OVERVIEW: What every practitioner needs to know
Are you sure your patient has an intracranial germ cell tumor? What are the typical findings for this disease?
Unlike their counterparts in the pelvis, testes, and elsewhere in the body, germ cell tumors (GCTs) in the central nervous system (CNS) are not strictly segregated by their underlying pathologic characteristics (e.g., germinoma, choriocarcinoma, embryonal carcinoma, endodermal sinus [yolk sac] tumor, immature teratoma, mature teratoma, and mixed GCT). Instead, CNS GCTs are classified simply into two entities, namely germinomas and nongerminomatous germ cell tumors (NGGCTs), with mature teratoma considered separately as a benign tumor. Both germinomas and NGGCTs are malignant CNS tumors. CNS germinomas appears histologically identical to ovarian dysgerminoma and testicular seminoma. Germinomas compose about two thirds of GCTs, with the remainder being NGGCTs and teratomas.
GCTs present most often in late childhood, the teenage years, or young adult years, and less often before age 5 years.
GCTs occur most commonly at the pineal region followed by the suprasellar region, involving the hypothalamic-pituitary-axis and less often at the cerebrum, or rarely elsewhere in the CNS. Accordingly, these tumors typically present with findings attributable to their location.
GCTs at the suprasellar area almost always present with diabetes insipidus over months to even years, plus or minus other endocrinologic disturbances (e.g., short stature, intolerance to cold, and delayed or precocious puberty). If a suprasellar tumor is greater than a couple of centimeters, there may be visual loss secondary to pressure on or involvement of the optic chiasm.
Tumors at the pineal region present with Parinaud syndrome—a combination of impaired vertical gaze, (mainly upgaze), convergence-retraction nystagmus on attempted upgaze (i.e, retraction of the eye into the orbit), light-near dissociation of pupils (i.e., pupils constrict with accommodation but do not react to light), impaired convergence, and sometimes a skewed eyes deviation.
There may be headache associated with obstructive hydrocephalus. Some GCTs, particularly germinomas, will present synchronously at both the pineal and suprasellar regions.
GCTs in children that present outside these areas usually present with motor dysfunction (e.g., weakness) or seizure. Behavioral disturbances are often seen when there is basal ganglia involvement with these tumors, and this presentation may be more common in Asians. Rarely, patients can present narcolepsy with the involvement of the hypothalamus.
GCTs have a strong sex predisposition. At the pineal region, 90% of patients are male individuals, and at the suprasellar region two thirds are male patients.
What other disease/condition shares some of these symptoms?
There are a host of other disease processes that can present with lesions at the suprasellar and pineal regions.
Craniopharyngioma: This tumor presents most often at the end of the second decade, commonly with both endocrine disturbance and visual impairment.
Astrocytoma: This tumor presents most often in the first 5 years of life, typically with visual loss and no endocrinologic disturbance.
Langerhans cell histiocytosis: This disease presents more often with a smaller lesion, especially involving the pituitary stalk, and children are younger, but they still display diabetes insipidus at presentation. The patient may have lytic lesions in the skull or other bones.
Lymphocytic hypophysitis: This is a monophasic, inflammatory process of the pituitary axis, perhaps viral or postviral in origin, and resulting in diabetes insipidus acutely. Neuroimaging (see below) tends not to show a large or discrete lesion, but rather a thick pituitary stalk.
Thickened pituitary stalk of adolescence: This is not a disease but rather an incidental finding in prepubertal or pubertal children that is found incidentally on magnetic resonance imaging (MRI) obtained for other reasons. Nevertheless, this entity is a diagnosis of exclusion and GCT, Langerhans cell histiocytosis, and lymphocytic hyophysitis must be given some consideration, particularly if there is any endocrine disturbance.
Pineoblastoma: This is an embryonal, or primitive neuroectodermal, tumor with a very aggressive course and a tendency to metastasize. This tumor will often present with Parinaud syndrome but is seen more often in infants and children than in adolescents or young adults. Both boys and girls are affected about equally. When pineoblastoma is found in a child already diagnosed with bilateral retinoblastoma, the syndrome is referred to as trilateral retinoblastoma.
Tectal glioma: This is a low-grade astrocytic tumor with enlargement of the posterior aspect of the midbrain adjacent to the pineal gland. Patients present in childhood or adolescence, with obstructive hydrocephalus, often of long standing, and minimal ocular findings, or sometimes impaired upgaze.
Pineal cyst: This is again an incidental, normal finding, arising when a brain MRI is obtained for other reasons (e.g., headache). The cyst does not enhance with gadolinium. These cysts are benign and asymptomatic. No intervention is required.
Very rarely in children, pineal tumors can also be pineocytoma, astrocytoma, meningioma, or lymphoma.
What laboratory studies should you request to help confirm the diagnosis? How should you interpret the results?
Although some children will first come to attention through head computed tomography (CT), brain MRI with and without gadolinium contrast is required and is the standard of care in all the diagnoses. If there is suspicion that the diagnosis is thickened pituitary stalk or pineal cyst, only observation may be required or one or more convalescent MRIs to ensure that the lesion is static. Sometimes, however, the nature of a peripituitary lesion or pineal mass is less clear. A more extensive work-up is then indicated.
Work-up for suprasellar lesions
1. MRI of the spine, with and without gadolinium, is performed to exclude metastatic lesions.
2. Assessment of pituitary function is carried out with serum free T4, thyroid-stimulating hormone, insulin-like growth factor-1, and insulin-like growth factor binding-protein as well as a first-morning urine void for specific gravity. Inability to concentrate the urine should prompt further evaluation for diabetes insipidus. At any point, consideration should be given to consultation with an endocrinologist.
3. Serum quantitative tumor markers are evaluated, specifically β-human chorionic gonadotropin (BHCG), alpha-fetoprotein (AFP), and placental alkaline phosphatatase (PLAP). Testing for PLAP may not be available in many institutions. (See below.)
4. A bone survey is needed to rule out lytic lesions of histiocytosis.
5. Consultation with an ophthalmologist should be sought to assess visual fields and acuity.
6. Lumbar puncture, if medically safe, is carried out to assess for tumor markers BHCG, AFP, and PLAP as well as cytologic findings with cytopsin for tumor cells.
Work-up for pineal lesions
This work-up is the same as for suprasellar lesions, but items 2 and 4 are unnecessary.
Survey for tumor markers in blood or CSF
Perhaps in up to 20% of cases, the diagnosis of a GCT can be made by tumor markers and may obviate the need for biopsy of the lesion. However, some experts now suggest to conduct a biopsy in every cases to confirm the diagnosis and for molecular testing.
Any serum or CSF elevation of PLAP alone is diagnostic of germinoma.
Any serum or CSF elevation of AFP greater than 10 ng/mL is diagnostic of NGGCT.
Any serum or CSF elevation of BHCG less than 50-100 IU/L alone, with or without elevation of PLAP, is viewed by most neurooncologists as diagnostic of germinoma and precludes the need for biopsy. With elevation of BHCG to greater than 500 IU/L, there is nearly universal agreement among neurooncologists that the child has a NGCCT. When levels are in the 50-500 U/L range, a biopsy should be conducted to confirm the diagnosis.
When tumor markers are uninformative, neurosurgical biopsy is required. Because extent of resection (complete versus subtotal) has never been demonstrated to affect outcome for GCT, there is a preference simply for biopsy by the neurosurgeon, performed stereotactically or by craniotomy.
Multiple specimens should be sought to minimize sampling error, as some NGGCTs contain elements of germinoma, and limited sampling could mistakenly lead to a final diagnosis of germinoma. If the tumor is a germinoma, an attempt at further resection is not indicated, as multiple studies have shown no benefit to radical or subtotal resection. For NGGCTs, there is benefit to tumor resection before other therapies (see below).
Would imaging studies be helpful? If so, which ones?
As already noted, brain and spine MRI are required in the initial evaluation. Germ cell tumors usually appear as a solid mass in the suprasellar or pituitary region. Germinomas tend to enhance avidly with gadolinium. NGGCTs tend to be heterogeneous with some enhancement and frequently old hemorrhage. Teratomas are frequently well circumscribed and frequently cystic.
Head CT may reveal long-standing calcification, characteristic of either NGGCT or teratoma more than germinoma. Imaging studies can also show hydrocephalus.
If the diagnosis of GCT has been made with markers or biopsy, and spine MRI has not yet been performed, that study is still required for staging to rule out any distant metastases. Other body imaging is not necessary, as CNS GCTs do not metastasize outside the brain and spine at diagnosis and only rarely in the disease course.
Extracranial spread to bone or lungs has been reported rarely. Likewise, non-CNS GCTs almost never spread to the CNS and do not present with CNS metastatic disease.
If you are able to confirm that the patient has this disease, what treatment should be initiated?
Once diagnosis of germinoma or NGGCT has been secured by tumor markers or diagnostic tumor tissue, the child requires treatment by a pediatric oncologist or neurooncologist, along with a radiation oncologist who has expertise in GCT. Consideration should be given to enrolling the patient, even a young adult, in a cooperative group trial in North America through the Children’s Oncology Group or in Europe through the International Society of Pediatric Oncology or other groups.
For germinoma, “standard” of care remains 2400-3600 cGy whole ventricular, or less commonly whole-brain, irradiation, with a boost up to 4000-4500 cGy. More than 90% of these tumors will be cured. Craniospinal irradiation is no longer standard as it was years ago. Nevertheless, most neurooncologists prefer a brief course of chemotherapy over 2 to 4 months to shrink the tumor and then lower the radiation dosage.
Up to 80%-90% of germinomas will disappear completely with chemotherapy, usually carboplatin or cisplatin and etoposide. However, chemotherapy alone will not cure the disease, as the tumor will very frequently reappear months or years later, sometimes with additional spread.
For NGGCTs, the disease is more aggressive and survival at 5 years approximates from 25%-70%. These widely discrepant outcomes likely reflect the mixed composition of NGGCT and the small samples often reported.
To date, standard treatment requires combined 2400-3600 cGy craniospinal irradiation plus boosts to 5400 cGy or more for bulky tumor, and chemotherapy before or after radiotherapy, often with agents including carboplatin, etoposide, and ifosfamide or cyclophosphamide, and less often bleomycin, vinblastine,vincristine, or paclitaxel.
Decreasing the field of radiation and/or dosage will likely be examined in future cooperative group trials. Myeloablative chemotherapy with autologous hematopoietic stem cell rescue has been considered in NGGCT, but the role of such treatment remains undefined.
Tumors that are exclusively mature teratoma do not require any treatment beyond subtotal or gross total excision by the neurosurgeon.
What are the adverse effects associated with each treatment option?
Acute: nausea, vomiting, dermatitis, alopecia
Subacute: somnolence and diminished appetite
Chronic: stroke, second malignancy, and cognitive decline
Stroke or secondary tumors may occur years to decades later in a small percentage of survivors. Cognitive decline is common with whole-brain or whole-ventricle radiation, probably because of radiation injury to the hippocampus and midline brain structures, and in younger children may cause loss of intelligence, whereas in teens and adults it leads to more subtle memory and learning issues.
Acutely, almost all chemotherapy can cause alopecia, nausea and vomiting, pancytopenia, and loss of appetite and weight loss, as well as lead to infection or kidney or hepatic dysfunction. Etoposide is associated years later particularly with acute myelogenous leukemia in a very small number of patients. Cyclophosphamide is associated with infertility.
Other late effects of chemotherapy are well detailed in the Children’s Oncology Group Long-Term Survivorship Follow-Up Guidelines at www.survivorshipguidelines.org .
What are the possible outcomes of this disease?
Well in excess of 90% of patients are cured of this malignant tumor. However, endocrinopathies do not reverse and persist lifelong. Most relapses occur in the first 2 years after diagnosis.
These tumors have a less sanguine outlook, and from 70% to only 25% of patients are cured. Whether this success is determined by the elements composing the NGGCT (e.g., extensive choriocarcinoma or endoderminal sinus tumor may be more ominous) or failure of the treatment regimen is unclear.
Very rarely, a germinoma will recur years later as a NGGCT. Whether this phenomenon occurs because of a sampling diagnosis at initial diagnosis or a transformation of the underlying disease is unknown.
What causes this disease and how frequent is it?
The cause of GCT is unknown. No environmental exposure has been associated with GCT. The very specific age distribution for these tumors and their sometime association with birth defects suggest a genetic predisposition, yet undefined.There is a higher incidence of GCT in patients with Klinefelter syndrome, which is characterized by a 47,XXY genotype, and Down syndrome (trisomy 21).
Peak incidence for germinomas is in the second decade of life, whereas for NGGCTs, the incidence is relatively constant in children and young adults. GCTs compose less than 5% of childhood CNS tumors, with the incidence about 1.5/1,000,000 children. Among Asians, GCTs compose up to 15% of all childhood CNS tumors.
How can this disease be prevented?
At present, there are no known preventive strategies for these cancers.
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- OVERVIEW: What every practitioner needs to know
- Are you sure your patient has an intracranial germ cell tumor? What are the typical findings for this disease?
- What other disease/condition shares some of these symptoms?
- Would imaging studies be helpful? If so, which ones?
- If you are able to confirm that the patient has this disease, what treatment should be initiated?
- What are the adverse effects associated with each treatment option?
- What are the possible outcomes of this disease?
- What causes this disease and how frequent is it?
- How can this disease be prevented?