Neoplasms of the pineal gland

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Neoplasms of the pineal gland

Neoplasms discussed in this chapter are pineal parenchymal neoplasms, the papillary tumor of the pineal region, and primary central nervous system (CNS) germ cell neoplasms. Nearly all primary CNS germ cell neoplasms arise in the pineal or suprasellar regions but very rare examples occur in other midline regions of the neuraxis, such as the spinal cord. Gliomas, meningiomas, and metastatic tumors may all occur in the region of the pineal gland, but are considered in other chapters.

NEOPLASMS IN THE PINEAL GLAND

These may present with:

Raised intracranial pressure due either to mass effect or aqueduct compression and subsequent hydrocephalus.

Brain stem compression, producing Parinaud syndrome (paralysis of gaze in the vertical plane), other gaze palsies, nystagmus, ataxia, or long tract signs.

PINEAL PARENCHYMAL NEOPLASMS

Approximately 20% of pineal parenchymal neoplasms are pineocytomas, 30% are pineoblastomas, and 50% are intermediate neoplasms.

Pineal parenchymal neoplasms represent 15–30% of pineal tumors, but only 0.5% of intracranial tumors.

Patients presenting with pineal parenchymal neoplasms are mostly in their 3 rd or 4th decade.

There is an equal incidence of pineal parenchymal neoplasms in males and females.

Pineoblastomas occur at a younger mean age (approximately 20 years of age) than pineocytomas (approximately 40 years of age).

Rarely, pineoblastomas are associated with bilateral retinoblastomas in children.

Classic pineocytomas respond relatively well to surgery and focal radiotherapy.

Other pineal parenchymal neoplasms may metastasize through cerebrospinal fluid pathways, and show a variable response to surgery and adjunctive therapies.

PINEAL PARENCHYMAL NEOPLASMS

The developed pineal gland consists of nests of pineocytes enclosed by fibrovascular septa. Pineocytes are neuroepithelial cells, contain abundant secretory granules, and have elongated processes with club-like endings that extend towards blood vessels. Melatonin, a hormone with effects on the sleep–wake cycle, and serotonin are the major products of the pineal gland and, like cells in the retina, pineocytes can produce S antigen. The principal types of pineal parenchymal tumor are:

pineocytoma

pineal parenchymal tumor of intermediate differentiation

pineoblastoma.

Many pineal parenchymal neoplasms are not readily classified as pineocytomas or pineoblastomas and end up in the intermediate category. The mixed pineal parenchymal tumor combines features of a pineocytoma and pineoblastoma and is very rare. The term pinealoma should no longer be used.

MACROSCOPIC APPEARANCES

Pineocytomas are firm gray neoplasms. Pineoblastomas are softer and sometimes gelatinous in texture and may contain areas of hemorrhage and necrosis. Although both types of neoplasm may be circumscribed, pineocytomas usually compress surrounding tissues (Fig. 39.1), while pineoblastomas tend to infiltrate the midbrain, third ventricle, or sometimes the thalamus and hypothalamus. Pineoblastomas frequently disseminate throughout the CNS along CSF pathways.

39.1 Pineocytoma.
Arising from the pineal gland, this neoplasm has partly invaded and distorted the rostral brain stem.

The pineocytoma consists predominantly of small monomorphic cells set in a fibrillary background (Fig. 39.2). The cells are generally arranged in sheets, though a nodular pattern may occasionally be evident. A characteristic feature is the formation of pineocytomatous rosettes, which are relatively large zones of fine, fibrillary processes surrounded by an oval arrangement of neoplastic cell nuclei (see Fig. 39.5). The neoplastic cells generally resemble the cells of normal pineal gland, with their argyrophilic processes which may have club-like terminal expansions. Their processes express NSE and synaptophysin, and at the ultrastructural level contain microtubules and a few dense core vesicles. Some cells label with antibodies to S antigen.

39.2 Pineocytoma.
(a) Pineocytomatous rosettes dominate this region of a typical pineocytoma. (b) In a smear preparation, the cells of this pineocytoma are characterized by uniformity, delicate cytoplasmic processes, and tiny nucleoli. (c) Silver impregnation of the neuritic processes in a pineocytomatous rosette. (d) Cytologic pleomorphism as marked as here may be seen in pineocytomas and intermediate pineal parenchymal neoplasms. In an otherwise typical pineocytoma with pineocytomatous rosettes, but without mitoses and focal increases in nuclear:cytoplasmic ratio, it is not thought to be an adverse prognostic sign. (e) Widespread immunoreactivity for neurofilament proteins is typical of pineocytomas.

Cytologic pleomorphism, manifesting occasionally as giant cells with misshapen, hyperchromatic nuclei, may be found in scattered groups of cells. Provided these cells are not accompanied by mitoses and other atypical cells with a high nuclear:cytoplasmic ratio, they are not thought to be an adverse prognostic sign. Mitoses are exceptional in pineocytomas. Ganglion cells may be found in some pineocytomas.

Cells in a pineocytoma are usually immunoreactive for neurofilament proteins. Immunolabeling for GFAP is confined to reactive astrocytes. Electron microscopy may reveal cilia with a 9 + 0 configuration, as well as dense core vesicles.

Intermediate or mixed pineal parenchymal neoplasms

Intermediate and mixed pineal parenchymal tumors occupy a middle ground between pineocytoma and pineoblastoma:

The pineal parenchymal tumor of intermediate differentiation is characterized by a syncytial or occasionally lobular architecture (Fig. 39.3). Some of its cells may resemble those of a pineocytoma, but it lacks the well-differentiated features of this tumor, including pineocytomatous rosettes. Collections of ‘blast’ cells are also missing. Cytologic pleomorphism is variable, but usually not marked. Mitoses are readily found. Ganglion cells and giant cells are occasionally evident. Immunoreactivity for neuronal markers may be prominent. This variant sometimes metastasizes throughout the CNS. Indicators of a more favorable outcome among intermediate tumors are immunoreactivity for neurofilament proteins, and a mitotic count of less than 6/10 hpfs.

39.3 Two examples of the intermediate pineal parenchymal tumor (a) and (b). These lacked pineocytomatous rosettes and embryonal cells and had a higher cell density than exhibited by pineocytomas. The expression of neurofilament proteins is variable, but was strong and widespread in this example associated with survival over more than 10 years (c). Mitotic figures are present, but usually not numerous, and Ki-67 immunolabeling is moderate (d), intermediate between levels seen in pineocytomas and pineoblastomas.

The rare mixed pineocytoma/pineoblastoma is characterized by groups of small, rapidly proliferating cells in a neoplasm which otherwise has the architecture and cytology of a pineocytoma. The small ‘blast’ cells confer the behavioral properties of a pineoblastoma upon this neoplasm.

Pineoblastoma

The pineoblastoma resembles the classic (non-desmoplastic) medulloblastoma, and was previously grouped with other embryonal neoplasms of neuroepithelial lineage in the broad category of primitive neuroectodermal tumors (Chapter 38). It contains round or polyhedral cells with a high nuclear:cytoplasmic ratio, which are arranged in sheets or lobules (Fig. 39.4). Mitoses and apoptotic bodies are generally plentiful. Neuroblastic (Homer Wright) and Flexner–Wintersteiner rosettes may occasionally be found, but pineocytomatous rosettes are not a feature of the typical pineoblastoma (Fig. 39.5), being found only in the rare mixed tumor. Necrosis and hemorrhage are common, while melanin-producing cells or signs of mesenchymal differentiation, such as striated muscle or cartilage, are exceptional. Immunoreactivity for neuronal markers may be local or widespread (Fig. 39.4), and pineoblastomas may label with antibodies to retinal S antigen.

39.4 Pineoblastoma.
(a,b) Monomorphic round cells with a high nuclear:cytoplasmic ration and variably hyperchromatic nuclei are evident. Mitotic figures are readily found. (c) The tumor has a propensity to disseminate within CSF pathways; this clump of cells was detected in lumbar CSF in a patient with several metastatic deposits in the spinal meninges. Lobules of neoplastic cells have labeled with antibodies (d) to neurofilament protein, and (e) to synaptophysin.

39.5 Rosettes in CNS neoplasms.
Diagrammatic representation of rosette-like structures in CNS neoplasms. The pineocytomatous rosette is larger than the rest.

PAPILLARY TUMOR OF THE PINEAL REGION

The papillary tumor of the pineal region (PTPR) is rare. Although of uncertain histogenesis, there is evidence to indicate derivation from specialized ependymal cells in the subcommissural organ. It presents in adults and children. The PTPR has yet to be accorded a WHO grade; however, local recurrence after surgery is common. Macroscopically, PTPR cannot be distinguished reliably from differentiated pineal parenchymal tumors.

MICROSCOPIC APPEARANCES

The tumor exhibits papillary projections or a syncytial pattern and consists of epithelioid cells, which may be cuboidal or columnar (Fig. 39.6). Cytoplasmic clearing is occasionally found. Rosette formation, either Homer Wright or Flexner–Wintersteiner, may be evident. Mitotic activity is generally low, but can rise to moderate levels in some regions.

39.6 A papillary architecture characterizes the PTPR (a), which consists of poorly defined epithelioid cells with sparse mitotic activity (b). All PTPRs show immunoreactivity for cytokeratins (c), but only rare examples have a small population of GFAP-positive cells (d).

Immunoreactivities for cytokeratins and CD56 are widespread. Membranous EMA immunolabeling is sparse, but may label the lumen of rosettes. There is no convincing immunoreactivity for NFP, or synaptophysin. In some PTPRs, occasional cells may show variable GFAP immunolabeling, but most tumors are GFAP-negative. Ultrastructural examination shows signs of ependymal differentiation.

PINEAL CYST

A pineal cyst is a common finding at necropsy. Although it distorts the pineal gland, it rarely causes symptomatic compression of other structures. However, a pineal cyst can present like other pineal neoplasms, tending to affect young adults.

BIOPSY OF PINEAL GLAND MASSES

The ease with which a pineal mass is diagnosed depends partly upon the amount of tissue obtained. Often the pathologist is presented with only a tiny piece of tissue and it is then important not to overstate any conclusions.

In addition to hematoxylin and eosin, histologic preparations should include periodic acid–Schiff, and reticulin (to assess lobularity).

Histology may reveal an obvious pathologic process, but be prepared to cut many sections for immunohistochemistry.

Useful antibodies for assessing pineal parenchymal neoplasms are those to synaptophysin, neurofilament protein, glial fibrillary acidic protein, and Ki-67.

Useful antibodies for assessing germ cell neoplasms are those to low molecular weight cytokeratins, placental alkaline phosphatase, CD117, OCT4, α-fetoprotein (AFP), and β-human chorionic gonadotropin (β-HCG).

If possible, keep a small piece of tissue for ultrastructural examination.

Diagnostic difficulties when only a small amount of tissue is available

Monomorphic round cells in a fibrillary background containing no mitoses may be normal pineal gland, pineocytoma, or (rarely) central neurocytoma (from third ventricle). Dystrophic calcification favors pineal gland. Lobularity of the pineal gland may be lost when it is compressed. Many pineocytomatous rosettes indicate a diagnosis of pineocytoma. Pineocytoma contains zonulae adherens junctions, unlike the neurocytoma.

Elongated cells with fibrillary processes plus scattered Rosenthal fibers may be seen in a pineal cyst or a pilocytic astrocytoma. Dense gliosis is seen at the edge of a pineal cyst. Nuclear pleomorphism and hyperchromasia, microcystic areas, and neovascularization favor a diagnosis of pilocytic astrocytoma.

MICROSCOPIC APPEARANCES

The pineal cyst has a thin wall typically composed of three layers; a fibrous outer layer, a rim of pineocytes and an inner layer of glial tissue containing Rosenthal fibers (Fig. 39.7). Reactive astrocytes of the inner rim have a variable nuclear:cytoplasmic ratio, and may show an atypia that is degenerative. Surrounding pineal gland may appear compressed.

39.7 Pineal cyst.
(a) The cyst cavity (right) is lined by a layer of gliotic tissue (arrow), around which a rim of pineocytes is evident (left). (b) The pineocytes are immunopositive for neurofilament proteins. (c) In this part of the cyst wall, astrocytic gliosis entraps pineocytes. Rosenthal fibers and dystrophic calcification are frequently found.

PRIMARY CNS GERM CELL NEOPLASMS

Primordial germ cells disseminate widely throughout the developing embryo. However, most germ cell tumors (GCTs) arise in:

the gonads

the diencephalon, mainly in the pineal and suprasellar regions

the mediastinum.

The pathology and biology of CNS GCTs are very similar to those of gonadal GCTs. Indeed, the World Health Organization (WHO) classification of GCTs at the different sites listed above is the same, the terms seminoma (testis), dysgerminoma (ovary), and germinoma (CNS) being interchangeable. A germinoma must first be differentiated from a nongerminomatous GCT because germinomas are particularly sensitive to radiotherapy. Nongerminomatous GCTs range from slowly growing mature teratomas to undifferentiated neoplasms that grow and spread rapidly. GCTs recognized in the WHO classification of neoplasms of the CNS are germinomas, embryonal carcinomas, yolk sac tumors (endodermal sinus tumors), choriocarcinomas, teratomas (mature, immature, and with malignant transformation – usually carcinoma or sarcoma), and mixed GCTs (Fig. 39.8).

39.8 Hypothetical scheme for the derivation of GCTs.

GERMINOMAS

MACROSCOPIC APPEARANCES

Germinomas are generally soft, friable, and well-circumscribed masses (Fig. 39.9). Diffuse invasion of adjacent structures is unusual, but may occur, simulating a glioma. Cysts may be present.

39.9 Pineal germinoma.

MICROSCOPIC APPEARANCES

Pineal and suprasellar germinomas have the same histologic features as ovarian dysgerminomas and testicular seminomas. Groups of plump, round neoplastic cells with prominent nucleoli are surrounded by aggregates of reactive T lymphocytes, which may be numerous and distract the pathologist from the true nature of the pathology (Fig. 39.10). The neoplastic cells often have clear, glycogen- rich cytoplasm. They label with antibodies to placental alkaline phosphatase in all but about 5% of cases, and sometimes with antibodies to cytokeratins. Immunoreactivity for CD117 is detected in many germinomas and is specific for this tumor among GCTs. OCT4 is almost always expressed by germinomas, but embryonal carcinomas may also be OCT4-positive. Granulomatous inflammation may be seen, and in small biopsies can cause confusion with sarcoidosis and tuberculosis.

39.10 Germinoma.
(a,b) Sheets of large cells, many with cytoplasmic clearing and prominent nucleoli, are divided by fibrous septa and admixed with a lymphocytic infiltrate. A few syncytiotrophoblastic giant cells may be present and are immunoreactive for β-HCG. Tumor cells in germinomas may demonstrate immunoreactivity for placental alkaline phosphatase (c), CD117 (d), or OCT4 (e).

The occurrence of isolated syncytiotrophoblastic giant cells reacting with antibodies to the β-subunit of human chorionic gonadotrophin has no prognostic significance in germinomas. However, if the β-HCG concentration is slightly raised in the CSF, an assiduous search should be undertaken for additional nongerminomatous elements. Similarly, an elevated α-fetoprotein (AFP) level indicates a probable diagnosis of mixed GCT.

CNS GERM CELL TUMORS (GCTS)

GCTs comprise germinomas (approximately 50%), teratomas (20%), mixed GCTs (25%), and pure nonteratomatous nongerminomatous GCTs (5%).

At presentation 75% of patients are 10–20 years of age, and 95% are under 33 years of age.

Germinomas occur most commonly around puberty.

Choriocarcinomas and teratomas tend to present earlier (i.e. before puberty).

GCTs show no familial tendency.

The male:female ratio of pineal region GCTs is 2:1.

Diabetes insipidus as a presenting symptom is most commonly associated with a suprasellar germinoma.

GCTs may metastasize throughout the CSF pathways (negative CSF cytology does not exclude this) and outside the CNS (this is more common for nongerminomatous than germinomatous GCTs).

GCTs are often treated without biopsy if serum or CSF markers (AFP, β-HCG) are raised.

If a mixed GCT is treated with radiotherapy or chemotherapy on the basis of raised markers it may relapse as a symptomatic teratoma (growing teratoma syndrome).

EMBRYONAL CARCINOMA, YOLK SAC TUMOR, AND CHORIOCARCINOMA

Examples of nongerminomatous GCTs with a pure histologic picture of embryonal carcinoma, yolk sac tumor, or choriocarcinoma are rare. Mixed GCTs predominate. Elevation of the levels of β-HCG or AFP in CSF or blood strongly suggests the presence of one of these neoplasms.

MICROSCOPIC APPEARANCES

Embryonal carcinoma

This appears microscopically as sheets of large, moderately pleomorphic cells with a glandular, cribriform, papillary or solid arrangement. Clear cytoplasm may be a feature of some cells. Mitoses and necrosis are evident. Immunohistochemistry reveals reactivity for CD30 and OCT4, the latter a feature shared with germinoma. There is also scattered reactivity for low molecular weight cytokeratins (Fig. 39.11), and cells may occasionally label with antibodies to placental alkaline phosphatase, β-HCG, and AFP (Table 39.1).

Table 39.1

Immunohistochemistry of germ cell tumors

+, usually immunoreactive; ±, may be focally immunoreactive; −, not immunoreactive; m.w., molecular weight; CK, cytokeratins; PLAP, placental alkaline phosphatase; AFP, a-fetoprotein; β-HCG, beta-human chorionic gonadotrophin.

^a Giant syncytiotrophoblastic cells show immunoreactivity with antibodies to β-HCG.

^b No immunoreactivity with antibodies to vimentin.

^c Very rare immunoreactivity with antibodies to CD117.

^d Syncytiotrophoblastic cells show immunoreactivity with antibodies to human placental lactogen.

39.11 Embryonal carcinoma.
This tumor shows a variable architecture. (a) Broad cords. (b) Acini. (c) A cribriform pattern. (d) Solid. (e) Focal cytokeratin immunoreactivity is characteristically present.

Differentiated teratomas are well circumscribed and usually have a lobulated or partly cystic appearance (Fig. 39.14). They may contain a mixture of tissues derived from three embryonic cell lines (i.e. ectoderm, mesoderm, and endoderm). Mature teratomas contain only adult tissues (Fig. 39.15), while embryonic tissues predominate in immature teratomas. Disorganized embryonic neuroepithelial tissue is commonly seen, often as a cluster of rosettes. Malignant transformation of a mature teratoma to carcinoma (Fig. 39.16), sarcoma, or even primitive neuroectodermal tumor may rarely occur. The term ‘mixed germ cell tumor’ encompasses any combination of the GCTs described above (Fig. 39.17). The recognition of mixed elements is clinically important, determining strategy for adjuvant therapy.