Neuropathology 2008; 28, 87–92 doi:10.1111/j.1440-1789.2007.00832.

C a se Repor t

Papillary tumor of the pineal region

Tibor Boco,1 Sophie Aalaei,2 Michael Musacchio,1 Richard Byrne1 and Elizabeth Cochran2,3
Departments of 1Neurosurgery, 2Pathology and 3Neurological Sciences, Rush University Medical Center, Chicago, Illinois,
USA

Primary pineal gland malignancies are uncommon and tumors the next most frequent neoplasms within this
seldom have papillary architecture. We report a case of a region. Although germ cell tumors may exhibit papillary
22-year-old male patient who presented with progressive architecture, pineal parenchymal tumors usually do not.
headache, horizontal nystagmus and worsening diplopia. Other regional neoplasms that may exhibit papillary
MRI of the brain showed a lesion in the pineal region. The features are ependymoma, meningioma, choroid plexus pa-
patient was taken for resection of the lesion which was pilloma, metastatic carcinomas, and papillary tumor of the
classified as papillary tumor of pineal region (PTPR). His- pineal region (PTPR).2–5 The PTPR has only recently been
tologically, the neoplasm was cellular, characterized by described, most prominently in a retrospective multicenter
eosinophilic cells with indistinct borders, large pleomor- study of 31 cases treated in France and Germany between
phic nuclei, numerous apoptotic figures without necrosis or 1979 and 2005.5 Whereas the literature seems to have accu-
microvascular proliferation. Prominent perivascular pseu- mulated a well-defined characterization of the histologic
dorosettes were seen. Diffuse immunoreactivity for cytok- features of PTPR, their prognosis is still uncertain.5 Fur-
eratin 8–18 was noted. Synaptophysin antibody showed thermore, the optimal treatment modalities, including the
membranous and cytoplasmic positivity. Weak staining value of adjunct radiotherapy or chemotherapy, are yet to
for GFAP, vimentin, S-100 protein, and neuron specific be determined. This is a report of a patient who underwent
enolase (NSE) were observed only focally. This is a case craniotomy for a pineal region tumor classified as PTPR. In
report of this rare pineal region neoplasm which only addition, this work gives an overview of the cases that have
recently has been described as a histopathologic entity. been classified as PTPR in the literature thus far.
Although the clinicopathological characteristics of this
tumor are not entirely understood, a brief review of the
literature as well as our contribution suggest an indolent CLINICAL SUMMARY
neoplasm with a tendency for local recurrence. Histologi-
cally, PTPR demonstrates a unique assortment of epithe- History
lial, ependymal, and neuroendocrine features. The A 22-year-old Caucasian man presented with a year-long
differential diagnosis of papillary neoplasms of the pineal history of worsening headache and progressive diplopia on
region is reviewed. lateral gaze. An ophthalmologist had previously seen the
patient and referred him for further work-up. At that point,
Key words: papillary neoplasm, pineal gland, pineal region, he was referred to a neurologist who obtained an MRI scan
pineal tumor, subcommissural organ. of the brain, which revealed hydrocephalus and a lesion in
the pineal region (Fig. 1).
INTRODUCTION
Pineal region tumors are uncommon, collectively constitut- Examination
ing less than 1% of all intracranial tumors.1 Germ cell Upon admission to the neurosurgical service, the patient
neoplasms are the most common with pineal parenchymal had a normal neurological examination with the exception
of mild bilateral horizontal nystagmus and diplopia
on lateral gaze. The MRI scan had revealed a well-
Correspondence: Tibor Boco, md, Department of Neurosurgery, Rush
circumscribed pineal region tumor extending roughly
University Medical Center, 1725 West Harrison Street, Suite 1115,
Chicago, IL 60612, USA. Email: tibor_boco@rush.edu 3.5 cm craniocaudally and 2.5 cm transversely in the quad-
Received 15 January 2007; revised and accepted 10 April 2007 rigeminal cistern (Fig. 1). The mass was radiographically

© 2007 Japanese Society of Neuropathology

88 T Boco et al.

Fig. 1 Left: preoperative axial (above)

and sagittal (below) T1-weighted post-
contrast MRI of the pineal-region tumor.
Right: corresponding postoperative
T1-weighted postcontrast MRI showing
successful total radiographic resection of
the lesion.

heterogeneous with cystic and necrotic components and therapy per radiation oncology at our institution. Clini-
enhanced with gadolinium. There was obstruction noted at cally, he still has mild bilateral end-gaze nystagmus but his
the aqueduct with hydrocephalic enlargement of the diplopia has resolved. Serial MRI has revealed little if any
lateral and third ventricles. There was tonsillar ectopy via interval change in the dilatation of the lateral and third
the foramen magnum of approximately 8 mm. MRI of the ventricles and chronic hydrocephalus has persisted. The
spine was negative for drop metastases in the spinal canal. pineal region has remained unchanged in morphology and
there is currently no evidence of tumor regrowth.
Management
A right frontal external ventricular drain (EVD) was HISTOLOGICAL EXAMINATION
placed without complications. Cerebrospinal fluid was col-
Microscopic examination revealed a moderately cellular
lected for analysis including cytology, acid-fast bacteria,
neoplasm exhibiting predominantly solid growth pattern
and human chorionic gonadotropin. Results were negative.
with focal papillary areas (Fig. 2). Prominently seen were
A preoperative four-vessel cerebral angiogram showed
perivascular pseudorosettes, with only sparse true ependy-
normal cerebrovascular anatomy without tumor blush.
mal rosettes (Fig. 3). Most cells had moderate amounts
A few days later, the patient was taken to the operating
of eosinophilic, non-fibrillary cytoplasm and indistinct
room for suboccipital craniotomy and tumor resection via
borders. Large pleomorphic nuclei displaying a dense chro-
infratentorial-supracerebellar approach. Using microsurgi-
matin pattern and, occasionally, a prominent nucleolus were
cal technique, the tumor was internally debulked and
present. Apoptotic figures were numerous. Mitoses were
removed down to normal-appearing surrounding struc-
sparse and necrosis was absent. Microvascular proliferation
tures. Postoperative MRI showed satisfactory radiographic
was not seen. The MIB-1 proliferative index was 4.5%. The
tumor removal. (Fig. 1) Eventually, the EVD was removed
neoplastic cells were diffusely immunoreactive for cytok-
and the patient recovered well with slow resolution of his
eratin 8–18 (Fig. 4A). Isolated and small clusters of
hydrocephalus.
cells were immunoreactive with synaptophysin antibody,
showing both membranous and cytoplasmic positivity
Postoperative course
(Fig. 4B). Only weak focal immunoreactivity with antibod-
The patient is currently at 26 months post-surgery and con- ies to GFAP, vimentin, S-100 protein, and neuron-specific
tinues to do well. He has been undergoing field radiation enolase was noted. The GFAP immunoreactivity was most

© 2007 Japanese Society of Neuropathology

Papillary tumor of the pineal region 89

Fig. 2 Photomicrograph. Low-power image illustrating papillary B

area of neoplasm. HE staining. Original magnification 100¥

Fig. 3 Photomicrograph. Solid pattern of neoplasm exhibiting an

ependymal rosette (arrow). HE staining. Original magnification
400¥

prominent in the cytoplasmic processes of papillary struc-

tures and in perivascular rosettes (Fig. 4C), areas that were
also immunoreactive for cytokeratin 8–18. Immunohis-
tochemistry with antibodies to epithelial membrane antigen
(EDTA-based retrieval solution used), cytokeratin AE1/
AE3, chromogranin, neurofilament, alpha-fetoprotein,
human chorionic gonadotropin, desmin, smooth muscle
actin and placental alkaline phosphatase was negative. The Fig. 4 (A) Intense cytokeratin 8–18 immunoreactivity in two
papillary structures. Original magnification 400¥. (B) Both mem-
tumor morphology and immunohistochemical profile was branous and cytoplasmic synaptophysin immunoreactivity is
typical of PTPR. present in isolated cells and small clusters. Original magnification
400¥. (C) Cytoplasmic GFAP immunoreactivity in processes of a
papillary structure. Original magnification 400¥.
DISCUSSION
The current case demonstrates many similarities to the
other cases of PTPR previously reported in the

© 2007 Japanese Society of Neuropathology

90 T Boco et al.

Table 1 Clinical data on reported cases of papillary tumor of the pineal region
Source Case # Age (years)/ Size (cm) Therapy Recurrence Follow-up
Sex (months)
Fèvre-Montange et al. 1 19 M 2.7 Surg, Rad, Chemo Yes 70
(previosly in Jouvet et al.)3,5 2 28 F 2.3 Surg, Rad Yes 103
3 56 F >3.0 Surg, Rad Yes 24
4 53 M 3.2 Surg, Rad, Chemo No 79
5 37 F >4.0 Surg, Rad, Chemo Yes, spinal 24
dissemination
6 42 F 2.6 Surg, Rad, Chemo Yes 36
Shibahara et al.4 7 29 F 3.0 Surg, Rad, Chemo No 9
Fèvre-Montange et al.5 8 43 M 2.0 Surg, Rad Yes 18
9 14 M N/A Surg No N/A
10 32 M 3.0 Surg, Rad Yes 201
11 66 M N/A Surg, Rad Yes 105
12 62 M 2.5 Surg, Rad No 50
13 38 F N/A Surg Yes 12
14 23 F 4.0 Surg No N/A
15 24 F N/A Surg, Rad, Chemo No 36
16 29 F 2.5 Surg No 7
17 27 M 5.0 Surg, Rad No 4
18 33 F 2.0 Surg, Rad, Chemo Yes 44
19 22 F 2.2 Surg, Rad Yes 59
20 46 F N/A Surg, Rad No 51
21 45 F 1.8 Surg, Rad, Chemo Yes 48
22 24 M N/A Surg No 7
23 5F 2.8 Surg, Rad, Chemo Yes 24
24 13 M N/A Surg, Rad No 5
25 14 M 5.0 Surg, Rad, Chemo Yes 102
26 35 M 2.8 Surg, Rad No 19
27 29 M 4.8 Surg, Rad Yes 21
28 11 F 3.0 Surg, Rad, Chemo Yes 79
29 28 F 5.0 Surg No 7
30 26 F 3.0 Surg, Rad Yes 131
31 29 F 1.7 Surg, Rad No 83
32 25 M 4.0 Surg Yes 144
Boco et al. 33 22 M 2.5 Surg, Rad No 26
Chemo, chemotherapy; Follow-up, length of follow-up after surgery in months; N/A, not reported; Rad, radiation therapy; Surg, surgical therapy
(including biopsy, partial, and complete resection).

literature.3–5 Patients range in age from 5 to 66 years, and recurrence could not find statistical correlation to either
are 18 women and 14 men. Clinical presentation was extent of gross total resection or cytologic mitotic actitvity.
mainly headache without focal neurological signs. The Of note is that spinal dissemination occurred in one
tumors measured from 1.7 to more than 5.0 cm and the patient3,5 (Table 1). One case reported by Shibahara et al.
majority were described as well-circumscribed. One had showed no reccurrence at 9 months after having been
prominent cystic as well as solid components.4 All patients treated by surgery, radiation and chemotherapy4 (Table 1).
underwent biopsy, and partial or complete resection. Reported cases of PTPR show papillary architecture
Fèvre-Montange et al. report detailed follow-up informa- and perivascular pseudorosettes. The tumors reported by
tion for 29 of their 31 cases within a mean interval of Fèvre-Montange et al. which include those reported by
4.2 years.5 Twenty-one patients demonstrated tumor pro- Jouvet et al. also exhibited true (ependymal) rosettes and
gression, 18 of them delayed recurrence, and, at the time of Shibahara’s report describes “microlumens” which appear
their last visit, seven patients had died presumably second- to be rosettes.3–5 The neoplastic cells are described as
ary to their disease.3,5 Twenty-five patients received adjunct having well-defined cell borders and cuboidal to columnar
radiation therapy including heterogenous radiotherapy shape, lacking fibrillary processes. Mitoses varied from
regimens after complete (n = 9) or incomplete (n = 6) sparse to frequent. Necrosis was seen in all cases reported
resection of the primary tumor.3,5 The rest received radia- by Jouvet, but vascular proliferation was not seen.3 In our
tion as primary therapy.3,5 Ten patients also received che- case, no necrosis was seen, and mitoses were sparse.
motherapy in addition to surgery and radiation.3,5 Kaplan- Our case as well as previously reported cases were immu-
Meier analysis provided an estimate for 5-year survival of noreactive to cytokeratin. Most cases were also immuno-
73%.5 Multivariate analysis regarding overall survival and reactive to synaptophysin, S-100, NSE and vimentin

© 2007 Japanese Society of Neuropathology

Papillary tumor of the pineal region 91

Table 2 Immunohistochemical profile of representative papillary tumor of the pineal region cases
Source Case S100 Keratin EMA Vim Synapto CH GFAP NSE
3
Jouvet et al. 1 Pos Pos Weak Pos Neg Neg Neg Pos
2 Pos Pos Weak Pos Weak Pos Neg Pos
3 Pos Pos Weak Weak Weak Pos Neg Pos
4 Pos Pos Weak Pos Weak Neg Neg Pos
5 Neg Pos Weak Weak Pos Pos Neg Pos
6 Pos Pos Weak Pos Pos Pos Neg Pos
Shibahara et al.4 7 Pos Pos Pos Neg Neg N/A Neg N/A
Boco et al. 8 Pos Pos Neg Weak Pos Neg Focal Weak
CH, chromogranin; EMA, epithelial membrane antigen; Focal, focally positive; N/A, not reported; Neg, negative; NSE, neuron-specific enolase;
Pos, positive; Synapto, synaptophysin; Vim, vimentin; Weak, weakly positive.

antibodies (Table 2). In contrast to other reported cases, this embryonal carcinoma, and teratomas would be most likely
neoplasm showed focal GFAP immunoreactivity while all to exhibit papillary features. Distinction of each of these
others were negative. Epithelial membrane antigen and germ cell neoplasms from PTPR could be based upon
chromogranin were variably immunoreactive in previously both morphology (Schiller-Duval bodies, presence of fetal
reported cases and negative in our patient. The MIB-1 tissues, multiple cell lineages) and immunohistochemistry
proliferative index, available in one other case, was 5%, and (placental leukocyte alkaline phosphatase, alpha feto-
in our patient’s neoplasm it was 4.5%.4 protein, CD30).9
Given the recent characterization and relative rarity of Ultrastructural analysis of two cases by Jouvet et al. pro-
PTPR, other papillary neoplasms occurring in this region vided findings to support the ependymal, secretory, and
must be considered. Despite an immunohistochemical neuroendocrine nature of the cells of the PTPR.3 These
reactivity profile similar to choroid plexus papilloma, the included microvilli, zipper-like junctions, abundant rough
PTPR cytology is not distinctly epithelial and the papillary endoplasmic reticulum, dilated cisternae, annulatae lamel-
formations are not as diffuse.6 The presence of both lae, dense core vesicles and microtubules.
ependymal rosettes and perivascular pseudorosettes Specialized ependymal cells of the pineal gland origi-
suggests papillary ependymoma. However, fibrillary nating in the subcommissural organ are hypothesized to be
cytoplasm was not prominent in PTPR and GFAP was the cell of origin of the PTPR supported by the above
not immunoreactive in reported cases and only focally described ultrastructure, similar morphology and transient
immunoreactive in our case. In addition, synaptophysin expression of CK during development.3 Of interest, cells of
immunoreactivity, not commonly found in ependymoma, is the subcommissural organ also transiently express GFAP,
seen in the present case and several of those previously which was focally positive in this patient’s neoplasm.3
reported. Cytokeratin is present in all reported PTPR
cases, but it is only focally identified in ependymomas when
CONCLUSION
antibodies other than AE1/AE3 are used.7 Two papillary
pineocytomas have been published; each GFAP negative With 32 cases reported thus far in the literature, the clini-
and containing various types of rosettes.1,8 These appear copathologic profile of the PTPR remains incomplete.
to overlap with PTPR as recently defined and illustrated Most tumors recurred locally and necessitated radiation
in this report. Without additional immunohistochemical and/or chemotherapy, and seven deaths due to tumor have
analysis (synaptophysin, cytokeratin) distinction from been reported with a mean follow-up of 4.2 years.3,5 Based
PTPR is difficult. Pineoblastoma, although grouped with upon light-microscopic, ultrastructural, and immunohis-
pineocytoma as part of pineal parenchymal tumors, is not tochemical findings reported in this neoplasm, PTPR has
reported with papillary formations. Papillary meningiomas a unique combination of epithelial, ependymal, and
usually have meningothelial appearing regions (whorls and neuroendocrine features. The patient presented here, a
psammoma bodies) in addition to the papillary features, 22-year-old man who is now at 26 months post-surgery and
lack true rosettes and are typically EMA immunoreactive radiation therapy, remains free of recurrence. However, as
and GFAP non-reactive.9 In addition to appearing more the literature suggests, the clinical course of PTPR is char-
distinctly epithelial and high-grade, metastatic papillary acterized by frequent local recurrence as well as potential
carcinomas are likely immunoreactive with cytokeratin mortality. The value of radiotherapy as well as chemo-
and EMA antibodies, but not reactive with S100, synapto- therapy on disease progression will have to be investigated
physin, or GFAP antibodies. (Table 2) in prospective trials which will provide important insight
Germ cell neoplasms, specifically germinoma, occur fre- into long-term management and may further our under-
quently in the pineal region. Within this group, yolk sac, standing of the histologic features of this neoplasm.

© 2007 Japanese Society of Neuropathology

92 T Boco et al.

ACKNOWLEDGMENTS 5. Fèvre-Montange M, Hasselblatt M, Figarella-Branger D

et al. Prognosis and histopathologic features in papillary
The authors want to thank Dr Peter C. Burger at Johns
tumors of the pineal region: a retrospective multicenter
Hopkins University Medical Center, Department of
study of 31 cases. J Neuropathol Exp Neurol 2006; 65:
Pathology, for his histological review of this neoplasm.
1004–1011.
6. Aguzzi A, Brandner S, Paulus W. Choroid plexus
tumors. In: Kleihues P, Cavenee WK, eds. World Health
REFERENCES
Organization Classification of Tumors. Pathology and
1. Vaquero J, Coca S, Martinez R, Escandon J. Papillary Genetics. Tumors of the Nervous System. Lyon: IARC
pineocytoma. Case report. J Neurosurg 1990; 73: 135– Press, 2000; 84–86.
137. 7. Vege KD, Giannini C, Scheithauer BW. The immu-
2. Ang LC, Taylor AR, Bergin D, Kaufman JCE. An nophenotype of ependymomas. Appl Immunohis-
immunohistochemical study of papillary tumors in the tochem Mol Morph 2000; 8: 25–31.
central nervous system. Cancer 1990; 65: 2712. 8. Trojanowski JQ, Taskos NA, Rorke LB. Malignant pine-
3. Jouvet A, Fauchon F, Liberski P et al. Papillary tumor of ocytoma with prominent papillary features. Cancer
the pineal region. Am J Surg Pathol 2003; 27: 505–512. 1982; 50: 1789.
4. Shibahara J, Todo T, Morita A, Mori H, Aoki S, 9. Burger PC, Scheithauer BW, Vogel FS. Surgical Pathol-
Fukayama M. Papillary neuroepithelial tumor of the ogy of the Nervous System and its Coverings, 4 edn.
pineal region. A case report. Acta Neuropathol 2004; Philadelphia, PA: Churchill Livingston, 2002; 62–68,
108: 337–340. 327–328.

© 2007 Japanese Society of Neuropathology