Pineal and Germ Cell Tumors

Main Text

Preamble

The region in and around the pineal gland is one of the most anatomically complex intracranial sites. There are many critical structures that surround the small gland, which makes surgery of pineal region masses challenging for our neurosurgical colleagues. Accurate preoperative assessment of lesions of the pineal region is essential. A broad spectrum of both neoplasms and nonneoplastic entities can arise from the pineal gland itself or the surrounding structures.

Overall, pineal region tumors are rare, accounting for 1-3% of all intracranial neoplasms. Neoplasms in this region can be grouped into three simple overarching categories. The two most important groups arise in the midline or from cells within the pineal gland itself: (1) Germ cell tumors (GCTs) and (2) tumors of pineal parenchymal cells. The third group includes tumors of “other cells,” including metastases, rare glial tumors and other rare tumors. We begin our discussion with a brief review of anatomy and then focus on the two major types of pineal neoplasms. We then close with a brief discussion of “other cell” tumors in the pineal gland and pineal region.

Pineal Region Anatomy

Preamble

The pineal region is located under the falx cerebri, near its confluence within the tentorium cerebelli. The pineal region includes the pineal gland, adjacent CSF spaces, brain parenchyma (corpus callosum splenium, quadrigeminal plate and upper vermis), vascular structures, and meninges (25-1).

Gross Anatomy

Pineal Gland

The pineal gland is a small, rounded endocrine organ that is in the midline nestled between the superior colliculi in the quadrigeminal cistern (25-1) (25-3) (25-4). It is attached to the diencephalon and posterior wall of the third ventricle by the pineal stalk. The pineal gland also connects with the habenular and posterior commissures. The pituitary gland is supplied primarily by the medial posterior choroidal artery from P2 branches of the posterior cerebral artery (PCA). The pineal gland is primarily composed of pineal parenchymal cells called pinealocytes. Other contents include neuroglial cells, predominately astrocytes. The pineal gland produces melatonin, which plays a role in regulating the sleep/wake cycle in humans. The pineal gland is also responsible for regulation of reproductive function, such as onset of puberty in humans.

Third Ventricle

The pineal gland is located at the posterior third ventricle and abuts the two posterior recesses. Just superior to the pineal gland is the suprapineal recess of the third ventricle, just below the splenium of the corpus callosum. There is a smaller pineal recess that points posteriorly, directly into the pineal gland.

There are two commissural fiber tracts that relate to the pineal gland. The habenular commissure lies just above the pineal gland, and the posterior commissure lies below the gland. The habenular commissure connects the habenular, amygdaloid nuclei, and hippocampi. The posterior commissure (25-3)has connections with the dorsal thalamus, superior colliculi, pretectal nuclei, and other nuclei. The medial longitudinal fasciculus fibers also cross at the posterior commissure.

Fornix and Velum Interpositum

The fornices are part of the limbic system and provide primary efferent outputs from the hippocampus (25-1) (25-4). The fornices are paired C-shaped nuclei that each has four parts. The fornix crura arch under the corpus callosum splenium and form part of the medial wall of the lateral ventricles. The commissure connects the two crura, which converge to form the body. The fornix body is attached to the inferior surface of septum pellucidum and is best seen on coronal imaging. The columns or “pillars” of the fornix extend to and terminate in the mammillary bodies.

The velum interpositum (VI) is formed by a double layer of pia known as the tela choroidea. The VI stretches between the bodies of the two fornices (25-4). The VI forms the roof of the third ventricle and is closed anteriorly at the foramen of Monro. If the VI is open posteriorly, it may communicate posteriorly with quadrigeminal cistern, a normal variant called the cavum of the VI. The VI also covers the pineal gland and habenular commissure but is not attached to these structures.

Vascular Structures

The internal cerebral veins (ICVs) are paired veins that course along the VI and terminate in the quadrigeminal cistern, where they unite. With the basal veins of Rosenthal, the ICVs form the great cerebral vein of Galen (25-2). The ICVs lie above the pineal gland.

The medial posterior choroidal arteries arise from the P2 segments of the PCAs and provide the main arterial supply to the pineal gland (25-3). The pineal gland lacks a blood-brain barrier and enhances avidly.

Imaging

Physiologic pineal calcification is common and increases with age. Studies have shown that 40% of pineal glands are calcified in patients < 30 years of age. More than 1/2 of all adults have calcified pineal glands. Pineal glands are typically ≤ 10 mm but may be larger, up to 14-15 mm.

Thin-section, small FOV sagittal and coronal MR are the ideal planes to evaluate pineal region lesions. A simple way to recall the relationship of the pineal gland to its adjacent structures can be identified using sagittal sequences. From the top down, the mnemonic “Famous V.I.P.” identifies the fornix, VI, ICVs, and the pineal gland (25-4). Lesions of the fornix, VI, and ICVs will displace the pineal gland inferiorly. Lesions that arise from the tectal plate displace the pineal gland anteriorly and superiorly, while lesions of the third ventricle displace it posteriorly.

Germ Cell Tumors

Overview of Germ Cell Tumors

The most common pineal gland neoplasms are germ cell tumors (GCTs), accounting for ~ 40% of pineal neoplasm. GCTs are divided into two basic groups, germinomas and nongerminomatous GCTs (NGGCTs). CNS GCTs account for 2-3% of all primary intracranial neoplasms and 3-8% of pediatric brain neoplasms.

Germinomas represent ~ 2/3 of all GCTs. 1/3 are NGGCTs. NGGCTs include both teratomas and a heterogeneous group of miscellaneous nongerminomatous malignant germ cell neoplasms. According to the 2021 WHO classification of CNS tumors, NGGCT types are mature teratoma, immature teratoma, teratoma with somatic-type malignancy, embryonal carcinoma, yolk sac tumor, choriocarcinoma, and mixed GCTs.

Germinoma

Etiology

The normal mature pineal gland does not contain germ cells. Once thought to arise from “aberrant migration” of primordial germ cell layers, recent studies show that activation of the MAPK &/or PI3K-AKT signaling pathway is the genetic driver of pure GCTs as well as NGGCTs.

Pathology

Location

Although GCTs may arise in many intracranial locations, they have a distinct predilection for midline structures (25-5) (25-6). Between 80-90% “hug” the midline, extending along the midline axis from the pineal gland to the suprasellar region (25-6) (25-7) (25-9). 1/2-2/3 are found in the pineal region with the suprasellar region, the second most frequent location, accounting for 1/4-1/3 of germinomas.

Off-midline germinomas occur in only 5-10% of cases (25-10A). The basal ganglia and thalami are the most common off-midline sites. Periventricular lesions are an uncommon presentation.

Size and Number

Pineal germinomas that do not invade the tectum or cause hydrocephalus can be as large as several centimeters at the time of initial diagnosis. Infundibular stalk germinomas may become symptomatic (usually causing central diabetes insipidus) before they can be detected on high-resolution, contrast-enhanced MRs. Therefore, in young patients with diabetes insipidus, follow-up MR is recommended.

Approximately 20% of intracranial germinomas are multiple. The most frequent combination is a pineal + a suprasellar (“bifocal” or “double midline”) germinoma (25-5).

Gross Pathology

Germinomas are generally solid masses that often infiltrate adjacent structures. Intratumoral cysts, small hemorrhagic foci, and CSF dissemination are common.

Microscopic Features

A biphasic pattern of neoplastic germinoma cells mixed with benign lymphocytes is typical (25-8). Some tumors exhibit such a florid immune cell infiltrate that it can obscure the neoplastic elements. Mitotic activity is common and may even be conspicuous, but frank necrosis is rare.

Clinical Issues

Demographics

Germinoma is the most common intracranial GCT and accounts for 1-2% of all primary brain tumors. More than 90% of patients are younger than 20 years of age at initial diagnosis. Peak presentation is 10-14 years. The M:F ratio for pineal germinoma is 10:1. Suprasellar germinomas have no sex predilection.

Presentation

Pineal germinomas typically present with headache and Parinaud syndrome (paralysis of upward gaze) related to compression or invasion of the tectal plate. Ataxia and precocious puberty have also been described. The most common presentation for suprasellar germinoma is central diabetes insipidus. Hypothalamic-pituitary dysfunction and visual symptoms may also be present.

CSF cytology is rarely positive for tumor cells. Elevated serum or CSF markers (α-fetoprotein, β-hCG) are rare in pure germinomas but common with mixed GCTs.

Natural History

CSF dissemination and invasion are common, but pure germinomas have a very favorable response to radiation therapy. The five-year survival for treated patients with pure germinoma is > 90%.

Treatment Options

Histologic documentation followed by radiation therapy is the standard first-line treatment, as germinomas are extremely radiosensitive. Adjuvant chemotherapy is reserved for disseminated or recurrent tumors.

Imaging

General Features

CSF dissemination is common, so MR imaging of the entire neuraxis should be performed in patients with suspected germinoma. Caution: Some suprasellar germinomas may present with diabetes insipidus long before lesions are visible on MR. In such cases, serial imaging in 3-6 months should be performed.

CT Findings

Germinomas are typically hyperdense on NECT. Pineal calcifications can appear “engulfed” and surrounded by tumor (25-6). Obstructive hydrocephalus is common. Strong uniform enhancement on CECT is typical.

MR Findings

Germinomas are iso- to slightly hyperintense to cortex on T1- and T2WI (25-7A). Variably sized intratumoral cysts are common, especially in larger and “ectopic” lesions. Hemorrhage is generally uncommon except in basal ganglionic germinomas. T2* (GRE, SWI) may show “blooming” due to intratumoral calcification. Because of their high cellularity, germinomas may show restricted diffusion (25-7B).

Enhancement is strong and usually homogeneous (25-9) (25-11). Nearly 20% of germinomas are multiple, so look carefully for a second lesion in the suprasellar region (anterior third ventricle recesses, infundibular stalk) (25-6)! CSF spread is common, so imaging of the entire neuraxis prior to surgery is recommended.

“Inflammatory” germinomas may show extensive, nonenhancing peritumoral T2/FLAIR hyperintensity that extends into adjacent structures, such as the midbrain and thalami. In such cases, biopsies—especially small stereotaxic samples—may disclose only granulomatous reaction and be mistaken for tuberculosis or neurosarcoid.

Differential Diagnosis

The major differential diagnosis of pineal germinoma is mixed GCT as well as NGGCTs. NGGCTs tend to be larger and more heterogeneous than germinomas. Bifocal lesions are almost always germinomas.

Some pineoblastomas may appear similar to germinoma but “explode” rather than “engulf” pineal calcifications. Pineal parenchymal tumor of intermediate differentiation (PPTID) usually occurs in middle-aged and older adults.

The major differential diagnosis of suprasellar germinoma is Langerhans cell histiocytosis (LCH). Both are common in children, often cause diabetes insipidus, and may be indistinguishable on imaging studies alone. However, LCH does not produce oncoproteins. Neurosarcoidosis in an adult can cause a suprasellar mass that resembles germinoma.

Teratoma

Teratomas are tridermic masses that originate from “misenfolded” or displaced embryonic stem cells. Teratomas recapitulate somatic development and differentiate along ectodermal, mesodermal, and endodermal cell types (25-13).

There are three recognized types of teratoma. These range from a benign well-differentiated “mature” teratoma to an immature teratoma to a teratoma with somatic-type malignancy. All three share some imaging features, such as complex masses with striking heterogeneity in density &/or signal intensity. Cysts and hemorrhage are common.

Although they may originate anywhere in the body, teratomas are most commonly found in sacrococcygeal, gonadal, mediastinal, retroperitoneal, cervicofacial, and intracranial locations. Teratomas preferentially involve the midline; intracranial lesions most often arise in the pineal or suprasellar region.

Teratomas account for 2-4% of primary brain tumors in children and almost 1/2 of all congenital (perinatal) brain tumors. Teratomas are more common in Asian patients and male patients.

Imaging of mature teratomas shows a complex-appearing multiloculated lesion with fat, calcification, numerous cysts, and other tissues (25-14). Hemorrhage is common. Enhancement is variable.

Immature teratomas contain a complex admixture of at least some fetal-type tissues from all three germ cell layers in combination with more mature tissue elements. It is common to have cartilage, bone, intestinal mucus, and smooth muscle intermixed with primitive neural ectodermal tissue. Hemorrhage and necrosis are common. CT or MR demonstrate almost complete replacement of brain tissue by a complex mixed-density or signal intensity mass.

Teratomas with somatic-type malignancy generally arise from immature teratomas and contain somatic-type cancers, such as sarcomas or carcinomas.

Other Germ Cell Neoplasms

Germinomas are by far the most common of the germ cell neoplasms. Nongerminomatous malignant GCTs (NGMGCTs) are rare neoplasms that contain undifferentiated epithelial cells and are often mixed with other germ cell elements (most often germinoma). These include yolk sac (formerly endodermal sinus) tumor, embryonal carcinoma, choriocarcinoma, and mixed GCT.

NGMGCTs generally occur in adolescents with a peak incidence at 10-15 years of age. Prognosis is usually poor with overall survival of < 2 years.

Differentiating intracranial germ cell neoplasms on the basis of imaging studies alone is problematic. All intracranial GCTs—whether benign or malignant—tend to “hug” the midline.

Serum and CSF biomarkers can be helpful in the preoperative evaluation of a pineal mass. Embryonal carcinomas, immature teratomas, and yolk sac tumors can cause elevated α-fetoprotein. Choriocarcinomas and germinomas are associated with elevated β-hCG. Germinomas are also associated with elevated lactate dehydrogenase and placental alkaline phosphatase.

Many pineal neoplasms express different oncoproteins, so immunohistochemical profiling of biopsied tissue is an essential part of the diagnosis.

Imaging of NGGCTs, including mixed GCTs, is nonspecific and may mimic the more common germinoma (25-15). However, these GCTs may appear more heterogeneous with areas of calcification or cysts (25-16). Choriocarcinomas have a tendency to hemorrhage.

Pineal Parenchymal Tumors

Preamble

Pineal parenchymal tumors (PPTs) are intrinsic primary tumors that arise from pinealocytes or their precursors. PPTs account for < 1% of all brain tumors but cause ~ 25-30% of pineal gland tumors.

Three grades are recognized: (1) Pineocytoma (WHO grade 1), (2) PPTID (WHO grades 2-3), and (3) pineoblastoma (WHO grade 4), the most malignant parenchymal cell tumors. The papillary tumor of the pineal region (PTPR) is a rare tumor that arises from the subcommissural organ. Lastly, the extremely rare desmoplastic myxoid tumor of the pineal region, SMARCB1-mutant, is a newly recognized tumor by the WHO classification of CNS tumors, 5th edition.

In the most recent epidemiologic studies, pineocytomas account for 20-25% of pineal parenchymal neoplasms (probably an underrepresentation, as many presumed cases are not resected or biopsied). PPTIDs represent nearly 45% of cases, and pineoblastomas account for ~ 35% of PPTs.

At present, the genetic alterations that drive PPTs are largely unknown, except for the subset of pineoblastomas that arise in patients with germline mutations in either RB1 or as part of their eponymous tumor predisposition syndromes.

Pineocytoma

These WHO grade 1 tumors may mimic benign pineal cysts or more aggressive PPTs. They are typically < 3 cm in size. In the most recent epidemiologic studies, pineocytomas account for ~ 20-25% of pineal parenchymal neoplasms.

Pathology

Grossly, pineocytomas are well-circumscribed, round or lobular, gray-tan masses that are located behind the third ventricle and rarely invade adjacent structures. Although “giant” tumors have been reported, most are < 3 cm in diameter.

Pineocytomas are composed of small, uniform cells that resemble pinealocytes and are positive for both synaptophysin and neurofilament. Large “pineocytomatous rosettes” are the most characteristic feature. Mitoses are absent. Pineocytomas are designated as WHO grade 1 neoplasms. CSF dissemination has not been reported.

Clinical Issues

Pineocytomas occur at all ages but are mostly tumors of adults. Mean age at diagnosis is 43 years. There is a slight female predominance (M:F = 0.6:1).

Many small pineocytomas are discovered incidentally on imaging studies. Larger lesions may compress adjacent structures or cause hydrocephalus. Headache and Parinaud syndrome (paralysis of upward gaze) are common in symptomatic patients.

Pineocytomas grow very slowly and often remain stable in size over many years. “Watchful waiting” is common with small lesions. Imaging is usually obtained only if the patient’s symptoms change. Complete surgical resection is generally curative without recurrence or metastatic tumor spread.

Imaging

Pineocytomas are globular, well-delineated masses that are mixed iso- to hypodense on NECT scans. Calcifications typically appear “exploded” toward the periphery of the pineal gland (25-17A).

Pineocytomas are well-demarcated, round or lobular masses that are iso- to hypointense on T1WI and hyperintense on T2WI and FLAIR (25-17B) (25-17C). T2* GRE may show “blooming” foci secondary to calcification or hemorrhage. Pineocytomas typically enhance avidly with solid, rim, or even nodular patterns (25-17D).

Differential Diagnosis

The major differential diagnosis of pineocytoma is a benign, nonneoplastic pineal cyst. Pineal cysts may be indistinguishable from pineocytomas on imaging studies.

Germinoma typically “engulfs” rather than “explodes” the pineal calcifications, is most common in male adolescents, and enhances intensely and uniformly. PPTID is a tumor of middle-aged and older patients. The imaging appearance of PPTIDs is more “aggressive” than that of pineocytoma.

Pineal Parenchymal Tumor of Intermediate Differentiation

Pineal parenchymal tumor of intermediate differentiation (PPTID) is intermediate in malignancy between pineocytoma and pineoblastoma. PPTID supersedes the terms “atypical” or “aggressive” pineocytoma.

Pathology

Grossly, PPTID is a large, heterogeneous mass with peripheral calcification and variable cystic changes. Microscopically, PPTIDs are moderate to highly cellular tumors that exhibit dense lobular architecture. Two morphologic subtypes, small cell and large cell, have been recently described.

PPTIDs can be either WHO grade 2 or 3, although definite histologic grading criteria remain to be defined.

Clinical Issues

PPTIDs are the most common PPT, representing ~ 45% of all cases. PPTIDs can occur at any age but are typically tumors of middle-aged adults. The medial patient age is 33 years.

Diplopia, Parinaud syndrome, and headache are the most common presenting symptoms. Biologic behavior is variable, and clinical progression can be seen in both grades 2 and 3 PPTIDs. Tumors tend to enlarge slowly and recur locally, although CSF dissemination may occur. Malignant degeneration into pineoblastoma has been reported in a few cases.

No serum or CSF biomarkers are currently available that inform the diagnosis or treatment of PPTIDs.

Imaging

PPTIDs have a more “aggressive” imaging appearance than pineocytoma (25-18). Extension into adjacent structures (e.g., the ventricles and thalami) is common. Size varies from < 1 cm to large masses that are 4-6 cm in diameter. CSF dissemination is uncommon but does occur, so imaging evaluation of the entire neuraxis should be performed prior to surgical intervention.

NECT scans show a heterogeneous mass centered in the pineal region that often have calcification “exploded” toward the periphery of the pineal gland (25-19A). PPTIDs generally enhance strongly and uniformly.

PPTIDs are mixed iso- and hypointense on T1WI, isointense with gray matter on T2WI, and hyperintense on FLAIR. T2* (GRE, SWI) scans may show hypointense “blooming” foci (25-18). Enhancement is generally strong but heterogeneous on T1 C+(25-18) (25-19).

Differential Diagnosis

The major differential diagnosis of PPTID is pineocytoma. A more aggressive-appearing pineal mass in a middle-aged or older adult is most consistent with PPTID. Pineoblastoma is typically a tumor of younger patients but may occur at all ages. Germinoma is more common in male adolescents. PTPR can appear identical on imaging studies but is very rare.

PINEAL PARENCHYMAL TUMOR OF INTERMEDIATE DIFFERENTIATION

Pathology

• 45% of pineal parenchymal tumors

• WHO grade 2 or 3

Clinical Issues

• Middle-aged adults

Imaging

• Appears more “aggressive” than pineocytoma

• Usually larger, more heterogeneous

• May disseminate via CSF

Differential Diagnosis

• Pineocytoma

• Pineoblastoma

• Germinoma

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