Approach Considerations
The workup for tumors in the pineal region requires high-resolution magnetic resonance imaging (MRI) of the brain and spine with and without contrast, and serum/cerebrospinal fluid (CSF) markers. Tissue biopsy may also be required.
MRI is crucial for assessing tumor size, vascularity, associated anatomic relationships, and degree of hydrocephalus if present. Pineal tumors typically displace superior vessels of the deep venous system, and consequently, identifying venous structures is especially important. [49]
CSF should be obtained, if lumbar puncture is considered safe for the patient, and examined cytologically. If lumbar puncture is deemed unsafe, CSF can be collected at the time of surgery. CSF and serum should be examined for markers, including alpha-fetoprotein (AFP) and beta human chorionic gonadotropin (beta-hCG). Significant increases in either of these markers can be pathognomonic for GCTs and eliminate the need for tissue diagnosis and surgery. [11, 12, 4, 13] In this circumstance, chemotherapy and radiation can be started right away. [4, 13] In the absence of those markers, radiographic, CSF, and serum studies may provide some insight into tumor type, but these studies should not replace tissue diagnosis. [15] [16]
For more information, see Pineal Germinoma Imaging.
Laboratory Studies
Tumor markers are most helpful in the workup of patients with germ cell tumors (GCTs). Because GCTs retain molecular characteristics of their primordial lineage, increased levels of AFP and beta-hCG are pathognomonic for certain GCTs. [11, 12, 50, 51, 52] See Table 2, below.
The presence of AFP suggests features of yolk sac tissue. Yolk sac tumors characteristically have considerably high levels of AFP, while embryonal cell carcinomas as well as immature teratomas may present with elevated, but lower, levels of AFP. Meanwhile, beta-hCG suggests the presence of trophoblastic tissue. Choriocarcinomas present with markedly high levels of beta-hCG, while some embryonal cell carcinomas and germinomas with syncytiotrophoblastic cells present with lesser elevations. [50, 12, 51, 13] Lastly, germinomas have been associated with elevated levels of placental alkaline phosphatase. [53]
In both serum and CSF, the standard upper limit of normal for AFP is 10 ng/mL, and that for beta-hCG is 50 mIU/mL. [54] However, a pathologic study of 58 intracranial GCTs by Hu et al recommended diagnostic cut-off points for beta-hCG of ≥ 8.2 IU/L in CSF and ≥ 2.5 IU/L in serum. [55] AFP levels > 1000 ng/mL are associated with poor prognosis, while similar levels of beta-hCG are not associated with any worse prognosis. [44]
Pineal parenchymal cell tumor markers are less well characterized than their GCT counterparts. Associated proteins include melatonin and the S antigen. [56, 57] Neither of those proteins has proved valuable in the diagnosis of pineal parenchymal tumors. [9, 4]
Imaging Studies
High-resolution MRI with gadolinium is necessary for evaluation of pineal region lesions. Tumor characteristics such as size, vascularity, and homogeneity can be assessed, as can the anatomic relationship with surrounding structures. Irregular tumor borders can be suggestive of tumor invasiveness and associated histologic malignancy. Although the type of tumor cannot be determined reliably from radiographic characteristics alone, some patterns are associated with specific tumors.
GCTs arise from the neoplastic transformation of residual primordial tissue derived from ectoderm, mesoderm, or endoderm. Each tumor subtype represents the malignant correlate of a distinct stage of embryonic development. In some cases, the stage of tissue development can be identified by distinct radiographic features. On MRI studies, germinomas are isointense or slightly hyperintense to adjacent brain on T1-weighted images, isointense or slightly hyperintense to adjacent brain on T2, and have strong homogeneous contrast enhancement. [58] (See Table 1, below.)
Additionally, due to hypercellularity, germinomas demonstrate greater restriction compared with adjacent tissue on diffusion-weighted imaging (DWI). The germinoma tumor itself does not calcify, but it promotes calcification of the pineal gland, and that calcification is subsequently engulfed by the tumor. [10]
On MRI, teratomas are typically lobular and multiloculated. They typically demonstrate widely heterogeneous features due to the presence of all 3 germ layers and include irregular or ring enhancement. [10, 7] The presence of fat and calcification may help to distinguish teratoma from other pineal tumor types. [10]
Differentiation of non-germinomatous germ cell tumors (NGGCTs) is not possible with imaging alone. [10] Choriocarcinoma is highly vascular and may present with areas of intratumoral hemorrhage. Embryonal carcinoma tends to present with a more cystic character compared with germinomas. Yolk sac tumors do not have characteristic imaging findings and are similar to other GCTs. [19]
Imaging of pineal parenchymal tumors reflects the biology of pineocytomas. Generally, pineocytomas will present more homogeneously, while pineoblastomas will present more heterogeneously and are typically larger. [47] Nevertheless, pineal parenchymal tumors share many radiographic features, making distinguishing among tumor types difficult. Unlike germinomas, pineal parenchymal tumors intrinsically calcify. Calcification occurs along the tumor periphery, giving rise to an “exploded” pattern, which directly contrasts with germinomas and their associated “engulfed” calcification pattern. However, like germinomas, solid components of these tumors are often hypercellular, demonstrating restricted diffusion on DWI. [10]
Pineocytomas and pineoblastomas are hypointense to isointense to adjacent brain on T1 imaging, and isointense to adjacent brain on T2. Papillary tumors are typically well-defined with variable T1 signal, but hyperintense to adjacent brain on T2. [59] Cystic areas are also commonly seen. [60]
Other lesions that can appear in the pineal region include astrocytomas, which can arise from the glial stroma of the pineal gland or surrounding tissue. These tumors are typically hypointense to adjacent brain on T1 and hyperintense to adjacent brain on T2. [61] However, they may have variable enhancement patterns. Calcium may also be present, potentially complicating diagnosis on imaging.
Meningiomas typically have intense homogeneous enhancement with well-circumscribed borders. They are typically isointense, but may be hypointense to grey matter on T1 and may be hyperintense to grey matter on T2. [62] Some meningiomas can have an enhancing dural tail. This sign was originally considered pathognomonic but was subsequently found in a variety of disorders. [63]
In addition to MRI, angiography is sometimes used in cases of suspected vascular anomalies. However, the anatomic and vascular information provided by MRI has largely circumvented the need for routine angiograms in the evaluation of pineal region neoplasms.
Benign cysts of the pineal gland are diagnosed more frequently with increased use of MRI for standard workups unrelated to the pineal region. Cysts are quite common, with reported rates as high as 40% in an autopsy series. They are typically oval, filled with proteinaceous or bloody fluid, and often have a thin rim of calcification. Patients are typically asymptomatic.
On MRI, pineal cysts are hypointense to isointence compared with grey matter on T1 and isointense to hyperintense compared with grey matter on T2. [64, 19] Pineal cysts may be difficult to distinguish from low-grade cystic astrocytomas on radiographic criteria alone. Any doubts about diagnosis should be addressed by careful observation of the patient via serial MRI scans to ensure that the lesion is not growing. If these cysts cause obstructive hydrocephalus or show evidence of progression, surgical resection is indicated.
Lastly, MRI of the spine with gadolinium should be performed upon presentation to assess for extent of disease.
Histologic Findings
The pineal gland has varying architecture. Some pineal glands have a lobular shape, separated by connective tissue, while others may have more abundant connective tissue, creating an insular pattern. [65] Regardless of the architecture, the pineal gland is made up of follicles and lines of pinealocytes and glial tissue. [66]
Pineal parenchymal tumors arise from pinealocytes, a type of parenchymal cell, or a pinealocyte precursor. They account for 15% to 30% of pineal gland tumors. [67, 68] Pinealocytes are modified neuronal cells similar to photoreceptors in the retina. [7, 24, 43] They stain positive for synaptophysin. [69] Among each subtype, tumors present with different grades and features.
Pineocytomas are World Health Organization (WHO) grade I/II tumors. They are made up of dense sheets of mature-appearing cells that are indistinguishable from normal pineal parenchyma. [2] Pseudorosettes are characteristic of pineocytomas and are not found in normal tissue. [29]
Pineoblastomas are WHO grade IV tumors derived from primitive neuroectoderm. [4] They are highly aggressive and associated with the worst prognosis among pineal parenchymal tumors. [6, 68] These tumors are made up of undifferentiated pineal cells. [47] Compared with pineocytomas, they are far less organized and more cellular. [70] They are made up of dense sheets of small round blue cells, due to their high nucleus-to-cytoplasm ratio. The growth pattern is not typically associated with any features. However, Homer-Wright or Flexner-Wintersteiner rosettes may be occasionally seen. [70] See the images below.
Pineoblastoma composed of highly cellular, poorly differentiated cells that form patternless sheets.
Macroscopically, pineal parenchymal tumors of intermediate differentiation appear similarly to pineocytomas with well-circumscribed borders. [70, 22] Microscopically, they have two patterns, which may even co-exist. A diffuse lobular pattern is characterized by loosely defined lobules separated by large vessels, while the diffuse pattern is characterized by large rosettes. [70, 22]
Papillary tumors are WHO grade II or III tumors, and they are uncommon. [2] They show similar histologic characteristics to pineocytomas, including rosette-like features. [7]
GCTs are the most prevalent neoplasms of the pineal region. [6] Germinomas make up 60-80% of all GCTs and 50% of all pineal gland tumors. [6] NGGCTs fall along a spectrum of differentiation. [71] The least differentiated is embryonal cell carcinoma, with further differentiation described as either embryonic or extraembryonic. Immature and mature teratomas result from maturation along embryonic cell lines, whereas the the yolk sac tumor and choriocarcinoma result from extra-embryonic differentiation. [72]
Description and classification of a given lesion may be confounded when more than one type of germ cell component is found in a surgical specimen. Mixed GCTs are the result of simultaneous differentiation along more than one pathway such that, at presentation, 2 or more characterized components are recognized. [73] An example of this is teratocarcinoma—an embryonal carcinoma that contains elements of an immature teratoma.
Germinomas are typically characterized by sheets or lobules of large, round tumor cells with large nuclei, prominent nucleoli, glycogen-rich cytoplasm and septal bands of connective tissue. In addition, capillaries, lymphocytes, and granulomas may be present. [34, 74] In these cases, periodic acid–Schiff staining and placental alkaline phosphatase staining help identify tumor cells. [74]
Similarly, embryonal cell carcinoma tumor consists of cells with large nuclei and prominent nucleoli arranged in papillary, glandular, or solid structures. [74] Typically, eosinophilic droplets are identified in the cytoplasm. [74]
Teratomas can be composed of a mixture of tissues derived from all 3 germinal layers, with varying degrees of differentiation. [7] Mature teratomas are made up of fully differentiated tissues with absent mitotic activity, while immature teratomas consist of embryonal tissues with high mitotic activity. [74] See the images below.
Immature teratoma of the pineal region with highly cellular primitive elements resembling fetal neural tube structure.
Micrograph from a mature teratoma of the pineal region that consists of well-differentiated tissue from all 3 germinal layers. This image demonstrates nonkeratinizing squamous cell epithelium alternating with areas of ciliated columnar epithelium.
Yolk sac tumors include either columnar or flattened epithelium-like cells arranged in reticular, papillary or endodermal patterns. [74] As in embryonal cell carcinoma, eosinophilic-hyaline globules may be present in the cytoplasm. The hallmark of yolk sac tumors are Schiller-Duval bodies present in the endodermal sinus patterns. [74] See the image below.
Lastly, choriocarcinoma is composed of cells either resembling cytotrophoblasts or syncytiotrophoblasts assembled in nest-like structures. [74]
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Gadolinium-enhanced MRI of a 33-year-old woman who presented with visual loss, amenorrhea, and diabetes insipidus. MRI shows germinomatous invasion of the pineal gland (large arrowhead), optic chiasm (long arrow), pituitary stalk (small arrowhead), and the floor of the third ventricle (short arrow).
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Noncontrast MRI of a pineocytoma in a 40-year-old man presenting with acute hydrocephalus. At surgery, the high signal area (arrow) turned out to be acute hemorrhage.
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MRI of a 21-year-old man with a germinoma in the pineal region. This T1-weighted noncontrast sagittal scan shows isointense tumor, which has obstructed the aqueduct of Sylvius (arrow) to cause hydrocephalus.
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MRI of a 21-year-old man with a germinoma in the pineal region. This T2-weighted noncontrast axial scan shows the tumor as hyperintense to brain matter but hypointense to cerebrospinal fluid (CSF).
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MRI of a 21-year-old man with a germinoma in the pineal region. Homogenous gadolinium enhancement of the tumor is shown on this T1-weighted contrast-enhancing sagittal scan.
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Sagittal MRI of a heterogeneous mixed germ cell tumor of the pineal region in a 21-year-old man who presented with hydrocephalus. After pathologic examination following complete surgical resection, the tumor was found to have multiple components, including endodermal sinus tumor, embryonal cell carcinoma, immature teratoma, and mature teratoma.
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Gross tissue specimens were obtained from a 21-year-old man who presented with hydrocephalus. After pathologic examination following complete surgical resection, the tumor was found to have multiple components, including endodermal sinus tumor, embryonal cell carcinoma, immature teratoma, and mature teratoma. Gross tissue specimens reflect heterogeneity of various germ cell components.
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T1-weighted contrast-enhancing sagittal MRI from a 41-year-old man with a pineocytoma. The tumor enhances homogeneously with gadolinium, except for a cystic portion.
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Micrograph from a mature teratoma of the pineal region that consists of well-differentiated tissue from all 3 germinal layers. This image demonstrates nonkeratinizing squamous cell epithelium alternating with areas of ciliated columnar epithelium.
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This micrograph shows osteoid bone with surrounding periosteal tissue and mesenchymal stroma occurring within a mature teratoma of the pineal region.
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This micrograph features cartilaginous tissue observed within a mature teratoma of the pineal region.
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Immature teratoma of the pineal region with highly cellular primitive elements resembling fetal neural tube structure.
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Endodermal sinus tumor with a characteristic Schiller-Duval body.
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Pineoblastoma composed of highly cellular, poorly differentiated cells that form patternless sheets.
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Pineocytoma consisting of benign, well-differentiated cells forming rosettes.
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MRI of a 44-year-old woman 10 years after resection of a mixed pineal cell tumor. The tumor has recurred in the pineal region (arrow) and has seeded the fourth ventricle (arrowheads).
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The right side of this image shows 3 operative approaches to the pineal region. Appropriate patient positioning for each approach is on the left. Number 1 is the supracerebellar-infratentorial approach, number 2 is the occipital-transtentorial approach, and number 3 is the parietal-interhemispheric approach.
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The left drawing is a sagittal view of a patient with a pineal region tumor. The right drawing shows a sagittal view of the supracerebellar/infratentorial approach to the pineal region.
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Biopsy specimen from an intracranial germ cell tumor. arge tumor cells with large nuclei; prominent nucleoli; and abundant, clear cytoplasm (rich in glycogen) are noted among reactive inflammatory cells.
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View during a infratentorial supracerebellar approach from the operative microscope. Courtesy of Elsevier [Kennedy BC, Bruce JN. Surgical approaches to the pineal region. Neurosurg Clin N Am. 2011 Jul;22(3):367-80. PMID: 21801985.].
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Pre and postoperative MRI from a patient with a pineal tumor resected via supracerebellar infratentorial approach. Courtesy of Elsevier [Kennedy BC, Bruce JN. Surgical approaches to the pineal region. Neurosurg Clin N Am. 2011 Jul;22(3):367-80. PMID: 21801985.].
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Demographics and imaging findings of pineal tumors.
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Markers of pineal tumors.
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Management of pineal tumor.
