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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Simrat Sarai, M.D. [2]

Overview

The term germinoma most often refers to a tumor in the brain that has a histology identical to two other tumors: dysgerminoma in the ovary and seminoma in the testis. It may be benign or malignant. Germ cell tumors (GCTs) are classified as extragonadal if there is no evidence of a primary tumor in either the ovaries or the testes. Extragonadal GCTs typically arise in midline locations, and specific sites vary with age of the patient. In infants and young children, intracranial GCTs and sacrococcygeal teratomas are more common than other locations. In adults, the most common sites are the anterior retroperitoneum, mediastinum, and the pineal and suprasellar regions. Intracranial germ cell tumors are a heterogeneous group of lesions which occur in children and adults.[1] Germinoma may be classified according to World Health Organization into two groups: germinomas and nongerminomatous germ cell tumors. Based on the tumor markers secreted into the cerebrospinal fluid (CSF) and serum, as well as by the presence of histochemical markers on tumor cells, intracranial germ cell tumors may be classified into either secreting or non secreting tumors. Based on the prognosis of the tumor, intracranial germ cell tumors may be classified into either good, intermediate, or poor prognosis.[2][3][4] On gross pathology, smooth and bosselated external surface, and soft, fleshy and either cream-colored, gray, pink or tan interior are characteristic findings of germinoma. On microscopic histopathological analysis, uniform cells that resemble primordial germ cells, consisting of large, round cells with vesicular nuclei and clear or finely granular cytoplasm that is eosinophilic are characteristic findings of germinoma. Genes involved in the pathogenesis of germinoma include gains of 1p, 8p, and 12q and losses of 13q and 18q, duplication of the short arm of chromosome 12, loss of 1p and 6q, alterations in sex chromosomes in children, alterations of the p14 gene, mutations of the c-kit gene, aberrations of CCND2 (12P13), and RB1, and gain-of-function mutations of KIT. The progression to germinoma usually involves the mutations of the KIT/RAS signalling or AKT1/mtor pathways and cyclin/CDK-RB-E2F pathway if CCND2 (12P13) and RB1 genes are aberrated.[5][6][7][8][9][10][11][12] The peak of germinoma occurs at ages 15-19 years: the median age at diagnosis is 10-12 years. CNS germ cell tumors commonly affects individuals between birth and 34 years of age. Males are more commonly affected with pineal germinoma than females. The male to female ratio is approximately 5-22 to 1. Females are more commonly affected with suprasellar germinoma than males. The female to male ratio is approximately 1.3:1. Symptoms of germinoma include headache, vomiting, papilledema, lethargy, somnolence, ataxia, behavioral changes, decline in academic performance, paralysis of upward gaze, paralysis of convergence, diabetes insipidus, delayed pubertal development, precocious puberty, isolated growth hormone deficiency, hypopituitarism (central hypothyroidism, adrenal insufficiency), decreased visual acuity from chiasmal or optic nerve compression, and visual field deficit (e.g, bitemporal hemianopsia). Presenting symptoms of patients with intracranial GCTs depend upon the location, size of the tumor, and the patient's age.[13][14][15] MRI of the brain and spine with and without gadolinium is the imaging modality of choice for germinoma. On MRI, intracranial GCTs appear isointense or hypointense on T1 sequences and hyperintense on T2 sequences.[16] The predominant therapy for CNS germ cell tumors is radiation therapy. Adjunctive chemotherapy and surgery may be required.[17][18][19][20] The feasibility of surgery depends on the type of the intracranial germ cell tumor at diagnosis. Surgery is not the first-line treatment option for patients with germ cell tumors. Surgery is usually reserved for patients with either NGGCTs, or in patients who have had an incomplete response to initial chemotherapy, and in patients with "growing teratoma syndrome".[21][22][13][23][24][25][26][27][17][28][29][30]

Historical Perspective

Classification

Germinoma may be classified according to World Health Organization into two groups: germinomas and nongerminomatous germ cell tumors. Based on the tumor markers secreted into the cerebrospinal fluid (CSF) and serum, as well as by the presence of histochemical markers on tumor cells, intracranial germ cell tumors may be classified into either secreting or non secreting tumors. Based on the prognosis of the tumor, intracranial germ cell tumors may be classified into either good, intermediate, or poor prognosis.[2][3][4]

Pathophysiology

On microscopic histopathological analysis, uniform cells that resemble primordial germ cells, consisting of large, round cells with vesicular nuclei and clear or finely granular cytoplasm that is eosinophilic are characteristic findings of germinoma. Genes involved in the pathogenesis of germinoma include gains of 1p, 8p, and 12q and losses of 13q and 18q, duplication of the short arm of chromosome 12, loss of 1p and 6q, alterations in sex chromosomes in children, alterations of the p14 gene, mutations of the c-kit gene, aberrations of CCND2 (12P13), and RB1, and gain-of-function mutations of KIT. The progression to germinoma usually involves the mutations of the KIT/RAS signalling or AKT1/mtor pathways and cyclin/CDK-RB-E2F pathway if CCND2 (12P13) and RB1 genes are aberrated.[5][6][7][8][9][10][11][12]

Causes

There are no established causes for germinoma. However, several theories have been postulated to define the cause of germ cell tumors. GCTs arise from primordial germ cells that migrate to the germinal ridges in the developing embryo. The process of migration appears to be under the control of complex molecular events. Alteration in any of these molecular pathways may give rise to GCTs. Rather than laterally to genital ridges, some primordial germ cells that have left the yolk sac endoderm migrate aberrantly cranially towards the diencephalic midline structures.[21][31][7][8][32][33][34] Biopsy may be helpful in the diagnosis of germinoma. Findings on biopsy diagnostic of germinoma include undifferentiated, uniform large cells with abundant glycogen-rich cytoplasm arranged in nests separated by bands of connective tissue along trophoblastic lines.[23]

Epidemiology and Demographics

The peak of germinoma occurs at ages 15-19 years: the median age at diagnosis is 10-12 years. CNS germ cell tumors commonly affects individuals between birth and 34 years of age. Males are more commonly affected with pineal germinoma than females. The male to female ratio is approximately 5-22 to 1. Females are more commonly affected with suprasellar germinoma than males. The female to male ratio is approximately 1.3:1.

Risk Factors

There are no established risk factors for germinoma.

Screening

According to the United States Preventive Services Task Force, screening for extramammary Paget's disease is not recommended among the general population.[35]

Differential Diagnosis

Germinoma must be differentiated from other lesions in the pineal and suprasellar region, such as glial tumors which include astrocytomas and gangliomas, granular cell tumor, hamartomas, xanthogranuloma, meningiomas, colloid cysts, craniopharyngioma, cysticercosis, metastatic cancer with unknown primary site, pineal tumors, and pituitary macroadenomas.[16]

Natural History, Complications, and Prognosis

If left untreated, more than 50% of patients may continue to suffer from endocrine abnormalities such as growth hormone deficiency, growth retardation, hypopituitarism, and hypothyroidism, and may require lifelong hormonal replacement therapy. Common complications of germinoma include secondary cancers such as acute myeloid leukemia and radiation-induced brain neoplasms. Prognosis is generally excellent for germinomas, and the 5-year survival rate of patients with germinoma is approximately 70-90%. However, prognosis in general depends on the histological diagnosis and staging of the extent of disease.

Diagnosis

Staging

There is no established system for the staging of germ cell tumors, and most investigators utilize the TM system employed for staging medulloblastomas. Predominantly because of their midline location, staging for the size of the tumor at the time of diagnosis or after surgery (T-stage evaluation), has not been routinely employed in germ cell tumors.

History and Symptoms

Symptoms of germinoma include headache, vomiting, papilledema, lethargy, somnolence, ataxia, behavioral changes, decline in academic performance, paralysis of upward gaze, paralysis of convergence, diabetes insipidus, delayed pubertal development, precocious puberty, isolated growth hormone deficiency, hypopituitarism (central hypothyroidism, adrenal insufficiency), decreased visual acuity from chiasmal or optic nerve compression, and visual field deficit (e.g, bitemporal hemianopsia). Presenting symptoms of patients with intracranial GCTs depend upon the location, size of the tumor, and the patient's age.[13][14][15]

Physical Examination

Common physical examination findings of germinoma include paralysis of upward gaze, pupils nonreactive to light perception and accommodation or pupils which react better to accommodation than light, nystagmus, failure of convergence, lid retraction, papilledema, ataxia, and neurologic examination may be abnormal depending on the location of the tumor.

Laboratory Findings

An elevated concentration of AFP and beta-hCG in the serum and CSF, and CSF cytology to detect malignant cells is diagnostic of intracranial germ cell tumors. In patients in whom endoscopic biopsy is not considered possible, detection of elevated tumor markers may be sufficient for diagnosis.

Chest X Ray

Chest x-rays may be performed to detect metastases of germinoma to the lungs.

CT

Head and neck CT scan may be diagnostic of germinoma. Findings on CT scan suggestive of germinoma include hyperdensity compared to adjacent brain, pituitary stalk enhancement and thickening, and presence of calcification in the pineal region in the pediatric population.[16]

MRI

MRI of the brain and spine with and without gadolinium is the imaging modality of choice for germinoma. On MRI, intracranial GCTs appear isointense or hypointense on T1 sequences and hyperintense on T2 sequences.[16]

Ultrasound

On ultrasound, germinoma is characterized by heterogeneous echogenic mass with cystic and solid components.

Other Imaging Findings

Other diagnostic studies for germinoma include PET scan.[36]

Other Diagnostic Studies

Biopsy may be helpful in the diagnosis of germinoma. Findings on biopsy diagnostic of germinoma include undifferentiated, uniform large cells with abundant glycogen-rich cytoplasm arranged in nests separated by bands of connective tissue along trophoblastic lines.[23]

Treatment

Medical Therapy

The predominant therapy for CNS germ cell tumors is radiation therapy. Adjunctive chemotherapy and surgery may be required.[17][18][19][20]

Surgery

The feasibility of surgery depends on the type of the intracranial germ cell tumor at diagnosis. Surgery is not the first-line treatment option for patients with germ cell tumors. Surgery is usually reserved for patients with either NGGCTs, or in patients who have had an incomplete response to initial chemotherapy, and in patients with "growing teratoma syndrome".[21][22][13][23][24][25][26][27][17][28][29][30]

Primary Prevention

There are no primary preventive measures available for germinoma.

Secondary Prevention

Secondary prevention strategies following germinoma include retreatment with the original regimen. For patients who received radiotherapy RT to a reduced volume, craniospinal irradiation CSI is considered the standard of care. Myeloablative high-dose chemotherapy with autologous stem cell rescue followed by additional RT can be considered, for patients who have already received craniospinal irradiation CSI.[37]

References

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