eMedicine Specialties > Oncology > Carcinomas of the Genitourinary Tract

Extragonadal Germ Cell Tumors

Author: Kush Sachdeva, MD, Private Practice, Southern Oncology and Hematology Associates, South Jersey Hospital System, Fox Chase Cancer Center
Coauthor(s): Issam Makhoul, MD, Associate Professor, Department of Medicine, Division of Hematology/Oncology, University of Arkansas for Medical Sciences; Brendan Curti, MD, Director, Genitourinary Oncology Research, Robert W. Franz Cancer Research Center, Earle A. Chiles Research Institute, Providence Portland Medical Center
Contributor Information and Disclosures

Updated: Aug 15, 2008

Introduction

Background

Extragonadal germinal cell syndromes are rare tumors that predominantly affect young males. Literature suggests that the only known risk factor for extragonadal germ cell tumors (EGCTs) is Klinefelter syndrome (47XXY), which is associated with mediastinal nonseminomatous germ cell tumors.1,2 They are characterized by their location on the midline from the pineal gland to the coccyx. In extragonadal germ cell tumors, no evidence of a primary malignancy is present in either the testes or ovaries by radiologic imaging or physical examination. Extragonadal germ cell tumors produce a rich symptomatology and may reach large volumes if they arise in silent areas. Histologically, they mirror their gonadal counterparts with which they share the same chemosensitivity and radiosensitivity. Modern approaches to diagnosis and treatment can result in high rates of long-term survival and even cure.

Pathophysiology

Controversy remains regarding the origin of extragonadal germ cell tumors (EGGCTs). These tumors can be found anywhere on the midline, particularly the retroperitoneum, the anterior mediastinum, the sacrococcyx, and the pineal gland. Other less common sites include the orbit, suprasellar area, palate, thyroid, submandibular region, anterior abdominal wall, stomach, liver, vagina, and prostate. The classic theory suggests that germ cell tumors (GCTs) in these areas are derived from local transformation of primordial germ cells misplaced during embryogenesis.

A recent alternative theory suggests that primary mediastinal presentations represent reverse migration of occult carcinoma in situ (CIS) lesions in the gonad; hence, they may be gonadal in origin. According to this theory, the differences in phenotypes expressed by mediastinal germ cell tumors (MGCTs) and gonadal germ cell tumors may be explained by differences in the cellular environment between the gonad and the anterior mediastinum. Some retroperitoneal extragonadal germ cell tumors may represent metastases from a testicular cancer, with subsequent spontaneous necrosis of the primary tumour.

To explain the origin of occult carcinoma in situ cells, 2 models have been proposed. The first suggests that fetal gonocytes whose development into spermatogonia is blocked may undergo abnormal cell division and then invasive growth mediated by postnatal and pubertal gonadotrophin stimulation. The second model postulates that the most likely target cell for transformation is the zygotene-pachytene spermatocyte. During this stage of germ cell development, aberrant chromatid exchange events associated with crossing over can occur. Normally, these cells are eliminated by apoptosis. In occasional cells, this crossing over may lead to increased 12p copy number and overexpression of cyclin D2. The cell carrying this abnormality is relatively protected against apoptotic death because of the oncogenic effect of CCND2, leading to re-initiation of cell cycle and genomic instability.

Malignant transformation of germ cells is the result of a multistep process of genetic changes. One of the earliest events is the increased copy number of 12p, either as 1 or more copies of i(12p) or as tandem duplications of chromosome arm 12p.3 This abnormality is found in occult carcinoma in situ lesions as well as more advanced disease. Further studies indicate that the CCND2 gene is present at chromosome band 12p13 and CCND2 is overexpressed in most GCTs, including CIS. Amplification of CCND2 activates cdk4/6, allowing the cell to progress through the G1-S checkpoint.

Hematologic malignancies are frequently associated with mediastinal germ cell tumors.4 Embryologically, hematopoietic stem cells arise in the yolk sac. Highly differentiated yolk-sac tumors make up 30% of mediastinal germ cell tumors, providing a possible basis for this association.

The balance of the p53-mdm2 interaction has been shown to be disrupted in intracranial germ cell tumors (ICGCTs). mdm2 sequesters p53 and inhibits its function as G1-S checkpoint controller and apoptosis inducer. In normal cells, mdm2 availability is controlled by ARF, the product of the p14ARF gene located on INK4a/ARF locus, which binds with mdm2 and induces its degradation.5 Mutation of ARF, reported in 71% of intracranial germ cell tumors, results in mdm2 accumulation and functional impairment of p53. This abnormality was reported in 90% of seminomatous and 55% of nonseminomatous intracranial germ cell tumors (NS-ICGCTs) examined.

Frequency

United States

Extra-gonadal germ cell tumors (EGGCTs) represent 5-10% of all germ cell tumor (GCTs).

International

In Norway, a recent study by Dueland et al estimated the incidence of extra-gonadal germ cell tumor (EGGCTs) at 0.5 per 100,000 population per year.6 This represents about 2% of the number of testicular cancers reported for the same period. Intracranial germ cell tumors (ICGCTs) represent 0.3-3.4% of primary intracranial tumors in Western countries and 2.1-12.7% in Japan.7

Mortality/Morbidity

For patients receiving intensive chemotherapy, 5-year survival rates of 40-65% have been reported. Extragonadal seminomas carry the best survival rates. Mortality due to the treatment may be seen in as many as 12% of patients with nonseminomatous extragonadal germ cell tumors (NS-EGGCTs).

  • Seminomas account for 30-40% of these tumors, and nonseminomatous germ cell tumors (NS-GCTs) account for 60-70%. Nonseminomatous germ cell tumors include yolk-sac tumors, embryonal carcinomas, choriocarcinomas, teratomas, and nonteratomatous combined germ cell tumors.
  • The most common site of extragonadal germ cell tumors (EGGCTs) is the mediastinum (50-70%) followed by the retroperitoneum (30-40%), the pineal gland (5%), and the sacrococcygeal area (less than 5%).
  • Pathology of postchemotherapy residual masses reveals necrosis in 24%, teratoma in 45%, sarcoma in 5%, and viable germ cell cancer in 26%. However, the smaller the residual mass, the lower the chance that it harbors viable tumor cells.

Sex

In children, benign and malignant extragonadal germ cell tumors (EGGCTs) occur equally in males and females. In adults, only benign extragonadal germ cell tumors (teratomas) occur at equal frequency in both sexes; more than 90% of malignant extragonadal germ cell tumors occur in males.

Age

Extragonadal germinal cell syndromes are rare tumors that predominantly affect young males.

Clinical

History

Symptoms vary depending on the site and the size of the tumor. Those arising in nonvital organs can reach large sizes before becoming symptomatic, but small tumors may result in significant symptoms if they obstruct, compress, or rupture into important structures.

  • Mediastinal germ cell tumors  
    • The mediastinum is the most common site of extragonadal germ cell tumors. Mediastinal germ cell tumors account for only 2-5% of all germinal tumors, but they constitute 50-70% of all extragonadal tumors. Mediastinal germ cell tumors account for 1-15% of adult anterior mediastinal tumors. Mature teratomas represent 60-70% of mediastinal germ cell tumors. Malignant mediastinal germ cell tumors (30-40%) are divided between seminomas (40%) and nonseminomatous germ cell tumors (60%). Although 90-100% of malignant germ cell tumors are symptomatic, only 50% of teratomas produce symptoms. Nonseminomatous mediastinal germ cell tumors (NS-MGCTs) are faster growing and metastasize earlier than mediastinal seminomas.
    • Although their incidence peaks in the third decade, several cases have been reported in patients older than 60 years.
    • Patients with mediastinal germ cell tumors may present with (in decreasing order) chest pain (39%), dyspnea (29%), cough (22%), weight loss (19%), superior vena cava syndrome (12%), Nausea (6%), fever (6%), postobstructive pneumonia, weight loss, night sweats, dysphagia, shoulder or arm pain, vocal cord paralysis, and hoarseness. In one third of patients the anterior mediastinal mass is an incidental finding of a routine chest radiograph (in most of these cases, a benign tumor is found).
    • Metastases to locoregional lymph nodes or to distant sites, such as the lungs, liver, or bone, may be present in 20-50% of cases on presentation. Distant metastases are seen only in malignant mediastinal germ cell tumors.
    • Mature teratoma rupture, teratoma with malignant transformation, and hematologic malignancies may complicate mediastinal germ cell tumors (see Complications).
  • Retroperitoneal germ cell tumors  
    • The second most common site of extragonadal germ cell tumors (30-40%), after the mediastinum, is the retroperitoneum. Retroperitoneal germ cell tumors (RGCTs) represent 10% of all malignant primary retroperitoneal tumors.
    • Often patients with retroperitoneal germ cell tumors present late, after their tumors have reached large dimensions.
    • Presenting symptoms are abdominal mass with or without pain, backache, and weight loss. Loss of ejaculation was reported in one case.
  • Intracranial germ cell tumors  
    • Very rare tumors of the adolescent and young adult, intracranial germ cell tumors (ICGCTs) are localized preferentially to the pineal and suprasellar regions. However, other midline structures can be involved. Although seminomas (60% of intracranial germ cell tumors) have a predilection for the suprasellar region, embryonal carcinomas, yolk-sac tumors, and choriocarcinomas mainly occur in the pineal region.
    • Pineal tumors present with headache, nausea, and vomiting because of increased intracranial pressure; they require early ventriculoperitoneal (VP) shunting. Deterioration of intellectual functions, gait abnormalities with frequent falls, and sphincteric incontinence are common. Choreic movements and ataxia of the limbs with spastic weakness appear in later stages of Parinaud syndrome.
    • In suprasellar tumors, precocious pseudopuberty, diabetes insipidus with or without anterior pituitary dysfunctions (eg, adrenocorticotropic hormone [ACTH] deficiency), central hypothyroidism, growth hormone (GH) deficiency, and hypogonadism may be seen. Decreased visual acuity, visual field defect, diplopia, obesity, psychosis, and obsessive-compulsive symptoms have also been reported.
    • A case of primary spinal seminoma has been reported in a patient with Klinefelter syndrome.8
  • Sacrococcygeal germ cell tumors  
    • In the literature to date, 17 cases have been reported.
    • Pain and bowel habit change are the main symptoms. Severe arthropathy of peripheral joints and evidence of hypertrophic osteoarthropathy were reported in one case.
  • Extragonadal germ cell cancer syndrome  
    • Midline fast-growing tumors (eg, of the mediastinum, retroperitoneum) occur in young males. Histologically, these tumors are poorly differentiated carcinomas with atypical features.
    • The germ cell origin of these tumors is suggested by the typical abnormalities of chromosome 12 and the elevation of beta human chorionic gonadotropin (bhCG) and/or alpha-fetoprotein (AFP).

Physical

Complete physical examination is required.

  • Mediastinal germ cell tumors (MGCTs) may be silent. Dullness caused by atelectasis or pleural effusion and localized wheezes because of airway compression may be present.
  • A large abdominal mass may be palpated in retroperitoneal germ cell tumors (RGCTs).
  • In suprasellar intracranial germ cell tumors (ICGCTs), decreased visual acuity and visual field defects, obesity, or signs of endocrine deficiencies may be present.
  • In pineal tumors, Parinaud syndrome (ie, paralysis of conjugate upward gaze, slightly dilated pupils that react on accommodation but not to light, with a lesion at the level of the superior colliculi) can be present. Gait abnormalities, papilledema, and grasp reflex because of hydrocephalus are present variably. Plantar reflexes are sometimes extensor.

Causes

See Pathophysiology.

More on Extragonadal Germ Cell Tumors

Overview: Extragonadal Germ Cell Tumors
Differential Diagnoses & Workup: Extragonadal Germ Cell Tumors
Treatment & Medication: Extragonadal Germ Cell Tumors
Follow-up: Extragonadal Germ Cell Tumors
References
[ CLOSE WINDOW ]

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Further Reading

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Keywords

extragonadal germ cell tumor, EGGCT, seminomas, germinomas, nonseminomatous germ cell tumors, NS-GCT, nongerminomas, nongerminomatous germ cell tumors, mediastinal germ cell tumors, MGCT, retroperitoneal germ cell tumors, RGCT, sacrococcygeal germ cell tumors, SCGCT, intracranial germ cell tumors, ICGCT, Klinefelter syndrome, Klinefelter's syndrome, 47XXY

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Contributor Information and Disclosures

Author

Kush Sachdeva, MD, Private Practice, Southern Oncology and Hematology Associates, South Jersey Hospital System, Fox Chase Cancer Center
Disclosure: Nothing to disclose.

Coauthor(s)

Issam Makhoul, MD, Associate Professor, Department of Medicine, Division of Hematology/Oncology, University of Arkansas for Medical Sciences
Issam Makhoul, MD is a member of the following medical societies: American Society of Clinical Oncology and American Society of Hematology
Disclosure: Nothing to disclose.

Brendan Curti, MD, Director, Genitourinary Oncology Research, Robert W. Franz Cancer Research Center, Earle A. Chiles Research Institute, Providence Portland Medical Center
Brendan Curti, MD is a member of the following medical societies: American College of Physicians, Oregon Medical Association, and Society for Biological Therapy
Disclosure: Nothing to disclose.

Medical Editor

Robert C Shepard, MD, FACP, Associate Professor of Medicine in Hematology and Oncology at University of North Carolina at Chapel Hill; Vice President of Scientific Affairs, Therapeutic Expertise, Oncology, at PRA International
Robert C Shepard, MD, FACP is a member of the following medical societies: American Association for Cancer Research, American College of Physician Executives, American College of Physicians, American Federation for Clinical Research, American Federation for Medical Research, American Medical Association, American Medical Informatics Association, American Society of Hematology, Association of Clinical Research Professionals, Eastern Cooperative Oncology Group, European Society for Medical Oncology, Massachusetts Medical Society, and Society for Biological Therapy
Disclosure: Nothing to disclose.

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: Nothing to disclose.

CME Editor

Rajalaxmi McKenna, MD, FACP, Consulting Staff, Department of Medicine, Southwest Medical Consultants, SC, Good Samaritan Hospital, Advocate Health Systems
Rajalaxmi McKenna, MD, FACP is a member of the following medical societies: American Society of Clinical Oncology, American Society of Hematology, and International Society on Thrombosis and Haemostasis
Disclosure: Nothing to disclose.

Chief Editor

Jules E Harris, MD, Clinical Professor of Medicine, Division of Hematology/Medical Oncology, Department of Internal Medicine, University of Arizona College of Medicine at Tucson; Consulting Staff, Arizona Cancer Center
Jules E Harris, MD is a member of the following medical societies: American Association for Cancer Research, American Association for the Advancement of Science, American Association of Immunologists, American Society of Hematology, and Central Society for Clinical Research
Disclosure: GlobeImmune Salary Consulting; Amplimed Consulting fee Consulting; FibroGen Consulting fee Consulting

 
 
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