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Germ Cell Seminoma

Editor: Farhan A. Khan Updated: 8/8/2023 12:28:36 AM


Germ cell tumors (GCT), derived from primordial germ cells, are a diverse group of neoplasms that arise in the gonads (testicles and ovaries) primarily and may also arise in the anterior mediastinum, pineal gland, and brain. They are clinically classified into two major categories, with significant clinical and prognostic implications: Seminomas and non-seminomas. Seminomas generally have a good prognosis, while non-seminomatous tumors are much more likely to present with metastatic disease as well as mixed germ cell tumors comprising of two or more than two different germ cell tumor components.[1] Although rare, GCT may also arise from extragonadal sites. Term “extragonadal germ cell tumor” (EGGCT) is implied in the absence of any primary gonadal neoplasm and represent 1% to 3% of all GCT. Seminoma constitutes 60% of all primary extragonadal GCT and is seen most notably in midline locations of the body like anterior mediastinum, central nervous system, and retroperitoneum. Seminoma in the retroperitoneum is generally metastatic disease from primary gonadal seminoma unless proven otherwise. In the central nervous system, the pineal gland and suprasellar regions are involved more frequently.[2][3] Germinoma, an intracranial counterpart of seminoma (extragonadal seminoma), comprises approximately two-third of all intracranial GCT.

Germinoma can be pure or mixed (coexisting with other GCT, classified as non-germinomatous GCT). Non-germinomatous GCT makes up the remaining one third, including embryonal carcinoma, yolk sac tumor, choriocarcinomas, teratomas, and mixed tumors (containing more than one histologic element). Less commonly involved sites include paraventricular regions of basal ganglia and thalamus. Very rarely, synchronous involvement of the pineal and the suprasellar region is observed, called bifocal germinoma. Germinoma is more common in young adolescents and is usually diagnosed in the second decade of life. The prognosis is good, with a 5-year survival rate greater than 90% since the tumor is highly radiosensitive.[4][5]


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The underlying mechanism for EGGCT is not entirely understood. Two theories have been proposed explaining the origin of these tumors, but clinical evidence is not sufficient and precise explanation of etiology is still controversial. The first theory states that during embryonic development, aberrant migration of primordial germ cells occurs, leading to their arrest in the midline locations of the body. Another hypothesis argues that reverse migration of germ cells occurs from gonad to other locations with subsequent development of the tumor. Fluorescence in situ hybridization (FISH) testing has identified isochromosome 12p to be more common in testicular seminoma.

Next-generation sequencing has identified several mutations implicated in the pathogenesis of intracranial GCT. Germinoma is found to be associated with the gain of function mutation in the tyrosine kinase receptor gene (c-KIT). Other pertinent findings are mutations in KRAS/ NRAS proteins, which are downstream regulators in the c-Kit receptor pathway. In addition, methylation profiling shows pure germinomas to be hypomethylated, a finding similar to the primordial germ cells, denoting the same origin.[6]


Primary intracranial germ cell tumors are uncommon and represent less than 5% of all CNS neoplasms and 3% to 11% of brain tumors in the pediatric population. It is very rare in the adult population constituting 0.4% to 1% of all intracranial tumors.[7] There is variation in the incidence of intracranial GCT geographically. Frequency is higher in Asians compared to other ethnicities (incidence rate of 0.136 per 100,000). The incidence rate of intracranial GCT in the United States is determined to be 0.10 per 100,000 person-years. Germinoma makes up the largest proportion of all intracranial GCT (65%). The peak age at diagnosis is usually between 10 and 12 years with a significant number of cases diagnosed before the age of 20 years. Males are much more likely to be affected compared to females. Most common sites involved by tumor are pineal gland and sellar/suprasellar region. Other sites can also be involved, although less frequently including the thalamus, basal ganglia, and ventricles. Interestingly, tumor sites may also vary by sex as pineal region tumors are more frequent in males while there is a slight female predominance in non-pineal tumors (sellar/suprasellar).[4][5]


Germinoma and other intracranial germ cell tumors have distinct biological characteristics compared to the tumors of neuroepithelial origin. Germinoma is morphologically identical to seminoma, but isochromosome 12p which is a most common genetic event in testicular GCT is rarely seen in intracranial GCT. Molecular profiling of germinoma revealed activating mutations in receptor tyrosine kinase protein c-KIT pathway and the downstream regulators like RAS-MAPK and PI3K (phosphoinositide 3-kinase). KIT signaling is normally involved in the proliferation and survival of primordial germ cells. This supports the germ cell theory of origin for germinoma.[8] The occurrence of germinoma in patients with Klinefelter syndrome (XXY) and Down syndrome (47, +21) have also been reported.[9][10][9]


On microscopic examination, pineal and suprasellar germinoma are morphologically identical to testicular seminoma and ovarian dysgerminoma. Tumor cells are arranged in sheets separated by bands of connective tissue admixed with small lymphocytes. Individual neoplastic cells are large, round to polygonal with pale to clear cytoplasm, large vesicular nuclei, and prominent nucleoli. In some cases, syncytiotrophoblast giant cells are present and may explain elevated human chorionic gonadotrophin in some patients.[11] Well-formed granulomas are also present in a few cases, obscuring the diagnosis as they are usually mistaken for tuberculosis or sarcoidosis. In such cases, immunohistochemistry (IHC) is helpful in highlighting the malignant cells.[12]

History and Physical

Size and tumor location are the most important factors which determine the clinical presentation of the disease. The involvement of the suprasellar region results in hypothalamic or pituitary dysfunction with significant endocrinal insufficiency. The patient develops polyuria and polydipsia due to diabetes insipidus. Growth failure, adrenal insufficiency, hypothyroidism, delayed puberty or precocious puberty may also be evident secondary to hypopituitarism. Dorsal extension of the tumor can cause compression of optic chiasm leading to abnormalities in the vision. However, symptoms may be subtle, leading to significant diagnostic delay.

Pineal region tumors usually present with signs and symptoms of increased intracranial pressure (headache, nausea, vomiting, papilledema) due to obstructive hydrocephalus. Neuroophthalmological abnormalities are also present, which include diplopia and Parinaud syndrome characterized by upward gaze paralysis, loss of light perception, loss of convergence, and nystagmus.[4]

Complete general physical examination is critical, especially ophthalmological and neurological assessment. Primary and secondary sexual characteristics should be evaluated. In young children, assessment of growth parameters is also important.


The diagnostic evaluation of germinoma requires imaging, measurement of serum and cerebrospinal fluid (CSF) oncoproteins, and biopsy for histological confirmation.


MRI is the preferred imaging modality for diagnosis and staging because of the higher sensitivity compared to CT scan. Germinomas form a homogenous mass with variable intensity and maybe isointense or hypointense on T1 and isointense or hyperintense on T2 weighted images. In more advanced disease, germinomas may become heterogeneous with a partially cystic appearance and may invade adjacent brain parenchyma. On CT scan, germinoma demonstrates engulfed calcifications in contrast to pineal parenchymal tumors in which calcifications are much more prominent. However, imaging alone cannot distinguish between germinoma, non-germinomatous GCT, and pineal parenchymal tumors. Therefore, a complete evaluation is crucial.[7]

Tumor Markers

Quantitation of tumor oncoproteins in serum and CSF aids in making a distinction between germinoma and non-germinomatous GCT. Alpha-fetoprotein (AFP) and beta-HCG levels are normal in germinoma. beta-HCG may be slightly elevated in germinoma with syncytiotrophoblast cells, but levels remain less than 50 IU/ml. Greater levels raise suspicion for choriocarcinoma.

CSF Cytology

CSF cytology is crucial from a therapeutic standpoint as the detection of neoplastic cells in CSF indicates metastatic disease.


Surgical biopsy is indicated for histological confirmation.


IHC is an essential adjunct to histology as the tumor shows membranous reactivity for c-kit (CD117), which is a specific marker for germinoma. Oct 3/4 is also positive, but it is non-specific and also expressed by embryonal carcinoma. Placental alkaline phosphatase (PLAP) with a membranous and cytoplasmic pattern is also expressed in germinoma.[4] D2-40 is also expressed by germinoma as a specific marker in comparison to other germ cell tumors.

The biopsy can sometimes be unreliable in identifying mixed GCT due to limited tissue sampling. Therefore, a careful correlation between imaging characteristics, tumor biomarkers, and histology is required for correct identification of the tumor.[6]

Treatment / Management

Germinoma has an excellent prognosis with high cure rates. It is highly sensitive to radiotherapy (RT) and chemotherapy (CT), and the 5-year survival rates are estimated to be greater than 90%. Whole-ventricular RT or CT combined with reduced dose ventricular RT is the standard of care for germinoma.


Craniospinal irradiation (CSI) of 36 grays (Gy) followed by 50 to 54 Gy boost to the primary tumor was recommended initially for patients with localized pure germinoma. Due to the significant side effects of CSI, it is no longer used in localized germinoma. Current practice is whole ventricular irradiation of 21 to 24 Gy with a local boost of 40 to 45 Gy. Whole ventricular irradiation is found superior to localized RT with lower chances of recurrence.


CT permits lowering the dose of irradiation, thus reducing the toxicity. Platinum-based CT is quite effective, and different combinations (carboplatin, etoposide, and ifosfamide or cisplatin, vincristine, and cyclophosphamide) are administered before a low dose, low volume whole ventricular irradiation. CT alone is associated with a higher risk of relapse.

In cases of disseminated germinoma evidenced by MRI or positive CSF cytology, CSI is used. The current practice utilizes 30 Gy CSI with a 45 Gy local boost for an effective outcome.[6]


The role of surgical resection in germinoma is not well established because of the associated risks of damage to adjacent brain structures. Surgical interventions are mainly limited to obtain a tissue sample for histological diagnosis and obstructive hydrocephalus. Second look surgery is considered in patients to remove any residual tumor unresponsive to standard treatment protocols. However, this is more common in patients with non-germinomatous GCT.[13]

Differential Diagnosis

Differential diagnosis mainly depends on the location of the lesion.

Pineal Region Germinoma

For tumors involving the pineal gland, pineal parenchymal tumors like pineocytoma, pineoblastoma, and papillary tumor of the pineal region need to be ruled out.

Suprasellar Germinoma

For sellar/suprasellar germinoma, pituitary adenoma/carcinoma, craniopharyngioma, meningioma are important considerations. 

Differentiation between germinoma and non-germinomatous GCT, particularly mixed GCT, is crucial because of the differences in treatment response and overall prognosis. The role of imaging is limited in making this distinction. Therefore, histological confirmation is mandatory. Both germinoma and mature teratoma can present with normal AFP and beta-HCG levels. Increased levels of serum or CSF AFP exclude the diagnosis of germinoma. Beta-HCG is elevated in a subset of germinoma, which has characteristic multinucleated syncytiotrophoblastic cells. Such tumors are more frequently associated with precocious puberty.

Surgical Oncology

The role of partial or complete surgical resection is not found to be promising in the management of germinoma. Surgical intervention is mainly utilized for diagnostic tissue sampling or treatment of hydrocephalus.[13]

Radiation Oncology

The mainstay of treatment in germinoma is RT. Dosage may vary depending on the extent of the tumor.

Localized Germinoma

Whole ventricular irradiation of 21 to 24 Gy with a local tumor boost of 40 to 45 Gy is quite effective in treating localized pure germinoma. This is a standard regimen when using RT alone. Traditionally, CSI was used to treat localized, pure germinoma. However, to reduce treatment-related toxicities, it was replaced with whole ventricular RT without any significant differences in outcome. Pure germinoma with beta-HCG secreting syncytiotrophoblastic cells is also treated as a localized disease. 

Disseminated Germinoma

CSI is still used in patients with metastatic disease evident by imaging or positive CSF cytology, as these tumors require more aggressive management. CSI of 3o Gy with a 45 Gy local tumor boost is currently being practiced. The 5-year survival rate of up to 98% has been reported in patients with the disseminated disease who received two cycles of CT before CSI of 24 Gy with 40 Gy local boost. It is still not clear whether to treat bifocal germinoma (tumor arising in both pineal and suprasellar region) as a localized or metastatic disease. CSI has yielded greater results in such cases compared to whole-brain irradiation.

Recurrent Germinoma

Relapse rates are higher in patients who are treated with localized RT or CT alone. Recurrences are treated with RT with or without CT. Myeloablative high dose CT along with autologous stem cell rescue, is also found to be therapeutically beneficial for the patient with relapses.[4][6]

Medical Oncology

Germinoma is a chemosensitive tumor and responds well to platinum-based CT. However, CT is more effective when combined with RT, decreasing the risk of morbidity associated with RT. A recurrence rate of 50% is observed in the patients treated with CT alone. This rate is reduced to 20% when combined treatment is executed.[6] Current treatment recommendations include 4 cycles of CT with carboplatin on day 1 and etoposide on days 1 to 3 at the dose of 600 mg/m^2/day and 150 mg/m^2/day, respectively. This is followed by a whole-ventricular RT of 18 Gy with a local tumor boost of 12 Gy.[4]


It is critical to determine the extent of disease before initiating treatment because the approach is different for localized versus disseminated germinoma. Neuroimaging with MRI and lumbar puncture for CSF cytology is essential for the staging of the tumor. Imaging can demonstrate the extent of central nervous system (CNS) involvement by the tumor. The presence of neoplastic cells in the CSF indicates metastatic disease, and patients are treated more aggressively with CSI for better outcomes. Direct visualization of the third ventricle can also be utilized in determining the involvement of the suprasellar region, not evident on initial imaging.[14]

There are no recommended TNM based staging guidelines for intracranial tumors. However, the modified Chang system for medulloblastoma can be employed.[4] 

  • M0: No evidence of metastatic disease
  • M1: Tumor cells detected on CSF cytology
  • M2: Intracranial metastases
  • M3: Spinal metastases


Germinoma responds well to treatment and five-year survival rates exceed 90%. However, late recurrences can occur after 10 to 15 years of follow up.[4] 


Complications related to treatment have been reported. Exposure to RT results in impairment of neurocognitive functions, vision abnormalities, hypopituitarism, and stroke. An increase in the risk of developing secondary malignancies of CNS like gliomas and meningiomas have also been reported in the patients. CT related side effects are also an important health concern in patients like cytopenia, ototoxicity, and alopecia.[4][15]


Regular surveillance is important following the primary intervention. The patient should be followed up with neuroimaging and tumor biomarkers evaluation to look for any residual disease or relapse.[4]

Deterrence and Patient Education

There are no known risk factors for germinoma. Therefore, screening is not recommended for the general population. Germinoma is a malignant tumor with excellent survival. 

Tumors arising in the suprasellar region can have a very gradual onset, and symptoms may go unrecognized for a long time. Subtle features like growth failure, drop in school performance, lethargy, sleep alterations, delayed puberty should not be neglected. It is essential to seek professional care when any sign or symptom related to endocrinal abnormalities is experienced, especially polyuria and polydipsia.[16]

Enhancing Healthcare Team Outcomes

The interprofessional approach is mandatory in the management of patients. Germinoma is a rare pediatric CNS tumor, but it is highly curable. Recent advances in the treatment modalities have shifted the level of care from increasing survival to improving quality of life. Longterm management is critical involving multidisciplinary teamwork requiring oncologists, pediatricians, neurosurgeons, endocrinologists, radiologists, pathologists, and nursing professionals. Patients may require lifelong hormonal therapy. Psychosocial support is also an essential component for a better outcome.


(Click Image to Enlarge)
<p>Ultrasound of Seminoma of the Testicle</p>

Ultrasound of Seminoma of the Testicle

Contributed by Dawn Light, MD, MPH



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