Gonadal and Germ Cell Neoplasms

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Chapter 497 Gonadal and Germ Cell Neoplasms

Cynthia E. Herzog, Winston W. Huh

Epidemiology

Malignant germ cell tumors (GCTs) and gonadal tumors are rare, with an incidence of 12 cases per million persons <20 yr of age. Most malignant tumors of the gonads in children are GCTs. The incidence varies according to age and sex. Sacrococcygeal tumors occur predominantly in infant girls. Testicular GCTs occur predominantly before age 4 yr and after puberty. Testicular GCTs occur much more often in whites than in blacks, whereas ovarian GCTs have a slight predominance in blacks. Klinefelter syndrome is associated with an increased risk of mediastinal GCTs; Down syndrome, undescended testes, infertility, testicular atrophy and inguinal hernias are associated with an increased risk of testicular cancer. The risk of testicular GCT is increased in first-degree relatives, and is highest among monozygotic twins.

Pathogenesis

The GCTs and non-GCTs arise from primordial germ cells and coelomic epithelium, respectively. Testicular and sacrococcygeal GCTs arising during early childhood characteristically have deletions at chromosome arms 1p and 6q and gains at 1q, and lack the isochromosome 12p that is highly characteristic of malignant GCTs of adults. Testicular GCT also may demonstrate loss of imprinting. Ovarian GCTs from older girls characteristically have deletions at 1p and gains at 1q and 21. Because GCTs may contain benign and mixed malignant elements in different areas of the tumor, extensive sectioning is essential to confirm the correct diagnosis. The many histologically distinct subtypes of GCTs include teratoma (mature and immature), endodermal sinus tumor, and embryonal carcinoma (Fig. 497-1). Non-GCTs of the ovary include epithelial (serous and mucinous) and sex cord–stromal tumors; non-GCTs of the testicle include sex cord/stromal tumors (e.g., Leydig cell, Sertoli cell).

image

Figure 497-1 A, Normal germ cell development. B, Model for the origin and histogenesis of different subtypes of testicular germ cell tumors. IGCNU, intratubular germ cell neoplasia unclassified; PGC, primary germ cell; TGCT, testicular germ cell tumor(s).

Clinical Manifestations and Diagnosis

The clinical presentation of germ cell neoplasms depends on location. Ovarian tumors often are quite large by the time they are diagnosed. Extragonadal GCTs occur in the midline, including the suprasellar region, pineal region, neck, mediastinum, and retroperitoneal and sacrococcygeal areas. Symptoms relate to mass effect, but the intracranial GCTs often present with anterior and posterior pituitary deficits (Chapter 491).

The serum α-fetoprotein (AFP) level is elevated with endodermal sinus tumors and may be minimally elevated with teratomas. Infants normally have higher levels of AFP, which fall to normal adult levels by about age 8 mo; therefore, high AFP levels must be interpreted with caution in this age group. Elevation of the β subunit of human chorionic gonadotropin (β-hCG), which is secreted by syncytiotrophoblasts, is seen with choriocarcinoma and germinomas. Lactate dehydrogenase (LDH), although nonspecific, may be a useful marker. If elevated, these markers provide important confirmation of the diagnosis and provide a means to monitor the patient for tumor response and recurrence. Both serum and cerebrospinal fluid should be assayed for these markers in patients with intracranial lesions.

Diagnosis begins with physical examination and imaging studies, including plain radiographs of the chest and ultrasonography of the abdomen. CT or MRI can further delineate the primary tumor. If germ cell malignancy is strongly suggested, preoperative staging with CT of the chest and bone scan is appropriate. Primary surgical resection is indicated for tumors deemed resectable. Ovarian tumors also require detailed surgical evaluation including pelvic washings for cytologic analysis for peritoneal spread. Diagnosis of intracranial lesions can be established with imaging and AFP or β-hCG determinations of serum and cerebrospinal fluid.

Gonadoblastomas often occur in patients with gonadal dysgenesis and all or parts of a Y chromosome. Gonadal dysgenesis is characterized by failure to fully masculinize the external genitalia. If this syndrome is diagnosed, imaging of the gonad with ultrasonography or CT is performed, and surgical resection of the tumor usually is curative. Prophylactic resection of dysgenetic gonads at the time of diagnosis is recommended, because gonadoblastomas, some of which contain malignant germ cell tumor elements, often develop. Gonadoblastomas may produce abnormal amounts of estrogen.

Teratomas occur in many locations, presenting as masses. They are not associated with elevated markers unless malignancy is present. The sacrococcygeal region is the most common site for teratomas. Sacrococcygeal teratomas occur most commonly in infants and may be diagnosed in utero or at birth, with most found in girls. The rate of malignancy in this location varies, ranging from <10% in children <2 mo of age to >50% in children >4 mo of age.

Germinomas occur intracranially, in the mediastinum, and in the gonads. In the ovary, they are called dysgerminomas; in the testis, seminomas. They usually are tumor marker negative despite being malignant. Endodermal sinus or yolk sac tumor and choriocarcinoma appear highly malignant by histologic criteria. Both occur at gonadal and extragonadal sites. Embryonal carcinoma most often occurs in the testes. Choriocarcinoma and embryonal carcinoma rarely occur in the pure form and are usually found as part of a mixed malignant GCT.

Non–germ cell gonadal tumors are very uncommon in pediatrics and occur predominantly in the ovary. Epithelial carcinomas (usually an adult tumor), Sertoli-Leydig cell tumors, and granulosa cell tumors may occur in children. Carcinomas account for about one third of ovarian tumors in females <20 yr of age; most of these occur in older teens and are of the serous or mucinous subtype. Sertoli-Leydig cell tumors and granulosa cell tumors produce hormones that can cause virilization, feminization, or precocious puberty, depending on pubertal stage and the balance between Sertoli (estrogen production) and Leydig cells (androgen production). Diagnostic evaluation usually focuses on the chief complaint of inappropriate sex steroid effect and includes hormone measurements, which reflect gonadotropin-independent sex steroid production. Appropriate imaging also is performed to rule out a functioning gonadal tumor. Surgery usually is curative. No effective therapy for nonresectable disease has been found.

Treatment

Complete surgical excision of the tumor usually is indicated, except for patients with intracranial tumors, where the primary therapy consists of radiation therapy and chemotherapy. For testicular tumors, an inguinal approach is indicated. When complete excision cannot be accomplished, preoperative chemotherapy is indicated, with second-look surgery. For teratomas, both mature and immature, and completely resected malignant tumors, surgery alone is the treatment. Cisplatin-based chemotherapy regimens usually are curative in GCTs that cannot be completely resected, even if metastases are present. Except for GCTs of the central nervous system, radiation therapy is limited to those tumors that are not amenable to complete excision and are refractory to chemotherapy.

Prognosis

The overall cure rate for children with GCTs is >80%. Age is the most predictive factor of survival for extragonadal GCTs. Children >12 yr of age have a 4-fold higher risk of death, and a 6-fold higher risk if the tumor is thoracic. Histology has little effect on prognosis. Nonresected extragonadal GCTs have a slightly worse prognosis.

Bibliography

Cushing B, Giller R, Cullen JW, et al. 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. 2004;22:2691-2700.

Einhorn LH, Williams SD, Chamness A, et al. High-dose chemotherapy and stem-cell rescue for metastatic germ-cell tumors. N Engl J Med. 2007;357:340-348.

Feldman DR, Bosl GJ, Sheinfeld J, et al. Medical treatment of advanced testicular cancer. JAMA. 2008;299:672-684.

Horwich A, Shipley J, Huddart R. Testicular germ-cell cancer. Lancet. 2006;367:754-764.

Kanetsky PA, Mitra N, Vardhanabhuti S, et al. Common variation in KITLG and at 5q31.3 predisposes to testicular germ cell cancer. Nat Genet. 2010;41:811-815.

Marina N, London WB, Frazier L, et al. Prognostic factors in children with extragonadal malignant germ cell tumors: a pediatric intergroup study. J Clin Oncol. 2006;24:2544-2548.

Rapley EA, Turnbull C, Olama AAA, et al. A genome-wide association study of testicular germ cell tumor. Nat Genet. 2001;41:807-810.

Rogers PC, Olson TA, Cullen JW, et al. Treatment of children and adolescents with stage I testicular and stages I or II ovarian malignant germ cell tumors: a pediatric intergroup study—Pediatric Oncology Group 9048 and Children’s Cancer Group 8891. J Clin Oncol. 2004;22:563-569.

U.S. Preventive Services Task Force. Recommendation statement—screening for testicular cancer. http://www.ahrq.gov/clinic/3rduspstf/testicular/testiculrs.pdf. Accessed August 24, 2010

Young JL, Wu XC, Roffers SD, et al. Ovarian cancer in children and young adults in the United States, 1992–1997. Cancer. 2003;97:2694-2700.

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