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SARCOMAS (Soft Tissue and Visceral)

• Adult soft tissue and visceral sarcomas (excluding GIST) are rare tumours, with an estimated incidence averaging 4–5/100 000/year in Europe [3]. STSs include
over 80 different histological subtypes, and the most frequent, liposarcomas and leio-myo-sarcomas (LMSs), each have an incidence <1/100 000/year. .
• The majority of sarcomas arise from the soft tissue (close to 75%), with 15% gastro intestinal stromal tumours (GISTs) and 10% bone sarcomas.
• STSs are ubiquitous in their site of origin and are often managed with multimodality treatment.
• Multidisciplinary approach is, therefore, mandatory in all cases. Management should be carried out in reference centres for sarcomas and/or within reference
networks sharing multidisciplinary expertise and treating a high number of patients annually. This centralized referral should be pursued as early as at the time of
the clinical diagnosis of a suspected sarcoma. referral of allpatients with a lesion likely to be a sarcoma would be recommended. This would mean
referring all patients with an unexplained deep mass of soft tissues, or with a superficial lesion of soft tissues having a diameter of>5 cm
DIAGNOSIS
• MRI (Gold Standard)
• CT scan has a role in calcified lesions, to rule out a myositis ossificans, and in retroperitoneal tumours, where the performance is identical to MRI
• A chest spiral CT scan is mandatory for staging purposes. Regional lymph node metastases are rare, with the exception of some histologies, e.g.
epithelioid sarcoma and clear cell sarcoma, for which regional assessment through CT/MRI may be added to the usual staging procedures. Likewise, an
abdominal CT scan may be added for limb myxoid liposarcoma. The brain CT scan may be added foralveolar soft part sarcoma, clear cell sarcoma and
angiosarcoma.
• Multiple core needle biopsies after imaging (14-16 Gauge needles) or Excisional biopsy for a < 3cm superficial lesion. It should be planned in such a way that the
biopsy pathway and the scar can be safely removed by definitive surgery [except for retroperitoneal sarco-mas (RPSs)]. The biopsy entrance point can be
tattooed. Pathological diagnosis should be made according to the 2013World Health Organization (WHO) classification [4]. A pathological expert validation is
required in all cases when the original diagnosis was made outside a reference centre/network
• Grading system distinguishes three malignancy grades based on differentiation, necrosis and mitotic rate. Grading cannot be assigned after preoperative medical
treatment, by which the tumour tissue undergoes major therapy-related changes.
• Tumour site should be properly recorded. Tumour size and tumour depth (in relation to the superficial fascia) should also be recorded, since they entail a
prognostic value, along with the malignancy grade
• (UICC) stage classification system, 8th edition (Table1)stresses the importance of the malignancy grade in sarcoma
MANAGEMENT OF LOCAL/LOCOREGIONAL DISEASE
SURGERY
• Surgery is the standard treatment of all patients with an adult type, localised STS. The standard surgical
procedure is a wide excision with negative margins (no tumour at the margin, R0).
• The minimal margin on fixed tissue to be considered adequate may depend on several factors, including
histological subtype, preoperative therapies and the presence of resistant anatomical barriers, such as
muscular fasciae, periosteum and epineurium; marginal excision can be acceptable in carefully selected
cases, in particular for extra-compartmental atypical lipomatous tumours
• Reoperation in reference centres must be considered in the case of R1 resections (microscopic tumour at the
margin), if adequate margins can be achieved without major morbidity, taking into account tumour extent
and tumour biology (e.g. re-excision can be spared in extra-compartmental atypical lipomatous tumours)
• In the case of R2 surgery (macroscopic tumour at the margin), reoperation in reference centres is
mandatory, possibly following preoperative treatments if adequate margins cannot be achieved, or if surgery is
mutilating. In the latter case, the use of multimodal therapy with less radical surgery is optional and
requires shared decision making with the patient in cases of uncertainty. Plastic repairs and vascular grafting
should be used as needed, and the patient should be properly referred as necessary.
• Mutilating surgery may be of choice in some cases. Options for limb-preserving surgery can be discussed
with the patient, including ChT and/or RT [III, A], or isolated hyperthermic limb perfusion with tumour
necrosis factor alpha (TNF-a) plus melphalan [III, A], if the tumour is confined to an extremity, or
regional hyperthermia combined with ChT [I, B] [16]. These options are also proposed for non-resectable
tumours, i.e. in truly locally advanced disease.
• Regional lymph node metastases should be distinguished from soft tissue metastases involving lymph nodes.
They are rare and constitute an adverse prognostic factor in adult-type STSs. More aggressive treatment
planning is, therefore, felt to be appropriate for these patients, although there is a lack of formal evidence
toindicate that this improves clinical results. Surgery through wide excision (mutilating surgery is
exceptionally done, given the prognosis of these patients) may be coupled with adjuvant RT and adjuvant
ChT for sensitive histological types, as the standard treatment of these presentations [IV, B]. ChT may be
administered as preoperative treatment, at least in part.
MANAGEMENT OF LOCAL/LOCOREGIONAL DISEASE
RX-THERAPY
• The typical wide excision is followed by radiotherapy (RT) as the standard treatment of high-grade (G2–3), deep, >5cm lesions [II, B] [11–13]. RT is not given in the case of
a currently unusual, truly compartmental resection of a tumour entirely con-tained within the compartment. High-grade, deep,<5 cm lesions are also treated with surgery,
followed by RT. RT is added in selected cases in the case of low- or high-grade, superficial, >5 cm and low-grade, deep, <5 cm STSs [II, B]. In the case of low-grade, deep,
>5 cm STSs, RT should be discussed in a multidisciplinary fashion, consider-ing the anatomical site and the related expected sequelae versusthe pathological aggressiveness.
• Local control and survival are not influenced by the timing of RT, but early and late complications are.
• If it is anticipated that wound complications will be severe, surgery followed by adjuvant RT may be the best option. RT should then be administered with the best technique
available, to a total dose of 50 Gy in 1.8–2 Gy fractions, possibly with a boost up to 66 Gy, depending on presentation and resection margins.
• If it is anticipated that wound complications will be a manageable problem, neoadjuvant RT, possibly in combination with chemotherapy (ChT) to a total dose of 50 Gy in
1.8–2 Gy fractions, followed by surgery may be considered
• The anticipated incidence of wound complications after preoperative RT is lower than historically published incidence rates. The main advantage of preoperative RT is that,
with prolonged follow-up, late morbidity(fibrosis, bone fracture, etc.) is lower, translating into improved long-term functional outcome and quality of life
• RT will follow marginal or R1–R2 excisions, if these cannot be rescued through re-excision, tailoring the decision depending on further considerations, including impact on
future surgeries.
MANAGEMENT OF ADVANCED/METASTATIC DISEASE
• The decision making is complex, depending on diverse presentations and histologies, and should always be multidisciplinary.
• Metachronous (disease-free interval </=1 year), resectable lung metastases without extrapulmonary disease are managed with surgery as standard treatment, if
complete excision of all lesions is feasible
• When surgery of lung metastases is selected, an abdominal CT scan and a bone scan or a fluorodeoxyglucose (FDG)-PET are mandatory to confirm that lung
metastases are ‘isolated’.
• ChT may be added to surgery as an option, taking into account the prognostic factors (a short previous recurrence-free interval and a high number of lesions are
adverse factors, encouraging the addition of ChT), although there is a lack of formal evidence that this improves outcome [IV, B]. ChT is preferably given before
surgery in order to assess tumour response and thus modulate treatment
• Extrapulmonary metastatic disease is treated with ChT as the standard treatment. In highly selected cases, surgery of responding metastases may be offered
as an option following a multidisciplinary evaluation, taking into consideration their site and the natural history of the disease in the individual patient.
Surgery, ablations or RT of extrapulmonary metastases may bean option without ChT in highly selected cases (e.g. some patientswith myxoid liposarcoma,
solitary fibrous tumour).
• Histology Driven Therapy if no partial response or stability of the disease.
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SPECIAL ENTITIES-Retroperitoneal sarcomas (RPS)
• Patients with suspected RPS need to be referred to high-volume sarcoma centres
• Chest, abdomen and pelvis intravenous (i. v.) contrast-enhanced CT are standard for staging; MRI is an option, especially for pelvic tumours, to assess specific
aspects of tumour extent.
• Functional assessment of the contralateral kidney is necessary (individual renal functions as estimated by 99mTc-DTPA )
• Pre-treatment biopsy for pathological diagnosisshould be carried out, to allow tailored present and future thera-peutic decisions, unless otherwise indicated by
a sarcoma tumour. A multiple core biopsy with an adequate coaxial needle ofsufficient size (14–16 G) is the standard procedure. Risk of needle track seeding is
minimal and should not be a reason to avoid a biopsy. Nonetheless, the pathway of the biopsy should be carefully planned to minimise contamination and
complications, and should not be carried out transperitoneally. Open or laparoscopic biopsies must be avoided. Histology-specific nomograms for RPS patients are
available that can help personalise risk assessment and clinical decision making
• The standard treatment of primary lesions is surgery, to be carried out by a surgeon with specific sarcoma expertise. Surgery should be aimed at achieving a one-
specimen en bloc, macroscopically complete resection, minimising microscopically positive margins. This is best done by resecting the tumour en bloc with
adherent structures, even if not overtly infiltrated [III, A][56,57]. Preservation of specific organs (i.e. kidney, head of the pancreas and/or liver) should be
considered on an individualised basis and mandates a specific expertise in the disease to make the right decisions. Judgement must be used in deciding which
neurovascular structures to sacrifice, weighing the potential for local control against expected long-term dysfunctions.
• Surgery of local recurrences could be offered on an individualised basis, especially to patients affected by well-differentiated liposarcoma and having a long
disease-free interval between initial resection and subsequent recurrence, and possibly to patients experiencing a response to medical therapies
• Grossly incomplete resection of RPSs is of questionable benefit and potentially harmful, and can only be regarded as potentially palliative in carefully selected
patients. Grossly incomplete resection is to be avoided by imaging review, thoughtful planning and referral to appropriate centres. Postoperative/adjuvant EBRT
following complete gross resection is of limited value, and is associated with significant short-and long-term toxicities
• Although no randomised trials of neoadjuvant therapy versus resection alone for RPS have been reported to date, neoadjuvant treatment, in the form of
ChT, external beam radiotherapy (EBRT),regional hyperthermia or combinations, is safe in wellselected patients and may be considered after careful review by
a multi-disciplinary sarcoma tumour board [IV, C]. This is particularly relevantin the case of technically unresectable/borderline resectable RPS that could be
surgically converted by downsizing, and in chemosensitive histologies such as synovial sarcoma. The sensitivity of solitary fibrous tumour to RT should also be
considered. The value of adjuvant ChT is not established, though the rarity of the subtypes of RPSs forces extrapolation of data available in other settings.
• Preoperative RT in resectable tumours has been investigated in a randomised clinical trial, which has completed its accrual. In principle, preoperative treatments
are not intended to change the extent of surgery, but to improve the quality of surgical margins.
FOLLOW UP AFTER SURGERY
• The malignancy grade affects the likelihood and speed at which relapses may occur. The risk assessment, based on tumour grade, tumour size and tumour
site, there fore helps in choosing a routine follow-up policy
• High-risk patients generally relapse within 2–3 years, whereas low-risk patients may relapse later, although it is less likely. Relapses most often occur to the lungs.
Early detection of local or metastatic recurrence tothe lungs may have prognostic implications, and lung metasta-ses are asymptomatic at a stage in which they
are suitable for surgery.
• Although the use of MRI to detect local relapse and CT to scanfor lung metastases is likely to pick up recurrences earlier, it hasnot been demonstrated that this is
beneficial, or cost effective,compared with the clinical assessment of the primary site and regular chest X-rays.
GENERAL RULE:
• Surgically-treated intermediate-/high-grade patients may be followed every 3–4 months in the first 2–3 years, then twice a year up to the fifth year, and once a
year there after;
• Surgically Treated low-grade sarcoma patients may be followed for local relapse every 4–6 months, with chest X-rays or CT scan at longer intervals in the first 3–5
years, then annually.
ENDOCRINE SURGERY
Adrenal Cortex and Glucocorticoid Synthesis
• Cholesterol is the precursor of steroid hormones. Cholesterol is mainly
synthesized in the liver.
• The mineralocortico(stero)ids aldosterone, corticosterone and 11-
desoxycorticosterone are synthesized in the glomerular zone of the adrenal
cortex
• Androgens are synthesized in the reticular zone of the adrenal cortex
• Cortisol transport. Most of the plasma cortisol is bound to transcortin, or
cortisol-binding globulin (CBG), a specific transport protein with a high-affinity
binding site for cortisol. Cortisol is released in response to conformational
changes of CBG due to inflammation etc.
• CRH and ACTH regulate cortisol synthesis and secretion
Receptor proteins for glucocorticoids can be found in virtually every cell.

Glucocorticoids are vital hormones that exert numerous effects, the most
important of which are listed below:
• Carbohydrate and amino acid (AA) metabolism. cortisol has a catabolic effect
(degrades proteins) that results in the increased excretion of urea.
• Cardiovascular function: Glucocorticoids increase myocardial contractility and
vasoconstriction due to enhancement of catecholamine effects
• Anti-inflammatory and anti-allergic effects because they stabilize lymphokine
synthesis and histamine release
• Gastric function: Glucocorticoids weaken the protective mechanisms of the
gastric mucosa
Stress: Physical or mental stress increases cortisol secretion as a result of

increased CRH secretion and increased sympathetic tone. In severe physical (e.g.,
sepsis) or mental stress (e.g., depression), the cortisol plasma conc. Remains at a
very high level (up to 10 times the normal value) throughout the day.
Adrenal Incidentaloma
• An adrenal incidentaloma is, by definition, an asymptomatic adrenal mass detected on radiographic examination performed for indications other than suspected
adrenal disease. Adrenal incidentalomas comprise a variety of pathologies ranging from nonfunctioning benign tumors to hormonally active tumors and
malignant tumors. There are four main critical steps to take in the management of an adrenal incidentaloma:
• (1) assess for adrenal hormone excess,
• (2) assess risk of malignancy,
• (3) identify patients who should have an operation and what operation, and
• (4) define appropriate follow up for lesions not surgically removed.
To assess for hypercortisolism, the clinician should ask about weight gain, central obesity, easy bruising, severe hypertension, diabetes, virilization, fatigue, or
proximal muscle weakness.
To assess for a pheochromocytoma, the patient should be asked about hypertension and spell-like symptoms including the development of sudden or severe
headaches, palpitations, sweating, or anxiety attacks
For patients with hyperaldosteronism, the inquiry should also include a history of hypokalemia, fluid retention, or hypertension. It is also important to ask about a
history of cancer, weight loss, or a smoking history because an adrenal incidentaloma could represent a metastatic lesion
Clinical
• Physical examination should include assessment of the patient’s blood pressure, heart rate, and physical appearance, looking for suggestive features of hormone
excess such as anxiety, central obesity, hirsutism, dorsocervical fat pad, facial plethora, proximal muscle weakness or wasting, violaceous striae, skin thinning, or
tremor.
Diagnosis
The major goal of imaging studies is to differentiate between benign and malignant lesions
CT SCAN:
ATTENUATION:The radiographic features of an adrenal incidentaloma, in addition to its size, should be considered in determining the risk of malignancy. Most
adrenal adenomas contain a significant amount of intracellular fat and, hence, have a low attenuation on noncontrast CT scans. In contrast, nearly all malignant
lesions have low intracellular lipid content; their CT attenuation is, consequently, higher. The threshold value typically used in the diagnosis of an adrenal adenoma by
unenhanced CT imaging is 10 Hounsfield units (HU): if the lesion is less than 10 HU on noncontrast CT, it is benign, whereas if it is greater than 10 HU, it warrants
further evaluation.
CT SCAN:
WASH-OUT:Another imaging feature that can prove useful in the characterization of adrenal
nodules when contrast-enhanced CT scans are performed is a phenomenon termed contrast
washout, in which adenomas take up the intravenous contrast rapidly but also rapidly lose the
contrast medium on delayed images. Malignant lesions usually enhance rapidly but have a slower
washout of the contrast medium. Lipid-poor adenomas, which have higher HU measurements
similar to malignant lesions on unenhanced CT, show a rapid contrast washout on contrast-
enhanced CT just like the lipid-rich adenomas. Thus, contrast washout kinetics allows a distinction
to be made between lipid-poor adenomas and malignant lesions.
SIZE: It is highly unusual for a malignant lesion, if left untreated, to remain stable in size for more
than 6 months. The primary concern regarding size is the risk of adrenocortical carcinoma, which
increases in lesions larger than 4 to 5 cm in diameter. In making the decision regarding
adrenalectomy, size must be considered in conjunction with the radiographic appearance of the
lesion. For example, a 4.5-cm adrenal lesion that has imaging characteristics diagnostic of an
adenoma may be observed depending on the clinical scenario, such as in an older patient
Fine-Needle Aspiration Biopsy: Fine-needle aspiration (FNA) biopsy has a very limited role in the
diagnostic evaluation of the adrenal incidentaloma. Mazzaglia and Monchik showed in their
retrospective analysis that cytopathology from an FNA biopsy was unhelpful in distinguishing
between benign and malignant primary adrenal lesions. Other studies evaluating the role of FNA
biopsy in the adrenal incidentaloma concluded that the FNA biopsy rarely changed management
and was associated with a significant risk of complications (including hematoma, pain, error or
delay in diagnosis, and inadvertent biopsy of a pheochromocytoma with resulting severe
hypertension) and subsequent increased difficulty of adrenalectomy.
ESMO:Biopsy of adrenal tumours is usually contraindicated because of the risk of tumour spillage,
poor diagnostic power to discriminate benign from malignant adrenocortical tumours and risk of
hypertensive crises in phaeochromocytoma. However, a biopsy might be indicated in an adrenal
mass without any hormone excess in patients with a history of extra-adrenal cancers to exclude
or prove an adrenal metastasis of an extra-adrenal malignancy, and in patients in whom tumour
sequencing is desired.
Clinicians can almost always make the decision to proceed with adrenalectomy based on
clinical, biochemical, and radiologic assessment alone.
ESMO: Most ACCs show an inhomogeneous appearance in CT or MRI with irregular margins and irregular enhancement of solid components after intravenous injection of
contrasted agent. Detection of local invasion or tumour extension into the inferior vena cava, as well as lymph node or other metastases including lung and liver is mandatory
before planning any surgery. Therefore, cross-sectional imaging of the chest, abdomen and pelvis is required preoperatively.
For PPGLs, conventional radiological imaging can be important to determine the presence of metastases. How ever, neither CT nor MRI can be used to determine whether
PPGLs are benign or malignant. Malignancy can only be determined from the presence of metastatic lesions at sites where chromaffin cells are normally absent. Without
such evidence, all PPGLs should be considered potentially malignant, with risk dependent on several factors as outlined below.
• tumour size >/=5 cm;
• any extra-adrenal paraganglioma;
• known succinate dehydrogenase complex iron sulfur subunit B (SDHB) germline mutation; or
• plasma methoxytyramine more than threefold above the upper cut-offs of reference intervals.
MOLECULAR BIOLOGY AND METASTATIC RISK. At least 35% of PPGLs result from germline mutations of over 18 tumour-susceptibility genes identified to date, Risk is
particularly high, reaching 70% in patients with PPGL due to mutations in the SDHB gene.34 The vast majority of all metastatic PPGLs, including disease due to SDHB
mutations, develop from noradrenergic or dopaminergic PPGLs with poorly developed secretory pathways. Nevertheless, a small minority of about 10% of metastatic PPGLs
develop from adrenal adrenergic tumours that are characterised by production of epinephrine, as manifested by increased plasma or urinary metanephrine.
Assessment for Adrenal Hormone Excess
Several factors should be considered when performing a biochemical evaluation in a patient with an adrenal nodule, including patient age, sex, medications, and limitation of
assays or varying reference ranges of tests
• Screening for Hypercortisolism If no clinical features of hypercortisolism, an overnight 1-mg dexamethasone suppression test should be performed. Here, the patient is
instructed to take 1 mg of dexamethasone the night before ablood draw. Serum cortisol levels are checked the following morning between 8 am and 9 am. In normal
individuals, the cortisol level should suppress to less than 1.8 μg/dL. A cortisol level above 5 μg/dL after administration of dexamethasone is usually diagnostic of
hypercortisolism. Cortisol levels between 1.8 and 5 μg/dL should spur further workup for possible hypercortisolism. The patient usually undergoes confirmatory testing
with an adrenocorticotropic hormone (ACTH) level as well as a 24-hour urinary cortisol level or a midnight solitary cortisol level. An elevated urinary cortisol and a low
or suppressed ACTH level further support the diagnosis.
• Screening for Hyperaldosteronism Plasma potassium, aldosterone, and renin activity are measured and a ratio of plasma aldosterone concentration to the plasma
renin activity is calculated. A ratio of more than 20 while not taking mineralocorticoid receptor antagonists such as spironolactone should spur further confirmatory
testing with aldosterone suppression testing: either a saline infusion test or a 24-hour urinary aldosterone test while the patient maintains a high sodium diet. Patients
should be off mineralocorticoid receptor antagonists for 6 weeks before testing. Once primary hyperaldosteronism is confirmed, it is important to differentiate
idiopathic hyperaldosteronism from bilateral cortical hyperplasia. Adrenal vein sampling for aldosterone and cortisol is recommended for all patients with bilateral
adrenal nodules, a unilateral nodule less than 1 cm, normal-appearing glands, or age older than 45 years to determine if there is unilateral aldosterone hypersecretion
which would be amenable to surgical management.
Assessment for Adrenal Hormone Excess
• Screening for Pheochromocytoma The simplest screening test to rule out pheochromocytoma is measurement of plasma free metanephrines (metanephrines and
normetanephrines). False-positive results, primarily with the normetanephrine component of the assay, can occur. If either the metanephrine or normetanephrine is
elevated mildly, then further testing with 24-hour urine for catecholamines and fractionated metanephrines should be done to confirm or rule out this diagnosis.
• Screening for Sex Hormone-Secreting Tumors Screening for virilizing or feminizing tumors is only performed if suggestive clinical features or suspicion for
adrenocortical carcinoma is present. Plasma dehydroepiandrostenedione sulfate levels should be measured. Elevated levels are concerning for an adrenocortical
carcinoma. 17-Estradiol can also be checked if clinical features of feminization are noted in men and postmenopausal women only.
STAGING AND RISK ASSESSMENT
ACC
• In the assessment of disease stage, the authors recommend the tumour, node, metastasis (TNM) classification proposed by the European Network for the Study of
Adrenal Tumours (ENSAT). As indicated above for correct staging, at least a CT of the chest, abdomen and pelvis (or FDG-PET/ CT including full-dose CT) is required.
Recent data suggest that lymph node involvement correlates with stage IV rather than stage III behaviour .
• ACC PROGNOSIS: Overall, the prognosis of ACC is limited. However, prospective data suggest that in patients with complete resection of a localised stage II tumour 5-
year overall survival (OS) can be as high as 90%.38 In metastatic ACC, median survival is about 15 months. However, even in this group, there is a subgroup of patients
with long-term survival. It is well established that disease stage and margin-free resection are currently the most important prognostic factors in ACC. (ESE)eENSAT
guidelines, a comprehensive literature search for prognostic factors has been carried out and only the proliferation marker Ki-67 and glucocorticoid excess showed a
robust association with prognosis [IV, A]
PPGL
• Phaeochromocytomas are catecholamine-producing neuroendocrine tumours arising from chromaffin cells of the adrenal medulla or extra-adrenal paraganglia. The
latter are usually called paraganglioma, leading to the combined term phaeochromocytomas and paragangliomas (PPGLs). For first-time patients without any history
of disease or known mutation, size and location of the primary tumour, and when available, any elevations of plasma methoxytyramine during biochemical testing
seem important to consider when evaluating risk for malignancy. ‘high risk of metastases’ when any patient presents with one or more of the following criteria:
• (i) adrenal phaeochromocytoma >/=5 cm;
• (ii) an extra-adrenal paraganglioma;
• (iii) a known SDHB germline mutation; or
• (iv) plasma methoxytyramine more than threefold above the upper limit of reference intervals.
Genetic counselling should be offered to all patients with PPGL.

MANAGEMENT
• Surgery is essential for treatment of both ACC and phaeochromocytoma. Adrenal surgery should be carried out only by surgeons with appropriate expertise and
experience. The recent ESEeENSAT guidelines on ACC suggest a minimal annual workload of six adrenalectomies per year, but with a preference for >20 surgeries
per year. For best clinical outcome, the entire operative team (including anaesthesiologists) should be well-trained in adrenal surgery.
ACC-MANAGEMENT OF LOCOREGIONAL DISEASE

• SURGERY: Open surgery with transperitoneal access is the standard treatment for all patients with localised (stage I-II) and locally advanced (stage III) ACC when
complete resection can be achieved. Resection status (R0, R1, R2) is a major predictor of prognosis for ACC. Therefore, a margin-free complete resection (R0
resection) is key to achieving long-term survival [V, A]. In order to obtain an R0 resection of a locally advanced ACC, it may be necessary to resect (parts of)
adjacent organs such as the wall of the vena cava, liver, spleen, colon, pancreas and/or stomach. Complete en bloc resection of the tumoural mass, including
periadrenal fat and adjacent organs if necessary, is mandatory to avoid tumour rupture or spillage that portends an adverse outcome. Locoregional
lymphadenectomy improves tumour staging and seems to lead to a favourable oncological outcome. Routine lymphadenectomy should include at least the
periadrenal and hilar nodes [IV, A], although the best extent of lymphadenectomy is still unknown. For ACC tumours not invading the kidney, concomitant
nephrectomy does not seem to improve disease-free survival and OS and can be avoided. In experienced hands, laparoscopic adrenalectomy seems to be a safe
and effective procedure in a selected group of patients with small ACC without evidence for local invasiveness, There is no evidence for the superiority of the
transperitoneal over the retroperitoneal approach in the literature. If during laparoscopic surgery, an involvement of the surrounding tissues is discovered, or there
is a risk of spillage, capsule injury or incomplete resection, immediate conversion to an open approach is required.
• As hormonal hypersecretion can increase the risk of perioperative complications, it is important to adopt measures to prevent postoperative adrenal crisis or
insufficiency. In all patients with glucocorticoid excess, either overt or ‘subclinical’, hydrocortisone must be administered during surgery (e.g. 150 mg/day) and
postoperatively [V, A].4 Hormone hypersecretion, in particular cortisol excess, may portend an increased risk of recurrence after complete tumour removal.
• Adjuvant treatment: More than half of the ACC patients who have undergone complete removal of the tumour have a relapse risk, often with metastases. This
aggressive behaviour provides the rationale for the use of adjuvant therapy. Mitotane has been the reference drug for the management of ACC for decades and is
increasingly used also in adjuvant settings following surgical removal of ACC. Two recent meta-analyses have reported that adjuvant mitotane treatment reduces
the risk of recurrence and death. On these bases, the recent ESEeENSAT guidelines on the management of ACC suggest that patients at high risk of recurrence
(stage III, or R1-RX resection, and/or Ki-67 index >10%) should be offered adjuvant mitotane [IV, B]. By contrast, adjuvant therapy has to be discussed on an
individual basis in patients fulfilling all the following criteria: stage I or II disease, histologicallyproven R0 resection and Ki-67expressed in </=10% of neoplastic
cells, which define the category of low risk of recurrence [V, B] There are no data regarding the optimal duration of adjuvant mitotane; however, the authors
recommend that adjuvant mitotane should be administered for at least 2 years [V, B], because the greatest frequency of disease recurrence is expected within
this time frame.
• Adjuvant radiotherapy (RT) is able to reduce the risk of local recurrence but does not prevent distant recurrences and, as a consequence, does not impact OS.4
Therefore, it is reasonable to associate mitotane with RT in selected patients with stage III ACC and/or R1 or RX resection, although the combination carries
increased toxicity [IV, B]
• Special considerations on mitotane. Mitotane is a difficult drug to manage, with a long half-life, dose-limiting toxicity and a narrow therapeutic window.
ACC-MANAGEMENT OF ADVANCED/METASTATIC DISEASE
• Prognosis of advanced ACC patients is limited, the 5-year OS being <15%. However, prolonged survival has been reported especially in patients with resectable
oligometastatic disease, with long intervals between recurrences.
• In general, first-line therapy in patients with advanced/metastatic disease is mitotane alone or mitotane plus chemotherapy (ChT). Surgery and locoregional
therapies should be adopted in addition to systemic therapy in selected patient populations (Figure 3). The goal of the therapy is to control tumour growth,
hypersecretion-related symptoms and prolong survival.
• Mitotane monotherapy. Mitotane is the only drug approved by the European Medicines Agency (EMA) in locally advanced inoperable and metastatic patients.
Response rates in metastatic ACC vary between 13% and 35% but much of these data are derived from retrospective series, including studies in 1960s with overall
variability in response criteria.
• Mitotane mono therapy is indicated in the management of patients with a low tumour burden and/or more indolent disease (i.e. patients with favourable
prognostic parameters). At disease progression, ChT with etoposide, doxorubicin and cisplatin (EDP) should be added to mitotane monotherapy [I, A].
• Cytotoxic ChT. The combination of EDP and mitotane (EDP-M) is recommended in first-line settings based on the FIRM-ACT trial results [I, A]
• In second-line settings, after failure of EDP-M, the treatment options are limited and enrolment of patients into clinical trials should be considered first. Most
patients with advanced ACC remain in good clinical condition but urgently seek therapy. In the absence of trials, possible options are the association of gemcitabine
plus capecitabine
• Surgery and local therapies. Surgery, including surgery of the primary tumour, may be recommended in all patients with oligometastatic ACC if a complete
resection of all tumoural lesions is feasible [V, B]. A cytoreductive resection may also be indicated in rare cases of severe symptomatic hormone excess, after
attempts to control the symptoms with a combination of fast-acting anti-secretory agents (i.e. metyrapone) and mitotane
• In case of a recurrence following ACC surgery, two critical questions must be addressed: (i) What is the time interval since the resection? and (ii) Did recurrence
occur during ongoing mitotane therapy (with effective blood levels)?
• If the disease-free interval is at least 12 months and another complete R0 resection/ablation seems feasible, then surgery or, alternatively, other local therapies
are clearly recommended [IV, A]. However, if this time interval is <6 months or if complete resection/ablation is not feasible, then, the EDP-M provides the
treatment of choice, especially if the recurrence occurred during ongoing mitotane treatment at therapeutic levels [IV, A].
• Management of hormone excess. In addition to sequelae of the malignant disease, patients with overt hypercortisolism suffer from immunosuppression, diabetes
and muscle weakness, which can significantly impact QoL. Similarly, severe androgen excess may dramatically impair well-being in women. Therefore, medical
therapy to control hormonal excess is recommended [V, A]. Mitotane is frequently able to diminish steroid excess, but its efficacy is often delayed by several weeks.
In these circumstances, steroidogenic enzyme inhibitors, such as metyrapone or ketoconazole, can be useful [V, B].
• Metyrapone is a well tolerated drug and its metabolism and elimination are not altered by concomitant mitotane. Therefore, it can be safely administered in
association with mitotane and cytotoxic ChT. Local therapies including liver embolisation may also be discussed. All patients with clinically overt hormone excess
should be managed by physicians experienced with these endocrine problems.
ESMO Recommendations ACC
LOCOREGIONAL
• Complete en bloc resection of all adrenal tumours suspected to be ACC by a
surgeon experienced in adrenal and oncological surgery is the mainstay of a
potentially curative approach. Open surgery is the standard treatment but in
tumours <6 cm without evidence of local invasion, laparoscopic adrenalectomy
is reasonable, if the surgeon has sufficient experience.
• Additionally,a locoregionallymphadenectomyissuggested.
• Perioperative hydrocortisone replacement is required in all patients with
autonomous cortisol secretion [V, A].
• Adjuvant mitotane is recommended in patients at high risk of recurrence (stage
III, or R1-RX resection, and/or Ki-67 index >10%) [IV, B].
• Adjuvant therapy has to be discussed on an individual basis in patients with
low risk of recurrence (stage I/II, R0 resection and Ki-67 index 10%) [V, B].
• Adjuvant RT is only suggested on an individualised basis (in addition to
mitotane) in patients with R1 or RX resection or in stage III [IV, B].
• After complete resection, radiological imaging every 3 months for 2 years, then
every 3-6 months for at least another 3 years is recommended [V, B].
-------------------------------------------------------------------------------------------------------------
ADVANCED
• In most patients with metastatic ACC, first-line therapy with mitotane alone or
mitotane plus ChT is recommended; EDP-M is the first-line treatment of choice
[I, A].
• In selected patients (e.g. low tumour burden and/or more indolent disease),
mitotane monotherapy is reasonable.
• Surgery and locoregional therapies should be adopted in addition to systemic
therapy in selected patient populations.
• Surgery is the treatment of choice only if all tumoural lesions can be removed
[V, B].
• Local therapies (e.g. RT, RFA, cryoablation, microwave ablation,
chemoembolisation) are of value for therapy in advanced ACC, and an
individualised treatment approach is required
PPGL-MANAGEMENT OF LOCOREGIONAL DISEASE
• As in ACC, the surgical excision of the tumour is the first line treatment of PPGLs. However, laparoscopic/ minimal invasive surgery is commonly the technique of first choice
for resection adrenal and extra-adrenal PPGLs [V, A], because local invasion is rare and the likelihood of rupture of the capsule seems less common than in ACC. It is obvious,
however, that the resection should be complete and if there is any risk that this cannot be achieved by laparoscopic surgery, an open approach should be carried out.
• In patients with PPGL, exposure to high levels of circulating catecholamines during surgery could cause hypertensive crises and arrhythmias. Therefore, all patients with
PPGL should receive preoperative preparation at least 10-14 days before surgery [V, A].5 Blood pressure targets for the treatment are <130/80 mmHg in the supine
position, and a systolic blood pressure preferably >90 mmHg in the upright position.
• The noncompetitive a-adrenoreceptor antagonist, phenoxybenzamine, is traditionally the most frequently used adrenergic blocking agent. A standard starting dose is 10 mg
twice daily with adjustments over the following days. Alternatively, doxazosin, a competitive and selective a1-adrenoreceptor antagonist, can be similarly effective. If the
target blood pressure is not reached, calcium antagonists (slow-release nifedipine) or metyrosine may be used. Blockade of b-adrenergic receptors is indicated in patients
developing tachyarrhythmias but should never be started before blockade of a-receptors. Beta blockers are not administered until adequate alpha blockade has been
established, because unopposed alpha-adrenergic receptor stimulation can precipitate a hypertensive crisis.
• Hypertensive crisis during surgery: such crises can be induced by other manipulations during surgical procedure (e.g. intubation, insufflation of peritoneum, direct
palpation of the PPGL) or administration of certain drugs (e.g. opioids, benzodiazepines). Therefore, it is strongly recommended that anaesthesia is supervised by an
experienced anaesthesiologist alert to the diagnosis of a catecholamine-producing tumour.
• Post-operative care should also focus on glucose levels because hypoglycaemia may occur after reduction of catecholamine levels.
• Cytoreductive debulking surgery (R2) in malignant phaeochromocytoma may improve QoL and survival by reducing tumour burden and controlling hormonal
hypersecretion [V, B]
• Despite a recurrence risk, there is no established indication of adjuvant treatment in PPGLs
PPGL-MANAGEMENT OF ADVANCED DISEASE

• The therapeutic strategy for metastatic PPGL primarily aims to control excessive catecholamine secretion and tumour burden, as there are no curative treatment options.
• Choices for treatment include a watch-and-wait policy (including alpha blocker to control hypertension), locoregional therapies, radiopharmaceutical agents, systemic
ChT and molecular-targeted therapies
• Surgery. Although there is little possibility of a cure for metastatic PPGLs, surgical resection of the primary tumour or metastatic lesions should be considered on a case-by-
case basis. Debulking surgery can improve symptoms and potentially prognosis by reducing secretion of catecholamines. Other local therapies are available for patients with
metastases, such as RT, RFA or chemoembolisation. Local measures are also important to prevent bone-related events.
• Radionuclide therapy. Radionuclide therapy is an effective treatment nd [131I]MIBG is one of the most frequent approaches. Approximately 50% of patients are eligible for
[131I]MIBG therapy based on uptake from diagnostic scans. Long-term survival of responders of over 6 years has been reported. [131I]MIBG therapy could be considered
as first-line approach in patients displaying avid uptake of [123I]MIBG in all tumoural lesions who have unresectable, progressive PPGL or high tumour burden [III, A]
• An alternative approach is a peptide receptor radioligand therapy using somatostatin analogues labelled with isotopes delivering a cytotoxic radionuclide. More than
80% of PPGLs are detectable by somatostatin-based imaging. In patients with high uptake of PET tracers, such as gallium-68 (68Ga)-labelled somatostatin analogues (e.g.
[68Ga]DOTATATE or DOTATOC or DOTANOC), treatment with yttrium- 90-labelled [90Y]DOTATOC or lutetium-177-labelled [177Lu] DOTATATE could be similarly effective as
MIBG-based therapy, although the number of published studies/case series is limited. Both radionuclide approaches can be applied repeatedly (with a minimum time
interval of 3-4 months). However, toxicity frequently becomes a limiting factor over time and benefit should be re-evaluated after every second therapy.
ESMO Recommendations PPGL
• Systemic ChT. Systemic ChT might be considered as a first-line treatment
in patients with PPGL who have no significant uptake of radiotracers or
that are also rapidly progressing and associated with high tumour burden
or are highly symptomatic [IV, B]
• ChT with cyclophosphamide- and dacarbazine-based regimens combined
with vincristine (CVD) and/or doxorubicin (CVDD or CDD) are the most
studied regimens
• Temozolomide, an oral alternative to dacarbazine, seems to be as
effective as the previous polyChT regimens.
• Targeted therapies. There is a rationale and some evidence on the

potential efficacy of antiangiogenic drugs in malignant
phaeochromocytomas, especially those bearing SDHB gene mutations.
There are currently several ongoing trials on sunitinib including a
randomised, placebo-controlled trial testing sunitinib in patients with
malignant PPGL, now closed for recruitment (FIRST-MAPPP trial,
NCT01371201).
Other Considerations
• Pheochromocytoma is associated with MEN 2A, MEN 2B,
neurofibromatosis,
• As with other diagnoses necessitating surgery during pregnancy, it is best
if adrenalectomy is delayed until after delivery. Should surgery be
required, it is best performed during the second trimester. Most
commonly, adrenal disorders encountered during pregnancy include
pheochromocytoma, Cushing’s syndrome, and adrenal cortical
carcinoma, all of which are extremely rare. For those with Cushing’s
syndrome, the scant amount of literature available suggests
adrenalectomy during the second trimester. For those with
pheochromocytoma, α-and β-blockade can be pursued and
adrenalectomy performed after delivery or at the time of delivery
ESMO Recommendations PPGL
LOCOREGIONAL
• Most PPGLs can be safely removed laparoscopically by an experienced
surgeon [V, A].
• Preoperatively, patients should be treated for 10-14 days with an alpha
blocker (e.g. phenoxybenzamine) [V, A].
• Meticulous perioperative management of hormonal, glucose,
electrolytes, cardiac and fluid/blood pressure abnormalities is a critical
component of patient care.
• Patients with resected PPGL should be followed at regular intervals for at
least 10 years (lifelong for patients with a germline mutation). Most
authors recommend only annual measurement of metanephrines in most
patients, but some authors carry out additionally regular imaging.
-------------------------------------------------------------------------------------------------------
------
ADVANCED
• Although there are no curative treatment options, treatment choices
include watch-and-wait, locoregional therapies, radiopharmaceutical
agents, systemic ChT and molecular-targeted therapies.
• In selected patients (e.g. with low tumour burden without relevant
symptoms), a watch-and-wait policy (including alpha blocker to control
hypertension) is preferred.
• In all patients with metastatic PPGL (debulking) surgery should be
considered.
• In patients with relevant symptoms, high tumour burden or progressive
disease, locoregional therapies, radiopharmaceutical agents (e.g.
[123I]MIBG [III, A] or radiolabelled somatostatin analogues [V, B]) or
systemic ChT [IV, B] should be applied in a case-by-case manner. The
follow-up of patients with inoperable disease should be carried out every
3-6 months during the first year (imaging plus metanephrines) and then
adjusted afterward.
Adrenal Incidentaloma- POSTOPERATIVE CONSIDERATIONS
• For those with evidence of hormone excess, most patients will need monitoring in the hospital for 24 to 48 hours to
assess electrolytes, volume status, and blood pressure.
• For those with primary aldosteronism, all antihypertensive medications and home potassium supplementation
regimens should be discontinued after surgery to allow for determination of cure and to assess the need for
reinstitution of any of these medications. It can take weeks to months for the body to reestablish a new baseline
blood pressure, and patients are encouraged to continue monitoring blood pressure after surgery for optimal titration
of medications.
• For those patients with overt signs of hypercortisolism, postoperative steroid supplementation will almost always be
required. A normal daily total dose of hydrocortisone is 15 to 30 mg, depending on the patient. The total dose is
divided two to three times daily, giving a larger dose in the morning and smaller dose in the mid-or late afternoon to
replicate the normal diurnal rhythm.
• Any patient undergoing adrenalectomy, whether unilateral or bilateral, should be warned about the possibility of
developing Addisonian crisis and the need for steroid supplementation to prevent or treat this life-threatening
situation
• Primary hyperaldosteronism is due to a problem of the adrenal glands themselves, which causes them to release too
much aldosterone. In contrast, with secondary hyperaldosteronism, a problem elsewhere in the body causes the
adrenal glands to release too much aldosterone. Tertiary aldosteronism as a separate entity remains controversial.
The entity is presumed to result from chronic elevations in plasma renin levels and secondary aldosteronism, which
eventually establishes a state of autonomous, unregulated aldosteronism with a histologic picture of mixed
hyperplasia and adenomas in the affected adrenocortical tissue. This clinicopathologic picture is considered to be the
irreversible end-result of prolonged neurohumoral effects on vascular resistance and “terminal” hypertrophy of the
aldosterone-producing adrenocortical tissue.
THYROID CANCER Thyroid Hormone Physiology
• The thyroid gland contains spherical follicles(50–500 μmin diameter). Follicle cells synthesize the two
iodine-containing thyroid hormones thyroxine (T4, tetraiodothyronine) and triiodothyronine (T3). T3
and T4 are bound to the glycoprotein thyroglobulin (!B2) and stored in the colloid of the follicles
• Thyroglobulin, a dimeric glycoprotein (660 kDa) is synthesized in the thyroid cells. TSH stimulates the
transcription of the thyroglobulin gene. Thyroglobulin is stored in vesicles and released into the colloid
by exocytosis
• Iodine uptake. The iodine needed for hormone synthesis is taken up from the bloodstream as iodide
(I–). TSH increases the transport capacity of basolateral Iodine uptake up to 250 times
• TSH also stimulates hormone synthesis of T3 and T4. TSH secretion by the anterior pituitary is
stimulated by TRH, a hypothalamic tripeptide (!p. 280) and inhibited by somatostatin (SIH). T3
reduces the density of TRH receptors in the pituitary gland and inhibits TRH secretion by the
hypothalamus. The secretion of TSH and consequently of T3 and T4 therefore decreases (negative
feedback circuit).
• Goiter (struma) is characterized by diffuse or nodular enlargement of the thyroid gland. Diffuse
goiter can occur due to an iodine deficiency, resulting in T3/T4 deficits that ultimately lead to
increased secretion of TSH. Chronic elevation of TSH leads to the proliferation of follicle cells, resulting
in goiter development (hyperplastic goiter). This prompts an increase in T3/T4 synthesis, which
sometimes normalizes the plasma concentrations of T3/T4 (euthyroid goiter). This type of goiter often
persists even after the iodide deficiency is rectified.
• Hypothyroidism occurs when TSH-driven thyroid enlargement is no longer able to compensate for the
T3/T4 deficiency (hypothyroid goiter).
• Hyperthyroidism occurs when a thyroid tumor (hot node) or diffuse struma (e.g., in Grave’s disease)
results in the overproduction of T3/T4, independent of TSH. In the latter case, an autoantibody against
the TSH receptor binds to the TSH receptor. Its effects mimic those of TSH, i.e., it stimulates T3/T4
synthesis and secretion.
• T3/T4 transport. T3 and T4 occur at a ratio of 1 : 40 in the plasma, where >99% of them (mainly T4)
are bound to plasma proteins: thyroxine-binding globulin (TBG), thyroxine-binding prealbumin (TBPA),
and serum albumin. TBG transports two-thirds of the T4 in the blood, while TBPA and serum albumin
transport the rest. Less than 0.3% of the total T3/T4 in blood occurs in an unbound (free) form,
although only the unbound molecules have an effect on the target cells. Certain drugs split T3 and T4
from protein bonds, resulting in increased plasma concentrations of the free hormones.
Management of Thyroid Nodules
Thyroid nodules are highly prevalent in the United States and are found in more than 50% of adults in some
studies. Whereas a majority are benign, 5% to 15% may be malignant. Because a majority of thyroid nodules will be
benign and a majority of malignant tumors will demonstrate indolent behavior, surgeons and clinicians must have a
thorough understanding of the most appropriate diagnostic and treatment techniques. The initial evaluation in all
patients with a thyroid nodule (discovered either by palpation or incidentally noted on a radiologic procedure)
includes:
• History and physical examination
• Measurement of serum thyroid-stimulating hormone (TSH)
TSH low — If the serum TSH concentration is subnormal, indicating overt or subclinical hyperthyroidism, the
possibility that the nodule is hyperfunctioning is increased and thyroid scintigraphy should be performed next.
Thyroid hormone production from some autonomous nodules (especially smaller nodules) may suppress TSH only
within the lower portion of the normal range (eg, <1 mU/L). Scintigraphy may be informative in such patients,
especially if prior TSH levels were subnormal, or when the results of an FNA suggest a follicular neoplasm.
TSH normal or high — If the serum TSH concentration is normal or elevated and the nodule meets sonographic
criteria for sampling (table 3 and table 4), the next step in the evaluation of a thyroid nodule is a palpation or
ultrasound-guided FNA biopsy (algorithm 1). FNA biopsy is the most accurate method for evaluating thyroid
nodules and identifying patients who require surgical resection [7,32]. FNA biopsy has resulted in improved
diagnostic accuracy, a higher malignancy yield at the time of surgery, and significant cost reductions
• Ultrasound to confirm the presence of nodularity, assess sonographic features, and assess for the presence of
additional nodules and lymphadenopathy.
Thyroid ultrasonography is used to answer questions about the size and anatomy of the thyroid gland and adjacent
structures in the neck. It provides considerably more anatomic detail than thyroid scintigraphy.
FNA should be performed in any nodule (regardless of size) with the following suspicious sonographic features: :
• Subcapsular locations adjacent to the recurrent laryngeal nerve or trachea
• Extrathyroidal extension
• Extrusion through rim calcifications
• Associated with sonographically abnormal cervical lymph nodes
FNA should be performed in nodules ≥1 cm (as determined by largest dimension) if they are solid and
hypoechoic with one or more of these suspicious sonographic features:
• Irregular margins
• Microcalcifications
• Taller than wide shape
• Rim calcifications with extrusion of soft tissue
• FNA can be considered in selected patients with nodules <1 cm if there is a strong family history of thyroid
cancer, known syndromes associated with thyroid cancer, young age, a history of therapeutic childhood head
and neck or whole body radiation, or preference for FNA over observation. However, most patients with
suspicious subcentimeter nodules can be observed
FNA technique — Tissue for histologic or cytologic examination may be obtained from the thyroid by several
different techniques, including cutting needle biopsy, large- or fine-needle aspiration, or fine-needle capillary
sampling. FNA biopsy is the most commonly used approach. A complete discussion of the techniques, their value
and limitations, and potential complications can be found elsewhere FNA is a simple and safe office procedure in
which tissue samples are obtained for cytologic examination using 23- to 27- gauge (commonly 25-gauge) needles
with or without local anesthesia. With experience, adequate samples can be obtained in 90 to 97 percent of
aspirations of solid nodules. Ultrasound-guided FNA biopsy can be performed for nonpalpable nodules and for
nodules that are technically difficult to aspirate using palpation methods alone, such as predominantly cystic or
posteriorly located nodules. In patients with large nodules (>4 cm), ultrasound-guided FNA directed at several
areas within the nodule may reduce the risk of a false-negative biopsy.
• Multiple nodules — Patients with multiple nodules have the same risk of malignancy as those with a single
nodule, although the risk of cancer in each individual nodule in a patient with multiple nodules is lower than the
risk of cancer in a nodule in a patient with only one nodule [19,35]. Thus, the sonographic features of each
nodule should be assessed independently to determine the need for FNA biopsy. If there are multiple coalescent
nodules and none have suspicious sonographic features, FNA biopsy of the largest nodule is reasonable [7]. The
nodules that are not biopsied should be monitored with periodic ultrasonography
• Thyroid scintigraphy — Thyroid scintigraphy is used to determine the functional status of a nodule. A subnormal serum TSH, indicating overt or subclinical hyperthyroidism,
increases the possibility that a thyroid nodule is hyperfunctioning. Since hyperfunctioning nodules rarely are cancer, a nodule that is hyperfunctioning on radioiodine imaging
does not require FNA. Radionuclide scanning is contraindicated during pregnancy. If a women is breastfeeding, breastfeeding should be held if a radionuclide scan is obtained.
The amount of time will depend on which isotope is used. Scintigraphy utilizes one of the radioisotopes of iodine (usually 123-I) or technetium-99m pertechnetate. Most
benign and virtually all malignant thyroid nodules concentrate both radioisotopes less avidly than adjacent normal thyroid tissue
• Nonfunctioning – Nonfunctioning nodules appear cold (uptake less than surrounding thyroid tissue) (image 1), and they may require further evaluation by FNA
• Autonomous – Autonomous nodules may appear hot (uptake is greater than surrounding thyroid tissue) (image 2) if they are hyperfunctioning. Autonomous nodules that do
not make sufficient thyroid hormone to suppress serum TSH concentrations will appear indeterminate on thyroid scintigraphy. Autonomous nodules account for only 5 to 10
percent of palpable nodules. Only a few patients with autonomous nodules have been found to have thyroid cancer [27-29], and only a few of these cancers were aggressive
[30]. Furthermore, in some of these patients, the cancer was adjacent to the autonomous nodule rather than within it. Since hyperfunctioning nodules rarely are cancer, a
nodule that is hyperfunctioning on radioiodine imaging does not require FNA.
• Indeterminate – Because scintigraphy is two dimensional, its limitations result from the superimposition of abnormal nodular tissue and normally functioning thyroid tissue.
Thus, while over 80 percent of nonautonomous nodules greater than 2 cm appear cold, smaller nodules present as a filling defect in less than one-third of cases [27]. The
remaining majority of smaller nodules are indeterminate on thyroid scintigraphy [31]. They could represent either small, nonfunctioning nodules anterior or posterior to
normally functioning thyroid tissue, or autonomous nodules that do not produce sufficient thyroid hormone to suppress TSH
• These indeterminate nodules should not be referred to as warm or functioning, since the majority are, in fact, nonfunctioning nodules. Indeterminate nodules on scintigraphy
should be evaluated by FNA if they meet sonographic criteria for sampling
FNA cytology — There are six major categories of results that are obtained from fine-needle aspiration (FNA), each
of which indicates different subsequent management.
Nondiagnostic (Bethesda I) — A nondiagnostic biopsy is cytologically inadequate. It is critical that the absence of
malignant cells not be interpreted as a negative biopsy if no or scant follicular tissue is obtained. For patients with
nondiagnostic FNA biopsies, we repeat the FNA in approximately four to six weeks, using ultrasound guidance if not
used for the first FNA. In a study of patients with a nondiagnostic cytology specimen after a palpation FNA, repeating
the FNA under ultrasound guidance significantly improved the diagnostic yield for both solid and cystic nodules
Benign nodules (Bethesda II) — Patients with benign nodules (macrofollicular or adenomatoid/hyperplastic nodules,
colloid adenomas, nodular goiter, and Hashimoto's thyroiditis) are usually followed without surgery. There is still
controversy concerning the efficacy of T4 (levothyroxine) therapy for these patients. In the absence of a history of
childhood neck irradiation, patients with benign nodules should not be treated with T4. We perform periodic
ultrasound monitoring of benign thyroid nodules, initially at 12 to 24 months, then at increasing intervals over time
(eg, two to five years), with the shorter intervals for large nodules or nodules with worrisome ultrasound features
and the longer interval for smaller nodules with classic benign ultrasonographic features. We repeat the FNA within
12 months if the nodule has highly suspicious ultrasound features despite a benign biopsy. reassessment is
warranted when there is any of the following [7,46]:Substantial growth (more than a 50 percent change in volume
or 20 percent increase in nodule diameter with a minimum increase in two or more dimensions of at least 2
mm)Appearance of suspicious ultrasound features New symptoms are attributed to a nodule
Indeterminate nodules (Bethesda III) The risk of malignancy with these cytologic classifications ranges from 10 to 40 percent. Unless a sample for molecular testing was
saved at the time of the initial biopsy, a repeat FNA with a sample for molecular testing (if available) after a 6- to 12-week interval (or earlier) is indicated in most
patients with indeterminate cytology. If the TSH is subnormal (indicating overt or subclinical hyperthyroidism) and the nodule shows architectural atypia (FLUS or
follicular neoplasm), the possibility that the nodule is hyperfunctioning is increased, and thyroid scintigraphy should be obtained (if not previously performed) prior
to repeating the FNA. Since hyperfunctioning nodules rarely are cancer, a nodule that is hyperfunctioning on radioiodine imaging does not require repeat (or even
initial) FNA. Repeat FNA should be performed in patients with nonfunctioning nodules. If molecular testing is available (either at initial or subsequent FNA), further
management then depends on the results of molecular testing.
For patients with indeterminate FNA cytology who have a benign molecular pattern on molecular testing, we suggest observation
For patients with a suspicious molecular pattern using these techniques, diagnostic lobectomy or total thyroidectomy is indicated in most patients.
Bethesda IV and V ---> Surgery

Thyroid Cancer (ESMO)
• Randomised clinical trial (RCT) data on the management of thyroid cancer (TC) are relatively scarce, and the quality of available evidence is suboptimal. The main
goals of any cancer treatment are to improve overall survival (OS) and quality of life (QoL).
• The last three decades have witnessed steady, worldwide increases in the incidence of TC [1, 2]. Figures from the European Network of Cancer Registries show
estimated incidence rates among females in 2012 that were approximately threefold higher than those for males (9.3 and 3.1 cases per 100 000 person-years,
respectively). Estimated TC-related mortality rates, by contrast, are low (0.7 and 0.5 cases per 100 000 person-years for women and men, respectively)
DTC and poorly differentiated TC

• Preoperative FNA for cytology is not required for nodules measuring </=1 cm. Decisions to aspirate larger nodules should be guided by lesion size and sonographic
appearance [8]. Cytology findings are classified into diagnostic categories associated with different risks of malignancy. FNA-based diagnosis of poorly differentiated
carcinoma is also challenging unless there is obviously increased mitotic activity and/or necrosis. FNA diagnosis can be facilitated by assessment of malignancy
markers (including proteins commonly overexpressed in tumours, e.g. HBME1 or galectin-3) and molecular alterations specifically associated with malignancy (e.g.
BRAF mutations, RET fusions, other novel gene alterations)
• (Excellent Prognosis)The newly defined ‘non-invasive follicular thyroid neoplasm with papillary-like nuclear features’ (NIFTP), which are usually classified as
indeterminate in the various thyroid cytology reporting schemes. NIFTP is associated with no reports of cancerrelated deaths and an estimated risk of recurrence of
<1%. This new entity shows partial overlap with the group of tumours defined in Europe as ‘well-differentiated tumours of uncertain malignant potential. They
account for up to 20% of cases in Europe. Correct identification of NIFTPs should reduce the unnecessary use of radical surgical procedures and the needless
administration of radioactive iodine (RAI) after a completion thyroidectomy.
• The diagnostic criteria for poorly differentiated carcinomas remain
controversial. They are invasive tumours with a
solid/trabecular/insular growth pattern plus at least one of the
following:
• mitotic index >/=3 per 10 high-power fields;
• necrosis;
• convoluted nuclei (slightly smaller and darker than those
typically seen in PTC, with irregular contours).
• Hurthle cell carcinomas are no longer classified as ‘follicular tumours’,
which are generally much less aggressive and less likely to present
with lymph nodemetastases [16]. Hu¨rthle cell carcinomas associated
with extensive vascular and/or capsular invasion should be managed
like other high-risk carcinomas
Primary tumour management
Surgery. Primary tumour management will be determined by the results
of the preoperative risk assessment (Algorithm 1). Active US surveillance
of the thyroid and neck lymph nodes (every 6— 12 months) can be
proposed for unifocal papillary microcarcinomas (</=10 mm) with no
evidence of extracapsular extension or lymph node metastases [III, B]
[31]. In these cases, the only known predictor of significant tumour
growth (>/=3 mm) or the onset of lymph node metastasis is age (10-
year estimated risks: 36% in patients <30 years old, 14% in those aged 30
—50, 6% in patients 50—60 years old)
For other TCs, total thyroidectomy is still considered the standard

surgical treatment. Two large database studies on surgical management
strategies found that, for selected low-risk tumours (T1a—T1b—T2, N0),
lobectomy alone does not reduce OS but it may be associated with a
slightly higher local recurrence
In risk-benefit analyses, it is important to recall that total thyroidectomy

can cause recurrent laryngeal nerve injury (2.5%, bilateral in rare cases)
and temporary or permanent hypoparathyroidism (8.1%), double the risks
compared to lobectomy.
CND. The use of prophylactic central neck dissection for low-risk tumours (T1b
—T2, N0) varies from centre to centre. For more invasive tumours (T3—T4),
prophylactic neck dissection may improve regional control [IV, C]
RAI therapy. RAI is administered after total thyroidectomy for several
reasons:
•to eliminate the normal thyroid remnant, thereby ensuring undetectable
serum Tg levels (in the absence of neoplastic tissue), which facilitate follow-
up (remnant ablation);
•to irradiate presumed foci of neoplastic cells, thereby reducing the
recurrence risk (adjuvant therapy); and/or
•to treat persistent or recurrent disease (treatment of known
disease)
In all three cases, RAI administration must be followed by an iodine-131

(131I) whole-body scan (WBS) to stage the disease and document the 131I
avidity of any structural lesion. The estimated level of risk for
persistent/recurrent disease will determine whether and how much RAI is
given. To optimize isotope uptake, RAI should be given after thyroid-
stimulating hormone (TSH) stimulation, which can be achieved by
withdrawing levothyroxine for 4—5 weeks, ideally until serum TSH levels
reach >30 mIU/ml. As shown in Figure 2, practice guidelines unanimously
recommend treatment with high RAI activities (>100 mCi, 3.7 GBq) for
patients with high risk of recurrence
RAI administration is not recommended for certain low-risk patients

[i.e. those with a small (</=1 cm) intrathyroidal DTC and no evi-
dence of locoregional metastases]
RAI therapy may be considered in intermediate-risk patients, decisions on

RAI dosage and TSH stimulation modalities are based on case features
(particularly the ex tent of lymph node involvement and the aggressiveness
of the pathological subtype)
Follow-up tools and schedules (Figure 3) vary according to the tumour histotype, initial
treatment, initial risk of persistent/recurrent disease (Table 3) and responses to treatment
(Table 4). Serum Tg assays and neck US are the mainstays of DTC follow up:
Serum Tg. Serum Tg is a sensitive marker for the presence of thyrocytes, but it cannot
discriminate between normal and malignant cells. Undetectable levels thus have high
negative predictive values, but detectable values can be false-positives. Serum Tg can be
assayed under basal conditions (i.e. during levothyroxine treatment) or after endogenous
(levothyroxine withdrawal) or exogenous (rhTSH injection) TSH stimulation. In patients
treated with total thyroidectomy plus RAI remnant ablation, stimulated serum Tg levels <1
ng/ml are highly predictive of
an excellent response to therapy, and subsequent stimulated Tg assays are unnecessary
•High-sensitivity (<0.2 ng/ml) assays of basal Tg can be used in lieu of TSH-stimulated Tg
testing to verify the absence of disease (excellent response) Almost 60% of patients who
have total thyroid dectomy without postoperative RAI administration will have basal serum
Tg levels (<0.2 ng/ml [56, 57], which indicates an absence of disease (i.e. an excellent
response to therapy).
•Serial measurements of basal Tg should be obtained when serum TG levels are detectable,
in patients on levothyroxine treatment with residual thyroid tissue (i.e. those treated with
total thyroidectomy and RAI remnant ablation that proved incomplete or with total
thyroidectomy alone) [IV, B]. A similar approach might be used following lobectomy [IV, C]
•Neck US is the most effective tool for detecting structural disease in the neck, particularly
when residual thyroid tissue is present
•Other imaging studies are indicated if locoregional and/or distant metastases are suspected
[IV, B], or in patients with known metastases [IV, A]
•The follow-up protocol for minimally invasive FTCs is often the same one used for low-risk
PTCs, although the evidence supporting such an approach is
insufficient [V, C]
•TSH levels should be maintained in the low-normal range (0.5–2 lIU/ml) in all patients with
excellent response to treatment and in low-risk patients
with biochemical incomplete or indeterminate responses to treatment [IV, B]
•Mild TSH suppression should be considered (0.1–0.5 lIU/ml) in patients at intermediate to
high risk of recurrence with biochemical incomplete or indeterminate responses to
treatment [IV, B
Follow-up tools and schedules (Continued)
Neck US. Neck US is the most effective tool for detecting structural disease in the neck, particularly when remnants of normal thyroid tissue are present. Combined
with the results of FNA cytology [58] and serum Tg assays, neck US findings can achieve an accuracy of nearly 100% [59]. The shortcomings of US include substantial
operator dependency [60], a high frequency of non specific findings [61] and the possibility of unsatisfactory visualisation of deep structures and those acoustically
shadowed by bone or air
Other imaging studies. Other imaging studies should be ordered if locoregional and/or distant metastases are known to be present [IV, A] or suspected (based, for
example, on rising serum Tg or TgAb levels in the absence of sonographically identifiable neck disease or in patients with intermediate-to-high risks of
persistent/recurrent disease, irrespective of the neck US findings)
• A Whole Body Scan with gamma camera can be carried out after the administration of diagnostic or therapeutic doses of RAI. Because its sensitivity is low (27%—
55%), diagnostic WBS is not indicated during follow-up [IV, A] [64]. Uptake is highly specific (91%—100%) for the presence of thyroid tissue, but false-positive
results are possible. In these cases, single-photon emission computed tomography or computed tomography (CT) offers better anatomic resolution
• (FDG—PET) combined with CT is useful for assessing the extent of disease and defining the prognosis [65, 66]. Its sensitivity is around 94%, and specificity is
between 80% and 84%. FDG—PET is more sensitive than therapeutic WBS for detecting persistent disease in patients with negative cross-sectional imaging studies,
serum Tg levels >10 ng/dl, and/or aggressive histotypes (e.g. aggressive PTC, poorly differentiated TC, widely invasive follicular carcinoma)
• CT is best for neck and chest imaging. Contrast enhancement is used for studies of the neck and mediastinal lymph nodes but not for the lungs. All forms of RAI
treatment should be deferred for at least 6 weeks after administration of any iodinated contrast medium.
• Contrast-enhanced magnetic resonance imaging (MRI) is appropriate for exploring the neck, liver, bones and brain [64]. MRI of the neck is subject to substantial
image degradation due to respiratory motion,and a CT scan is often a better alternative.
• Suspected aerodigestive-tract involvement should always be assessed endoscopically.
Follow-up strategies. All patients with DTC should have neck US and serum Tg and TgAb assays 6—18 months after primary treatment (surgery 6RAI therapy). The
subsequent follow-up schedule will depend on the initially estimated risk of persistent/recurrent disease and responses to therapy (Figure 3).
• PTC patients at low risk for recurrence who have no evidence of structural disease at the first follow-up visit can be monitored with periodic (12—24 months) Tg
and TgAb assessments. Repeat neck US scans can be carried out as needed, depending on serum Tg and TgAb levels
• Low- or intermediate-risk PTC patients with a biochemical incomplete or indeterminate response to treatment should have serum Tg and TgAb assays and a neck
US every 6—12 months. Rising Tg or TgAb levels warrant further imaging studies
• In patients with high-risk PTCs, poorly differentiated TCs or widely invasive FTCs, serum Tg and TgAb levels should be assessed every 6—12 months if the response
to therapy is excellent or biochemical indeterminate/incomplete. Cross-sectional or functional imaging studies should be repeated if detectable Tg levels persist [IV,
B]
Management of advanced/metastatic disease
Radioactive iodine therapy

•Patients with distant metastases should receive 100–200 mCi (3.7–7.4 GBq) of 131I after TSH
stimulation [IV, A]
•Non-RAI-avid lesions and those that lose their ability to concentrate RAI or progress despite
RAI avidity should be considered RAI-refractory [IV, A]
•Between treatments, suppressive doses of levothyroxine are given to maintain serum TSH
levels <0.1 lIU/ml (unless there are specific contraindications)
[III, B]
Locoregional therapy
•Single lesions that are symptomatic or progressive may be eligible for locoregional treatments
(e.g. palliative surgery, EBRT, percutaneous therapies)
•Bone resorption inhibitors (bisphosphonates and denosumab) can be used alone or combined
with locoregional treatments in the management of thyroid cancer-related bone metastases [V,
B]
•There is limited evidence that conservative techniques (RFA, cryotherapy) are effective for
treating TC-related bone lesions [V, B]
•Metastasectomy is not the standard approach for lung metastases but it may be considered
for oligometastasis in patients with good PS [V, C]
•RFA is a possibility for solitary lung lesions or those causing a specific symptom due to their
volume and location [V, C]
•Invasion of the upper aerodigestive tract should always be excluded in TC patients with
locoregional disease
Systemic therapy and personalised medicine

•TSH suppression (serum level <0.1 lIU/mL) is recommended for all TC patients with persistent
structural disease in the absence of specific contraindications [III, B]
•Decisions on whether or not to use MKIs must always be based on patient preference after a
careful discussion with the managing physician of the
expected benefits and risks associated with specific drugs (tumour burden, the Eastern
Cooperative Oncology Group (ECOG) PS, lesion characteristics (e.g. paratracheal loca-
tion or other features likely to cause symptoms) and disease progression [defined using
Response Evaluation Criteria in Solid Tumours (RECIST) v1.1 as a 20% increase in the sum of
target lesions or the appearance of new lesion)
•Lenvatinib and sorafenib should be considered the standard first-line systemic therapy for
RAI-refractory DTC [I, A; ESMO-MCBS v1.1 scores: 3 for lenvati-
nib, 2 for sorafenib
Management of advanced/metastatic disease (Continued)
• Distant metastases occur in fewer than 10% of patients with DTC. Half are present when the tumour is first discovered; the others are found later, sometimes decades after initial treatment.
• Metastases are observed most frequently in patients with aggressive histological subtypes (e.g. tall-cell, hobnail, solid, diffuse sclerosing and columnar-cell variants): vascular invasion, large
primary tumours, macroscopic extrathyroidal extension, bulky locoregional nodal disease. The most common sites are lungs and bones (involved in 49% and 25% of all cases, respectively).
Bone metastases are more common in FTC than in PTC. The overall mortality rates 5 and 10 years after diagnosis of distant metastases are 65% and 75%,respectively
• One-third of patients have lesions that are not RAI-avid and are considered RAI-refractory. If the distant metastases are RAI-avid, 131I is administered every 6 months for 2 years and less
frequently thereafter. Between treatments, suppressive doses of levothyroxine are given to maintain serum TSH levels below 0.1 mIU/ml (unless there are specific contraindications) When
distant metastases lose their ability to concentrate RAI or structural progression occurs within 6—12 months after RAI administration, the disease is considered RAI-refractory
• Overall, one out of three patients with distant metastases will be cured with RAI and have a near-normal life expectancy
• Bone metastases: The relatively long survival perspective places TC patients with bone metastases at high risk of skeletal-related events (SREs), i.e. pathological fractures, spinal cord
compression, need for radiation (for pain or impending fracture) or surgery and hypercalcaemia. Up to 37% of TC patients experience SREs, and they are associated with poorer prognoses.
Recommended use of bone resorption inhibitors (bisphosphonates or denosumab) [V, B], external beam radiotherapy (EBRT) or other locoregional treatments in reducing SREs. If the
bone metastases are RAI-avid, RAI therapy may control the disease for some time and alleviate or delay symptoms, but it is unlikely to eliminate these lesions. Surgery followed by EBRT is
associated with the best outcomes, at least for limb lesions [88]. If surgery is not feasible, bone lesions associated with pain or a high fracture risk should be treated with fractionated (20 Gy
in five fractions or 30 Gy in 10 fractions) or single-fraction (8 Gy) EBRT and/or with interventional radiology techniques, including cementoplasty and thermal ablation
• Lung metastases: The lung is a common site of TC metastasis. The lesions are usually multiple, bilateral, of varying size (from a few millimetres to 1 cm) and asymptomatic. Metastasectomy is
not the standard approach for these lesions, but it may be considered for oligometastasis in patients with good performance status (PS) [V, C]. RFA is also a possibility for solitary lesions or
those causing a specific symptom due to their volume and location [V, C]. RFA is considered for lesions <2—3 cm in patients not eligible for surgery or those requiring an extensive resection
• Liver metastases: Liver metastases are rare in DTC but more common in MTC. Liver involvement usually presents with multiple lesions, but if true solitary lesions are detected, they may be
candidates for local ablation. In MTC patients with a dominant lesion that is growing more rapidly than the background disease, local ablation (e.g. RFA) may be useful for controlling
symptoms, systemic ones in particular, such as diarrhoea. The outcome of RFA will depend on the size of the lesion (optimally <30 mm), its location (at least 3 mm from all vessels) and its
visibility on US. If both surgery and RFA are contraindicated, hepatic intra-arterial embolisation with drug-eluting beads might be an option.
• Invasion of upper aerodigestive tract: Invasion of the upper aerodigestive tract should always be excluded in TC patients with locoregional disease. Suspicious symptoms
include haemoptysis and dysphagia. In selected cases (e.g. bleeding, exophytic lesions), local treatment (e.g. laser excision) is advisable before starting antiangiogenic
multikinase inhibitor (MKI) therapy
• Systemic therapy and personalised medicine. TSH suppression (serum level <0.1 lIU/ml) is recommended for all TC patients with persistent structural disease in the absence
of specific contraindications [III, B] [77]. Not all patients with RAI-refractory disease require systemic MKI therapy immediately. Lenvatinib and sorafenib should be considered
the standard first-line systemic therapy for progressive, metastatic, RAI-refractory DTC.
• Adverse Effects of MKIs: AEs occurred in 98.6% of patients receiving sorafenib during the DECISION trial [96]: hand—foot syndrome,diarrhoea, alopaecia, rash or
desquamation, fatigue, weight lossand hypertension were the most common. Serum TSH levels exceeding 0.5 mIU/ml were observed in 33.3% patients in the sorafenib arm.
TSH increases are a recognised AE of sorafenib and other MKIs, and levels should be checked monthly to ensure that suppression is maintained. 37.2% (77/207) of the
sorafenib-treated participants. Nine developed a second malignancy: squamous-cell skin cancer in seven cases (one patient also had melanoma), acute myeloid leukaemia and
bladder cancer in the remaining two cases. Skin cancer is a consequence of sorafenib’s paradoxical activation of mitogen-activated protein kinase signalling in keratinocytes
harbouring mutated or activated RAS.
ANAPLASTIC THYROID CANCER
• ATCs are very rare tumours that usually present at an advanced stage, display
extremely aggressive behaviour, and are associated with a very poor prognosis. They
are morphologically heterogeneous and must be distinguished from other neck
tumours, including squamous carcinoma of the larynx, sarcomas and lymphomas.
Preoperative biopsy assessment includes diagnostic immunomarkers that can
differentiate ATC from large cell lymphoma or pleomorphic sarcoma. The molecular
profile of ATC includes mutations of the TERT promoter (associated with BRAF or RAS
mutations) and TP53 [21, 22], as well as targetable abnormalities (e.g. NTRK and ALK
rearrangements).
• In the eighth edition of the UICC TNM staging system [23], diagnosis of ATC is no
longer associated with pT4 stage by default. Cases treated with resection are staged
like other TC histotypes, based on tumour size and extension
• ATCs are considered one of the most aggressive solid tumours in humans. The median
survival after the initial diagnosis is 4 months and only one out of five patients
survives more than 12 months (1-year survival rates: 10%—20%). Long-term survival
has been reported, but the estimated rate at 10 years is <5%. The dismal prognosis
stems from the fact that over 40% of the patients present at diagnosis with large
primary tumours (mean size: 6 cm), gross extrathyroidal extension and locoregional
and distant metastases, which make complete resection unlikely
• Surgery. ATC is rarely amenable to complete resection (Figure 5). Total thyroidectomy
with bilateral central neck dissection may be carried out in those very rare cases of
localised ATC in M0 patients. Tracheostomy may be needed to alleviate symptoms in
patients with moderately progressive disease
• Radiotherapy. Optimal outcomes in terms of survival and local disease control in ATC
require complete or near-complete [no residual tumour (R0) or microscopic residual
tumour (R1)] resection followed by high-dose EBRT, with or without concomitant ChT .
• Palliative EBRT: In patients with unresectable disease, EBRT has a role in symptom
control [V, C] [133]. The aim is usually to reduce the rate of growth of the neck mass
and thereby the pressure symptoms.
• To date, cytotoxic ChT has been the primary treatment for metastatic disease, but it
is associated with very low response rates and significant toxicities [133].
Recommended regimens consist of single-agent therapy with paclitaxel or doxorubicin
or combined treatments (e.g. carboplatin/paclitaxel, docetaxel/doxorubicin)
administered weekly or every 3—4 weeks
• Patients with BRAF V600E-positive malignancies should be treated with the BRAF
inhibitor dabrafenib (150 mg twice daily) plus the MEK inhibitor trametinib (2 mg
once daily) if they are available [V, B
MEDULLARY THYROID CANCER
• MTC is morphologically heterogeneous and can mimic virtually all other primary
thyroid tumours. Demonstration of calcitonin (Ctn) expression is mandatory for
the diagnosis. Medullary thyroid cancer is a form of thyroid carcinoma which
originates from the parafollicular cells (C cells), which produce the hormone
calcitonin. Medullary tumors are the third most common of all thyroid cancers
and together make up about 3% of all thyroid cancer cases.
• Basal serum calcitonin concentrations usually correlate with tumor mass but also
reflect tumor differentiation, and they are almost always high in patients with a
palpable tumor [6]. Most MTCs also secrete carcinoembryonic antigen (CEA),
which, like calcitonin, can be used as a tumor marker [11,12]. In addition, the
expression of CEA on MTC cells has led to the use of anti-CEA antibodies for
immunotherapy. Rare primary Ctn-negative neuroendocrine carcinomas of the
thyroid exist and must be distinguished from metastases from neuroendocrine
neoplasms of the lung. In these cases, carcinoembryonic antigen (CEA)
determination can be useful, being the only neck tumour expressing this marker.
The preoperative diagnosis can also be challenging in the absence of a consistent
immunophenotype.
• RET and RAS proto-oncogene mutations are detected in 90% of MTCs and are
considered the predominant drivers of these tumours [141]. RET mutations occur
sporadically, as somatic events, or can be inherited as germline events associated
with familial MTC or the multiple endocrine neoplasia syndromes type 2A and 2B
(MEN2A and MEN2B). All patients with MTC should thus be offered genetic
counselling and be screened
• Ctn and CEA are valuable diagnostic, prognostic and predictive markers for use
with MTC. Their serum concentrations are directly related to the C-cell mass
• An analysis of 300 consecutive cases of MTC treated with total thyroidectomy and compartment oriented lymph node dissections found that preoperative serum Ctn levels <20 pg/ml (normal
reference range: <10 pg/ml) were associated with almost no risk of nodal metastases. Ctn levels exceeding 20 pg/ml were associated with nodal metastases to the ipsilateral compartments of
the neck (central and lateral); higher levels were associated with increasingly extensive locoregional spread (levels >50 pg/ml: nodes of the contra lateral central compartment of the neck;
levels >200 pg/ml: nodes of the contralateral lateral compartment; levels >500 pg/ ml: upper mediastinal nodes). Serum Ctn levels exceeding 500 pg/ml suggest distant metastatic disease and
should be explored with additional whole-body imaging procedures
• Serum Ctn should be measured 60—90 days after thyroidectomy
• Doubling times for postoperative serum Ctn and CEA levels (defined as the interval of time in which the tumour markers levels have doubled) are established prognostic markers in MTC [IV,
B] [148—150]. They are currently considered the best available predictors of tumour behaviour, recurrence and cancer related death. A Ctn doubling time exceeding 6 months is associated
with 5- and 10-year survival rates of 92% and 37%, respectively; shorter doubling times predict markedly worse survival (25% and 8% at 5 and 10 years, respectively)
• Preoperative screening for pheochromocytoma and hyperparathyroidism is highly recommended for all patients with MTC
MEDULLARY THYROID CANCER
• Neck US should be carried out to identify regional metastases;
• if sonographic (or clinical) findings are suspicious, contrast-enhanced CT of the neck and
chest is indicated.
• Work-up for distant metastases, including chest CT, liver and axial bone MRI and 6-fluoro-
(18F)-L-dihydroxyphenylalanine (FDOPA)-PET scan (if available), should be done if serum
Ctn levels exceed 500 pg/ml or clinical findings are suspicious.
• Neck dissection, when needed, should be done by surgeons with substantial experience
in TC surgery. The initial approach will depend on preoperative serum Ctn levels and neck
imaging findings
• For carriers of germline mutations, the recommended age for prophylactic total
thyroidectomy depends on the type of mutation.
• Individuals with germline M918T mutations should undergo total thyroidectomy within
the first year of life. For those with a C634F or A883F mutation (also considered high
risk), surgery can be postponed until age 5 unless Ctn levels increase. Those with other
mutations should be monitored from age 5 on with Ctn assays and neck US, and surgery
should be done if Ctn levels increase or if the parents request it .
Follow Up
• Ctn and CEA monitoring should both be included in the early and long-term
postoperative staging work-ups [IV, B] [150]. Serial measurements allow the calculation of
doubling times, which provide useful information as described above. Currently available
data indicate that Ctn doubling times should be based on at least four consecutive
measurements, preferably obtained over a 2-year period
• Contrast- enhanced whole-body (brain, neck, thorax, abdomen and pelvis) CT with ultra-
thin reconstructions is sensitive and specific enough to allow one to estimate the burden
of systemic disease and to assess and identify target lesions. As indolent tumours, MTCs
generally display low avidity for FDG, so FDG—PET—CT is not recommended for their
staging, but it can be useful for assessing advanced disease characterized by
dedifferentiation and rapid progression
• The systemic therapies currently approved for MTC have not been shown to improve OS,
so evidence-based guidance is lacking on when to start these drugs and how patients
with indolent disease should be followed. Decisions are based mainly on clinicians’
experience.
Systemic therapy and personalised medicine
•Cabozantinib [I, A] and vandetanib [I, A; ESMO-MCBS v1.1 score: 2] are the first-line systemic therapy for patients with progressive, metastatic MTC
•In patients with RETM918T or RAS-mutant MTCs, cabozantinib offers significant PFS and OS advantages over wild-type MTCs [II, C]
•There is little evidence to support the use of either ChT or radionuclide therapy in patients with MTC, although either might be considered whenMKIs are contraindicated

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SARCOMAS (Soft Tissue and Visceral)

Receptor proteins for glucocorticoids can be found in virtually every cell.

Stress: Physical or mental stress increases cortisol secretion as a result of

Genetic counselling should be offered to all patients with PPGL.

ACC-MANAGEMENT OF LOCOREGIONAL DISEASE

PPGL-MANAGEMENT OF ADVANCED DISEASE

• Targeted therapies. There is a rationale and some evidence on the

Bethesda IV and V ---> Surgery

DTC and poorly differentiated TC

For other TCs, total thyroidectomy is still considered the standard

In risk-benefit analyses, it is important to recall that total thyroidectomy

In all three cases, RAI administration must be followed by an iodine-131

RAI administration is not recommended for certain low-risk patients

RAI therapy may be considered in intermediate-risk patients, decisions on

Radioactive iodine therapy

Systemic therapy and personalised medicine

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