2020 NPB-15

This case was originally published in 2020. The information provided in this case was accurate and correct at the time of initial program release. Any changes in terminology since the time of initial publication may not be reflected in this case.

The patient is a 29-year-old man who was pronounced deceased after having seizure-like activity while incarcerated. History reportedly includes schizophrenia, bipolar disorder, and catatonic behavior. Autopsy revealed an atraumatic adult man with no significant natural disease. Neuropathologic examination revealed a 1.3 x 1.0 x 0.8-cm mass in the dorsal midbrain and pons with a soft, fleshy, gray/tan cut surface. The tumor was well-demarcated from the adjacent brainstem parenchyma and showed mass effect on the left superior and inferior colliculi and periaqueductal gray matter with compression of the cerebral aqueduct (Image A and Image B).

Tissue Site
Brainstem

The whole slide image provided is an H&E-stained slide of the brainstem from autopsy.

The tumor is comprised of lobules and trabeculae of neoplastic cells separated by thin fibrovascular septa (Image C). Tumor cells display central round nuclei, prominent nucleoli, and relatively-abundant cytoplasm (Image D). There are numerous infiltrating small lymphocytes, and nearby intraparenchymal vessels show perivascular lymphocytic cuffing. Focal palisading necrosis is noted at the junction of the tumor and the midbrain tectum (whole slide image). Tumor cells show membranous immunoreactivity for D2-40 (Image E), nuclear immunoreactivity for OCT4 (Image F), and cytoplasmic immunoreactivity for PLAP (Image G) and CD117 (not shown); they are negative for pancytokeratin (not shown). The malignancy in this case is invading the tectal plate (whole slide image) with mass effect on the brainstem and compression of the cerebral aqueduct, features that put the patient at risk for sudden death.

Germinoma is the most common primary CNS germ cell tumor and often arises in the midline, frequently in the pineal gland or suprasellar region. Patients are typically adolescent or young adult males, although females can also be affected. Clinical manifestations of midline germinomas are often insidious and may include headache, Parinaud syndrome, progressive hydrocephalus with associated increased intracranial pressure, diabetes insipidus, and visual field deficits. Neuroimaging of germinoma characteristically shows a solid, contrast-enhancing mass. Histopathologic characteristics typically include large, epithelioid cells in sheets, lobules, and cords/trabeculae with central nuclei, prominent nucleoli, and relatively abundant cytoplasm, often with optical clearing and strong PAS positivity due to glycogen content. Lymphoplasmacytic inflammation is a common feature and may be so prominent that it masks the presence of tumor cells. Granulomatous inflammation can also occasionally be seen. Tumor cells show membranous immunoreactivity for CD117 (eg, KIT or c-Kit) and D2-40 and cytoplasmic immunoreactivity for PLAP. Nuclear OCT4 immunoreactivity is more specific and sensitive for the diagnosis of intracranial germinoma than the above markers but can also be positive in embryonal carcinoma. SALL4 is another highly-sensitive pan-germ cell marker but it can also be positive in atypical teratoid/rhabdoid tumor (AT/RT).

The histologic differential diagnosis includes a variety of small round blue cell tumors, including AT/RT, Ewing sarcoma (ES), and pineoblastoma, among others. AT/RT is a CNS embryonal tumor most commonly seen in infants and young children. It frequently harbors neoplastic cells with rhabdoid morphology (eg, eccentrically-placed nuclei, prominent nucleoli, and abundant cytoplasm with well-defined cell borders). AT/RT is defined by the inactivation of SMARCB1 (INI1) or very rarely SMARCA4 (BRG1). Therefore, loss of nuclear immunoreactivity for SMARCB1 (INI1) is a sensitive and specific diagnostic marker. AT/RT may also show immunoreactivity for glial or neuronal markers such as GFAP or synaptophysin. ES is a small round blue cell tumor of bone or soft tissue that rarely involves the CNS and may do so by direct extension from the skull or spine or as a primary dural neoplasm. ES is characterized by sheets of uniform cells with round nuclei, small inconspicuous nucleoli, and scant cytoplasm with indistinct cell membranes. CD99 IHC shows a strong and diffuse membranous staining pattern. Approximately 90% of ES demonstrate a characteristic translocation, t(11;22)(q24;q12), which results in EWS-FLI1 fusion; FLI1 nuclear immunoreactivity is therefore a sensitive but nonspecific marker for diagnosis. Pineoblastoma is a poorly-differentiated embryonal neoplasm of the pineal gland most commonly seen in children and adolescents. It is characterized by sheets of small round blue cells with scant cytoplasm and occasional Homer Wright or Flexner-Wintersteiner rosettes. Pineoblastomas are typically immunoreactive for neuronal markers, and nuclear immunoreactivity for SMARCB1 (INI1) is consistently retained.

Germinomas are exceptionally sensitive to radiotherapy, and the five-year survival rate with radiation alone is in excess of 90%. Studies have investigated the role of chemotherapy in the management of germinomas and have shown that chemotherapy and combined chemotherapy/radiotherapy regimens with low-dose radiotherapy are less effective at preventing recurrence than higher dose radiotherapy alone that covers the entire ventricular space. Surgical resection is not part of the current standard therapy for germinomas.

• Germinoma is the most common primary CNS germ cell tumor, often arising in the pineal gland or the suprasellar region.
• OCT4 IHC is more specific and sensitive for germinoma than other markers (such as PLAP, CD117, D2-40), but it is also positive in embryonal carcinoma.
• Germinomas are exceptionally sensitive to radiotherapy, and the five-year survival rate with radiation alone is in excess of 90%.

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