Key-words:
Cytokeratin - papillary - pineal - pineocytoma
Introduction
Pineal tumors comprise <1% of all central nervous system (CNS) tumors in adults and
approximately 3%–5% of all CNS tumors in children.[[1]] Although papillary tumors of the pineal region (PTPR) were officially recognized
in the WHO classification of CNS tumors in 2007, they were probably known and reported
earlier as papillary pineocytomas.[[2]] This tumor occurs exclusively in the pineal region, most frequently in adults (mean
age of 31 years), with a marginal predilection for the female sex.[[3]] Surgical excision is imperative, not only to improve the overall survival (OS)
but also for the need to obtain adequate specimens for immunohistochemical diagnosis
which may not always be feasible by biopsy alone.
Case Report
A 29-year-old male presented to the clinic with a history of blurring of vision 9
years ago for which he was evaluated and diagnosed as a case of pineal region tumor
[[Figure 1]]a. He underwent subtotal resection of the same and the pathology report was suggestive
of a pineocytoma. Subsequently, he had a turbulent clinical course, developing acute
hydrocephalus within 1 month of the surgery for which a ventriculoperitoneal (VP)
shunt was inserted. Postoperatively, there was a stable residue of <2 cm which was
observed for 2 years [[Figure 1]]b. The residue then started increasing in size and adjuvant three-dimensional conformal
radiation therapy (RT) (54 Gy in 30#) was given. Post-RT imaging showed no tumor residue
[[Figure 1]]c. For 4 years, he was clinically asymptomatic following which he developed shunt
malfunction. He underwent multiple shunt revisions (VP and ventriculo-pleural) and
eventually an endoscopic third ventriculostomy was performed with removal of previous
shunts. A recurrence of the lesion was noted 8 years after the first surgery with
clinical worsening, i.e., imbalance on walking and diplopia. The pineal mass was lobulated,
solid-cystic, and heterogeneously enhancing in nature [[Figure 2]]. Spine screening showed no evidence of metastasis. A redo surgery was performed
through the previous supracerebellar infratentorial approach and subtotal resection
with debulking was achieved. Histopathology showed a tumor composed of cuboidal cells
and perivascular rosettes. There was absence of pineocytomatous rosettes, mitosis,
necrosis, or microvascular proliferation. Immunohistochemistry (IHC) analysis showed
negative glial fibrillary acidic protein, focally positive synaptophysin and epithelial
membrane antigen, positive S100, and pancytokeratin (AE1/AE3). Ki-67 proliferation
index was <1%. These findings were consistent with a PTPR (WHO Grade II) [[Figure 3]]. The pathology findings were reconfirmed by a second pathologist in another institute.
Due to the low proliferative index and absence of mitosis, it was decided to withhold
any form of adjuvant treatment. However, the symptoms recurred within 6 months of
the second surgery and there was radiological progression of the lesion without spine
metastasis [[Figure 4]]a. A re-exploration was performed to debulk the tumor further [[Figure 4]]b. The tumor now showed additional features of necrosis and a markedly increased
Ki-67 score of 9%. A VP shunt was later re-inserted for ventriculomegaly. Cerebrospinal
fluid (CSF) was devoid of any malignant cells. He was referred for RT which has been
unfortunately delayed due to the nationwide lockdown currently. At 6 months of follow-up
[[Figure 4]]c, the patient is now clinically stable and able to perform day-to-day chores with
some help.
Figure 1: (a) Magnetic resonance imaging of the brain T1-weighted axial, T1-weighted sagittal,
FLAIR coronal (Left to Right) images showing a 3 cm ͯ 2.5 cm solid mass in the pineal
gland with few cystic areas. Lesion hyperintense on T1-weighted images. (b) Magnetic
resonance imaging brain FLAIR, T2-weighted and postcontrast (Left to Right) axial
images after the first surgery showing the hyperintense residue which was heterogeneously
enhancing. (c) Magnetic resonance imaging brain T1-weighted axial, T1-weighted sagittal,
T2-weighted axial, postcontrast axial (Left to Right) images after radiation therapy
showing the resolution of the lesion without recurrence
Figure 2: (a) Magnetic resonance imaging brain T1-weighted axial image showing a 5 cm ͯ 3 cm
ͯ 2 cm recurrence of the pineal mass. Lesion showing patchy hyperintensity on T1 sequence.
(b) Magnetic resonance imaging of the brain T2-weighted axial image denoting the solid
cystic characteristic of the lesion. (c) Magnetic resonance imaging brain postcontrast
axial image showing heterogeneous enhancement within the lobulated lesion (d) Magnetic
resonance imaging brain postcontrast coronal image showing heterogeneous enhancement
within the lobulated lesion
Figure 3: (a) Histopathology image with hematoxylin and eosin stain (Magnification x 100) showing
perivascular pseudorosettes (black arrow) and red blood cells (white arrow). (b) Immunohistochemistry
analysis showing positive S-100 (yellow arrow). (c) Immunohistochemistry analysis
showing positive pan-cytokeratin (orange arrow). (d) Immunohistochemistry analysis
showing a focally positive epithelial membrane antigen (blue arrow)
Figure 4: (a) Magnetic resonance imaging of the brain T1 weighted axial, T1 weighted sagittal,
T2-weighted axial, postcontrast axial (Left to Right) images showing the residual
lesion after subtotal resection. (b) Magnetic resonance imaging of the brain T1 weighted
axial, T1 weighted sagittal, T2-weighted axial, postcontrast axial (Left to Right)
images showing the rapid increase in the size of the residual lesion within 6 months
of the previous scan. (c) Magnetic resonance imaging brain T1-weighted axial, T2-weighted
axial, postcontrast axial (Left to Right) images showing the stable residue after
the third surgery with ventriculomegaly for which a ventriculoperitoneal shunt was
inserted later
Discussion
The pineal gland is histologically composed of a mixture of primary cells known as
pinealocytes, glial cells, and germ cells. Correspondingly, the predominant primary
pineal tumors can be classified as pineal parenchymal tumors, pineal germ cell tumors
or glial tumors. The 2016 update of CNS tumors by the WHO lists pineal tumors as pineocytoma
(WHO Grade I), pineal parenchymal tumor of intermediate differentiation (WHO Grade
II/III), pineoblastoma (WHO Grade IV), and the relatively new, pathological entity
papillary tumor of the pineal region (WHO Grade II/III).[[4]] PTPR, as a separate pathology, was described in 2003 by Jouvet et al.[[5]] Their case series of six patients with uniform pathological features, hypothesized
them to be of ependymal origin from the circumventricular subcommissural organ.
PTPR is composed of an admixture of epithelial cells, papillae, and cells of ependymal
differentiation. WHO grades them as either Grade II or III tumors. This differentiation
can be done on the basis of mitotic count (< or > than 5/10 hpf) and MIB-1 score (<
or >10%).[[6]] Recurrence is fairly common and strongly dependent on the mitotic rate and proliferation
index with rates as high as 63%–68% reported in the two largest series of PTPR in
literature.[[3]],[[7]] PTPR shows a propensity to spread to the brain parenchyma rather than showing spinal
leptomeningeal metastasis, which tends to occur in higher grades of pineal parenchymal
tumors.[[6]] IHC for cytokeratin marker is essential to rule out a pineocytoma (Grade I) from
a PTPR (Grade II/III), since pineocytomas too can show pseudopapillae formation.[[8]]
In our case, the pathology findings 8 years ago showed small uniform round cells with
rosettes classically suggestive of a pineocytoma. An IHC analysis for cytokeratin
markers was not done which, in hindsight, would have most probably confirmed the diagnosis
of PTPR masquerading as a pineocytoma. This tumor was then effectively controlled
with adjuvant radiation for 8 years till a recurrence of PTPR was noted with MIB-1
index <1%. The second recurrence within 6 months and a markedly increased MIB-1 of
9% shows a unique tumor capable of recurrence even after 9 years of follow-up.
Radiologically, these tumors are solid-cystic, well-defined in nature with a characteristic
T1 hyperintensity and show mild heterogeneous enhancement on contrast administration.[[9]] The lesion is usually centered on the posterior commissure and obstructive hydrocephalus
due to blockage of the aqueduct is fairly common.
The common differential diagnosis includes pineal parenchymal tumors, choroid plexus
papilloma, papillary ependymoma, papillary metastatic carcinoma, and papillary meningioma.
Although there have been reports favoring the role of a biopsy[[10]] followed by adjuvant radiation or radiosurgery,[[11]] a multicenter study of 44 cases of PTPR[[12]] has found that only gross total resection along with younger age group statistically
influences OS. Maximal safe resection of the lesion with a concurrent CSF diversion
maneuver also provides adequate tissue samples for immunohistochemical analysis. The
same study has also reported an average progression-free survival of around 5 years.
Adjuvant RT offers substantial local control in appropriate cases[[13]] and hence may be offered to patients with subtotal resection or if the lesion pathologically
shows a high mitotic count (≥3/10 hpf) with a high MIB-1 index (≥10%). Adjuvant chemotherapy
or targeted therapy in the form of bevacizumab (antibody against vascular endothelial
growth factor)[[14]] must be reserved for patients with recurrence or proven metastasis.
Conclusion
Primary pineal tumors by itself are a rare entity and papillary pineal tumors are
even rarer to occur. Their description has been gradually increasing in literature
since 17 years ago when it was formally described. IHC for cytokeratin marker is necessary
for its diagnosis as it shares pathological features with a more benign pineocytoma.
Although these tumors can show an aggressive histology with a WHO grading of II or
III, gross total resection and younger age groups are known to offer a good outcome.
The role of adjuvant treatment in the form of radiation or chemotherapy is not yet
proven, though it may be considered in cases of incomplete resection or a high proliferative
index. There is marked tendency for recurrence to occur, even as late as 10 years,
and hence a long-term follow-up is essential to diagnose it early.
