Pediatrics

Extracranial Germ cell neoplasms

OVERVIEW: What every practitioner needs to know

Are you sure your patient has a malignant germ cell tumor?

Malignant germ cell tumors (MGCTs) derive from the primordial germ cell (stem cell) destined to become either the egg or the sperm. The embryologic migration of the primordial germ cells (PGCs) from the head of the embryo into the gonad explains the many possible sites, mostly midline, in which this tumor can arise. In general, these tumors are highly curable. However, the wide spectrum of disease in terms of age at presentation, histologc type, and site of occurrence requires the practitioner to incorporate many factors into their medical decision making and understanding of prognosis.

Most MGCTs secrete a tumor marker, either alpha-fetoprotein (AFP) or β-human chorionic gonadotropin (β-HCG). Elevation of one of these markers, in conjunction with a heterogeneous mass in a site known to be commonly involved in GCTs, is very suggestive of a GCT. Definitive diagnosis, however, requires a biopsy and histologic pathologic diagnosis.

The most common signs and symptoms are site specific.

Testicular tumors: swelling and pain

Ovarian tumors: abdominal mass, distentions, and pain; if the ovary torses, can present as acute abdomen

Sacrococcygeal tumors: constipation, pain, palpable gluteal mass

Mediastinal tumors: cough, shortness of breath, superior vena cava syndrome

What other disease/condition shares some of these symptoms?

Elevations in AFP are seen in hepatoblastoma as well, but imaging would clarify the likely source of tumor marker. Elevations in β-HCG are a marker of pregnancy, and an adolescent girl is often presumed to be pregnant when she has an abdominal mass and an elevated B-HCG level.

What caused this disease to develop at this time?

There are two peaks in the incidence of germ cell tumors: the first peak is immediately after birth until about age 4 years, suggesting that perinatal exposures are likely important in terms of cause. The second peak begins with the onset of puberty through about age 40 years. The underlying etiologies of the tumors, however, are not well understood.

Testicular cancer is the most frequent cancer diagnosis in young adult men, although incidence rates vary widely between countries ranging from 0.5/100,000 men in Gharbiah, Egypt to 9.6/100,000 men in Norway. This dramatic variation in rates strongly suggests that enviromental and/or genetic factors also contribute significantly to incidence. A higher percentage of pediatric GCTs occur in extragonadal sites (40%-50% compared with 5%-10% in adults), again suggesting an aberration in embryologic development and migration of PGCs into the gonad.

Cyrptoorchidism is a well-established risk factor for testicular cancer. Several studies have shown that the boys born to women exposed to estrogen during pregnancy, such as women who took diethylstilbestrol, have a higher incidence of testicular cancer. Other enviromental exposures that may be linked to the development of germ cell tumors are actively being explored. For instance, several reports have linked marijuana use to testicular cancer.

What laboratory studies should you request to help confirm the diagnosis? How should you interpret the results?

GCTs often secrete AFP or β-HCG. LDH is often elevated as well and should be measured.

Would imaging studies be helpful? If so, which ones?

The first imaging study to obtain would be a study of the primary tumor. To evaluate for metastatic spread, a scan of the regional lymph nodes should be obtained as well as computed tomography of the chest to look for pulmonary metastases. GCT can also spread to bone and brain, but scanning of these sites is usually restricted to patients with either known pulmonary metastases (stage IV disease) or those who have symptoms suggestive of involvement. GCTs are more likely to metastasize to brain or bone if the underlying histologic features include choriocarcionoma.

Confirming the diagnosis

The International Germ Cell Classication Consensus (IGCCC) was developed using data from more than 5000 men with advanced-stage testicular cancer. In the IGCCC, men with a nongonadal primary site, extrapulmonary visceral metastases, and/or AFP levels greater than 10,000 IU/mL, β-HCG levels greater than 5000 IU/L, or LDH levels greater than 10 times normal are considered "poor risk," with an expected event-free survival (EFS) of only about 50%.

The IGCCC does not adequately risk stratify pediatric GCTs. Pediatric GCTs are composed of different histologic types (predominantly yolk sac tumor in younger patients) and occur in different sites than tumors in adult men (for instance, sacrococcygeal tumors in infants). How the IGCCC operates in girls and women with ovarian GCTs has never been examined either.

The US and UK GCT clinical trial groups have amalgamated their clinical data amassed from 25 years of clinical trials to create a classification system that reflects the pediatric context. The study identified poor risk patients as those older than 11 years with one of the following: stage IV ovarian, stage III/IV extragonadal, or IGCCC intermediate or poor risk testicular cancer. These patients have an expected EFS of <70%, and they should be studied on clinical trials of new therapies for this risk group, if there are trials available, so as to contribute to the improvement in outcomes for this risk group.

If you are able to confirm that the patient has an extracranial germ cell neoplasm, what treatment should be initiated?

The decision on treatment will depend on the stage and site in the patient. In patients with testicular and ovarian GCTs, the first step will usually be surgical resection followed by chemotherapy for patients with greater than stage I disease. For patients with extragonadal tumors, the decision to attempt primary resection should be tempered by the fact that the majority of GCTs respond quickly and substantially to upfront chemotherapy, making the likelihood of a complete resection higher if the surgery is delayed. Complete resection of the tumor is associated with a much lower failure rate and delay of the primary resection does not adversely affect outcome.

For patients with stage I testicular cancer that has been resected, the next treatment decision is either to proceed with a retroperitoneal lymph node dissection or active surveillance. (Some specialists who treat adult testicular cancer have advocated for reduced-intensity chemotherapy for patients with stage I testicular cancer, but this approach is not advised generally in the United States at this time.) Approximately 30% of patients with stage I testicular cancer will eventually manifest evidence of residual disease, discovered at the time of the RPLND, found through a rise in tumor markers, or on surveillance imaging. These patients will then be treated with chemotherapy.

In pediatric stage I testicular cancer patients, the vast majority of these recurrences are apparent by 6 months after surgery and nearly 100% by 1 year after surgery. (Salvage with standard chemotherapy: three cycles of BEP [bleomycin, etoposide, and cisplatin]) is as effective at the time of recurrence as it would be given at the time of initial diagnosis with an expected EFS of greater than 95%.

Surveillance is an option for patients with stage I ovarian GCTs as well, although the likelihood of recurrence is higher than it is for patients with testicular cancer (recurrence rate among clinical stage I ovarian GCT patients is 50%). There is less experience with salvage in this setting, but several studies suggest that salvage will be as high as it is with patients with testicular cancer .

The optimal surveillance schedule for patients with stage I GCT is being actively debated. Obtaining monthly tumor marker levels is recommended in the first year. These can be spaced to every 2 months in the second year after surgery, given that most relapses occur in the first year.

How often to do surveillance scans and which modality to use is undergoing review and debate. The standard had been to get a computed tomographic scan of the primary lesion and sites of nodal spread, as well as a chest computed tomographic scan, every 3 months in the first year and every 6 months in years 2 and 3. However, this amounts to quite a substantial amount of radiation exposure in a patient population with a relatively low risk of relapse. Alternative strategies with less frequent imaging and shifting the imaging modality to magnetic resonance imaging (MRI), including full-body MRI, are being proposed.

Patients with more advanced GCT at diagnosis should be treated with three to four cycles of bleomycin, etoposide, and cisplatin. In younger children, the bleomycin is given only once per cycle to avoid the pulmonary fibrosis associated with bleomycin. This regimen is called PEb. In adolescents and adults, the bleomycin is given weekly. This regimen is called BEP. The number of cycles is determined in part by age, site, stage, and response. Generally, patients with less advanced disease are effectively treated with three cycles of BEP. Even patients with metastatic stage IV testicular cancer with good prognostic characteristics using the IGCCC classification system are treated as effectively with three cycles as with four. "Poor risk" patients with testicular stage IV are treated with four cycles of BEP. The standard for patients with stage IV ovarian or extragonadal cancer is generally four cycles of BEP, although this has been less systematically studied.

An alternative to BEP, particularly in younger prepubertal children wtih GCTs, is to substitute carboplatin for cisplatin. The British have successfully used JEB (carboplatin, etoposide, and bleomycin) for several decades with excellent results that appear comparable to those with BEP. The advantage of carboplatin is that it causes less ototoxicity in young children and it is associated with fewer late effects than observed with BEP, although this has not been studied prospectively to date.

Optimal therapy for patients at high risk of failure is under active study. A number of alternatives to standard-dose BEP have been studied, but to date none has shown a survival advantage in adult men with testicular cancer.

A recent study comparing standard BEP to BEP + high-dose chemotherapy (HDCT) with stem cell transplantation did show a survival advantage for those who underwent HDCT with stem cell transplantation, but only among those men who had a slower than expected decline in their tumor markers (an indication of resistant disease). This was not the original intent of the study but was discovered in post hoc analysis and needs confirmation in other studies.

What are the adverse effects associated with each treatment option?

In terms of short-term adverse effects, cisplatin can cause both renal toxicity and ototoxicity. After receiving a course of BEP, about 50% of patients will experience grade IV neutropenia. Long-term studies among men treated several decades ago for testicular cancer with BEP show a doubling in risk of second malignancies (primarily solid gastointestinal malignancies) and also a doubling in risk of cardiovascular disease. There is also a suggestion, although less well established, that treatment with BEP is associated with a premature decline in cognitive function.

What are the possible outcomes of extracranial germ cell neoplasms?

For most subgroups of patients, the prognosis is excellent with an expected EFS of greater than 90%. Higher risk groups include postpubertal patients with advanced-stage (either stage III or IV) disease. Among these patients, the expected EFS ranges from 50%-80%. Certainly among those with lower expected EFS, a more aggressive experimental approach to therapy is warranted, and enrollment in a clinical trial should be encouraged.

What causes this disease and how frequent is it?

See the section on epidemiology above.

A family history of testicular cancer is a strong risk factor for testicular cancer in siblings and offspring.

What complications might you expect from the disease or treatment of the disease?

See section on adverse effects.

Are additional laboratory studies available; even some that are not widely available?

The use of positron emission tomography (PET) is not well established yet in non-seminomatous GCTs. Mature and immature teratomas are not PET avid, so a negative scan is not a useful predictor of the absence of disease. More malignant histologic types, such as yolk sac tumor, choriocarcinoma, and embryonal carcinoma are generally PET avid and PET has been helpful in localizing occult disease in the setting of rising tumor markers. PET is usually positive in seminomas; however, seminomas are uncommon in pediatric patients.

How can extracranial germ cell neoplasms be prevented?

GCTs are not preventable.

What is the evidence?

Cushing, B, Giller, R, Cullen, JW. " Randomized comparison of combination chemotherapy with etoposide, bleomycin, and either high-dose or standard-dose cisplatin in children and adolescents with high-risk malignant germ cell tumors: a pediatric intergroup study—Pediatric Oncology Group 9049 and Children's Cancer Group 8882". J Clin Oncol. vol. 22. 2004. pp. 2691-700.

Ries, LAG, Smith, MA, Gurney, JG. " Cancer incidence and survival among children and adolescents: United States SEER Program 1975-1995". National Cancer Institute. 1999.

Manecksha, RP, Fitzpatrick, JM. "Epidemiology of testicular cancer". BJU Int. vol. 104. 2009. pp. 1329-33.

Schnack, TH, Poulsen, G, Myrup, C. " Familial coaggregation of cryptorchidism, hypospadias, and testicular germ cell cancer: a nationwide cohort study". J Natl Cancer Inst. vol. 102. 2010. pp. 187-92.

Tretli, S, Gaard, M. "Lifestyle changes during adolescence and risk of breast cancer: an ecologic study of the effect of World War II in Norway". Cancer Causes Control. vol. 7. 1996. pp. 507-12.

Trabert, B, Sigurdson, AJ, Sweeney, AM. "Marijuana use and testicular germ cell tumors". Cancer. vol. 117. 2011. pp. 848-53.

" International Germ Cell Cancer Collaborative Group". J Clin Oncol. vol. 15. 1997. pp. 594-603.

Frazier, AL, Rumcheva, P, Olson, T. "Application of the adult international germ cell classification system to pediatric malignant nonseminomatous germ cell tumors: a report from the Children's Oncology Group". Pediatr Blood Cancer. vol. 50. 2008. pp. 746-51.

Schneider, DT, Wessalowski, R, Calaminus, G. "Treatment of recurrent malignant sacrococcygeal germ cell tumors: analysis of 22 patients registered in the German protocols MAKEI 83/86, 89, and 96". J Clin Oncol.. vol. 19. 2001. pp. 1951-60.

de Wit, R, Fizazi, K. "Controversies in the management of clinical stage I testis cancer". J Clin Oncol. vol. 24. 2006. pp. 5482-92.

Schlatter, M, Rescorla, F, Giller, R. "Excellent outcome in patients with stage I germ cell tumors of the testes: a study of the Children's Cancer Group/Pediatric Oncology Group". J Pediatr Surg. vol. 38. 2003. pp. 319-24.

Mann, JR, Raafat, F, Robinson, K. "The United Kingdom Children's Cancer Study Group's second germ cell tumor study: carboplatin, etoposide, and bleomycin are effective treatment for children with malignant extracranial germ cell tumors, with acceptable toxicity". J Clin Oncol. vol. 18. 2000. pp. 3809-18.

Motzer, RJ, Nichols, CJ, Margolin, KA. "Phase III randomized trial of conventional-dose chemotherapy with or without high-dose chemotherapy and autologous hematopoietic stem-cell rescue as first-line treatment for patients with poor-prognosis metastatic germ cell tumors". J Clin Oncol. vol. 25. 2007. pp. 247-56.

Travis, LB, Beard, C, Allan, JM. "Testicular cancer survivorship: research strategies and recommendations". J Natl Cancer Inst. vol. 102. 2010. pp. 1114-30.

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