Workup
Laboratory Studies
- Measurements of serum and CSF tumor markers are a valuable component of the preoperative evaluation. As with radiologic studies, these results can be suggestive of tumor type but only occasionally provide the physician diagnostic information.
- Markers have been most helpful in the workup of patients with germ cell tumors. In addition to their histologic characteristics, germ cell tumors retain molecular characteristics of their primordial lineage. Therefore, the expression of embryonic proteins, such as alpha-fetoprotein (AFP) and bhCG, are indicative of malignant germ cell elements. Other biological markers for germ cell tumors include lactate dehydrogenase isoenzymes and placental alkaline phosphatase, although these are less specific. Serum and CSF measurements can be used for diagnostic purposes and for monitoring a response to therapy. In general, CSF measurements are more sensitive than serum measurements, and a CSF-to-serum gradient may be consistent with an intracranial lesion. However, active debate continues in the literature regarding the diagnostic value of CSF and serum measurements.
- AFP is a glycoprotein produced by fetal yolk sac elements and is produced by a wide range of cancers, including gastric, liver, and colon adenocarcinoma, as well as extracranial germ cell tumors. Serum levels of AFP are greatest in newborns and decline thereafter. The biological half-life of AFP is approximately 5 days, and levels always should be normalized to known age standards to prevent false-positive results. AFP is markedly elevated with endodermal sinus tumors and elevated to a lesser degree with embryonal cell carcinomas. Although teratomas do not secrete AFP, the less-differentiated immature teratomas can produce detectable amounts.
- BhCG is a glycoprotein with a half-life of 15-20 hours and is usually produced by placental trophoblastic cells. Choriocarcinomas secrete large amounts of bhCG, and lesser elevations can occur in patients with embryonal cell carcinomas. The presence of syncytiotrophoblastic giant cells in mixed germinomas may result in detectable levels of bhCG, but most germinomas are nonsecretory.
- Significant variability in expression of tumor markers is such that the absence of AFP or bhCG does not rule out a mixed germ cell tumor. Although recent studies suggest a less favorable prognosis for patients with germinomas secreting bhCG, no established prognostic significance of tumor markers exists. Determination of AFP and bhCG levels prior to surgical resection is extremely important because it provides a reference point that can be used to assess recurrence during follow-up.
- Pineal parenchymal cell tumor markers are less well characterized than their germ cell counterparts and include melatonin and the S antigen. Neither of these proteins has proven valuable in the diagnosis of pineal parenchymal cell tumors. Some authors have reported using melatonin levels in follow-up for patients with pineocytoma after surgical treatment.
Imaging Studies
- High-resolution MRI with gadolinium is necessary in the evaluation of pineal region lesions. Tumor characteristics, such as size, vascularity, and homogeneity, can be assessed, as well as 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 the radiographic characteristics alone, some patterns are associated with specific tumors.
- Non–germ cell tumors can derive from pineal parenchymal cells, as well as from surrounding tissue. Pineocytomas and pineoblastomas typically are hypointense to isointense on T1-weighted images, have increased signal on T2, and demonstrate homogenous enhancement after administration of gadolinium. Pineoblastomas can be distinguished by their irregular shape and large size (ie, some >4.0 cm).
- Astrocytomas, which can arise from the glial stroma of the pineal gland or surrounding tissue, are also hypointense on T1 and hyperintense on T2. However, astrocytomas have variable enhancement patterns. Calcium may be present in either pineal cell tumors or astrocytomas.
- Meningiomas typically enhance homogenously and have smooth, distinct borders. Tentorial meningiomas can have an enhancing dural tail of origin and are anatomically distinguished by their dorsal location relative to the deep venous system.
- Germ cell tumors 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 have distinct radiographic features. Germinomas are isointense on T1-weighted MRI studies, are slightly hyperintense on T2, and have strong homogenous enhancement. Germinomas can have evidence of calcification, which surrounds the pineal gland as the germinoma grows. In contrast, pineocytomas commonly have intratumoral calcium. Intratumoral cysts can exist as well. Unlike germinomas, teratomas typically have heterogenous MRI signals because they can contain tissue from all 3 germinal layers.
- Teratomas are well-circumscribed benign tumors characterized by their heterogeneity, multilocularly, and irregular enhancement. These tumors can also demonstrate ring enhancement. In some cases, a well-circumscribed teratoma has areas of low attenuation that correlate with adipose tissue, which serves to further distinguish it from other pineal region tumors. Malignant nongerminomatous germ cell tumors can also have a heterogeneous appearance due to a mixture of benign and malignant germ cell components. Areas of intratumoral hemorrhage may distinguish specific subtypes, such as choriocarcinoma.
- In addition to MRI, angiography sometimes is 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.
Histologic Findings
Germ cell tumors are the most prevalent neoplasms of the pineal region in children and are histologically indistinguishable from those found at extracranial locations, including the mediastinum and gonads. These extracranial locations most commonly are midline. Intracranial germ cell tumors commonly are divided into 2 categories: germinomas and tumors derived from totipotential germ cells.
Germinomas make up 60-70% of all pediatric germ cell tumors. Nongerminomatous germ cell tumors fall along a spectrum of differentiation. The least differentiated is the 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 endodermal sinus tumor or yolk sac tumor and the choriocarcinoma are a result of extraembryonic differentiation.
Description and classification of a given lesion sometimes is confounded when more than one type of germ cell component is found in a surgical specimen. Mixed germ cell tumors are a result of simultaneous differentiation along more than one pathway such that, at presentation, 2 or more characterized components are recognized. An example of this is the teratocarcinoma, an embryonal carcinoma containing elements of an immature teratoma.
The germinoma is most likely to occur in pure form and is characterized histologically by large round tumor cells interspersed with lymphocytes and septae of fibrous tissue. At low-power magnification with hematoxylin and eosin staining, the contrast between the smaller, darkly staining lymphocytes and the larger, pale staining cytoplasm of neoplastic cells is virtually pathognomonic. At higher magnification, germinoma cells are characterized by a nucleus with an open chromatin structure and prominent nucleoli. The cytoplasm is glycogen-rich, making these cells periodic acid-Schiff (PAS)–positive and diastase labile. Characteristic cytoarchitecture of these cells includes cellular junctions in the form of simplified desmosomes and focal microvilli within intercellular lumina. The presence of microvilli is one of the few histologic characteristics that distinguish the intracranial lesion from its extracranial correlate.
The pathologic diagnosis of a germinoma can be confounded when the specimen examined contains an infiltrating portion of the tumor or tumors amidst significant inflammation.
Infiltrating germinomas can elicit an atypical gliosis, which may be confused with malignant glial neoplasms. This is true particularly of specimens taken from the periphery of the germinoma.
Noncaseating granulomatous inflammation accompanied by multinucleated giant cells also can be found in biopsy samples taken from the periphery of some germinomas. An important consideration is that the degree of inflammation can vary significantly among specimens, underscoring the need to obtain an adequate amount of diagnostic tissue during surgical intervention.
Nongerminomatous germ cell tumors are more likely to arise in the pineal region than in the suprasellar region.
Embryonal cell carcinoma tumor consists of cuboidal-to-columnar cells arranged in sheets and cords with large nuclei, prominent irregular nucleoli, and significant mitotic activity. Unlike germinomas, little or no lymphocytic infiltrate is present. Signs of differentiation of embryonal cell carcinomas are observed in cases of mixed germ cell tumors and can proceed along embryonal cell lineage toward teratoid cells or along extraembryonic cell lineage toward yolk sac or placental elements.
Teratomas can be composed of a mixture of tissues derived from all 3 germinal layers, with varying degrees of differentiation. Structured variants of teratomas may resemble adult tissue histologically, whereas unstructured examples do not recapitulate known tissue.
Hosoi first used the term teratoid in 1930 to describe less structured tumors in which derivatives of all 3 germinal layers could not be identified easily. Current classification of these tumors divides them into mature and immature teratomas. Mature teratomas contain fully differentiated ectodermal, mesodermal, and endodermal elements, whereas immature teratomas have more primitive elements that closely resemble embryonic histology.
The spectrum of differentiation that exists within the teratoma lineage precludes definitive descriptions of immature versus mature lesions. However, some general microscopic characteristics can help guide the physician in making the diagnosis. Mature lesions often contain solid or cystic foci of squamous epithelium, cartilage, or glandular elements embedded in tubular structures lined with mucin-secreting columnar epithelium. Mesenchymal stroma consisting of smooth muscle can be observed interspersed among these well-differentiated tissue elements. Immature teratomas usually are composed of primitive cells derived from 1 of the 3 germinal layers. The pattern of these small round cells when viewed at lower magnification can resemble the hypercellularity of a medulloblastoma. Lesions containing primitive cells from all 3 germinal layers have also been described.
Extraembryonic differentiation of embryonal cell carcinoma results in either an endodermal sinus tumor or a choriocarcinoma. These 2 entities represent differentiation towards the yolk sac and trophoblast respectively, and, as with the teratomas, these tumors can be admixed with germinomas. The yolk sac carcinoma is derived from the endoderm, and, consequently, it contains endodermal sinuses or Schiller-Duval bodies. These pathognomonic glomeruloid structures contain a tumor cell–lined space with an invaginated vascular pedicle covered by a single layer of tumor cells. Other characteristic cytoarchitecture includes perivascular endodermal cells and thin-walled cystic spaces. At higher magnification, globules of PAS-positive and diastase-resistant proteins easily can be observed within endodermal sinus cells and the surrounding extracellular stromal matrix. These globules of protein correlate with the presence of AFP in the CSF and blood, a marker associated with endodermal sinus tumors.
Trophoblastic differentiation can result in isolated syncytiotrophoblasts expressing gonadotropins or bilaminar arrangements of syncytiotrophoblasts and cytotrophoblasts typified by the choriocarcinoma. Unlike other nongerminomatous germ cell tumors, the choriocarcinoma very rarely appears as an isolated lesion. At low magnification, the bilaminar cytotrophoblastic and syncytiotrophoblastic cells can be identified by surrounding blood. Intratumoral hemorrhage is common in choriocarcinoma and correlates with these blood-filled sinuses.
Non–germ cell tumors of the pineal region arise from the pineal gland or its surrounding tissue. The rarity of pineal cell lesions and the lack of an extracranial correlate have complicated the classification of these tumors. Currently, pineal parenchymal tumors are divided into high- and low-grade variants based on the extent of differentiation. The primitive pineoblastoma and the differentiated pineocytoma exist at opposite ends of the spectrum, with intermediate-grade variants in between.
Russell and Rubinstein (1989) have described a more specific classification such that pineoblastomas include types without differentiation; those with pinocytic differentiation; and those with neuronal, glial, or retinoblastic differentiation.4 Similarly, pineocytomas have been divided into types without further differentiation, with neuronal differentiation only, with astrocytic differentiation only, and those with divergent neuronal and astrocytic differentiation (eg, the ganglioglioma). In general, pineoblastomas are found in younger patients and pineocytomas are found in adults. However, numerous clinical exceptions arise.
Pineoblastomas consist of dense populations of small primitive cells that can form neuroblastic rosettes or Homer Wright rosettes. Less common examples of pineoblastoma cytoarchitecture are the Flexner-Wintersteiner rosettes, which have a ciliary 9 + 0 configuration similar to that of the retinal photoreceptor. Further differentiation of the pineoblastoma can be observed in some cases of familial bilateral retinoblastoma in which a pineoblastoma with retinoblastic features is found.
This rare syndrome has been referred to as trilateral retinoblastoma. The pineoblastoma is an aggressive tumor and resembles the medulloblastoma with respect to age of presentation and its propensity to seed the subarachnoid space. The pineocytoma is significantly less aggressive than the pineoblastoma. It usually presents during adolescence and rarely seeds the subarachnoid space. Pineocytomas consist of small cells similar to those of the pineoblastoma. However, they appear more spread out, more lobular, and are further distinguished by large hypocellular zones containing fibrillary stroma. These fibrils contain microtubules and dense core granules at the ultrastructural level. The healthy pineal gland tissue contains lobular cells of uniform size with an easily identified astroglial stroma, 2 features that can be used to distinguish healthy gland from pineocytoma.
Neoplasms derived from glial cells occur second most frequently in children with pineal region tumors, exceeded only by germinomas in 2 large series that include children with pineal region tumors. The histologic and macroscopic appearances are similar to malignant glial neoplasms found in other areas of the CNS. Glial-derived neoplasms in the pineal region can include low-grade and high-grade lesions.
Nonneoplastic lesions: Benign cysts of the pineal gland are diagnosed more frequently with the increased use of MRI for standard workups unrelated to the pineal region. These incidental lesions appear radiographically as cystic structures with peripheral calcification and rimlike contrast enhancement. They are normal variants of pineal gland anatomy, and, once documented, they require no treatment unless they grow. When causing obstructive hydrocephalus or showing evidence of progression, surgical resection is indicated with excellent results. Pineal cysts may be difficult to distinguish from low-grade cystic astrocytomas based exclusively on radiographic criteria. Any doubts of diagnosis should be addressed by carefully observing the patient via serial MRI scans to make sure that the lesion is not growing.
Staging
Currently, no formal staging designation is available for patients with pineal region tumors. However, a postoperative MRI within 48 hours of surgery is an important means of assessing the degree of resection. In addition, surveillance scans of the spine are used to assess the presence of drop metastasis.
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Further Reading
Keywords
pineal, tumors, pineal tumor, pineal tumors, pineal gland, pineal gland tumors, pineal gland tumor, pineal region tumors, pineoblastomas, pineocytomas, pineal germ cell tumors, germinomas, pineal gliomas, pineal metastasis, obstructive hydrocephalus, vertical gaze palsy, astrocytomas, meningiomas, teratomas, pineal cyst, pineal cysts
