Pathology of Pineal Parenchymal Tumors

Tumors of the pineal region can arise from multiple cellular origins and thus represent a very heterogeneous group of pathologies. Such tumors include pineal parenchymal tumors, germ cell tumors, astrocytomas, ependymomas, and papillary pineal tumors. Within the subgroup of pineal parenchymal tumors, there is a histopathologic spectrum ranging from pineocytoma to pineal parenchymal tumors of intermediate differentiation to pineoblastoma. The current World Health Organization classification and the pathologic features of each of the pineal parenchymal tumor subtypes are reviewed in this article.

Neoplasms of the pineal region are a rare group of tumors accounting for less than 1% of all intracranial tumors, and represent a very clinically and pathologically heterogeneous group of tumors including pineal parenchymal tumors, germ cell tumors, astrocytomas, ependymomas, and papillary pineal tumors. Many investigators have therefore stressed the importance of a tissue-based diagnosis for patient management. Tumors thought to arise from the parenchymal cells of the pineal gland, also referred to as pineal parenchymal tumors, consist of approximately one-third of all tumors of the pineal region. The latest World Health Organization (WHO) classification scheme, released in 2007, categorizes pineal parenchymal tumors into 3 subtypes with up to 4 different grade categories: (1) WHO Grade I pineocytomas, (2) WHO Grade II or III pineal parenchymal tumors of intermediate differentiation, and (3) WHO Grade IV pineoblastomas. This review focuses on the spectrum of pathologic features found in these pineal parenchymal tumors.

Pineocytomas

Pineocytomas are the lowest grade (WHO Grade I) tumors with the most favorable prognosis. The 5-year survival has been reported to range from 64% to 91%, although the latter figure is probably more accurate when strictly defined using the most current criteria. These tumors are found most commonly in the adult population, and clinically appear to progress slowly, although symptomatic recurrences have commonly been reported even after aggressive resection. Pineocytomas grossly are well circumscribed and cause symptoms by local growth with local compressive mass effect.

The histologic features of pineocytomas include their cellular resemblance to mature pineocytes, and they are primarily composed of well-differentiated cells. However, in contrast to the normal pineal gland’s lobular architecture created by gliovascular septae ( Fig. 1 A), pineocytomas are arranged in sheets of rounded tumor cells with variable oligodendroglioma-like clear haloes ( Fig. 1 B). Portions of the tumor are occasionally found to have focal ganglionic and/or astrocytic differentiation, and at times cells displaying features of ganglion cells and astrocytes can be found within the same tumor. Early studies have suggested a more benign clinical course for pineocytomas with neuronal or neuronal and astrocytic differentiation, with a greater tendency to remain localized as compared with pineocytomas with astrocytic differentiation. More recent studies, however, have failed to establish this correlation. Pineocytomatous rosettes ( Fig. 1 C), also referred to as pineocytic rosettes, are frequently observed, and are believed to be a distinct feature of pineocytomas. These rosettes consist of tumor cells surrounding pink neuropil (collections of neuronal processes) and are similar in appearance to Homer-Wright rosettes, but are formed by mature rather than primitive cells and tend to be somewhat larger and more irregular. Despite the occasional resemblance to oligodendrogliomas, neuronal differentiation is evident in the form of diffuse synaptophysin immunoreactivity ( Fig. 1 D) and often strong positivity for neurofilament protein ( Fig. 1 E), the latter occasionally highlighting bulbous axonal swellings typical of pineal differentiation (arrows in Fig. 1 E). The level of proliferative activity is relatively low in pineocytomas, with mitoses being rare and MIB-1 (Ki-67) labeling indices averaging around 1.6% ( Fig. 1 F) (the MIB-1 labeling index is the fraction of tumor cells that is labeled by Ki-67). In one study, the MIB-1 labeling index was significantly different for each of the 3 pineal parenchymal tumors, and the investigators suggest its use as an additional measure to differentiate between the 3 subtypes.

Cytogenetic studies of pineocytomas have revealed high expression of genes related to phototransduction of the retina (OPN4, RGS16, and CRB3), as well as those related to biosynthesis of melatonin (TPH and HIOMT). Alterations in chromosomes X, 1, 5, 11, and 22 have been demonstrated in karyotypes from pineocytomas, but on comparative genomic hybridization analysis chromosomal changes were uncommon, with most samples having no such changes.

Pineal parenchymal tumors of intermediate differentiation

Pineal parenchymal tumors of intermediate differentiation (PPTID) share some features with both pineocytomas and pineoblastomas, but generally lack the more definitive diagnostic features that define these two extremes. The addition of this third intermediate group of tumors in between the two ends of the spectrum of degree of cellular differentiation was proposed by Schild and colleagues in 1993.

At present no definite criteria exist for PPTIDs, but the tumor cells generally have moderate nuclear atypia, mitotic counts are higher (0–16 per 10 high-power fields [HPF]) than pineocytomas, and pineocytic rosettes are inconspicuous, consistent with a partial loss of differentiation. Accordingly, the MIB-1 labeling index is generally higher than in pineocytomas, ranging from 8% to 11.8%. Less common features include endothelial hyperplasia and necrosis, but PPTIDs lack the primitive small round cell appearance seen in pineoblastomas. Morphologically, PPTIDs exist in 3 separate subtypes, including (1) the endocrine-like subtype with lobulated growth pattern and increased vascularity ( Fig. 2 A), (2) the oligodendroglioma/neurocytoma-like type with diffuse growth patterns, and (3) transitional type with areas of lobulated and/or diffuse growth patterns intermixed with focal pineocytoma-like regions containing well-formed pineoctyomatous rosettes. Multiple studies have noted the impact of the range of histologic features found in pineal parenchymal tumors, even within PPTIDs, on the prognosis of the patients. In a study by Jouvet and colleagues, the investigators proposed a new system dividing PPTIDs into two subgroups based on their histology. Low-grade PPTIDs, representing WHO Grade II, can have any of the 3 growth patterns described (transitional, lobulated, or diffuse), and have high expression of neurofilament, similar to pineocytomas. The low-grade PPTIDs also have 0 to 5 mitoses per 10 HPF ( Fig. 2 B), with moderate MIB-1 indices ( Fig. 2 C). High-grade PPTIDs are WHO Grade III, do not contain any pineocytoma-like regions, and hence have lobulated or diffuse growth patterns with very limited neurofilament expression, reflecting a more limited degree of neuronal differentiation in comparison with lower-grade examples. The mitotic index is also higher, with typically more than 5 mitoses per 10 HPF encountered, and high MIB-1 labeling indices ( Fig. 2 D). Vascular proliferation and necrosis are also more commonly found in high-grade PPTIDs.