Sabato 27 ottobre 2012 - Pacini Editore

RElaziONi
Pineal parenchymal tumors
S. Rossi
Ospedale Regionale di Treviso
This presentation focuses on the classification and grading of
pineal parenchymal tumors and includes a discussion on the
differential diagnosis with the other entities encountered in
the pineal region.
Pineal parenchymal tumors are histogenetically linked to the
pineocyte, which is a cell with photosensory and neuroendocrine
functions. During the late stages of the intrauterine life
and the early post-natal period, the pineal gland consists of rosettes
with abundant melanin and cilia, similar to those of the
developing retina. Progressively the pigmented cells decrease
and NSE-positive pineocytes accumulate, by post-natal age
of 1 year representing the predominant cells. To some extent,
the pineal parenchymal tumors mimic the developmental
stages of the pineal gland, since they constitute a morphologic
continuum from the most mature pineal tumor (pineocytoma
WHO grade I) to pineal parenchymal tumors of intermediate
differentiation (PPTIDs; further stratified into WHO grades II
or III) to the highly aggressive small round cell tumor, pineoblastoma
(WHO grade IV) somewhat reminiscent of the fetal
pineal gland. Coherently, pineal tumors tend to express synaptophysin,
NSE and neurofilament from diffusely in the more
mature tumor forms to focally in pineoblastoma. They also
may express neuronal markers and retinal S-antigen. These
tumors may compress adjacent structures including the cerebral
aqueduct, brain stem, and cerebellum. Signs and symptoms
therefore relate to obstructive hydrocephalus, increased
intracranial pressure and neuro-ophthalmologic dysfunction
(Parinaud syndrome). On magnetic resonance imaging, they
are T2 bright with contrast enhancement on post-gadolinium
T1 sequences.
PINEOCYTOMA. At the most mature/differentiated end of
the spectrum lies the pineocytoma (1,2). Most pineocytomas
occur in adults. At low power, they are moderately cellular
and feature a diffuse to loosely nested-growth pattern. At high
power, they are composed of medium-sized neoplastic cells
resembling mature pineocytes with round to oval nuclei and a
delicate or “salt and pepper” chromatin. Pineocytomatous rosettes
are a distinctive feature of pineocytomas, but they vary
in number and size. These structures are composed of neuropil
surrounded by neoplastic cells with non-regimented nuclei
and club-shaped terminations oriented toward the center. Notably,
some pineocytoma feature multinucleated/bizarre cells.
PINEOBLASTOMA. At the most malignant end of the
spectrum, lies the pineoblastoma, a WHO grade IV tumor
which occurs commonly in children with a mean age of 12.6
years 1 2 . They are accompanied by leptomeningeal seeding
in as many as 45% of cases and rarely by extracranial metastases.
Extent of disease at diagnosis, extent of resection and
radiotherapy affect the prognosis. Histologically they resemble
CNS PNET. At low power, they look as diffuse, highly
cellular tumors sometimes featuring either Homer-Wright or
Flexner-Wintersteiner rosettes. Interestingly, the presence of
the Flexner-Wintersteiner, as well as the possible expression
of the retinal S-antigen and the rare occurrence of the trilateral
retinoblastoma syndrome indicate the ontogenic relation with
the retinal cells. At high power, pineoblastomas are composed
of round cells with scant cytoplasm and high nuclear/cytoplasmic
ratio, with frequent molding, feature high mitotic activity
and, often, necrosis. Desmoplastic foci and anaplastic cytology
may be encountered. Interestingly, mixed tumors with
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areas of pineocytoma and areas of pineoblastomas juxtaposed
are seldom observed.
PINEAL TUMORS OF INTERMEDIATE DIFFERENTIA-
TION. In between the 2 extremes of differentiation, the pineal
parenchymal tumor of intermediate differentiation has clearly
been the most problematic category in terms of both classification
and treatment 1 2 . The reported incidence of these
tumors is highly variable reflecting the difficulties in establishing
reproducible criteria. It was first introduced by Schild
et al. In 1993 3 . PPTIDs can have 3 different morphologic
subtypes: a lobulated pattern, a diffuse pattern mimicking
oligodendroglioma or neurocytoma, and a transitional form
with lobulated and/or diffuse architecture areas intermixed
with regions containing pineocytoma-like regions featuring
the typical rosettes. Sometimes, they feature a papillary architecture
4 . The tumor cells in PPTIDs generally have less cytoplasm
than pineocytomas and show moderate nuclear atypia.
Mitotic index is variable (0 to 16 per 10 HPFs) The average
Ki-67-labeling index is 10.1% (range: 8%-11.8%.
On the base of Jouvet et al’s study 5 on PPTIDs and recently
adopted by the WHO 1 , these tumors can further be divided
in 2 subgroups although definite criteria have yet to be established.
In general, low-grade PPTIDs (corresponding to WHO
grade II) consist of transitional, lobulated, or diffuse growth
patterns, strongly express neurofilament protein, and have
fewer than 6 mitoses per 10 HPFs. High-grade PPTIDs (WHO
grade III) consist of lobulated or diffuse growth patterns (ie,
no pineocytoma-like regions) with 6 or more mitoses per 10
HPFs and limited neurofilament immunostaining. The Ki-67labeling
index is higher in the latter group. Focal necrosis,
leptomeningeal infiltration, and vascular proliferation may
also be observed.
Differential diagnosis
The main differential diagnoses of pineocytoma include normal
pineal gland and pineal cyst. While the pineocytomas
generally form sheets or expanded lobules, normal pineal
gland has small lobules and well-formed fibrovascular septae.
In the pineal cyst 3 layers are typically identified: piloid
gliosis with numerous Rosenthal fibers, compressed pineal
parenchyma, and leptomeningeal tissue.
Regarding PPTID, other entities that may occur in the third
ventricle come to the differential, the papillary tumor of the
pineal region, ependymoma, oligondroglioma and germ cell
tumors. The papillary tumor of the pineal region (PTPR)
was first described as a distinct entity in 2003 by Jouvet
et al. 6 and formally codified in the 2007 edition of WHO
Classification of Tumours of the Central Nervous System 1 .
PTPR arises exclusively in the pineal region and occurs most
commonly in adults (mean, 31.5 years). PTPRs are usually
well-circumscribed, large (2.5-4.0 cm) lesions sometimes
cystic. Histologically, at low power, they feature discrete
borders and consist of papillary areas and solid cellular
areas in variable proportion. In the papillary component,
vessels are often hyalinized and are covered by large, paleto-eosinophilic
cells arranged in a pseudostratified columnar
layering. The solid areas are composed of round to oval cells
with eosinophilic/clear/vacuolated cytoplasm or with PASpositive
inclusions variably arranged in pseudorosettes/true
rosettes/tubules. Pleomorphic nuclei may be seen in some
cases. Mitotic activity varies, ranging from 0 to 10 mitoses
per 10 HPF. Necrosis is usually found to some extent in most
tumors. Fevre-Montange et al. 7 reviewed the prognosis of
PTRP. Detailed follow-up information was obtained in 29 of
31 cases. Five-year estimates of overall and progression-free
survival were 73% and 27%, respectively. Seven patients