lymphoid Neoplasms (2022)
2022)
Cutaneous T-Cell Lymphomas Mature T-cell and NK-cell neoplasms Mature T-cell and NK-cell neoplasms
Sézary syndrome Sézary syndrome Sézary syndrome
Primary cutaneous T-cell lymphoid proliferations and
lymphomas
Mycosis fungoides (MF) Mycosis fungoides Mycosis fungoides
MF Variants
• Folliculotropic MF
Not included Not included
• Pagetoid reticulosis
• Granulomatous slack skin
Primary cutaneous CD30-positive T-cell Primary cutaneous CD30-positive T-cell Primary cutaneous CD30-positive T-cell
lymphoproliferative disorders lymphoproliferative disorders lymphoproliferative disorders:
• Lymphomatoid papulosis • Lymphomatoid papulosis • Lymphomatoid papulosis
• Cutaneous anaplastic large cell lymphoma • Primary cutaneous anaplastic large cell lymphoma • Primary cutaneous anaplastic large cell lymphoma
Subcutaneous panniculitis-like T-cell lymphoma Subcutaneous panniculitis-like T-cell lymphoma Subcutaneous panniculitis-like T-cell lymphoma
Primary cutaneous peripheral T-cell lymphoma, rare
subtypes
• Primary cutaneous CD4+ small/medium T-cell Primary cutaneous CD4-positive small or medium Primary cutaneous CD4-positive small or medium
lymphoproliferative disorder (provisional) T-cell lymphoproliferative disorder T-cell lymphoproliferative disorder
• Primary cutaneous gamma-delta T-cell lymphoma Primary cutaneous gamma-delta T-cell lymphoma Primary cutaneous gamma/delta T-cell lymphoma
• Primary cutaneous acral CD8-positive T-cell Primary cutaneous acral CD8-positive Primary cutaneous acral CD8-positive
lymphoma (provisional) lymphoproliferative disorder lymphoproliferative disorder
• Primary cutaneous aggressive epidermotropic CD8+ Primary cutaneous CD8-positive aggressive Primary cutaneous CD8-positive aggressive
cytotoxic T-cell lymphoma (provisional) epidermotropic cytotoxic T-cell lymphoma epidermotropic cytotoxic T-cell lymphoma
• Primary cutaneous peripheral T-cell lymphoma, NOS Not included Primary cutaneous peripheral T-cell lymphoma, NOS
With permission, Willemze R, Cerroni L, Kempf W, et al. The 2018 update of the WHO-EORTC classification for primary cutaneous lymphomas. Blood 2019;133:1703-1714.
Alaggio R, Amador C, Anagnostopoulos I, et al. The 5th edition of the World Health Organization Classification of Haematolymphoid Tumours: Lymphoid
Neoplasms. Leukemia 2022;36:1720-1748.
The International Consensus Classification of Mature Lymphoid Neoplasms: A Report from the Clinical Advisory Committee. Blood 2022;140:1229-1253.
ST-2

Table of Contents
ABBREVIATIONS
ABC activated B-cell GCB germinal center B-cell MRSA methicillin-resistant
Staphylococcus aureus
ALCL anaplastic large cell lymphoma GVHD graft-versus-host disease
MF mycosis fungoides
ANA antinuclear antibody GTV gross tumor volume
ASC absolute Sézary cell GVHD graft-versus-host disease
NKTL natural killer T-cell lymphoma
ATLL adult T-cell leukemia/lymphoma
NB-UVB narrowband ultraviolet B
HCT hematopoietic cell transplant
NGS next-generation sequencing;
BSA body surface area HLH hemophagocytic
lymphohistiocytosis NOS not otherwise specified
HSV herpes simplex virus
CSF cerebrospinal fluid
HTLV human T-cell lymphotropic virus OARS organ(s) at risk
C/A/P chest/abdomen/pelvis
HTS high-throughput sequencing OS overall survival
CGH comparative genomic
hybridization
CBC complete blood count IHC immunohistochemistry
CMV cytomegalovirus ICOS, inducible T-cell co-stimulator
CNS central nervous system Continued
ISH in situ hybridization
CR complete response
ISRT involved-site radiation therapy
CTCL cutaneous T-cell lymphoma
IVF in vitro fertilization
CTV clinical target volume
JC John Cunningham;
DLBCL diffuse large B-cell lymphoma
LCT large-cell transformation

EBER- Epstein-Barr encoding region-in
LDH lactate dehydrogenase
ISH situ hybridization
LDi longest diameter
EBRT external beam radiation therapy
LN lymph node
EBV Epstein-Barr virus
LPD lymphoproliferative disorder
ECP extracorporeal photopheresis
LyP lymphomatoid papulosis
FISH fluorescence in situ hybridization

FL follicular lymphoma
FMF follicular folliculotropic mycosis
fungoides
FNA fine-needle aspiration
ABBR-1

Table of Contents
ABBREVIATIONS
OARS organ(s) at risk SPEP serum protein electrophoresis

SS Sézary syndrome
PC- primary cutaneous anaplastic
ALCL large cell lymphoma TCR T-cell antigen receptor
PC-BCL primary cutaneous B-cell TSEBT total skin electron beam therapy
lymphoma
PC- primary cutaneous diffuse large
UVB ultraviolet B
DLBCL B-cell lymphoma
PC-FCL primary cutaneous follicle center
lymphoma VZV varicella zoster virus
PCL primary cutaneous lymphoma
PC-MZL primary cutaneous marginal zone
lymphoma
PCR polymerase chain reaction
PD-1 programmed cell death protein 1
PID primary immunodeficiency
PJP pneumocystis jirovecii pneumonia
PML progressive multifocal
leukoencephalopathy
PR partial response
PTCL- peripheral T-cell lymphoma not
NOS otherwise specified
PTV planning target volume
PUVA psoralen plus ultraviolet A
RF RF, rheumatoid factor
ABBR-2

Table of Contents
NCCN Categories of Evidence and Consensus

Category 1 Based upon high-level evidence, there is uniform NCCN consensus that the intervention is appropriate.
Category 2A Based upon lower-level evidence, there is uniform NCCN consensus that the intervention is appropriate.
Category 2B Based upon lower-level evidence, there is NCCN consensus that the intervention is appropriate.
Category 3 Based upon any level of evidence, there is major NCCN disagreement that the intervention is appropriate.
All recommendations are category 2A unless otherwise indicated.
NCCN Categories of Preference

Interventions that are based on superior efficacy, safety, and evidence; and, when appropriate,
Preferred intervention affordability.
Other recommended Other interventions that may be somewhat less efficacious, more toxic, or based on less mature data;
intervention or significantly less affordable for similar outcomes.
Useful in certain
Other interventions that may be used for selected patient populations (defined with recommendation).
circumstances
All recommendations are considered appropriate.
CAT-1
NCCN Guidelines Version 2.2024

Primary Cutaneous Lymphomas
This discussion corresponds to the NCCN Guidelines for Primary Cutaneous Lymphomas. Last updated: May 6, 2024.
Discussion
Table of Contents
Overview .............................................................................................................................................................................................................. MS-2
Guidelines Update Methodology ........................................................................................................................................................................... MS-2
Sensitive/Inclusive Language Usage .................................................................................................................................................................... MS-2
Primary Cutaneous B-Cell Lymphomas................................................................................................................................................................. MS-2
Mycosis Fungoides and Sézary Syndrome.......................................................................................................................................................... MS-16
Primary Cutaneous CD30+ T-Cell Lymphoproliferative Disorders ........................................................................................................................ MS-53
Version 2.2024 © 2024 National Comprehensive Cancer Network© (NCCN©), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN.
MS-1

Overview Sensitive/Inclusive Language Usage

Primary cutaneous lymphomas (PCL) are a heterogenous group of NCCN Guidelines strive to use language that advances the goals of
extranodal B-cell and T-cell non-Hodgkin lymphomas (NHL) originating in equity, inclusion, and representation. NCCN Guidelines endeavor to use
and usually confined to the skin. In the Surveillance, Epidemiology, and language that is person-first; not stigmatizing; anti-racist, anti-classist,
End Results (SEER) database population-based analysis of 3884 cases of anti-misogynist, anti-ageist, anti-ableist, and anti-weight-biased; and
PCL diagnosed in the United States from 2001 to 2005, the incidence of inclusive of individuals of all sexual orientations and gender identities.
cutaneous B-cell lymphomas (CBCL) and cutaneous T-cell lymphomas NCCN Guidelines incorporate non-gendered language, instead focusing
(CTCL) accounted for 29% and 71%, respectively.1 on organ-specific recommendations. This language is both more accurate
and more inclusive and can help fully address the needs of individuals of
The World Health Organization-European Organization for Research and all sexual orientations and gender identities. NCCN Guidelines will
Treatment of Cancer (WHO-EORTC) classification for cutaneous continue to use the terms men, women, female, and male when citing
lymphomas was first published in 2005 and was subsequently updated in statistics, recommendations, or data from organizations or sources that do
2018.2,3 The most common subtypes of PCL that are covered in the NCCN not use inclusive terms. Most studies do not report how sex and gender
Clinical Practice Guidelines in Oncology (NCCN Guidelines®) are listed data are collected and use these terms interchangeably or inconsistently.
below: If sources do not differentiate gender from sex assigned at birth or organs
present, the information is presumed to predominantly represent cisgender
• Cutaneous B-Cell Lymphomas individuals. NCCN encourages researchers to collect more specific data in
 Primary cutaneous marginal zone lymphoma (PCMZL) future studies and organizations to use more inclusive and accurate
 Primary cutaneous follicle center lymphoma (PCFCL) language in their future analyses.
 Primary cutaneous diffuse large B-cell lymphoma, leg type
(PCDLBCL, leg type)
Primary Cutaneous B-Cell Lymphomas
• Cutaneous T-Cell Lymphomas Primary cutaneous B-cell lymphomas (PCBCL) account for mainly three
 Mycosis fungoides (MF) and Sézary syndrome (SS) subtypes: PCMZL, PCFCL, and PCDLBCL, leg type.2,3 PCFCL is the most
 Primary cutaneous CD30+ T-cell lymphoproliferative disorders common subtype of the CBCL, diagnosed in 57% of patients followed by
(PCTLD) PCMZL (24%–31%) and PCDLBCL, leg type (11%–19%).4,5
Guidelines Update Methodology In addition to these three subtypes, PCDLBCL, not otherwise specified
(PCDLBCL-NOS) with clinicopathologic features intermediate between
The complete details of the Development and Update of the NCCN
PCFCL and PCDLBCL, leg type has also been described.6,7 In the revised
Guidelines are available at www.NCCN.org.
2018 WHO-EORTC classification, rare cases that cannot be classified as
either PCDLBCL, leg type or PCFCL are classified as PCDLBCL-NOS.3
MS-2

PCFCL is more prevalent in the scalp, face, and the forehead, whereas While the diagnosis of PCMZL is generally straightforward and
the trunk and extremities are the most common sites for PCMZL.4,5 reproducible among pathologists, it is more difficult to distinguish between
PCMZL and PCFCL are generally indolent or slow growing and both are PCFCL and PCDLBCL, leg type, partly because the cell size (large vs.
associated with excellent prognosis. PCMZL is now recognized as a small) is not a defining feature as it is in nodal B-cell lymphomas.
distinct entity from other mucosa-associated lymphoid tissue (MALT) Disease-specific characteristics identified by molecular and gene
lymphomas in both the International Consensus Classification (ICC) and expression profiling (GEP) studies (as described below) may be helpful
the updated 2022 WHO classification (WHO5).8,9 In the ICC, PCMZL are to distinguish the subtypes of CBCL.10
defined as primary cutaneous marginal zone lymphoproliferative
disorders because of their indolent disease course.9 PCMZL can be divided into two subgroups with different prognosis based
on the immunoglobulin (Ig) heavy chain usage, with the vast majority
PCDLBCL, leg type is found most commonly on the leg, although it can being CXCR3-negative and Ig class-switched subtype (IgG, IgA, and
arise at other sites.4,5 PCDLBCL, leg type is usually aggressive and IgE) and a small subset being CXCR3-positive and IgM-positive.11-14
associated with a generally poorer prognosis (mainly due to the higher Emerging data suggest that Ig class-switched subtype may be
frequency of extracutaneous relapses).4,5 In a large Italian series of 467 categorized as a clonal chronic lymphoproliferative disorder due to its
patients with PCBCL, extracutaneous involvement was reported in 17% indolent disease course.14,15
with PCDLBCL, leg type compared to 6% of patients with PCMZL and
11% with PCFCL.4 The 5-year overall survival (OS) rate was significantly GEP studies have shown that PCFCL is characterized by a germinal
higher for patients with PCMZL and PCFCL than for patients with center B-cell (GCB) phenotype and PCDLBCL, leg type is most commonly
PCDLBCL, leg type (97%, 96%, and 73%, respectively; P < .0001).4 In characterized by activated B-cell (ABC) phenotype.16 Thus, a germinal (or
patients with PCMZL and PCFCL, the disease-free survival (DFS) and OS follicle) center phenotype and large cells in a skin lesion is consistent with
rates were significantly higher for patients with single lesions compared PCFCL with a diffuse population of large cells (PCFCL-LC) and not with
with those with regional or disseminated lesions (5-year DFS, 62% vs. DLBCL.16 In nodal DLBCL, the GCB phenotype is associated with a better
44%; 5-year OS, 97% vs. 85%), whereas the difference in outcomes prognosis than the ABC phenotype. Immunohistochemical and
between single and regional or disseminated lesions was not significant in GEP-based algorithms used to classify nodal DLBCL into GCB or
patients with PCDLBCL, leg type (5-year DFS rate 55% vs. 44%; 5-year non-GCB subtypes based on cell of origin (COO) have also shown to be
OS rate 79% vs. 67% for single and regional or disseminated lesions, useful to distinguish PCFCL from PCDLBCL, leg type.17-19 However, these
respectively).4 In the report from the Dutch Cutaneous Lymphoma Registry algorithms may be of limited utility in the differentiation of PC-DLBCL, leg
that included 300 patients with PCBCL, the incidence of extracutaneous type and PCFCL-LC.19 While all cases of PCFCL-LC were uniformly
relapse was 47% among patients with PCDLBCL, leg type compared to classified as GCB phenotype by both immunohistochemical and
11% and 9%, respectively, for patients with PCFCL and PCMZL.5 The GEP-based algorithms, the classification based on COO was
5-year disease-specific survival rates in this series were 95%, 98%, and heterogenous in patients with PC-DLBCL, leg type.19
50% for PCFCL, PCMZL, and PCDLBCL, leg type, respectively.
MS-3

A high prevalence of MYD88 L265P mutation has been reported in lacking are based on the panel’s review of lower-level evidence and
patients with PCDLBCL, leg type and is associated with inferior clinical expert opinion.
outcomes.17,20 In a retrospective analysis of 61 patients (58 patients with
interpretable results) diagnosed with PCDLBCL, leg type, MYD88 L265P Diagnosis
mutation was detected in 59% of patients.20 It was also associated with PCMZL are negative for BCL6 and CD10, but are often positive for CD20
shorter disease-specific survival and was an independent adverse and BCL2.22 PCFCL is consistently BCL6-positive, whereas CD10 and
prognostic factor for OS. The 3-year and 5-year disease-specific survival BCL2 are expressed in only a few cases with a follicular growth pattern
rates for those with MYD88 L265P mutation were 66% and 60%, and the detection of BCL2 rearrangement is generally associated with
respectively, compared to 85% and 72%, respectively, for patients with the extracutaneous spread.23-26
wild-type allele. In the aforementioned report that evaluated the
clinicopathologic and molecular characteristics of patients with PCFCL (25 PCDLBCL, leg type tumors express CD20, IRF4/MUM1, FOXP1, and
patients) and PCDLBCL, leg type (32 patients), MYD88 L265P mutation BCL2; many cases express BCL6 and lack expression of CD10.5,16,17,27-29
was detected only in patients with PCDLBCL, leg type (n = 22; 69%).17 PCDLBCL, leg type also has a high incidence of MYC rearrangements
These findings suggest that determination of MYD88 L265P mutation and MYC rearrangements are not detected in PCFCL.30 In addition,
status could be helpful to further distinguish PCDLBCL, leg type from PCFCL is usually IRF4/MUM1-negative while PCDLBCL, leg type is
PCFCL. usually IRF4/MUM1-positive and shows strong expression of FOXP1.28,29
Assessment of FOXP1 expression is helpful to distinguish PCDLBCL, leg
Literature Search Criteria type from PCFCL since all cases of PCFCL are FOXP1-negative.29
Prior to the update of this version of the NCCN Guidelines for Primary GEP-based algorithms and modified Hans immunohistochemical algorithm
Cutaneous Lymphomas, a literature search was performed to obtain key including CD10 and MUM1 have been shown to be useful to distinguish
literature on PCBCL published since the previous Guidelines update, PCFCL from PCDLBCL, leg type with optimal diagnostic value without the
using the following search terms: cutaneous diffuse large B-cell need for BCL-6.17,18
lymphoma, cutaneous follicle center lymphoma, and cutaneous marginal
The diagnosis of PCBCL is established by adequate biopsy of skin
zone lymphoma. The PubMed database was chosen as it remains the
lesions. Multiple biopsies may be necessary to capture the pathologic
most widely used resource for medical literature and indexes
variability of disease at diagnosis. Incisional, excisional, or punch biopsy is
peer-reviewed biomedical literature.21
preferred to shave biopsy, as PCBCL have primarily dermal infiltrates,
The search results were narrowed by selecting studies in humans often deep, which are less well-sampled and can be missed by a shave
published in English. The data from key PubMed articles deemed as biopsy. Review of the slides by a pathologist with expertise in the
relevant to these guidelines have been included in this version of the diagnosis of PCBCL is recommended. Adequate immunophenotyping of
Discussion section. Recommendations for which high-level evidence is the biopsy sample is essential for the diagnosis of the exact subtype of
PCBCL. In addition, immunophenotyping is also useful to rule out
MS-4

cutaneous lymphoid hyperplasia (also known as pseudolymphoma or useful to differentiate PCMZL (negative for CD5 and cyclin D1) from MCL
lymphocytoma cutis)31-33 and in the differential diagnosis of intravascular (positive for CD5 and cyclin D1).
large B-cell lymphoma, which often manifests in skin and is associated
with a poor prognosis.34 Workup
The absence of extracutaneous disease at diagnosis is part of the
The initial immunohistochemistry (IHC) panel should include CD20, CD3, definition of PCBCL. The initial workup is geared toward evaluating extent
CD5, CD10, BCL2, BCL6, and IRF4/MUM1. Under certain circumstances, of disease on the skin and seeking extracutaneous disease.38
evaluation of additional immunohistochemical markers such as Ki-67,
CD43, CD21, CD23, cyclin D1, and kappa/lambda may be useful to further The initial workup should include a complete physical examination, a
establish the lymphoma subtype. Additionally, assessment of surface IgM, comprehensive skin examination, complete blood count (CBC) with
IgD, and FOXP1 expression may also be helpful in distinguishing differential, comprehensive metabolic panel, and CT and/or PET/CT of the
PCDLBCL, leg type from PCFCL.28,29,35 Epstein-Barr virus (EBV)-positive chest, abdomen, and pelvis. Peripheral blood flow cytometry will be useful
mucocutaneous ulcer is also included as a new provisional entity in the in selected cases, if CBC demonstrates lymphocytosis. Imaging is
updated WHO-EORTC classification and Epstein-Barr encoding region-in effective in identifying systemic involvement in patients with indolent
situ hybridization (EBER-ISH) may be useful under selected CBCL.39 However, it can be omitted if clinically indicated in patients with
circumstances.3 low-grade indolent PCBCL.40 PET/CT may have higher sensitivity in the
detection of both local and distant metastases than CT.41 However, this is
The t(14;18) translocation on FISH analysis has been observed only in a not validated and the higher rates of false-positive findings can create
small number of cases with PCFCL, and the detection of a t(14;18) confusion.
translocation suggests the presence of systemic follicular lymphoma
(FL).25,36 Cytogenetics or FISH to detect t(14;18) may be useful if systemic Bone marrow biopsy is essential for PCDLBCL, leg type, since this is an
FL is suspected. The feasibility of flow cytometric immunophenotyping of aggressive lymphoma that will probably require systemic treatment;
skin biopsies for the assessment of B-cell clonality has been reported, however, it appears to have a more limited value in PCFCL and PCMZL,
although it has not been widely used.33 If adequate biopsy material is and may be considered only in selected patients.38,40,42 Senff et al
available, molecular analysis to detect Ig heavy chain gene rearrangement evaluated 275 patients with histologic features consistent with marginal
or flow cytometry could be useful to determine B-cell clonality. zone lymphoma (MZL; n = 82) or follicle center lymphoma (FCL; n = 193)
first presenting in the skin.42 Bone marrow involvement was seen in
Mantle cell lymphoma (MCL) is not a cutaneous lymphoma and finding it in approximately 11% of patients in the FCL group compared with 2% in the
the skin requires a careful search for extracutaneous disease. Clinical MZL group. Among patients with FCL, a positive bone marrow was
presentation on the leg and blastoid cytology along with high proliferative associated with significantly worse prognosis compared with those with
index and expression of BCL2, IRF4/MUM1, and IgM would often skin lesions only; the 5-year OS rate was 44% and 84%, respectively.42
represent MCL with skin involvement.37 The use of cyclin D1 may be
MS-5

The International Society of Cutaneous Lymphomas (ISCL) and the disease-specific survival (44%) compared with PCFCLs occurring at
EORTC Task Force recommend that bone marrow biopsy be obtained for other sites (25% and 99%, respectively).45
cutaneous lymphomas with intermediate to aggressive behaviors and
should be considered for cutaneous lymphomas with indolent behavior In another retrospective study of 42 patients with biopsy-proven PCFCL
and when there is any evidence of extracutaneous disease, as indicated and PCMZL, RT resulted in CR in all patients.47 The 10-year RFS and
by other staging assessments (eg, radiographic evidence or serologic OS rates were 71% and 87%, respectively, for the entire cohort, after a
clues such as elevated monoclonal or polyclonal Ig).38 median follow-up of 9.5 years. The 5-year RFS rate was higher for
patients with trunk lesions and single lesions (89% and 84%,
The NCCN Guidelines recommend considering bone marrow biopsy for respectively) compared to those with extra-trunk lesions and multiple
patients with unexplained cytopenias or if there is a clinical suspicion of lesions (67% and 57%, respectively). Low-dose ISRT (4 Gy in 2 fractions)
PCDLBCL, leg type. is an effective treatment option for palliation of symptoms in patients with
persistent (initial) lesions or recurrent symptomatic disease.48 The results
Treatment Options of a more recent retrospective study also showed that RT less than or
Involved-site radiation therapy (ISRT) is very effective when used as equal to 12 Gy (4 Gy for relapsed disease) was equally effective as RT
initial therapy as well as for cutaneous relapses in most patients with greater than 12 Gy in patients with indolent PCBCL (42 patients; 16
indolent PCBCL.43-47 patients had PCFCL).49
In a retrospective study of 34 patients with PCBCL treated with RT, ISRT and excision result in higher response rates compared to
5-year relapse-free survival (RFS) rates ranged from 62% to 73% for chemotherapy in patients with indolent histologies, but were generally
PCFCL and PCMZL but were only 33% for patients with PCDLBCL, leg used for those with more limited disease; therefore, a direct comparison
type.44 The 5-year OS rate was 100% for PCFCL and PCMZL but was cannot be made.4,50-53 In a large retrospective analysis by the Italian Study
67% for PCDLBCL, leg type. Senff et al evaluated the outcome of 153 Group for Cutaneous Lymphomas involving 467 patients with PCBCL, the
patients with PCBCL (25 with PCMZL; 101 with PCFCL; and 27 with CR rate and the 5- and 10-year OS rates for all patients with PCFCL and
PCDLBCL) who were initially treated with RT with a curative intent.45 PCMZL who received first-line treatment (RT in 53%, with total dose of
Overall, 45% of patients had single lesions while localized or 35–45 Gy; chemotherapy in 25%, mainly with CHOP; surgery in 23%)
disseminated lesions were seen in 43% and 12% of patients, were 92% to 95%, 96% to 97%, and 89% to 91%, respectively.4 The
respectively. Complete response (CR) was obtained in 151 of 153 relapse rate was 44% to 47% and extracutaneous spread was observed in
patients (99%). Relapse rates for PCMZL, PCFCL, and PCDLBCL, leg 6% to 11% of patients. Relapse rate did not vary by the type of initial
type were 60%, 29%, and 64%, and the 5-year disease-specific survival therapy. In patients with PCDLBCL, leg type, the CR rate and 5- and
rates were 95%, 97%, and 59%, respectively. The PCFCLs presenting 10-year OS rates were 82%, 73%, and 47%, respectively. PCDLBCL, leg
on the legs also had a higher relapse rate (63%) and a lower 5-year type was associated with higher relapse rates (55%) and higher
incidences of extracutaneous spread (17%)—a higher relapse rate was
MS-6

confirmed both for patients with single or regional lesions treated with RT Several case reports have shown the effectiveness of skin-directed
and for patients with disseminated cutaneous involvement treated with therapy (steroids, imiquimod, and nitrogen mustard or bexarotene gel) for
chemotherapy.4 In a retrospective analysis of 137 patients with PCMZL, patients with multifocal lesions.63-67 Interlesional steroids have also been
initial treatment with surgical excision, RT, or a combination of both used in the management of PCFCL or PCMZL, although only limited data
resulted in a CR rate of 88% (93% for patients with solitary or localized are available.50,68,69 Systemic therapy (rituximab monotherapy or
disease and 71% for those with multifocal lesions).52 Although there were combination chemoimmunotherapy) is often more appropriate for those
no significant differences in the rate of recurrences between the treatment with generalized disease (skin only; T3) in patients with PCFCL or
modalities, surgery alone was associated with more recurrences at the PCMZL.54-58,63,70-72
initial site.
Because there are no data from randomized clinical trials, the treatment
Rituximab monotherapy (intravenous and intralesional ) has been
54-58 59-61
recommendations included in the NCCN Guidelines are derived from the
shown to be effective for PCMZL and PCFCL. Intravenous rituximab may management practices of patients with PCBCL at NCCN Member
be more effective for patients with multiple lesions that cannot be Institutions based on the limited data from retrospective analyses and
managed effectively with local therapy.54-58 In a retrospective analysis of studies involving a small cohort of patients.
15 patients with indolent PCBCL, rituximab resulted in an overall response
rate (ORR) of 87% (60% CR). The ORR was 100% for patients with Primary Cutaneous Marginal Zone Lymphoma and Primary
Cutaneous Follicle Center Cell Lymphoma
PCFCL and 60% for PCMZL. With a median follow-up of 36 months, the
median duration of response was 24 months.57 In another series of 16 While PCMZL and PCFCL respond to initial therapy, disease relapse is
patients with PCBCL, 14 patients (88%) achieved a CR with rituximab common in the majority of patients with regional or generalized disease,
monotherapy; 35% of these patients with CR eventually relapsed between regardless of type of initial treatment. However, relapses are generally
6 and 37 months.58 In an observational multicenter study conducted by the confined to the skin in which case survival does not appear to be affected.
Spanish Working Group on Cutaneous Lymphoma (17 patients with In a retrospective analysis that assessed the efficacy of various treatment
PCMZL and 18 patients with PCFCL), intralesional rituximab induced CR modalities (55 patients; majority of patients had indolent PCBCL; 25
and partial response (PR) in 71% and 23% of patients, respectively, with a patients with PCMZL and 24 patients with PCFCL), the type of treatment
median DFS of 114 weeks.59 The response rates were similar among modality (skin-directed vs. definitive RT with or without systemic therapy)
patients with PCMZL and PCFCL. In a small series that evaluated the did not affect the time to first recurrence among patients with T1 and
efficacy of intravenous and intralesional rituximab in treatment of patients T2/T3 lesions.73 The rates of recurrence were higher for T2/T3 lesions
with PCMZL and PCFCL, although intralesional rituximab resulted in compared to T1 lesions (58% and 31%, respectively). The time to first
response rates similar to that of intravenous rituximab, within a 12-month recurrence for T1 lesions was 33% and 29%, respectively, for patients with
follow-up period, relapses were more frequent among patients treated with PCMZL and PCFCL; however, the difference was not significant. Among
intralesional rituximab.62 patients with T2/T3 lesions, there was a non-significant trend toward
MS-7

higher rate of recurrence for PCMZL than PCFCL (73% and 38%, treatment. Observation is appropriate in asymptomatic patients. In patients
respectively). with very extensive or symptomatic disease, other combination
chemotherapy regimens recommended for FL or nodal MZL may be
Additional imaging studies during the course of treatment are not needed used.70-72
after negative initial staging for systemic involvement and clinical follow-up
without routine imaging may be appropriate for patients with PCMZL.39 Observation is recommended for patients with disease responding to initial
PET/CT (preferred) or CT with contrast may be repeated at the end of therapy, and those with refractory disease should be treated with an
treatment for assessment of response and can be repeated if there is alternate initial treatment option.
clinical suspicion of progressive disease.
Patients with relapse localized to skin should be treated with an alternate
Solitary or Regional Lesions (T1–T2) initial treatment option. Patients with extracutaneous relapse or those with
Local ISRT (24–30 Gy) is a preferred initial treatment option. Excision or cutaneous relapse that is not responding to any of the initial treatment
skin-directed therapy or intralesional steroids may be used for selected options should be treated as described for extracutaneous disease.
patients. Observation is an option when RT or excision is neither desired
nor feasible (eg, lesions on the scalp where hair loss is a major concern). Extracutaneous Disease
Extracutaneous disease should be managed according to FL or nodal
Observation is also recommended for patients with disease responding to MZL as outlined in the NCCN Guidelines for B-Cell Lymphomas.70-72
initial therapy, and those with refractory disease should be treated as
described for generalized disease below. Primary Cutaneous Diffuse Large B-Cell Lymphoma, Leg Type
RT alone is less effective in patients with PCDLBCL, leg type. While these
Low-dose RT (4 Gy) may be adequate for relapsed or refractory lesions do respond to RT, remissions are often short-lived and higher
disease.48,49,69 Patients with regional relapse should be treated with an rates of dissemination to extracutaneous sites may occur.
alternate initial treatment option and those with generalized disease
relapse confined to the skin should receive treatment options The potential utility of chemoimmunotherapy for the treatment of
recommended for generalized disease at presentation. PCDLBCL, leg type has been described only in retrospective analyses and
case reports.74-79 In a retrospective multicenter study from the French
Patients with extracutaneous relapse or those with cutaneous relapse that Study Group on 60 patients with PCDLBCL, leg type, patients treated with
is not responding to any of the initial treatment options should be treated anthracycline-based chemoimmunotherapy had a more favorable
according to the FL or nodal MZL as outlined in the NCCN Guidelines for short-term outcome, although no particular therapy (RT or multiagent
B-Cell Lymphomas. chemotherapy with or without rituximab) was significantly associated with
improved survival outcomes.74 Among 12 patients treated with
Generalized Disease (skin only; T3)
anthracycline-based chemoimmunotherapy, the CR rate was 92%
Skin-directed therapy, local ISRT (24–30 Gy) for palliation of symptoms,
intralesional steroids, or rituximab are included as options for initial
MS-8

compared to 62% for patients who received other therapies. The 2-year
OS rate for these two groups was 81% and 59%, respectively.
Multiagent chemoimmunotherapy regimens have been associated with

excellent outcomes.77-79 In a report from the French Study Group (115
patients), the 3- and 5-year survival rates were 80% and 74%,
respectively, for patients who received multiagent chemoimmunotherapy
compared to 48% and 38%, respectively, for patients who received
less-intensive therapies.77 In a more recent retrospective analysis
involving 28 patients with PCDLBCL, leg type treated in a single center,
R-CHOP with ISRT resulted in significantly longer median PFS compared
to R-CHOP without ISRT as front-line therapy (58 vs. 14 months; P =
.04).79
PCDLBCL, leg type has a poorer prognosis than other types of PCBCL
and is generally treated with more aggressive chemoimmunotherapy
regimens used for systemic DLBCL as outlined in the NCCN Guidelines
for B-Cell Lymphomas.
MS-9

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MS-14

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MS-15

Mycosis Fungoides and Sézary Syndrome Due to the rarity and diversity of the condition and the need for an
Overview individualized approach, the NCCN Guidelines Panel recommends that
patients diagnosed with MF and SS be treated at specialized centers with
Cutaneous T-cell lymphomas (CTCL) are a group of non-Hodgkin
expertise in the management of this disease.11
lymphomas (NHL) that primarily present in the skin, and at times
progress to involve lymph nodes, blood, and visceral organs.1-3 Literature Search Criteria
Mycosis fungoides (MF) is the most common subtype and is usually Prior to the update of this version of the NCCN Clinical Practice Guidelines
associated with an indolent clinical course with intermittent, stable, or in Oncology (NCCN Guidelines®) for Primary Cutaneous Lymphomas, an
slow progression of the lesions.4 Extracutaneous involvement (lymph electronic search of the PubMed database was performed to obtain key
nodes, blood, or less commonly other organs) or large cell literature on MF and SS published since the previous Guidelines update
transformation (LCT) may be seen in advanced-stage disease. Sézary using the following search terms: cutaneous T-cell lymphomas, mycosis
syndrome (SS) is a rare erythrodermic, leukemic variant characterized by fungoides, and Sézary syndrome. The PubMed database was chosen as it
significant blood involvement, erythroderma, and often remains the most widely used resource for medical literature and indexes
lymphadenopathy.4-6 MF is caused by the malignant transformation of peer-reviewed biomedical literature.12
skin-resident effector memory T cells while SS is thought to arise from
The search results were narrowed by selecting studies in humans
thymic memory T cells, supporting the contention that SS is a process
published in English. Results were confined to the following article types:
distinct from MF.5 Cases presenting as an overlap of these two conditions
Clinical Trial, Randomized Controlled Trial; Phase II; Clinical Trial, Phase
also exist.
III; Guideline; Meta Analysis; Systematic Reviews; and Validation Studies.
Folliculotropic MF (FMF), hypopigmented MF, granulomatous slack skin, The data from key PubMed articles deemed as relevant to these
and pagetoid reticulosis are recognized as distinct clinicopathologic guidelines have been included in this version of the Discussion section.
variants of MF in the World Health Organization-European Organization Recommendations for which high-level evidence is lacking are based on
for Research and Treatment of Cancer (WHO-EORTC) classification.2 the panel’s review of lower-level evidence and expert opinion.
FMF and LCT are histologic features that can occur irrespective of stage,
Staging
but the incidence of LCT is higher in patients with advanced-stage
disease.7-9 Expert dermatopathology and/or hematopathology review is The T (skin), N (node), M (visceral), and B (blood involvement)
needed to confirm the diagnosis. This is especially true for the less classification and clinical staging developed by the International Society
common variants of the disease, which can be difficult to distinguish from for Cutaneous Lymphomas (ISCL) and EORTC are outlined on MFSS-3
other lymphoproliferative disorders. Genomic studies have demonstrated and MFSS-4.13
further biologic diversity within MF.4,10
The extent of skin involvement is based on the percentage of body surface
area (BSA) where the patient’s palm (without digits) is equivalent to 0.5%
BSA and the palm with all five digits is approximately 1% BSA. In the
MS-16

revised staging system, T1 disease (limited skin involvement) is defined as Prognosis

patches, papules, and/or plaques covering less than 10% BSA. T2 Age at presentation, overall stage, extent and type of skin involvement (T
(skin-only disease) is defined as patches, papules, and/or plaques classification), presence of extracutaneous disease, extent of peripheral
covering 10% or greater BSA. Patch diagnosis is noted as T1a or T2a and blood involvement (as defined by flow cytometric measurements of Sézary
plaque diagnosis is noted as T1b or T2b. T3 (tumor-stage disease) is cell counts), elevated lactate dehydrogenase (LDH), and presence of LCT
defined by the presence of one or more tumors (≥1 cm in diameter with have been identified as the most significant factors for disease
nodular quality). T4 (erythrodermic disease) is defined as confluence of progression and/or survival in patients with MF.14-20 In a retrospective
erythema covering 80% or greater BSA. However, this criterion of 80% is cohort study of 525 patients with MF or SS, patient age, T classification,
subjective and the BSA can fluctuate in patients with erythrodermic MF or and presence of extracutaneous disease retained independent prognostic
SS. Thus, other features including keratoderma, ectropion, or leg edema value in a multivariate analysis.15 The risk of disease progression,
should also be evaluated in patients with erythrodermic MF or SS. development of extracutaneous disease, or death due to MF correlated
with initial T classification. Limited patch or plaque disease has an
Lymph node biopsy for staging is recommended only for clinically
excellent prognosis compared to patients with widespread plaque-type or
abnormal nodes (>1.5 cm in longest diameter). Lymphadenopathy can be
tumor-type skin disease or erythrodermic skin involvement, and
clinically reactive or dermatopathic; thus, not all enlarged lymph nodes are
extracutaneous disease is associated with a poor prognosis.17,18
sampled. The designation “Nx” may be used for abnormal lymph nodes
without histologic evaluation. The designation “Mx” can be used for LCT is also an independent prognostic factor of shorter overall survival
presence of abnormal visceral sites without histologic evaluation. Visceral (OS) in patients with SS. In an analysis of 117 patients with SS, LCT was
disease with the involvement of an organ (eg, spleen, liver) other than the present in 6% of patients at the time of diagnosis and the median OS
skin, nodes, or blood should be documented using imaging studies. was 35 months for those with LCT compared to 80 months for those
without LCT.21 The presence of ulceration, decreased levels of CD8+
Blood involvement is classified into three groups: B0, B1, and B2 based on
cells in peripheral blood, maximum total BSA, and peak LDH were
the number of immunophenotypically abnormal T cells in the blood
predictors for LCT in patients with SS.22
(MFSS-3). Patients with lymphopenia (defined as <1000 absolute
lymphocytes) may potentially have an underestimation of aberrant In the Cutaneous Lymphoma International Consortium (CLIC) study that
lymphocyte burden if assessed only by the absolute number and not also evaluated the relevance of prognostic markers on OS in 1275 patients with
by the percentage of immunophenotypically abnormal lymphocytes.13 B1 advanced-stage MF and SS, stage IV disease, aged 60 years, LCT and
or B2 is best characterized by both flow cytometry and the presence of LDH levels were identified as independent prognostic markers that could
clonally related neoplastic T cells as in the skin by TCR gene be used together in a prognostic model to identify three risk groups with
rearrangement analysis. A diagnosis of SS requires B2 level of blood significantly different survival outcomes.20 The 5-year survival rates were
involvement. 68%, 44%, and 28%, respectively, for low-risk, intermediate-risk, and
high-risk groups. A prospective international study by CLIC (Prospective
MS-17

Cutaneous Lymphoma International Prognostic Index [PROCLIPI] specified. This variant usually presents as a sudden onset of multiple
international study) is underway to identify any new prognostic markers plaques and nodules characterized by the expression TFH markers such
and validate the refined prognostic index model to optimize the as CXCL13, ICOS, and programmed cell death protein 1 (PD-1).31,32
risk-stratified approach for the treatment of patients with MF or SS.23-25 Identification of these markers along with other clinical and
histopathologic features would be useful to distinguish MFSS from CTCL
Diagnosis of TFH origin.33,34
Biopsy of suspicious skin sites along with immunohistochemistry (IHC) of
biopsy specimen are essential to confirm the diagnosis. Biopsy of Molecular analysis to detect clonal TCR gene rearrangements is useful
enlarged lymph nodes (ie, palpable nodes >1.5 cm in diameter and/or firm, to support the diagnosis of MF and SS as well as to distinguish MF from
irregular, clustered, or fixed nodes) or extracutaneous sites is inflammatory dermatoses, especially if identical clones are demonstrated
recommended. Excisional or incisional biopsy is preferred over core in more than one skin site.35,36 However, results showing clonal TCR
needle biopsy. Fine-needle aspiration (FNA) alone is not sufficient for the gene rearrangements should not be interpreted as the sole and defining
initial diagnosis. Bone marrow biopsy is not required for disease staging, test for malignancy since clonal TCR rearrangements can at times be
but may be helpful in those with an unexplained hematologic abnormality. seen in non-malignant conditions or may not be demonstrated in all
cases of MF and SS. TCR rearrangement analysis by high throughput
MF and SS cells are typically characterized by the following sequencing (or next-generation sequencing) is a more sensitive and
immunophenotype: CD2+, CD3+, CD5+, CD4+, CD8-, CCR4+, specific test of clonality that can identify the clones by the genetic
TCR-beta+, and CD45RO+ and they lack certain T-cell markers, CD7 and sequence of the TCR.37,38 Demonstration of identical clones in the skin,
CD26.26 However, there are variants of MF that are CD8+ (especially the blood, and/or lymph nodes may be helpful both for diagnosis and
hypopigmented variant) or CD4/CD8 dual negative (in those with LCT and differentiating MF and SS from benign inflammatory skin diseases.
hypopigmented variant), although rare.27-29 The IHC panel of skin biopsy
should include CD2, CD3, CD4, CD5, CD7, CD8, CD20, and CD30. Assessment of peripheral blood involvement optimally by flow cytometry
is important for staging and is also useful to differentiate CTCL with
Additional immunohistochemical markers such as CD25, CD56, TIA1, peripheral blood involvement from other forms of leukemic T-cell
granzyme B, TCR beta, and TCR delta may be useful in selected lymphomas (eg, T-cell prolymphocytic leukemia, lymphocytic variant of
circumstances. The loss of CCR4 expression and emergence of CCR4 hypereosinophilic syndrome, adult T-cell leukemia/lymphoma [ATLL]).
genomic alterations might be associated with resistance to Flow cytometry allows for the assessment and quantitation of an
mogamulizumab.30 IHC for CCR4 may be useful to confirm resistance to expanded population of CD4+ cells with abnormal immunophenotype
mogamulizumab in patients with progressive or refractory disease while on (CD4+/CD26- or CD4+/CD7- or other aberrantly expressed phenotype).39
treatment with mogamulizumab. Assessment of TRBC1 expression by flow cytometry is also useful for
the detection of clonality, especially in cases where CD7 or CD26 are not
Primary cutaneous follicular helper T-cell (TFH) lymphoma is a recently lost.40-42 Human T-cell lymphotrophic virus (HTLV)-1 status, assessed
described variant of peripheral T-cell lymphoma (PTCL)-not otherwise
MS-18

either by HTLV-1 serology or other methods, may be useful in populations are contraindicated or are of unknown safety in pregnancy. Therefore,
at risk to exclude the diagnosis of ATLL (which is usually pregnancy testing is recommended for individuals of childbearing age.
HTLV-1-positive).
Treatment Considerations
Workup While MF and SS are treatable, they are not curable with conventional
The initial workup of patients diagnosed with MF or SS involves a history systemic therapy and the symptoms of the disease have significant
and complete skin examination (assessment of the extent of disease [ie, impact on the quality of life. Patients with MF, particularly those with
percent of BSA] and type of skin lesion [eg, patch/plaque, tumor, early-stage disease, can have very good prognosis and may live with the
erythroderma]), palpation of peripheral lymph nodes, and palpation for disease for decades.17,18
organomegaly.13
The optimal treatment for any patient at any given time should be
Laboratory studies should include a complete blood count (CBC), Sézary individualized based on overall goals of therapy (improve the disease
flow cytometric study (optional for T1 disease), comprehensive metabolic burden and quality of life, attain adequate response to reduce/control
panel, and assessment of LDH levels. Analysis of clonal TCR gene symptoms, and minimize the risk of progression), route of administration,
arrangement of peripheral blood lymphocytes is recommended if blood and toxicity profile. Discussions regarding cumulative toxicity of therapy,
involvement is suspected. impact of therapy on quality of life, and supportive care for symptom
control are a key part of the treatment of patients with MF and SS. Most
CT with contrast of the chest, abdomen, and pelvis or integrated of the treatment options do not result in durable remissions and are often
whole-body PET/CT scan is recommended for patients with T3 or T4 given in an ongoing or maintenance fashion to achieve disease control
disease and should be considered for patients with T2a (patch disease with as little impact on quality of life as possible.
with ≥10% BSA), T2b (widespread plaque-type skin disease), FMF or
LCT, palpable adenopathy, or abnormal laboratory studies. In an analysis Patients with a clinical benefit and/or those with disease responding to
of 375 patients with stage T1/T2 MF enrolled in the PROCLIPI primary treatment can be considered for maintenance or tapering of
international study, the presence of plaques was associated with a regimens to optimize response duration. Patients with disease that does
significant increase in the identification of radiologically enlarged or not have adequate response to a systemic therapy regimen are generally
involved lymph nodes in patients with early-stage MF.24 treated with an alternative regimen recommended for primary treatment
before moving on to treatment for refractory disease. This supports the
A CT scan of the neck may be useful in some circumstances. Integrated therapeutic principle of initial treatment with less toxic regimens before
PET/CT was found to be more sensitive for the detection of lymph node moving on to treatment options that carry a higher risk of cumulative
involvement than CT alone and can help direct biopsies.43 PET scan may toxicity and/or immunosuppression. Disease relapse (with the same
also be preferred in patients with extranodal disease that may be stage) after discontinuation of therapy often responds well to
inadequately imaged by CT. Many skin-directed and systemic therapies re-treatment with previous therapy.
MS-19

Selection of Therapy Based on Clinical and Pathologic Features been evaluated in randomized studies, as discussed in the section
Skin-directed therapies (topical therapy, phototherapy, radiation therapy Systemic Therapies. Therefore, a clinical trial should be considered
[RT], or total skin electronic beam therapy [TSEBT]) that can provide when appropriate and available.
disease control without major cumulative toxicities are recommended for
Data from clinical trials that have evaluated various treatment strategies
patients with early-stage disease and limited skin involvement (stage IA or
(skin-directed therapy, systemic therapy, and combination therapies) are
stage IB–IIA). Stage IA MF most often can be treated with skin-directed
discussed below.
therapies (alone or in combination with other skin-directed therapies).
While stage IB–IIA patch/plaque disease can be effectively treated Skin-Directed Therapies
predominantly with skin-directed therapies, systemic therapy can be
Topical therapy with corticosteroids, mechlorethamine (nitrogen mustard),
considered for stage IB–IIA with higher skin disease burden, concerning
topical retinoids or topical imiquimod, or RT are indicated for patients with
pathologic features (eg, LCT or FMF), predominantly plaque disease,
localized disease. Phototherapy and TSEBT are indicated for patients with
and/or inadequate response to skin-directed therapy.
widespread skin involvement. Topical retinoids are not recommended for
Systemic therapy is recommended for advanced-stage disease (≥ stage generalized skin involvement because these treatments can cause
IIB). However, stage IIB patients with single or few T3 lesions can be substantial irritation.
treated with external beam RT (EBRT) with further delay of systemic
Topical Corticosteroids
therapy and TSEBT may be used for patients with stage IB–IIB disease,
Topical corticosteroids are effective for early-stage MF (especially for the
with excellent response expected. In the PROCLIPI study, the use of
treatment of patch-stage MF), resulting in measurable improvement in
systemic therapy was significantly associated with higher clinical stage,
BSA involvement and high ORR of 94% (63% complete response [CR];
presence of plaques, and FMF.25 In a multivariate analysis, the presence
13% partial response [PR]) and 82% (25% CR; 57% PR) in patients with
of plaques and FMF were significantly associated with the use of systemic
stage T1 and T2 disease, respectively.44-46
therapy and skin-directed therapy was superior to systemic therapy even
in patients with these disease characteristics. The overall response rate Optimal use of topical steroids is often dependent on lesion type and
(ORR) to first-line skin-directed therapy was 73% compared to 57% for disease site. This is best done in consultation with a dermatologist or
systemic therapy. physician with experience in the use of topical steroids. In general,
high-potency steroids may be less well-tolerated in intertriginous body
Systemic therapy can be and often is combined with skin-directed
areas or other areas such as the face. Long-term use of a topical steroid
therapy to maximize clinical responses in the skin compartment and also
may lead to skin atrophy or striae formation and the risk becomes greater
to provide additive efficacy without cumulative toxicities. For those who
with increased potency of the steroid. Moreover, high-potency steroids
require systemic therapy, due to either advanced-stage disease or
used on large skin surfaces may lead to systemic absorption.
inadequate disease control on skin-directed therapy, there are many
options; however, given the rare nature of this disease, only a few have
MS-20

Topical Mechlorethamine (nitrogen mustard) Topical Retinoids
Topical mechlorethamine has been used for the management of MF for Bexarotene gel is the only FDA-approved synthetic topical retinoid for the
many decades resulting in an ORR of 83% (50% CR). Patients with T1 treatment of MF and SS. In the phase I–II trial of 67 patients with
disease had a higher ORR (93% vs. 72%), CR rate (65% vs. 34%), longer early-stage MF, the ORR was 63% (21% CR) and the estimated median
median OS (21 vs. 15 months), and higher 5-year OS rate (97% vs. 72%) response duration was 99 weeks.49 Response rates were higher among
than those with T2 disease.47 The efficacy was similar for aqueous and the patients who had had no prior therapy compared with those who had
ointment preparations, although the ointment was associated with reduced received prior topical therapies (75% vs. 67%). In the phase III multicenter
hypersensitivity reactions. study of 50 patients with early-stage refractory MF, the ORR was 44% (8%
CR).50
A topical gel formulation of mechlorethamine was approved by the U.S.
Food and Drug Administration (FDA) in 2013 based on the results of a Tazarotene 0.1% topical gel/cream was reported to be a well-tolerated and
multicenter, randomized, phase II trial that demonstrated the non-inferiority active adjuvant therapy by clinical and histologic assessments in a small
of topical gel formulation compared to the compounded ointment series of patients with early patch or plaque MF lesions (stable or
formulation for the treatment of stage IA or IIA MF in patients (n = 260) refractory to therapy).51,52
who had not been treated with topical mechlorethamine within 2 years of
Topical Imiquimod
study enrollment and had not received prior therapy with topical
mechlorethamine.48 Response rate based on Composite Assessment of Imiquimod has also demonstrated activity in a small number of patients
Index Lesion Severity was 59% for the topical gel formulation compared to with early-stage MF refractory to other therapies.53-56 Topical imiquimod
48% for the ointment formulation. No study treatment-related serious can be considered (often in consultation with a dermatologist or physician
adverse events were reported, and no systemic absorption was detected. with experience in its safety and use) for areas with few
patches/plaques/small tumors that are recalcitrant to treatment or on
Topical mechlorethamine has no significant systemic absorption, and can sun-damaged skin such as forearms, scalp, and face.
be used alone or in combination with other skin directed therapies, in
Topical Carmustine
particular topical steroids. The use of topical gel formulation of
Topical carmustine is an effective treatment for patch/plaque early-stage
mechlorethamine can be complicated by dermatitis and can result in skin
MF resulting in high response rates of 92% and 64% in patients with T1
irritation when used on the face and intertriginous body areas. Initiation at
and T2 disease, respectively, at 36 months.57,58 Topical carmustine is
less than daily use can be useful to determine tolerability. Topical steroids
included with a category 2B recommendation.
can be considered as needed to alleviate skin reactions from topical gel
formulation. If used in combination with phototherapy, topical Topical Calcineurin Inhibitors
mechlorethamine gel should be applied after exposure to ultraviolet light. In a phase II multicenter study of 39 patients with stage IA–IIA MF, topical
Topical mechlorethamine is prohibited in the genital skin. pimecrolimus (1% cream) resulted in an ORR of 56% and was well
tolerated (grade 1 transient mild burning or pruritus was the most common
MS-21

adverse event reported in 21% of patients).59 Topical calcineurin inhibitors comparable to the ORRs achieved with standard-dose TSEBT (≥30 Gy).65
can be considered for patients with early-stage MF as a steroid-sparing The OS and progression-free survival (PFS) rates were not significantly
treatment for early-stage skin lesions in the perioral and periorbital areas. different by dose groups and were comparable to that of standard-dose
TSEBT (≥30 Gy).
Radiation Therapy
MF is extremely radiosensitive and unilesional or stage IA MF may be Lower-dose TSEBT (10–12 Gy over a period of 2–3 weeks) is shown to be
treated effectively with local RT alone (without adjuvant therapy), resulting sufficiently active and may also be associated with fewer short-term
in an ORR of 97% to 100%.60,61 Recent studies have shown that complications and better ability to re-treat progressive disease (PD) or
low-dose involved-field RT (IFRT) also results in high response rates cutaneous relapses.68-73 A pooled analysis of three phase II clinical trials
without any toxicity in patients with MF.61-63 In a study that included 31 that evaluated low-dose TSEBT (12 Gy; 1 Gy per fraction over 3 weeks) in
patients with MF, low-dose RT (4 Gy in 2 fractions) resulted in a CR rate of 33 patients with MF reported an ORR of 88% (including 9 patients with a
only 30%, whereas increasing the dose to 8 Gy in two fractions yielded a CR).69 The median time to response and median duration of clinical
CR rate of 92%.62 Patients with disease not responding to low-dose RT benefit were 8 weeks and 71 weeks. In a cohort of 103 patients with MF
were re-treated with 20 Gy in eight fractions. In a large series of 58 treated with low-dose TSEBT (12 Gy in 8 fractions for 2 weeks; the
patients treated with 8 Gy in a single fraction, the CR rate was 94% for majority of patients had stage IB or IIB disease), after a median follow-up
individual lesions after a median follow-up of 41 months.63 of 21 months, the ORR was 87% (18% CR and 69% PR) and the median
PFS was 13 months.72 The median PFS was significantly longer for
Optimal management of individual plaque and tumor lesions is with EBRT patients with stage IB disease (27 months) compared to 11 months and 10
(8–12 Gy, 8 Gy may be given in a single-fraction; 24–30 Gy is months, respectively, for those with stage IIB or stage III disease.
recommended for more durable duration of response or for unilesional Low-dose TSEBT (12 Gy in 6–7 fractions) was also associated with
presentation).61,63 favorable outcomes and significantly fewer grade 2 acute toxicities
Total Skin Electron Beam Therapy
compared with conventional-dose TSEBT (30 Gy).71,74,75 Further studies
TSEBT (conventional dose [30–36 Gy] or low dose [<30 Gy]) either alone are warranted to confirm these findings and the use of low-dose TSEBT in
or in combination with adjuvant therapy has been shown to be effective for combined modality regimens.
the treatment of early-stage MF.64-67 TSEBT at a conventional dose of The recommended dose range for TSEBT is 12–36 Gy (generally 4–6 Gy
greater than or equal to 30 Gy was associated with a non-significant trend
per week). Lower total dose is associated with fewer short-term
towards better clinical benefit and was also associated with better complications and better ability to re-treat relapsed disease. It is common
outcomes in patients with T2 disease compared to those with T3
practice to follow TSEBT with systemic therapies such as interferon (IFN)
disease.66,67 In a retrospective study that evaluated low-dose TSEBT in or bexarotene to maintain response, for patients with stage IB–IIA disease
102 patients with T2 to T4 disease (excluding those with extracutaneous
with higher skin disease burden. Adjuvant systemic therapy can be
disease), TSEBT doses of 10 Gy to less than 20 Gy and 20 Gy to less
than 30 Gy resulted in ORRs of 98% and 97%, respectively, which were
MS-22

considered to improve response rate and PFS in patients with stage IIB immunosuppressive medication due to the increased risk of UV
(tumor stage) disease receiving TSEBT.76,77 radiation-associated skin malignancies in this patient population. The risk
and benefits of phototherapy should be considered in patients with a
TSEBT may not be well tolerated in patients with erythrodermic disease history of BCC, SCC, or melanoma. There are limited safety data for the
and should be used with caution. In these patients, TSEBT may be used use of phototherapy in combination with vorinostat or romidepsin.
with lower doses and slower fractionation. Antibiotic therapy should be
considered since patients with erythrodermic disease are at increased risk Systemic Therapies
of developing secondary infections. The selection of systemic therapy regimens is dependent on clinical (eg,
extent of patch/plaques; disease burden profile in the skin, lymph nodes,
Phototherapy
and blood; prior therapies; and comorbidities) and pathologic features (eg,
Ultraviolet B (UVB including narrowband-UVB)78-82 and psoralen plus
LCT or FMF) and IHC data (eg, CD30 positivity). In general, systemic
ultraviolet A1 (PUVA/UVA-1)83-86 are effective treatment options for
therapy regimens that can be tolerated for longer durations of therapy with
patients with early-stage MF. Narrowband UVB is the most common
lower rates of cumulative toxicity, less immunosuppression, and/or higher
phototherapy approach and less skin damaging than PUVA/UVA-1. While
efficacy are used in earlier lines of therapy. Regimens with lower
some retrospective studies have reported that PUVA results in better
side-effect profiles and an absence of cumulative toxicity are often given in
responses and improved disease-free survival (DFS),87-89 others have
an ongoing or maintenance fashion to improve and maintain disease
reported that UVB is as effective as PUVA for the treatment of
control and quality of life. In patients requiring chemotherapy, single
early-stage MF.90,91 However, these modalities have not been compared
agents are preferred over combination chemotherapy, due to the higher
in randomized clinical trials.
toxicity profiles associated with multiagent regimens and the short-lived
PUVA may be associated with a small increase in the risk of developing responses seen with time-limited combination chemotherapy.
basal cell carcinoma (BCC), while there was no significant association
Brentuximab vedotin, bexarotene, histone deacetylase (HDAC) inhibitors
between the use of narrowband UVB and the risk of developing BCC,
(vorinostat and romidepsin), methotrexate, pralatrexate, mogamulizumab,
squamous cell carcinoma (SCC), or melanoma.92 More recent reports also
alemtuzumab, and pembrolizumab are effective systemic therapy options
confirmed that the use of UV radiation (including UVA and narrowband
for patients with advanced MF and SS. Bexarotene, brentuximab vedotin,
UVB) was not associated with an increased risk of developing BCC, SCC,
mogamulizumab, vorinostat, and romidepsin are approved by the FDA for
or melanoma except in patients receiving immunosuppressive
the treatment of MF and SS. The efficacy of brentuximab vedotin and
therapy.93,94
mogamulizumab compared to standard therapy has been demonstrated in
It may be more beneficial to start with narrowband UVB than PUVA in phase III randomized trials (ALCANZA and MAVORIC, respectively).97-99
patients with early patch-stage or thin-plaque disease, since narrowband Bexarotene,100,101 vorinostat,102-104 romidepsin,105-107 and other systemic
UVB has less skin toxicity than broadband UVB and PUVA.92,95,96 therapies such as pralatrexate,108-110 alemtuzumab,111-116 and
Phototherapy should be used with caution in patients with a history of pembrolizumab117 have been evaluated only in phase II studies. IFNs (alfa
MS-23

and gamma) and methotrexate also offer clinical benefit but have not been favorable tolerability profile without significant cumulative toxicity, we
evaluated in phase II studies in the era of modern staging of MF and consider bexarotene for patients with early-stage MF who have insufficient
SS.118-120 Peginterferon alfa-2a is the only IFN available for clinical use in disease control with skin-directed therapy. Bexarotene is also used in
the United States and it may be substituted for other IFN combination with phototherapy or ECP for early-stage disease with
preparations.121-123 inadequate response to single-agent therapy and in patients with
advanced-stage disease.142-145 It is important to note that bexarotene is
Extracorporeal photopheresis (ECP) is an immunomodulatory therapy in associated with hypertriglyceridemia and central hypothyroidism, which
which patient’s leukocytes are removed by leukapheresis, treated necessitates laboratory monitoring for triglycerides, and free thyroxine
extracorporeally with 8-methoxypsoralen and UVA, and then returned to (T4), often requiring additional management.
the patient.124-126 ECP may be a more appropriate systemic therapy for
patients with some level of blood involvement (B1 or B2). Retinoic-acid receptor (RAR) agonists such as acitretin and isotretinoin
(13-cis-retinoic acid) have also been shown to be effective for the
Gemcitabine127-134 and pegylated liposomal doxorubicin134-139 also have treatment of early-stage MF.146-148 In a small cohort of 35 patients with
substantial activity in patients with advanced MF and SS. Multiagent early-stage MF, acitretin and isotretinoin resulted in ORRs of 64% and
chemotherapy regimens used for the treatment of systemic PTCLs have 80%, respectively (although the CR rates were low at 4% and 8%,
activity but are associated with greater toxicity and a potentially higher risk respectively).147
of death when used in earlier lines of treatment.140,141 Therefore,
multiagent chemotherapy regimens are generally reserved only for Brentuximab Vedotin
refractory disease to multiple prior therapies or bulky lymph node or solid In the ALCANZA trial, brentuximab vedotin, an anti-CD30 antibody drug
organ disease, and/or as a bridge to allogeneic hematopoietic cell conjugate, was more effective than methotrexate or bexarotene in patients
transplant (HCT). with previously treated MF (≥ stage IB).97 The final analysis confirmed that
brentuximab vedotin resulted in significantly improved ORR lasting for at
Data supporting the use of some of these agents in patients with MF and least 4 months (ORR4; 55% vs.13%), median PFS (17 vs. 4 months), and
SS are discussed below. The data for systemic therapy agents, patient-reported symptom burden compared to methotrexate or
particularly those studied in larger prospective phase II and III studies, are bexarotene in patients with CD30-positive MF.98 Peripheral neuropathy
also summarized in Table 1. was the most common adverse event reported in 44 (69%) patients. At the
median follow-up of 46 months, 86% (38 of 44) of patients had complete
Systemic Retinoids
resolution or improvement to grades 1 and 2.
Bexarotene, an oral retinoid, can have prolonged disease control without
cumulative toxicity and is often considered for patients with higher skin In the ALCANZA trial, CD30 positivity was defined as CD30 expression in
burden with plaque disease.100,101 In phase II–III studies, oral bexarotene ≥10% of total lymphoid cells in at least 1 skin biopsy (43% of patients had
(≥300 mg/m2) was well tolerated, resulting in an ORR of 45% to 67% in at least 1 sample with CD30 <10%).97 The results of an exploratory
patients with early-stage and advanced-stage disease.100,101 Given the analysis showed that brentuximab vedotin resulted in higher ORR4 and
MS-24

improved PFS in patients with ≥10% CD30 expression, regardless of LCT previously treated MF (≥ stage IB) and SS. Mogamulizumab resulted in
status.149 The ORR4 (41% vs. 10% for <10% CD30min expression; 57% vs. significantly higher ORR (28% vs. 5%) and median PFS (8 vs. 3 months)
10% for ≥10% CD30min expression) and median PFS (17 months vs. 2 compared with vorinostat and the ORR was higher in patients with SS
months for <10% CD30min expression; 16 months vs. 4 months for ≥10% than those with MF (37% vs. 21%).99 Patients with LCT at study entry
CD30min expression) were significantly higher for brentuximab vedotin were excluded from this trial. In a post hoc analysis, the number of prior
compared to vorinostat across all CD30 expression levels. therapies did not impact the ORR, PFS, and duration of response
observed with mogamulizumab.156 Among the 186 patients randomly
In other phase II studies, clinical responses with brentuximab vedotin were assigned to vorinostat, 136 patients (109 patients with disease
observed across all CD30 expression levels (including negligible CD30 progression and 27 patients after intolerable toxicity) crossed over to
expression) and in patients with high blood Sézary cell count.150,151 mogamulizumab. The ORR was 31% for the 133 patients who crossed
Lesions with less than 5% CD30 expression had a lower likelihood of over from vorinostat to mogamulizumab and subsequently received
global response than those with greater than or equal to 5% CD30 mogamulizumab. The most common adverse events associated with
expression (P < .005), but responses are still seen in those with CD30 mogamulizumab were mostly grade 1–2 and manageable (infusion-related
positivity of greater than or equal to 1% or non-detectable CD30 by IHC reactions [37%], skin eruptions [25%], and diarrhea [14%]). Pyrexia (4%)
using light microscopy.150,151 While responses were observed in patients and cellulitis (3%) were the most common grade 3 adverse events in the
with very low or absent CD30 expression, the likelihood and/or depth of mogamulizumab group. Patients with the greatest symptom burden and
response may be lower in these situations and further studies are needed functional impairment derived the most benefit from mogamulizumab in
to define the activity of brentuximab in this setting. Real world cohort terms of quality of life.157
studies have also reported favorable outcomes with brentuximab vedotin
in patients with previously treated MF and SS and variable CD30 The clinical benefit with mogamulizumab was higher in patients with stage
positivity.152,153 III or stage IV disease, especially in patients with B1 and B2 blood
involvement.99,158,159 In the post-hoc subgroup analysis by clinical stage,
Brentuximab vedotin is a more effective treatment option than the ORRs for mogamulizumab were 23% and 36%, respectively, for
methotrexate or bexarotene for patients with CD30-positive MF but carries patients with stage III or stage IV disease compared to 19% and 16%,
greater risk, particularly a cumulative risk of peripheral neuropathy.154 respectively, for patients with stage IB/IIA disease or stage IIB disease.99
Patients with SS were excluded from the ALCANZA trial and the efficacy Mogamulizumab also resulted in higher ORR than vorinostat across all
of brentuximab vedotin in patients with SS in the setting of refractory disease compartments. The compartment-specific ORRs for
disease or low CD30 skin expression has only been demonstrated in a mogamulizumab were 42%, 68%, and 17%, respectively, for skin, blood
small case series of 13 patients.155 involvement, and lymph nodes. The corresponding ORRs for vorinostat
were 16%, 19%, and 4%, respectively. The overall disease control rate
Mogamulizumab
was 79% (76% for MF and 82% for SS) and improved with long-term
In the MAVORIC trial, mogamulizumab, a humanized anti-CCR4
exposure to mogamulizumab.160 This trial, however, was not powered to
monoclonal antibody, was more effective than vorinostat in patients with
MS-25

detect OS differences between the two groups within the defined follow-up pretreated MF and SS.104 While cumulative toxicities were rare with
period. vorinostat, patients need to be monitored for gastrointestinal toxicity,
including nausea, diarrhea, and resultant dehydration, which could be
The post-hoc analyses that evaluated the efficacy of mogamulizumab more detrimental for older patients.
based on blood tumor burden showed that blood involvement was
associated with improved ORRs, PFS, and time to next treatment (TTNT) Romidepsin has demonstrated clinical activity across all disease
for patients treated with mogamulizumab.158,159 The ORRs were 26% and compartments.105-107 The median duration of response is 13 to 15 months
37%, respectively, for patients with B1 and B2 blood involvement for patients with disease responding to romidepsin.105,106 Importantly,
compared to 16% for those with B0 blood involvement.158 The median romidepsin was associated with a high rate of reduction in pruritus score
PFS was 11 months and 8 months, respectively, for patients with B2 and irrespective of clinical objective response. The compartment-specific
B1 blood involvement compared to 5 months for those with B0 blood ORRs were 40%, 35%, 32%, and 27%, respectively, for skin involvement,
involvement.159 The TTNT was 20 months for those with B2 blood erythroderma, blood involvement, and lymphadenopathy.107 It is important
involvement compared to 12 months and 7 months, respectively, for to initially monitor for QTc prolongation when administering romidepsin,
those with B1 and B0 blood involvement.159 Mogamulizumab also was particularly with the concomitant use of antiemetics that also prolong QTc.
associated with sustained reductions seen in CD4+ CD26- cell counts Romidepsin is included as a preferred regimen for patients with SS with
and CD4:CD8 ratios in patients for all B classes of blood involvement. high Sézary cell burden.
A drug-induced skin eruption that has variable clinical and pathologic Alemtuzumab
features (and can mimic CTCL) was the most frequent adverse event Alemtuzumab (a humanized anti-CD52 monoclonal antibody) has
leading to treatment discontinuation in the MAVORIC trial.99,161-164 significant clinical activity in patients with previously treated advanced MF
Mogamulizumab-associated skin rash has also been identified as a and SS.111-116 The ORR with alemtuzumab (30 mg IV) was higher in
potential marker for tumor response.165 Skin biopsy (with adequate patients with erythroderma or SS than those with advanced MF; however,
immunohistochemical stains and clonality assessment) is recommended it was associated with myelotoxicities and infectious complications.112,116
to rule out disease progression in patients experiencing drug-induced Reduced-dose subcutaneous alemtuzumab (3–15 mg per administration)
skin eruptions or mogamulizumab-associated skin rash.163,166 given for a shorter duration was equally effective with lower incidence of
infectious complications in patients with SS.113 While alemtuzumab is no
Histone Deacetylase Inhibitors longer commercially available, it may be obtained for compassionate use
Vorinostat was the first HDAC inhibitor to be approved for the treatment of for patients with CTCL and other hematologic malignancies.
MF and SS. In the initial phase IIB registration study, vorinostat resulted in
an ORR of 30%.103 A post-hoc subset analysis of patients who Pembrolizumab
experienced clinical benefit with greater than or equal to 2 years of In a phase II trial, pembrolizumab (an immune checkpoint inhibitor)
vorinostat therapy in the phase IIB study provided some evidence for the resulted in durable responses in both MF and SS with an ORR of 38% and
long-term safety and efficacy of vorinostat in patients with heavily median duration of response not reached at a median follow-up of 58
MS-26

weeks.117 Pembrolizumab was associated with a skin flare reaction, In a phase II EORTC multicenter trial of 49 patients with
occurring exclusively in patients with SS; the flare reaction correlated with relapsed/refractory advanced MF (stage IIB, IVA, or IVB) after at least two
high PD-1 expression on Sezary cells and it should be distinguished from prior systemic therapies, pegylated liposomal doxorubicin resulted in an
disease progression. ORR of 41% (6% CR), with a median duration of response and median
time to progression (TTP) of 6 months and 7 months, respectively.137
Pralatrexate
Pegylated liposomal doxorubicin was well tolerated with no grade 3 or 4
Pralatrexate is a folate analog with demonstrated activity in patients with hematologic toxicities; the most common grade 3 or 4 toxicities included
heavily pretreated MF and SS.108-110 In a multicenter dose-finding study dermatologic toxicity other than hand and foot reaction (6%), constitutional
that evaluated pralatrexate (10–30 mg/m2 given weekly for 2 of 3 weeks or symptoms (4%), gastrointestinal toxicities (4%), and infection (4%).
3 of 4 weeks) in 54 patients with relapsed or refractory MF and SS, the
ORR for all evaluable patients was 41% (6% CR).108 Among the 29 In a single-center study of 32 patients (MF, n = 25; SS, n = 7) treated with
patients who received the recommended dose (15 mg/m2 weekly for 3 pegylated liposomal doxorubicin for heavily pretreated MF (n = 25) and SS
weeks of a 4-week cycle), the ORR was 45% (3% CR).108 In the subgroup (n = 7), the ORR was 58% for the entire study population (71% in skin,
of patients with relapsed/refractory LCT of MF treated on the PROPEL 44% in blood, and 33% in lymph nodes).134 The toxicity profile was also
trial, pralatrexate (30 mg/m2) resulted in an ORR of 58% (25% by consistent with that reported in the phase II study, with fatigue, peripheral
independent review).109 The median PFS and OS were 5 months and 13 edema, anemia, hyperpigmentation, and hand-foot syndrome being the
months, respectively. most common toxicities of all grades. Another real-life cohort study (36
patients; MF, n = 34; SS, n = 2) also confirmed the activity of pegylated
Gemcitabine
liposomal doxorubicin for advanced MF and SS, especially in patients with
Gemcitabine monotherapy is an effective treatment option for patients with tumor stage disease.139
heavily pretreated advanced-stage MF and SS.127-134 In a retrospective
observational study of 25 patients with advanced MF and SS, after a Extracorporeal Photopheresis
long-term follow-up of 15 years, the estimated OS, PFS, and DFS rates ECP has been demonstrated as an effective treatment option in many
were 47%, 9%, and 40%, respectively.131 In a single-center study of 14 retrospective studies, resulting in an ORR of 42% to 74%.125,167-174 In a
patients with heavily pretreated MF (n = 12) and SS (n = 2), gemcitabine meta-analysis involving more than 400 patients with MF and SS, ECP as
resulted in an ORR of 57% (all were in the skin compartment) and the monotherapy resulted in a 56% ORR with a 15% CR.168 The
median time-to-next treatment was 12 months.134 Retrospective studies corresponding response rates were 58% (15% CR) for erythrodermic
have also reported favorable clinical outcomes (ORR and PFS) with disease (T4) and 43% (10% CR) for SS. In one retrospective study of 39
low-dose gemcitabine in patients with previously treated MF and SS.132,133 patients with MF and SS (31 patients with T4 disease and 8 patients with
T2 disease), ECP resulted in a skin ORR of 74% (33% of patients
Liposomal Doxorubicin
achieved ≥50% partial skin response and 41% of patients achieved ≥90%
Pegylated liposomal doxorubicin has shown single-agent activity in
improvement).171 After a median follow-up of 72 months, the median OS
patients with pretreated, advanced, or refractory MF and SS.134-139 was 9 years from diagnosis and 7 years from the initiation of treatment
MS-27

with ECP. Another retrospective study of 50 patients with MF reported an combination arm, although the differences were not significant.142 This trial
ORR of 42% and an OS of 72 months with no statistically significant was closed prematurely due to low patient accrual.
differences in OS among patients with early-stage and late-stage disease
(77 months and 69 months, respectively; P = .077).173 A small prospective study evaluated the combination of low-dose
bexarotene in combination with PUVA maintenance in 21 patients with MF
The degree of blood involvement, CD4/CD8 ratio, and amount of and SS (stages IB–IV) resistant or intolerant to previous therapies.180 The
circulating CD3+CD8+ cells or CD4(+)CD7(-) lymphocytes have been ORR was 86% after induction therapy with bexarotene (93% for
identified as predictors of clinical response.124,125,175 ECP is generally given early-stage disease and 66.6% for advanced disease). At the end of
for at least 6 months and may be more appropriate as systemic therapy for maintenance, the ORR was 76% (33% CR) and the median event-free
patients with or at risk of blood involvement (B1 or B2; erythrodermic stage survival (EFS) for the whole group was 31 months.
III disease or IVA with SS).168,174
In a retrospective analysis of 128 patients with MF (118 patients had
Combination Therapies early-stage disease; stage ≤IIA), acitretin (either as monotherapy or in
Skin-Directed + Systemic Therapies combination with phototherapy or topical steroids) resulted in an ORR of
Phototherapy is most commonly used in combination with either IFN176-179 77% (44% CR and 33% PR) with a trend towards better response rate in
or systemic retinoid.142,148,180-182 the combination arm compared to monotherapy.148 The median duration of
response was 24 months.
In a prospective randomized study that evaluated IFN combined with
PUVA versus IFN combined with retinoids in patients with stage I or II ECP used in combination with TSEBT or phototherapy (narrowband UVB
CTCL (n = 82 evaluable), the combination of IFN with PUVA resulted in or PUVA) has also resulted in high durable clinical response in patients
significantly higher CR rates in this patient population (70% vs. 38%).176 In with erythrodermic MF and SS.183,184 In a retrospective study of 44 patients
another prospective phase II trial in patients with early-stage MF (stages with erythrodermic MF, the combination of TSEBT with ECP (concurrent or
IA–IIA; n = 89), the combination of low-dose IFN alfa with PUVA resulted sequential following TSEBT) significantly improved PFS compared with
in an ORR of 98% (84% CR).178 TSEBT alone.183 The 2-year PFS and OS rates were 36% and 63%,
respectively, for patients treated with TSEBT alone compared with 66%
In a phase III randomized study from the EORTC that evaluated the and 88% for those treated with TSEBT + ECP.
combination of bexarotene with PUVA compared with PUVA alone in
patients with early-stage MF (stage IB and IIA; n = 93), the ORR for the There are limited efficacy and safety data for the use of TSEBT in
combination of bexarotene with PUVA was 77% (31% CR) compared to combination with systemic retinoids, HDAC inhibitors (vorinostat or
71% (22% CR) for PUVA alone; the median duration of response was 6 romidepsin), or mogamulizumab.
months and 10 months, respectively.142 A trend towards fewer PUVA
sessions and lower UVA doses to achieve CR was observed with the
MS-28

Systemic Combination Therapies based on clinical parameters. Imaging with the same modalities used in
Systemic combination therapy regimens have been shown to improve workup is indicated when there is suspicion of disease progression or
response rates in patients with early-stage disease with inadequate extracutaneous disease.
response to single-agent therapy or those with advanced-stage CTCL.
All patients (stage IA–IV) with a clinical benefit and/or those with disease
ECP with IFN and/or systemic retinoid and IFN with systemic retinoid are responding to primary treatment should be considered for maintenance or
the most commonly evaluated combination therapies for patients with tapering of regimens to optimize response duration. Disease relapse (with
CTCL.143-145,185-187 The combination of oral isotretinoin and IFN alfa the same stage) after discontinuation of therapy often responds well to
resulted in an ORR of 85% and the estimated 5-year OS rate was 94% for re-treatment with previous therapy. Patients with persistent disease
patients with early-stage MF and 35% for advanced-stage MF.143 ECP in following completion of primary treatment should be treated with the other
combination with IFN and/or systemic retinoids resulted in a response rate primary treatment options not received before to improve response before
of 84% in patients with advanced CTCL and the 5-year OS rates for the moving onto treatment for refractory disease.
subgroups of patients with stage IIIB, IVA1, IVA2, and IVB were 80%,
80%, 76%, and 0%, respectively.186,187 Other systemic combination Currently there is no definitive treatment for refractory disease that can
therapy regimens have also been studied.188-190 produce reliable durable remissions or curative results. Participation in a
clinical trial is recommended for all patients with refractory disease.
However, aforementioned studies that have evaluated the systemic Multiagent chemotherapy regimens recommended for PTCL can be
combination regimens are limited by small sample size and there are no considered for the treatment of refractory disease to multiple prior
data from prospective randomized clinical studies to support the use of a therapies.
specific systemic combination therapy regimen.
Special Considerations for Clinical Situations with Specific
Additional Therapy Based on Response to Primary Treatment Pathologic Features
Historically, the response criteria for MF and SS were poorly defined and Folliculotropic Mycosis Fungoides
validated response assessments were lacking. Response criteria for MF FMF is characterized by the infiltration of hair follicles by atypical T
and SS have not been demonstrated to correlate with prognosis, and lymphocytes and resultant alopecia. Disease typically presents as plaques
responses can vary between the different disease compartments (ie, skin, and tumors mainly on the head/neck and the risk profile varies with stage
blood, lymph nodes). of the disease.20,192-195 Recent studies have reported that FMF presents
with two distinct patterns of clinicopathologic features with different
More recent studies have incorporated consensus response assessments prognostic implications (early stage and advanced stage). In a subgroup of
and newer FDA-approved agents have undergone central review for patients with early skin-limited disease, FMF has an indolent disease
efficacy outcomes. A proposal for the standardization of definition of course and a favorable prognosis, with early-stage cutaneous disease
response in skin, nodes, blood, and viscera has been published.191 The associated with significantly higher disease-specific survival compared to
decisions to continue with or switch treatment regimens are often made advanced-stage cutaneous disease.196-198
MS-29

In a report from the Dutch Cutaneous Lymphoma Group that evaluated patients with localized LCT (ie, restricted to one or few T3 lesions or
the treatment outcomes in patients with FMF (203 patients; 84 patients stage IA–IIA plaque disease) could be treated with EBRT alone, with
with early-stage FMF, 102 patients with advanced-stage FMF, and 17 continuation of other treatment modalities used prior to transformation.
patients with extracutaneous FMF), treatment with topical steroids and Depending on the goals of treatment, multiagent chemotherapy regimens
phototherapy with UVB or PUVA were more effective in patients with recommended for PTCL may be appropriate for the management of LCT
early-stage FMF resulting in an ORR of 83% (28% CR), 83%, and 88%, that is refractory to multiple prior therapies or when significant
respectively.199 Local RT, TSEBT, and PUVA combined with RT were extracutaneous disease is present.
more effective in patients with advanced-stage FMF resulting in an ORR
of 100% (63% CR), 100% (59% CR), and 75% (5% CR), respectively. Role of Allogeneic Hematopoietic Cell Transplant in MFSS
Allogeneic HCT has a role in a subset of patients with advanced-stage
Patients with early-stage FMF may benefit from standard skin-directed MF and SS who have received multiple lines of therapy as shown in
therapies used for the treatment of early-stage MF, and those with retrospective studies and small prospective series of patients with
generalized indolent/plaque FMF (without evidence of LCT) should initially advanced MF and SS.201-208
be considered for single-agent systemic therapy regimens before receiving
multiagent chemotherapy regimens. In a multicenter retrospective analysis of 37 patients with advanced-stage
primary CTCL treated with allogeneic HCT (24 patients [65%] had stage IV
Large-Cell Transformation MFSS or disseminated nodal or visceral involvement), after a median
LCT is diagnosed when large cells are present in greater than 25% of follow-up of 29 months, the incidence of relapse was 56% and the
lymphoid/tumor cell infiltrates in a skin lesion biopsy, and the incidence estimated 2-year OS and PFS rates were 57% and 31%, respectively.201
of LCT is strongly dependent on the disease stage at diagnosis (1% for
early-stage disease, compared with 27% for stage IIB disease and 56%– In a retrospective analysis of patients with advanced-stage MF and SS in
67% for stage IV disease).7-9 LCT is often, but not always, aggressive. the European Group for Blood and Marrow Transplantation (EBMT)
CD30 expression is associated with LCT in MF or SS in 30% to 50% of database (n = 60) treated with allogeneic HCT, the 5-year PFS and OS
cases, and this finding may have potential implications for CD30-directed rates were 32% and 46%, respectively. The corresponding 7-year survival
therapies.7-9,200 However, it should be noted that CD30 expression is rates were 44% and 30%, respectively.202 The non-relapse mortality
variable in MF and SS, with the leukemic Sézary cells typically being (NRM) rate at 7 years was 22%. Outcomes were not significantly different
CD30-negative. between histology types. However, patients with advanced-stage disease
had an increased risk of relapse or progression as well as lower PFS, and
Systemic therapy (brentuximab vedotin, gemcitabine, liposomal myeloablative conditioning was associated with poorer NRM and OS. In
doxorubicin, pralatrexate, romidepsin, or pembrolizumab) with an updated analysis, advanced-stage disease (refractory disease or PD
skin-directed therapies is the initial treatment for generalized cutaneous after ≥3 lines of systemic therapy prior to transplant), a short interval
or extracutaneous lesions with LCT. In addition, concurrent management between diagnosis, and transplant (<18 months) were independent
of coexisting disease based on clinical stage is recommended. Selected
MS-30

adverse prognostic factors for PFS; advanced-stage disease and the use was also lower in the allogeneic HCT group (45% compared to 86% in
of unrelated donors were independent adverse prognostic factors for the non-allogeneic HCT group).
OS.206
Autologous HCT is not recommended for patients with CTCL, due to
In a case series of 47 patients with advanced-stage MF and SS who short duration of response despite its toxicity, thus limiting its utility.212
underwent allogeneic HCT after disease progression on conventional While the majority of the deaths among patients undergoing autologous
therapy, the estimated 4-year OS and PFS rates were 51% and 26%, HCT may be attributable to PD, deaths associated with allogeneic HCT
respectively.204 While there was no statistical difference in the OS in may be more due to NRM (the incidence of 1-year NRM in published
patients who had MF without LCT, SS, MF with LCT, or SS with LCT, the reports with allogeneic HCT is approximately 11%–25%).201-205
4-year PFS rate was superior in patients who had SS versus those who
did not (52% vs.10%; P = .02). Another multicenter retrospective study, The use of TSEBT with non-myeloablative allogeneic HCT has also been
although limited by small sample size (26 patients; MF, n = 17; SS, n = evaluated in patients with advanced MF and SS.213-215 In a study of 19
9), reported superior outcomes with allogeneic HCT in patients with SS patients with advanced CTCL, the use of TSEBT prior to allogeneic HCT
compared to MF.208 After a median follow-up of 5 years, patients with SS provided improved disease control with an ORR of 68% (58% CR) with
had lower relapse rates (11% at 5 years), longer TTNT (not reached), median OS not reached at the time of the report; the treatment-related
higher treatment-free survival (89% at 5 years) and OS (5-year OS rate mortality (TRM) rate was 21%.213 The safety and efficacy of a
was 100%) compared to those with MF (74%, 24 months, 16% and 52%, non-myeloablative conditioning regimen consisting of TSEBT and total
respectively). Other systematic review and meta-analysis have reported lymphoid irradiation (TLI) + anti-thymocyte globulin (ATG) has also been
pooled PFS and OS rates of 36% and 59%, respectively, following demonstrated in prospective clinical studies.216,217 In a prospective clinical
allogeneic HCT in patients with advanced-stage MF and SS.209,210 study of 35 patients with advanced-stage disease (13 patients with MF
and 22 patients with SS), this regimen was associated with 1-year and
The survival benefit of allogeneic HCT in patients with advanced MF and 2-year NRM of 3% and 14%, respectively.216 The 2-year incidence of
SS was confirmed in a prospective, multicenter, propensity moderate/severe chronic graft-versus-host disease (GVHD) was 32%.
score-matched, controlled trial (99 patients with advanced MF and SS; With a median post-transplant follow-up of 5 years, the 2-year, 3-year, and
55 patients assigned to the allogeneic HCT group and 44 patients 5-year OS rates were 68%, 62%, and 56%, respectively. The 5-year PFS
assigned to the non-allogeneic HCT treatment option of investigator’s rate was 41%. Patients >65 years at the time of transplant had similar
choice).211 After a median follow-up of 13 months, the median PFS was clinical outcomes compared with younger patients. This study also
significantly longer in the allogeneic HCT group (9 months vs. 3 months evaluated the utilization of high-throughput sequencing (HTS) to monitor
in the non-allogeneic HCT group; P < .0001). The 1-year PFS rates were minimal residual disease (MRD), and molecular remission after allogeneic
51% and 14%, respectively, for patients in the allogeneic HCT group and HCT (achieved in 43% of patients) was associated with a lower incidence
non-allogeneic HCT group. The 1-year cumulative incidence of relapse of PD or relapse. In another prospective study that evaluated the same
non-myeloablative conditioning regimen (TSEBT + TLI + ATG) in 41
MS-31

patients with advanced-stage disease (34 patients with MF and 7 patients for patients.219-221 Patients should be evaluated for pruritus at each visit.
with SS), the 1-year and 2-year NRM rates were 10% and 13%, Other potential causes of pruritus (eg, contact dermatitis, atopic dermatitis,
respectively.217 Grade ≥2 acute and chronic GVHD were reported in 32% psoriasis, other inflammatory skin conditions) should be ruled out. The
and 24% of patients, respectively. After a median follow-up of 5 years after extent of pruritus (localized vs. generalized) and potential correlation
transplant, the 5-year OS rate was 38% for the entire study population between disease site and localization of pruritus should be noted.
(37% for MF and 57% for SS). The 5-year cumulative incidence of disease
progression or relapse was 53% for all patients and these rates were The treatment of pruritus requires optimizing skin-directed and systemic
significantly lower for patients achieving CR following transplant (21% treatments. Daily use of moisturizers and emollients are helpful in
compared to 71% in those not in CR; P = .006). maintaining and protecting the skin barrier. Topical steroids (with or
without occlusion) can be effective in managing the disease and
Allogeneic HCT may be considered for appropriate patients with stage accompanying pruritus in early-stage disease.221,222 First-line options
IIB–IV disease that is refractory to multiple primary treatment options. include H1 antihistamines (single-agent or combination of antihistamines
Based on the limited evidence, patients with erythrodermic MF and SS from different classes) or the anticonvulsant gabapentin.219,223,224
appear to receive the most benefit from allogeneic HCT, despite high Neurokinin-1 (NK-1) receptor antagonist aprepitant,225-227 the tetracyclic
post-transplant relapse rate. Allogeneic HCT is generally reserved for antidepressant mirtazapine, or selective serotonin reuptake inhibitors
patients with systemic disease and/or extensive skin involvement that is (SSRIs) may be considered in the second-line setting.228,229 Treatment with
refractory to or progressive after multiple lines of systemic therapy options. the oral opioid receptor antagonist naltrexone may be considered if
When appropriate, TSEBT may be considered as cytoreductive therapy symptoms of pruritus do not resolve with the above agents.230
before transplant.213,216 Novel conditioning regimens are being explored to
Prevention and Treatment of Infections
provide improved disease control while limiting transplant-related
complications. Infectious complications are frequent among patients with MF and SS,
particularly cutaneous bacterial infections and cutaneous herpes viral
The ideal timing for allogeneic HCT is when the disease is well controlled infections (eg, herpes simplex virus [HSV] or herpes zoster virus [HZV]
with induction therapy and before the disease has progressed to a state infections).231 Bacteremia/sepsis and bacterial pneumonia were reported
where the chance of response or survival with allogeneic HCT is low.218 A as the major cause of death due to infections in a retrospective cohort
transplant decision requires careful counseling to weigh the significant study of patients with MF and SS.231 Several preventive measures such as
risks of this procedure versus the likelihood of long-term benefits and maintaining/protecting the skin barrier (routine use of skin moisturizers
availability of alternate treatments. and/or emollients), bleach baths or soaks (for limited areas only),
avoidance of central lines (particularly for erythrodermic patients), and
Supportive Care prophylactic use of mupirocin in cases of Staphylococcus aureus
Management of Pruritus colonization can be incorporated to minimize infectious complications.
Symptoms of pruritus can be present in a large majority (nearly 90%) of HSV prophylaxis with acyclovir or equivalent should be considered for
patients with CTCL, and may be associated with decreased quality of life patients with frequent recurrence of HSV infection. Patients undergoing
MS-32

treatment with alemtuzumab-containing regimens should be closely

monitored for cytomegalovirus (CMV) reactivation and preemptively
treated with antivirals to avoid overt CMV disease.
Cultures from skin swab and nares (nostrils) should be taken to evaluate
for S. aureus colonization/infection in patients with erythroderma and an
active or suspected infection. Antimicrobial treatments may include
intranasal mupirocin and/or oral dicloxacillin or cephalexin. Bleach baths
or soaks may be helpful if the affected area is limited. Doxycycline or
trimethoprim/sulfamethoxazole (TMP/SMX) should be considered for
patients with suspected methicillin-resistant S. aureus (MRSA) infection. If
no improvements in infection status are observed with the above agents,
or if bacteremia is suspected, vancomycin should be initiated.
Infection with Gram-negative rods is common in necrotic tumors, and may

lead to serious complications such as bacteremia/sepsis. For active or
suspected infections in patients with ulcerated and necrotic tumors, blood
cultures should be obtained and empiric therapy with antibacterials should
be considered even in the absence of a fever. An antimicrobial agent with
broad-spectrum coverage (including coverage for both Gram-negative
rods and Gram-positive cocci) should be chosen initially. The role of
skin/wound culture is not clear in this setting.
Further information on empiric therapy in patients with cancer at risk for

infections is included in the NCCN Guidelines for the Prevention and
Treatment of Cancer-Related Infections.
MS-33

Table 1. Systemic Therapy for MF and SS
Disease Stage and Median

Trial Regimen/Dose Patient Characteristics ORR Median PFS
No. of Patients (n) Follow-up
Brentuximab vedotin ECOG PS 0-2;

Stage IA–IVB MF ≥18 years with relapsed or refractory 55%
(1.8 mg/kg every 3 weeks; 16 17 months
(n = 48) CD30-expressing MF* (≥1 prior systemic (17% CR)
3-week cycles)
ALCANZA trial therapy or RT); Patients with MF and B1
Oral methotrexate (5–50 mg once
(Phase III RCT)98 blood involvement were considered eligible; 46 months
per week) for 48 weeks
Stage IA–IVB MF Patients with SS (B2 blood involvement) 13%
and those with disease progression on prior 4 months
Oral bexarotene (300 mg/m² once (n = 49) (2% CR)
per day) for 48 weeks methotrexate and bexarotene were
excluded.
Mogamulizumab
ECOG PS 0-1;
(1 mg/kg IV on a weekly basis for the Stage IB–IVA 28% 8 months
≥18 years with relapsed or refractory MF
MAVORIC trial first 28-day cycle, then on days 1 (n = 186) (23% by IR) (7 months by IR)
and SS (≥1 prior systemic therapy);
(Phase III RCT)99 and 15 of subsequent cycles) 17 months
Patients with LCT at study entry were
excluded. CCR4 expression was not a
Vorinostat (400 mg daily) Stage IB–IVA requirement for participation in the trial. 5% 3 months
(n = 186) (4% by IR) (4 months by IR)
300 mg/m2/day Stage IA–IIA

≥18 years with refractory or persistent MF — 54%
Phase II and III100 Bexarotene (n = 28)
(after ≥2 prior therapies: phototherapy or
>300 mg/m2/day Stage IA–IIA TSEBT or topical mechlorethamine) —
67%
(n = 15)
Stage IIB–IVB —
300 mg/m2/day 45%
Phase II and III101 (n = 56) ≥18 years with refractory or persistent MF
Bexarotene
Stage IIB–IVB and SS — 55%
>300 mg/m2/day
(n = 38) (13% CR)
Continued on next page
*CD30 expression in ≥10% of total lymphoid cells in at least one skin biopsy.
CR, complete response; IR, independent review; LCT, large cell transformation; MF, mycosis fungoides; ORR, overall response rate; PFS, progression-free survival; PS, performance status; RT, radiation
therapy; RCT, randomized control trial; SS, Sézary syndrome; TSEBT, total skin electronic beam therapy;
MS-34

Table 1. Systemic Therapy for MF and SS
Regimen/Dose Disease Stage and Median

Trial Patient Characteristics ORR Median PFS
No. of Patients (n) Follow-up
ECOG PS 0–2;
Vorinostat (400 mg daily) Stage IB–IVA ≥18 years with progressive, persistent, or
Phase IIB103 — 30%
(n = 74) recurrent MF and SS (after ≥2 prior
systemic therapies including bexarotene)
Romidepsin (14 mg/m2 as a 4-hour ECOG PS 0–1;
Phase II106 IV infusion on days 1, 8, and 15 of Stage IB–IVA 34%
≥18 years with relapsed or refractory MF —
each 28-day cycle for up to 6 cycles) (n = 96) (6% CR)
and SS (≥1 prior systemic therapy)
PDX-010 Pralatrexate (15 mg/m2, weekly for 3 ECOG PS 0–2;

Stage IB–IVA — 45%
(Dose-escalation out of 4 weeks) ≥18 years with progressive MF and SS Not reached
(n = 29)
study)108 (after ≥1 prior systemic therapy)
WHO PS ≤2;
55%
Alemtuzumab (IV 30 mg) Stage II or IV ≥18 years with CD52-positive relapsed or —
Phase II112
(n = 22) refractory MF and SS (≤5 prior systemic (32% CR)
therapy)
Median age 72 years;

Alemtuzumab (SC 10 mg maximum 86%
Subcutaneous Previously untreated (n = 3) or — Median survival
per administration) SS (n = 14)
alemtuzumab113 relapsed/refractory (n = 11) SS with high (21% CR) (35 months)
counts of circulating Sézary cells
ECOG PS 0–1;
Phase II Pembrolizumab (2 mg/kg IV, every 3 Stage IIB–IVB — 38% 65%
≥18 years with relapsed or refractory MF
(CITN-10)117 weeks) (n = 24) (1-year PFS rate)
and SS (≥1 prior systemic therapy)
CR, complete response; MF, mycosis fungoides; ORR, overall response rate; PFS, progression-free survival; PS, performance status; SS, Sézary syndrome;
MS-35

8. Vergier B, de Muret A, Beylot-Barry M, et al. Transformation of mycosis

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220. Sampogna F, Frontani M, Baliva G, et al. Quality of life and
psychological distress in patients with cutaneous lymphoma. Br J 228. Demierre MF, Taverna J. Mirtazapine and gabapentin for reducing
Dermatol 2009;160:815-822. Available at: pruritus in cutaneous T-cell lymphoma. J Am Acad Dermatol
221. Meyer N, Paul C, Misery L. Pruritus in cutaneous T-cell lymphomas:
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2010;90:12-17. Available at: chronic pruritus with the selective serotonin re-uptake inhibitors paroxetine
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https://www.ncbi.nlm.nih.gov/pubmed/16574401. topically applied opiate receptor antagonist. J Am Acad Dermatol
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223. Eschler DC, Klein PA. An evidence-based review of the efficacy of https://www.ncbi.nlm.nih.gov/pubmed/17320241.
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231. Axelrod PI, Lorber B, Vonderheid EC. Infections complicating

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Primary Cutaneous CD30+ T-Cell Lymphoproliferative increased risk of secondary lymphomas such as mycosis fungoides (MF),
Disorders PC-ALCL, systemic ALCL, or Hodgkin lymphoma.12-17 Older age, positive
Primary cutaneous CD30+ T-cell lymphoproliferative disorders (PCTLD) TCR gene rearrangement, or diagnosis of mixed-type LyP have been
represent a spectrum that includes primary cutaneous anaplastic large-cell reported as prognostic indicators of disease progression to lymphoma.13,15
lymphoma (PC-ALCL), lymphomatoid papulosis (LyP), and “borderline”
Literature Search Criteria
cases with overlapping clinical and histopathologic features.1,2 Primary
cutaneous disease, spontaneous regression, and absence of Prior to the update of this version of the “NCCN Clinical Practice
extracutaneous spread are associated with a better prognosis.3,4 Guidelines in Oncology (NCCN Guidelines®), an electronic search of the
PubMed database was performed to obtain key literature on PCTLD
PC-ALCL represents approximately 8% of all cutaneous T-cell lymphomas published since the previous Guidelines update using the following
(CTCL) and is histologically characterized by diffuse, cohesive sheets of search terms: primary cutaneous anaplastic large cell lymphoma and
large CD30-positive (in >75%) cells with anaplastic, pleomorphic, or LyP. The PubMed database was chosen as it remains the most widely
immunoblastic appearance.5 Patches and plaques may also be present, used resource for medical literature and indexes peer-reviewed biomedical
and some degree of spontaneous remittance in lesions may also be seen. literature.18
PC-ALCL typically follows an indolent course with an excellent prognosis,
although cutaneous relapses are more common.6-8 Clinical features The search results were narrowed by selecting studies in humans
typically include solitary or localized nodules or tumors (often ulcerated); published in English. The data from key PubMed articles deemed as
multifocal lesions occur in approximately 20% of cases. Extracutaneous relevant to these guidelines have been included in this version of the
disease occurs in approximately 10% of cases, usually involving regional Discussion section. Recommendations for which high-level evidence is
lymph nodes.7 The presence of multiple cutaneous lesions at presentation, lacking are based on the panel’s review of lower-level evidence and expert
extensive skin lesions on the leg, disease progression to extracutaneous opinion.
disease, early cutaneous relapse, and nodal progression are associated
Diagnosis
with poorer outcomes.9-11
As described earlier, PCTLD is a spectrum of clinical presentation
LyP is histologically heterogenous with large atypical anaplastic, including LyP (mostly papular and always regressing), PC-ALCL (mostly
immunoblastic, or Hodgkin-like cells in a marked inflammatory nodular and persistent), and also “borderline” presentations where lesions
background.2 Several histologic subtypes have been defined based on the regress but take longer or are larger and not papular as in LyP.5 Clinical
evolution of skin lesions. Clinical features include chronic, recurrent, and pathologic correlation is essential for distinguishing within the
spontaneously regressing papulonodular (grouped or generalized) skin spectrum of PCTLD as well as distinguishing PCTLD from other
lesions. LyP is not considered a malignant disorder and has an excellent cutaneous CD30+ disorders (ie, systemic ALCL, adult T-cell
prognosis with an overall survival (OS) rate of 92% at 5 and 10 leukemia/lymphoma [ATLL], peripheral T-cell lymphoma [PTCL], MF with
years.8 However, LyP has also been reported to be associated with an large cell transformation (MF-LCT) and benign disorders such as
MS-53

lymphomatoid drug reactions, arthropod bites, viral infections, and others. between MF-LCT and CD30+ PCTLD.23 MF-LCT was associated with a
MF and PCTLD can coexist in the same patient. Lymphomatoid drug strong/diffuse expression of GATA3 while the CD30+ PCTLD showed
reactions have been linked with certain drugs (eg, amlodipine, variable/moderate expression of GATA3. MUM1 expression is valuable to
carbamazepine, cefuroxime) and may be associated with CD30+ atypical distinguish between LyP and PC-ALCL, since the majority of cases of LyP
large cells in histology. Classic Hodgkin lymphoma (CHL) is less often (87%) are positive for MUM1 staining compared to only 20% of cases with
associated with MF and PCTLD than previously thought; however, PC-ALCL.24
coexpression of CD30 and CD15 in these T-cell lymphomas may lead to a
mistaken diagnosis of CHL.19 It is therefore important not to diagnose The IHC panel may include CD3, CD4, CD8, CD20, CD30, CD56, and
CD30+ T-cell lymphomas in lymph nodes as Hodgkin lymphoma. ALK. Additional markers such as CD2, CD5, CD7, CD25, TIA1, granzyme
B, perforin, TCR beta, and TCR delta, IRF4/MUM1, and EMA may be
Complete skin examination (for any sign of benign or malignant skin useful in selected circumstances. Abnormal T-cell phenotype and perforin
lesions), adequate biopsy (punch, incisional, or excisional) of suspicious expression are significantly more frequent in PC-ALCL than in transformed
skin lesions, and immunohistochemistry (IHC) of skin biopsy specimen are MF and may be useful for the differential diagnosis between PC-ALCL and
essential to confirm the diagnosis. Molecular analysis to detect clonal TCR CD30-expressing transformed MF.25
gene rearrangements, excisional or incisional biopsy of suspicious lymph
nodes, and assessment of human T-cell lymphotropic virus type 1 DUSP22-IRF4 (6p25.3) gene rearrangement has been described in
(HTLV-1) serology to identify CD30+ ATLL would be helpful in selected patients with PC-ALCL and LyP but is not associated with prognostic
circumstances. However, TCR gene rearrangement may not be significance.26-28 In a large multicenter study that investigated the clinical
demonstrated in all cases of PCTLD and TCR rearrangements can also be utility of detecting IRF4 translocations in skin biopsies of T-cell
seen in patients with non-malignant conditions. Demonstration of identical lymphoproliferative disorders, fluorescence in situ hybridization (FISH) for
clones in skin, blood, and/or lymph nodes may be helpful in selected IRF4 had a specificity and positive predictive value of 99% and 90%,
cases.20 Identification of clonal TCR gene rearrangement has no definitive respectively, for cutaneous ALCL.26 FISH to detect ALK and
established prognostic value; however, it could be helpful to determine DUSP22-IRF4 rearrangements would be useful in selected circumstances.
clinical staging or assess relapsed or residual disease. HTLV-1 status, assessed either by HTLV-1 serology or other methods,
may be useful in populations at risk to exclude the diagnosis of
PCTLD are characterized by the following immunophenotype: CD30+ CD30-positive ATLL (which is usually HTLV-1 positive).
(>75% cells), CD4+, variable loss of CD2/CD5/CD3, and CD8+ (<5%)
cytotoxic granule-associated proteins positive. ALK-positive PC-ALCL is Workup
extremely uncommon and t(2;5) translocation is typically absent in CD30+ The initial workup involves a history and complete physical examination
PCTLD.21,22 ALK positivity and differential expression of t(2;5) can help to including entire skin, palpation of peripheral lymph node regions, and liver
distinguish between CD30+ PCTLD and ALCL of nodal origin. GATA3 or spleen. Laboratory studies should include complete blood count (CBC)
expression by IHC has been proposed to be useful to differentiate with differential, a comprehensive metabolic panel, and assessment of
MS-54

lactate dehydrogenase (LDH) levels. Many skin-directed and systemic follow-up of 61 months, subsequent skin-only relapse and extracutaneous
therapies are contraindicated or are of unknown safety in pregnancy. disease were reported in 41% and 10% of patients, respectively.
Therefore, pregnancy testing is recommended for individuals of
childbearing age. A multicenter retrospective analysis of patients with PC-ALCL (n = 56)
eligible to receive RT (primary therapy or after surgical excision) reported
Biopsy of enlarged lymph nodes or extracutaneous sites is recommended a clinical complete response (cCR) rate of 95% and a local control rate of
if biopsy of skin is non-diagnostic. Fine-needle aspiration (FNA) biopsy 98% after a median follow-up of 4 years.30 Although the median RT dose
alone is not sufficient for the initial diagnosis. Excisional or incisional was 35 Gy (range, 6–45 Gy), CRs were seen with doses as low as 6 Gy
biopsy is preferred over core needle biopsy. In certain circumstances, and the achievement of cCR was independent of the RT dose, suggesting
when a lymph node is not easily accessible for excisional or incisional that lower RT dose of less than 30 Gy may be appropriate for the
biopsy, a combination of core needle biopsy and FNA biopsy in management of localized lesions. The efficacy of low-dose RT (≤20 Gy)
conjunction with appropriate ancillary techniques may be sufficient for for the treatment of solitary or localized PC-ALCL was also confirmed in
diagnosis. Bone marrow evaluation has limited value in the staging of other recent reports.31-33
patients with PC-ALCL and is not required for disease staging.29 Bone
marrow aspiration and biopsy may be considered for solitary PC-ALCL or Involved-site RT (ISRT) alone or surgical excision (with or without ISRT)
PC-ALCL without extracutaneous involvement on imaging. are recommended for patients with solitary or grouped lesions.6-8,34-37 ISRT
alone is an appropriate option in selected patients with cutaneous ALCL
Contrast-enhanced CT scan of the chest, abdomen, and pelvis or regional lymph node involvement ± primary skin lesions.
integrated whole-body PET/CT is recommended for PC-ALCL. PET scan
Systemic Therapy
may be preferred for patients with extranodal disease, which is
inadequately imaged by CT. In LyP, imaging studies and bone marrow In the ALCANZA study that included 31 patients with previously treated
evaluation are done only if there is suspicion of systemic involvement by PC-ALCL, overall response rate (ORR) lasting for 4 months or more was
an associated lymphoma. significantly higher for brentuximab vedotin compared to the physician’s
choice of treatment with methotrexate or bexarotene (75% vs. 20%), and
Primary Cutaneous ALCL the proportion of patients achieving CR was also higher with brentuximab
Radiation Therapy vedotin than with physician’s choice (31% vs. 7%).38
In a report from the Dutch Cutaneous Lymphoma Group that evaluated the
In a multicenter study that evaluated the efficacy of treatment options in
long-term outcome of patients with PCTLD (118 patients with LyP, 79
patients with multifocal lesions included in the Dutch Registry for
patients with PC-ALCL, and 11 patients with PC-ALCL with regional node
Cutaneous Lymphomas prior to the FDA approval of brentuximab vedotin
involvement), radiation therapy (RT) or surgical excision as initial therapy
(24 patients with initial presentation and 17 patients with relapsed
(given for 48% and 19% of patients, respectively) resulted in a complete
disease), RT (n = 21), systemic chemotherapy (n = 9), and low-dose
response (CR) rate of 100% in patients with PC-ALCL.7 After a median
methotrexate (n = 7) were the most common treatment options resulting
MS-55

in ORRs of 100% (100% CR), 100% (78% CR), and 57% (43% CR), data. Peginterferon alfa-2a is the only interferon available for clinical use in
respectively.39 The presence of greater than 5 skin lesions was associated the United States and it may be substituted for other interferon
with a higher risk of extracutaneous relapse (56% vs. 20% for the preparations.51-53 Observation (if asymptomatic) is appropriate for patients
presence of 2–5 skin lesions). with multifocal lesions.
In the aforementioned report from the Dutch Cutaneous Lymphoma Group Brentuximab vedotin + CHP is included as an option under other
that evaluated the long-term outcome of 219 patients with PCTLD, 9 of 11 recommended regimens for the primary treatment for patients with
patients (82%) with PC-ALCL and regional node involvement received cutaneous ALCL with regional nodes.40 Multiagent chemotherapy (CHOP
CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone)-like or CHOEP [cyclophosphamide, doxorubicin, vincristine, etoposide, and
multiagent chemotherapy as initial therapy (82%), resulting in a CR in prednisone]) with or without ISRT is included as an option for selected
eight patients (88%).7 However, five out of these eight patients patients with regional lymph node involvement.7,54
experienced skin relapses during follow-up. After a median follow-up of 58
months, disease-related 5-year survival rate was 91%. Lymphomatoid Papulosis
It is important to be reminded that LyP is not a malignant disorder but a
In November 2018, the FDA approved brentuximab vedotin in combination recurrent, benign, self-regressing lymphoid proliferation. Although
with cyclophosphamide, doxorubicin, and prednisone (CHP) for the multiagent chemotherapy often leads to reduction or clearance of lesions,
treatment of previously untreated systemic ALCL or other CD30‐positive rapid recurrence shortly after or even during treatment is a consistent
PTCL based on the results of the ECHELON‐2 trial, which showed that finding in patients with LyP.
brentuximab vedotin + CHP was superior to CHOP for patients with
CD30-positive PTCL as shown by a significant improvement in In the aforementioned report from the Dutch Cutaneous Lymphoma Group
progression-free survival (PFS) and OS.40 This trial, however, excluded that included 118 patients with LyP, topical steroids and phototherapy
patients with PC-ALCL. However, since CHOP is included as an option for were the most common skin-directed therapies used as initial treatment in
primary treatment (other recommended regimens) for cutaneous ALCL 56% and 35% of patients, respectively.7 Although CR or partial response
with regional nodes, the panel acknowledged that brentuximab vedotin + (PR) were common, none of these therapies resulted in sustained CR. In a
CHP would also be an appropriate option for these patients. retrospective multicenter study of 252 patients with LyP, topical steroids
and phototherapy were the most common first-line treatments (prescribed
Systemic therapy is indicated only for multifocal lesions (± skin-directed in 35% and 14% of the patients, respectively) resulting in a CR rate of
therapy) and for those with regional node involvement (± ISRT). 48%.55 The overall estimated median disease-free survival (DFS) was
Brentuximab vedotin is the preferred systemic treatment option based on 11 months, but the DFS was longer for patients treated with phototherapy
the results of the ALCANZA study.38 Low-dose methotrexate (50 mg (23 months; P < .03). The presence of type A LyP and the use of first-line
weekly),41,42 pralatrexate,43 systemic retinoids (bexarotene for multifocal treatment other than phototherapy were significantly associated with
lesions),44-47 and interferon (multifocal lesions)44,48-50 are included as increased risk of early cutaneous relapse.
options for other recommended regimens based on the limited available
MS-56

In a retrospective study of 45 patients with LyP and other CD30+ PCTLD, Brentuximab vedotin is included as an option for LyP that is refractory to
low-dose methotrexate (≤25 mg) resulted in satisfactory disease control in multiple primary treatment options.66,67 In a phase II study of 12 patients
87% of patients, and the median total duration of treatment was greater with refractory LyP, brentuximab vedotin resulted in an ORR of 100% and
than 39 months for all patients.56 After discontinuation, 25% of patients a CR rate of 58%.67 The median duration of response was 20 weeks.
remained free of disease relapse during the follow-up period of 24 to 227 Grade 1 or 2 peripheral neuropathy was the most common adverse event
months. Another study that evaluated the efficacy of low-dose reported in 10 patients (83%). Further studies are needed to optimize the
methotrexate in a cohort of 28 patients with LyP reported that satisfactory dosing to minimize the incidences of peripheral neuropathy.
disease control could be achieved at 7.5-mg to 10-mg weekly doses of
methotrexate.41 Regular follow-up (including complete skin examination) is essential during
observation since these patients can develop associated hematologic
Observation is preferred for patients with asymptomatic disease. Topical malignancies (particularly MF or ALCL) over time.55,68 Life-long follow-up
steroids or phototherapy are appropriate initial treatment options for limited (including thorough skin examination) is warranted for patients with LyP
lesions (in symptomatic patients) or extensive lesions.7,45,57-59 In patients (even for patients with disease responding to initial treatment) due to high
receiving phototherapy, narrowband ultraviolet B (UVB) is generally risks for second lymphoid malignancies.
preferred over psoralen plus ultraviolet A (PUVA). Systemic therapy is
indicated only for patients with extensive lesions. Methotrexate is widely
used for the treatment of LyP.41,55,56,60-65 Systemic retinoids (bexarotene)
are included as an option based on limited available data mainly from case
reports.44-47
Follow-Up and Treatment for Relapsed/Refractory Disease

Patients with a clinical benefit and/or those with disease responding to
initial treatment can be considered for maintenance or tapering of
regimens to optimize response duration. Patients with disease that does
not have adequate response to initial treatment are generally treated with
an alternative regimen recommended for initial treatment before moving
on to treatment for refractory disease. Disease relapse often responds well
to the same treatment. In patients with PC-ALCL, refractory disease to
multiple prior therapies should be managed with systemic therapy options
recommended for MF with LCT.
MS-57

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NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®)

NCCN Guidelines Version 2.2024 NCCN Guidelines Index

NCCN Guidelines Version 2.2024 NCCN Guidelines Index

NCCN Primary Cutaneous Lymphomas Panel Members

NCCN Guidelines Version 2.2024 NCCN Guidelines Index

Mycosis Fungoides/Sézary Syndrome

NCCN Guidelines Version 2.2024 NCCN Guidelines Index

NCCN Guidelines Version 2.2024 NCCN Guidelines Index

Primary Cutaneous CD30+ T-Cell Lymphoproliferative Disorders

Principles of Radiation Therapy

NCCN Guidelines Version 2.2024 NCCN Guidelines Index

NCCN Guidelines Version 2.2024 NCCN Guidelines Index

PRINCIPLES FOR PRIMARY CUTANEOUS B-CELL LYMPHOMAS (PCBCL)

Note: All recommendations are category 2A unless otherwise indicated.

NCCN Guidelines Version 2.2024 NCCN Guidelines Index

Note: All recommendations are category 2A unless otherwise indicated.

NCCN Guidelines Version 2.2024 NCCN Guidelines Index

PRIMARY CUTANEOUS MARGINAL ZONE LYMPHOMA OR FOLLICLE CENTER LYMPHOMAh

Note: All recommendations are category 2A unless otherwise indicated.

NCCN Guidelines Version 2.2024 NCCN Guidelines Index

PRIMARY CUTANEOUS MARGINAL ZONE LYMPHOMA OR FOLLICLE CENTER LYMPHOMAh

Note: All recommendations are category 2A unless otherwise indicated.

NCCN Guidelines Version 2.2024 NCCN Guidelines Index

TNM CLASSIFICATION OF CUTANEOUS LYMPHOMA OTHER THAN MF/SSa,b

Note: All recommendations are category 2A unless otherwise indicated.

NCCN Guidelines Version 2.2024 NCCN Guidelines Index

BODY REGIONS FOR THE DESIGNATION OF T (SKIN INVOLVEMENT) CATEGORYa,d,e

Note: All recommendations are category 2A unless otherwise indicated.

NCCN Guidelines Version 2.2024 NCCN Guidelines Index

Note: All recommendations are category 2A unless otherwise indicated.

NCCN Guidelines Version 2.2024 NCCN Guidelines Index

PRINCIPLES FOR MYCOSIS FUNGOIDES/SÉZARY SYNDROME (MF/SS)

General Principles on MFSS/INTRO-2

Note: All recommendations are category 2A unless otherwise indicated.

NCCN Guidelines Version 2.2024 NCCN Guidelines Index

PRINCIPLES FOR MYCOSIS FUNGOIDES/SÉZARY SYNDROME (MFSS)

Note: All recommendations are category 2A unless otherwise indicated.

NCCN Guidelines Version 2.2024 NCCN Guidelines Index

PRINCIPLES FOR MYCOSIS FUNGOIDES/SÉZARY SYNDROME (MFSS)

Note: All recommendations are category 2A unless otherwise indicated.

NCCN Guidelines Version 2.2024 NCCN Guidelines Index

Note: All recommendations are category 2A unless otherwise indicated.

NCCN Guidelines Version 2.2024 NCCN Guidelines Index

a Principles of Molecular Analysis in Primary Cutaneous Lymphomas

Note: All recommendations are category 2A unless otherwise indicated.

NCCN Guidelines Version 2.2024 NCCN Guidelines Index

T1 T1A Patch only lesions

T2 T2A Patch only

NCCN Guidelines Version 2.2024 NCCN Guidelines Index

Note: All recommendations are category 2A unless otherwise indicated.

NCCN Guidelines Version 2.2024 NCCN Guidelines Index

CLINICAL STAGING OF MF AND SSy

Clinical Stagez T (Skin) N (Node) M (Visceral) B (Blood Involvement) Guidelines Page

IIA T1–2 N1–2 M0 B0 or B1 MFSS-7

IIIB T4 N0–2 M0 B1 MFSS-10

IVA1 (Sézary syndrome) T1–4 N0–2 M0 B2 MFSS-11

IVA2 (Sézary syndrome or T1–4 N3 M0 B0 or B1 or B2 MFSS-11

IVB (Visceral disease) T1–4 N0–3 M1A or M1B B0 or B1 or B2 MFSS-11

Large-cell transformation (LCT)aa MFSS-12