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Controversies in the Management of Intracranial Germinomas

Controversies in the Management of Intracranial Germinomas

ABSTRACT: Intracranial germinomas are uncommon tumors. In the past, patients have traditionally been diagnosed with a trial of focal radiotherapy without biopsy. If the tumor was radiosensitive, it was presumed to be a germinoma. Because of the minimal morbidity and mortality associated with microsurgical techniques, almost all patients now have a histologic diagnosis and can be treated appropriately. Radiation therapy has been employed for the past three decades in the curative management of this disease. The long-term results have been excellent; however, current approaches have explored the possibility of reducing or even eliminating radiation therapy. This article provides a brief overview of intracranial germinomas and explores the controversies in the surgical, radiotherapeutic, and chemotherapeutic management of this tumor. [ONCOLOGY 13(4):513-521, 1999]

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.

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