Controversies in the Management of Intracranial Germinomas

Introduction

Intracranial germinomas are rare and account for 1% of all intracranial tumors in the Western hemisphere. In Japan, intracranial germinomas are more common, comprising 4% of all central nervous system neoplasms. Approximately, two-thirds of germinomas arise in the pineal gland region and one-third in the suprasellar region.[1] Multiple midline tumors defined as 2 or more separate tumors arising in the pineal, suprasellar or parasellar regions, can occur.[2] Intracranial germinoma develops most frequently in young adolescents; males are more likely to be affected than females.

Histologically, germinomas are identical to testicular seminomas or ovarian dysgerminomas. On light microscopy, germinomas are composed of large, monotonous round primitive cells with eosinophilic cytoplasm and vesicular nuclei intermixed with small lymphocytes; placental alkaline phosphatase staining is positive.[3]

Signs and symptoms at presentation depend on the location of the tumor. For pineal region lesions, headaches, papilledema, nausea, vomiting and lethargy may occur secondary to obstruction of the posterior third ventricle and aqueduct of Sylvius. Parinaud’s syndrome (inhibition of upward gaze, diminished pupillary response to light with preservation of accommodation) may occur when the tumor compresses the midbrain tegmentum and quadrigeminal plate. Hypothalamic and pituitary dysfunction may occur with suprasellar germinomas; these may include diabetes insipidus, growth failure, and delayed or precocious puberty.

The work-up of patients with intracranial germinoma includes a computed tomographic scan (CT) of the brain with contrast. Magnetic resonance imaging (MRI) with gadolinium will further delineate the tumor’s extent and location. Magnetic resonance imaging of the spinal axis or myelogram, in addition to cerebrospinal fluid (CSF) cytology, is performed because of the possibility of tumor spread. Cerebrospinal fluid and serum alpha fetoprotein (AFP) and human chorionic gonadotropin (HCG) are evaluated since an elevated AFP rules out a pure germinoma and may be secondary to an endoderminal sinus tumor (yolk sac tumor). Mild to moderate elevation of HCG (< 2000 mIU/mL) may be associated with germinoma with syncytiotrophoblastic giant cells. Significantly high elevation of HCG is seen in non-germinomatous germ-cell tumors, specifically, choriocarcinoma. Because disease outside the CNS is rare, other systemic work-up is not warranted unless the patient is symptomatic.

Diagnosis

Is Tissue Diagnosis Necessary?

Tumors of the pineal region are in close proximity to various vascular and brain structures.[4] In earlier reports, operative mortality after direct surgery and/or biopsy ranged from 30% to 70% with a morbidity of 65%.[5,6] Because surgery and biopsy were associated with a high mortality and morbidity, many institutions utilized a trial of 2,000 cGy radiation therapy to a local field as a means of “radiodiagnosis” and treatment. (Computed tomographic scans of the brain in patients with pathologically verified pure germinoma have shown marked tumor response to a trial dose of £ 2,000 cGy.[7,8]) If the tumor was radioresponsive, the tumor was thought to be a germinoma, and further treatment included craniospinal irradiation to a dose of 3,000 cGy.If the tumor was radioresistant or slow to respond, further radiation to a local field or surgical resection was sometimes suggested.

At present, most clinicians would recommend obtaining a tissue diagnosis. In one large multi-institution study conducted in France, stereotactic biopsy for tumors of the pineal gland between the years 1975 to 1992 resulted in a mortality of 1.3%, morbidity of 0.8%, and diagnostic yield of 94%.[9] Improvements in microsurgical techniques and open biopsy are also associated with low mortality and morbidity . Some investigators prefer an open biopsy because of the possibility of a sampling error in a heterogeneous tumor.[10-12]

Tissue diagnosis of a pineal or a suprasellar lesion is imperative in the management of the patient’s disease. Because the majority of those affected are children and adolescents, radiation therapy can be avoided in those with benign lesions. Craniospinal irradiation and chemotherapy is indicated in patients with primitive neuroectodermal tumors (PNET). whereas local irradiation and chemotherapy after maximal surgical resection is used for those with high-grade gliomas.

In one series, histologic verification of pineal and suprasellar region lesions showed that 61% were germ-cell tumors, 15% were pineoblastomas (PNETs of the pineal gland), 17% were gliomas, and 7% were benign tumors.[1] Of the germ-cell tumors, approximately two-thirds were pure germinomas and one-third non-germinoma germ-cell tumors . Furthermore, pineoblastomas and some nongerminomas may shrink with a trial of radiotherapy and may be mistaken for a pure germinoma.[13,14] Thus, because of the wide spectrum of histologies and different treatments, we advocate obtaining tissue diagnosis, especially since current neurosurgical techniques are associated with minimal morbidity.

What is the Incidence of CSF Cytology Positivity?

The positivity rates of CSF cytology in patients with intracranial germinoma vary considerably (range, 0% to 100%).[15-18] The wide variation in incidence may be attributed to the fact that the majority of series have included “radiographic “ or non-histologically verified germinomas. Table 1 shows recent reports of histologically verified germinomas and the incidence of CSF cytology positivity; the incidence varies from 7.7% to 17.6%.[18-23] There does not seem to be a higher incidence of subarachnoid seeding with suprasellar lesions.[18,19]

In one study of 42 patients, 16 with a histologic and 26 with a clinical /radiologic diagnosis, the CSF cytology was positive in 52%. The authors noted that the method of detection (wet film, membrane filter cytocentrifugation, millipore filter/cell culture) may influence CSF cytology positivity, with those detected by cytocentrifugation having a higher positivity rate.[24]

Surgical Management

Is CSF Shunting Contraindicated?

Children with germinomas may present with hydrocephalus secondary to occlusion of CSF pathways by tumor. The use of ventriculo-peritoneal (VP) shunts has been successful in alleviating symptoms from increased intracranial pressure. There has been some concern regarding the use of VP shunts because of the possibility that tumor cells from the brain may spread to the abdomen. In a review of the literature, Rickert found 35 VP shunt-related abdominal metastases from pediatric brain tumors.[25] The most common type of tumor implicated was germinoma, followed by medulloblastoma.

In a review of 25 cases of pineal region tumors treated at Stanford University, Fuller and colleagues noted that only 1 of 15 patients who had VP shunt placement developed abdominal metastases.[26] In another study, the risk of tumor seeding via a shunt catheter was 3.8%.[27] In conclusion, although there have been reports of tumor seeding via shunts, the risk of such an occurrence is small and should not be a contraindication to shunting a patient.

What is the Role of Radical Resection?

Surgical debulking is a critical part of the treatment of many pediatric brain tumors, such as gliomas and PNETs. In general, radical resection of these tumors offers the patient a better chance of cure. Because nearly all germinomas are curable with radiation therapy and/or chemotherapy, the question arises as to whether radical resection offers any additional benefit.

In a retrospective study of 29 patients who underwent surgery for germinoma, 16 had a biopsy performed, 5 had a partial resection, and 8 had a gross total resection.[28] The majority received chemotherapy and radiation therapy after the planned surgery.

There was no significant difference in outcome related to the extent of surgery. Transient surgical complications were observed in 5 patients who underwent partial or total resection of the tumor, whereas none of the 16 patients in whom biopsy specimens were obtained experienced complications.

The authors concluded that the primary goal of surgery should be to obtain sufficient tissue for histologic examination. Radical resection of intracranial germinomas offers no benefit over biopsy since all patients still require radiotherapy and/or chemotherapy.

As mentioned above, some physicians prefer open surgical biopsy to stereotactic biopsy in order to obtain sufficient tissue to minimize the likelihood of missing a mixed germ cell tumor.