Pathology of Pineal Region Tumors in Children

Pathophysiology

• Normal pineal gland: The pineal gland is composed of pineocytes (95%) and supporting glial cells (5%) (22, 34).  Pineocytes are the principal parenchymal neurons of the pineal gland and function as neuroendocrine transducers.  Pineocytes release melatonin and serotonin in response to light signaling detected by retinal ganglion cells and transmitted through the suprachiasmatic nucleus of the hypothalamus.  The pineal gland also receives noradrenergic signaling through the sympathetic cervical ganglion.  The release of serotonin and melatonin is therefore synchronized with sleep-wake cycles to influence secretory function of the hypothalamus and pituitary gland (22, 73).
• Three groups of pineal tumors: Tumors of the pineal region are classified into three groups on the basis of the cell of origin: germ cell tumors, pineal parenchymal tumors, and tumors of glial and miscellaneous cell origin.

Germ cell tumors

• Arise from misplaced germ cells: Germ cell tumors arise from pluripotent germ cells and exhibit a range of differentiation and malignancy potential (30).  Primordial germ cells originate in the yolk sac wall in the third week of gestation and migrate into the genital ridge via the dorsal mesentery of the hindgut in the sixth week of gestation (30).  Primordial germ cells may also widely disseminate to a variety of tissues in the early embryo, and it is theorized that misplaced embryonic tissues incorrectly enfolded into the CNS at the time of neural tube formation are the source of intracranial germ cell tumors (76).  Germ cells exhibit neoplastic transformation during puberty, a process thought to occur in response to changing levels of gonadotropins due to their carcinogenic effect on these displaced cells (41).
• Two classes: Germ cell tumors are classified as germinomatous or nongerminomatous Germinomatous germ cell tumors are more commonly referred to as germinomas.  NGGCTs include germinomas, embryonal carcinomas, endodermal sinus tumors (yolk sac carcinomas), teratomas, and choriocarcinomas.  Mixed germ cell tumors with different coexisting germ cell tumor types may also occur.
• Midline parasellar/pineal predilection: Germ cell tumors have a predilection for the midline, with 80–90% occurring within the axis from the suprasellar cistern and infundibulum to the pineal gland.  Synchronous suprasellar and pineal tumors may occur.

Pineal parenchymal tumors

• Derived from pineocytes: Pineal parenchymal tumors are derived from pineocytes within the pineal gland.  
• Three types: Pineal parenchymal tumors are classified as pineoblastoma, pineocytoma, or intermediate types on the basis of the extent and nature of cellular differentiation (24).
• Potential to differentiate: Neoplastic pineal cells have significant differentiation potential along neurosecretory or neurosensory cell lines, and may give rise to neuronal, astrocytic, ependymal retinoblastomatous and mesenchymal elements (44, 62).  Pineal parenchymal tumors may also be mixed, containing both pineocytic and pineoblastic components (24).

Glial and other tissues 

• Tumor from surrounding tissue: Tumors of the pineal region may also arise from nearby glial or mesenchymal tissue (7). 
• Non-neoplastic cysts: In addition, non-neoplastic cystic lesions of the pineal region can occur (23).

Molecular/Genetic Pathology 

Germ cell tumors

• Cytogenetic abnormalities:  Intracranial germ cell tumors have a number of characteristic molecular abnormalities, including gain of 12p, loss of 13q, and X hypomethylation.  Additionally, there can be other alterations in sex chromosomes including gain of the X chromosome. TP53 mutation and MDM2 amplification in germ cell tumors.  c-KIT mutation is common in germinoma.

Histopathology

• Tissue immunohistochemistry: Tissue immunohistochemistry plays a significant role in the diagnosis of germ cell tumors of the pineal region.  Staining characteristics for tumor markers may help to differentiate tissue pathology, particularly in cases of mixed germ cell tumor.   α-fetoprotein (AFP), a glycoprotein produced by the fetal yolk sac, may be detected in endodermal tumors, embryonal carcinomas and teratomas.  Beta human choriogonadotropin (β-HCG), a glycoprotein secreted by syncytiotrophoblastic tissue, may be detected in germinomas, choriocarcinomas, and embryonal tumors.  Germinoma tissue may exhibit immunopositivity for placental-like alkaline phosphatase (PLAP) and OCT4.  PLAP positivity may also be found in choriocarcinomas, yolk sac tumors, and embryonal carcinomas.

Germ cell tumors

Intracranial germ cell tumors have histological and immunohistochemical features similar to their gonadal counterparts.

• Germinomas: On histological examination, germinomasare composed of large, uniform, undifferentiated cells with glycogen-rich cytoplasm and vesicular nuclei.  Nests of tumor cells are surrounded by a stroma of trophoblastic cells and small reactive lymphocytes.  Mitotic figures are common, but necrosis and atypia are not usually seen.  Germinomas of the CNS have cellular and histological characteristics similar to those of testicular seminomas and ovarian dysgerminomas. Germinomas commonly exhibit c-kit overexpression, and syncytiotrophoblasts secreting β-HCG may be detected.

Germinoma H&E Stain: Note relative homogeneity of cells without evidence of necrosis or nuclear atypic

Germinoma stained for C-Kit: Immunohistochemical stain showing over expression of C-Kit

• Embryonal carcinomas: These tumors are composed of pluripotent germ cells and may give rise to embryonal tumors containing all three germ layers, which include mature and immature teratomas.  Cohesive nests and sheets of large cells with high mitotic index are viewed on histopathological examination. 

Embryonal Carcinoma H&E Stain: Note sheets of cells with scattered mitoses

• Teratomas: Teratomas are composed of fully differentiated tissues with an organoid pattern.  Mature teratomas are well-differentiated benign tumors containing mature endodermal, mesodermal, and ectodermal tissue elements with low mitotic activity.  In contrast, immature teratomas are poorly differentiated, malignant tumors containing primitive elements derived from any or all three germ layers.  Highly cellular stromal regions of immature mesenchymal and neuroectodermal tissue are seen with formation of neuroepithelial rosettes.  Sarcomatous malignant transformation to rhabdomyosarcoma or squamous cell carcinoma may also occur.

Mature Teratoma H&E Stain: Shown is mesenchymal tissue within teratoma

Mature Teratoma H&E Stain: Shown are rosettes of neuroepithelial tissue within a mature teratoma

• Choriocarcinomas: These are highly malignant tumors that exhibit extraembryonic trophoblastic differentiation, with characteristic β-HCG–secreting syncytiotrophoblasts detected on histopathological examination.  Areas of hemorrhage and necrosis are often seen. 

Choriocarcinoma H&E Stain: Shown are syncytiotrophoblasts (large, multinuclear cells in central portion of illustration)

Choriocarcinoma immunohistochemical stain: Stain showns cells secreting HCG

• Endodermal sinus or yolk sac tumors: These highly malignant tumors arise through yolk sac differentiation and are composed of epithelial cells with a primitive appearance similar to the extraembryonic mesoblast in a myxoid matrix.  Histopathological examination reveals characteristic Shiller-Duval bodies, glomerular or papillary structures formed by epithelial cells projecting around a central capillary.  Eosinophilic hyaline bodies with PAS positivity are typical, and immunopositivity for AFP is a characteristic feature.
• Mixed germ cell tumors: Mixed germ cell tumors with different coexisting germ cell tumor types may also occur.  Detection of mixed tumor types is on the rise due to increased frequency of tissue biopsy and use of tumor marker studies.  Germinoma and teratoma are the most commonly detected elements in mixed germ cell tumors.  Choricarcinomatous elements may also be detected. 

Pineal parenchymal tumors

Pineal parenchymal tumors include pineocytoma and pineoblastoma. Pineoblastomas are considered PNETs with similar histology.

• Pineocytomas: Pineocytomas are well-differentiated, benign W.H.O.grade I tumors of the pineal gland.  Pineocytomas exhibit moderate cellularity and large pineocytomatous pseudorosette formation.  Ganglionic and pleomorphic multinucleated giant cells may be present, and the MIB-1 index is typically low. Pineocytomas exhibit strong immunopositivity for synaptophysin.  Neuronal markers and neurofillament proteins may also be detected. There are no known cytogenetic or molecular alterations associated with pineocytomas.

Pineocytoma H&E stain: Shown is moderate cellularity with low mitotic rate and pseudo rosettes

• Pineoblastomas: In contrast to pineocytomas, pineoblastomas are poorly differentiated, malignant W.H.O. grade IV tumors of tightly packed small cells with scant cytoplasm, dense chromatin, and irregular or round nuclei.   Mitotic figures are typically observed, and the MIB-1 index is high.  While neuroblastic Homer-Wright rosettes may be detected, larger pineocytomatous structures are not present. Neurofillament proteins and markers of melanocytic or mesenchymal components may also be expressed. As in pineocytomas, immunostaining is positive for synaptophysin. The incidence of pineoblastomas is higher in patients with familial retinoblastoma due to RB1 mutation (trilateral retinoblastoma), but there are no known cytogenetic or molecular alterations associated with sporadic pineoblastomas.

Pineoblastoma H&E stain: Shown is a sheet of small cells tightly packed with nuclear atypic and frequent mitotic figures.

Pineoblastoma synaptophysin stain: Tissue is staining strongly positive for the immunohistochemical stain for synaptophysin

Tumors of glial and miscellaneous cell origin

• Gliomas: Glial cells in the supporting stroma of the pineal gland and nearby structures of the pineal region can be a source of tumor formation. True astrocytomas of pineal gland origin are very rare.   Astrocytomas are the most commonly diagnosed glial tumor and typically arise from the thalamus or midbrain. Papillary tumor of the pineal gland, recently recognized in the W.H.O. 2007 classification, arises from the ependymocytes in the subcommissural gland.  Glioblastomas, astroblastomas, and oligodendrogliomas can also arise in the pineal gland.
• Other tumor types:  Other types of tumors can arise in the proximity of the pineal gland but not from the gland per se.  they include ependymomas, choroid plexus papillomas, and medulloepitheliomas.  Meningiomas, hemangiomas, and cavernomas may also occur.
• Non-neoplastic cysts: Pineal cysts result from focal degeneration of the pineal gland. These lesions contain gelatinous material within a cell wall composed of an outer fibrous layer, a middle pineal parenchymal cell layer containing variable calcification, and an inner hypocellular glial tissue layer.   Other developmental cysts of the pineal region include epidermoid, dermoid, and arachnoid cysts.