Germ Cell Tumors

Abstract

Germ cell tumors (GCTs) are a very heterogeneous group of tumors that range from benign (teratoma) to highly malignant (choriocarcinoma). Many tumors contain mixed elements. This chapter describes the current diagnosis, staging, and treatment of GCTs. Coordination of chemotherapy and surgery is essential. With the advent of effective chemotherapy, significant improvement in survival for patients with GCTs has been achieved.

Keywords

Germ cell tumor, teratoma, immature teratoma, seminoma, germinoma, dysgerminoma, yolk sac tumor, embryonal carcinoma, choriocarcinoma, mixed germ cell tumor, sacrococcygeal teratoma

Germ cell tumors (GCTs) are neoplasms that develop from primordial germ cells of the human embryo, which are normally destined to produce sperm or ova. Primordial germ cells appear to originate in the yolk sac endoderm and migrate around the hindgut to the genital ridge on the posterior abdominal wall where they become part of the developing gonad. Figure 29.1 depicts the histogenesis of tumors of germ cell origin. Viable germ cells arrested along this path of migration may form neoplasia in midline sites, such as the pineal region (6%), mediastinum (7%), retroperitoneum (4%), sacrococcygeal region (42%) or in the ovary (24%), testis (9%), and other sites (8%).

Incidence

Tumors of germ cell origin account for approximately 2–3% of childhood malignancies. The incidence of GCTs is 2.5 per million in white children and 3.0 per million in African-American children under 15 years of age with a male:female ratio of 1.0:1.1. GCTs are more common in the ovaries and testes than in extragonadal sites.

Pathology

The germ cells are the precursors of sperm and ova and retain the potential to produce all the somatic (embryonic) and supporting (extraembryonic) structures of a developing embryo. Yolk sac tumors ( YSTs ) ( endodermal sinus tumors ) are derived from a totipotential germ cell that differentiates to extraembryonic structures. Teratomas are embryonal neoplasms that contain tissues from all three germ layers (ectoderm, endoderm, and mesoderm). Teratomas are mature or immature and may occur with or without malignant germ cell elements (endodermal sinus tumors, choriocarcinomas, embryonal carcinomas, or germinomas) or rarely malignant somatic elements (such as primitive neuroectodermal tumors in children).

The malignant histologic variants of GCTs are:

1.

Germinoma.
- a.
  
  Dysgerminoma (ovary).
- b.
  
  Seminoma (testis).
2.

Immature teratoma.
3.

Embryonal carcinoma.
4.

YST (endodermal sinus tumor).
5.

Choriocarcinoma.

Table 29.1 describes the pathology of GCTs and associated biochemical markers.

Table 29.1

Pathology of Germ Cell Tumors and Associated Markers

Histologic variant	Morphology	Common sites of origin	Markers ^a
Histologic variant	Morphology	Common sites of origin	AFP	β-hCG	PLAP
Germinoma	• Cells are round with discrete membranes, abundant clear cytoplasm. • Round nucleus with one to several prominent nucleoli. Cells arranged in nest or lobules separated by fibrous stroma. Areas of necrosis with granulomatous reaction. Multinucleated giant cells may be present	• Ovary: dysgerminoma • Testis: seminoma • Anterior mediastinum	−	−	+
Mature teratoma	• Mature tissue derived from: • Ectoderm: squamous epithelium, neuronal tissue • Mesoderm: muscle, teeth, cartilage, bone • Endoderm: mucous glands, gastrointestinal and respiratory tract Lining • No mitoses seen	• Sacrococcygeal/presacral • Gonads • Mediastinum	−	−	−
Immature teratoma	• Immature tissue derived from the three germinal layers. Lesions are graded histologically: • Grade 1: Some immaturity with neuroepithelium absent or limited to a rare low magnification (×40) field and not more than one such field in any slide • Grade 2: Immaturity and neuroepithelium present but does not exceed three low-power microscopic fields in any slide • Grade 3: Immaturity and neuroepithelium prominent; occupying four or more low magnification microscopic fields	• Sacrococcygeal/presacral • Gonads • Mediastinum	−	−	−
Embryonal carcinoma	Tumor cells polygonal with abundant pink vacuolated cytoplasm with ill-defined cellular membranes. Nucleus irregular and pleomorphic with prominent nucleoli. Cells arranged in solid sheets with scanty stroma or in tubules, acini, or papillary structures. Typical and atypical mitoses present	Testis (young adult)	−	±	±
Yolk sac tumor (endodermal sinus)	• Characteristics as seen microscopically: • Aggregates of small undifferentiated embryonal cells • Areas of stellate mesodermal cells • Areas of perivascular formation consisting of a mesodermal core with a capillary in the center lined by columnar cells (Schuller–Duvall body)	• Testis (infant) • Ovary • Presacral	+	−	−

AFP, α-Fetoprotein; β-hCG, beta subunit of human chorionic gonadotropin; PLAP, placental alkaline phosphatase.

Cytogenetic analysis has identified isochromosome 12p (i12p) as a specific abnormality in more than 80% of GCTs in postpubertal patients. Isochromosome 12p has also been identified in one-third of GCT in children under 5 years of age, suggesting that similar mechanisms for GCT generation may exist.

Clinical Features

The signs and symptoms of GCTs are dependent on the site of origin. Table 29.2 lists the clinical features of GCTs at different sites. In addition, certain histologic variants may have associated clinical findings, as listed in Table 29.3 .

Table 29.2

Clinical Features of Germ Cell Tumors

Tumor type	Median age year	Relative frequency (%)	Features
PEDIATRIC OVARIAN TUMORS
Dysgerminoma	16	24	Rapidly developing; 14–25% with other germ cell elements; very radiosensitive
Yolk sac tumor (endodermal sinus tumor)	18	16	↑ AFP; 75% Stage I; all patients require chemotherapy because of high risk of relapse even in low-stage disease
Teratoma mature (solid, cystic)	10–15	31	Neuroglial implants may occur with cystic or solid teratomas, but do not affect prognosis; surgery is mainstay of treatment
Immature inversely	11–14	10	Grading system based on amount of neuroepithelium present; prognosis related to stage and grade; 30% with ↑ AFP
Embryonal carcinoma	14	6	47% prepubertal; ↑β-hCG and precocious puberty common; chemotherapy indicated
Malignant mixed germ cell tumor	16	11	40% premenarchal; 30% sexually precocious; AFP/β-hCG may be increased
Gonadoblastoma both	8–10	1	Associated with dysgenetic gonads and sexual maldevelopment; removal of gonads is treatment of choice
Other (polyembryoma, choriocarcinoma)	NA	<1	Rare in children
PEDIATRIC TESTICULAR TUMORS
Yolk sac tumor (endodermal sinus tumor)	2	26	Most common of malignant germ cell tumors of the testes; ↑AFP; compared to adult cases, pediatric tumors are pure histologically; 85% Stage I; chemotherapy reserved for higher-stage or recurrent disease
Teratoma	3	24	Poorly differentiated histologic features do no impart a malignant course in children. Surgery alone is usually sufficient treatment
Embryonal carcinoma on stage	Late teens	20	Uncommon in young children; ↑AFP±β-hCG; managed as for adults, with retroperitoneal lymphadenectomy±chemotherapy±irradiation based
Teratocarcinoma	Late teens	13	80% stage I with 75% survival after surgery alone; more advanced disease requires multimodality therapy
Gonadoblastoma	5–10	<1	Associated with sexual maldevelopment syndromes; bilateral involvement in 30%; bilateral removal of gonads is treatment of choice
Other (polyembryoma choriocarcinoma)	NA	16	Rare in children

AFP, α-fetoprotein; β-hCG, beta subunit of human chorionic gonadotropin.

Source: Pizzo and Poplack (2002) , with permission.

Table 29.3

Clinical Association of Different Histologic Variants of Germ Cell Tumors

Histology	Clinical association
Teratoma	Musculoskeletal anomalies
	Rectal stenosis
	Congenital heart disease
	Microcephaly
Ovarian dysgerminoma (postpubertal)	Amenorrhea
	Menorrhagia
	46XY (male pseudohermaphrodite)
Ovarian embryonal carcinoma	Precocious puberty
	Amenorrhea
	Hirsutism

Although GCTs are a diverse group histologically, all originate from primordial germ cells and have a common pattern of spread, irrespective of the primary site as follows:

1.

Lungs.
2.

Liver.
3.

Regional nodes.
4.

Central nervous system (CNS).
5.

Bone and bone marrow (less commonly).

Diagnostic Evaluation

The following evaluations should be carried out:

1.

History.
2.

Physical examination.
3.

Complete blood count.
4.

Liver function tests, electrolytes, blood urea nitrogen, creatinine.
5.

α-Fetoprotein (AFP).
6.

Human chorionic gonadotropin (β-hCG).
7.

Lactic dehydrogenase (LDH) isoenzyme 1. LDH may also correlate with disease activity such as:
- a.
  
  Tumor bulk.
- b.
  
  Residual tumor after surgery.
- c.
  
  Response to chemotherapy and radiotherapy.
- d.
  
  Tumor recurrence.
8.

Radiographic evaluation of primary site and regional disease.
- a.
  
  Mediastinum: chest and upper abdominal computed tomography (CT).
- b.
  
  Ovary: ultrasound, pelvic and abdominal CT or magnetic resonance imaging (MRI).
- c.
  
  Sacrococcygeum: pelvic and abdominal CT or MRI.
- d.
  
  Testis: ultrasound, pelvic and abdominal CT or MRI.
9.

Radiographic evaluation for distant metastases.
- a.
  
  Chest radiographs (posteroanterior and lateral).
- b.
  
  Chest CT.
- c.
  
  Bone scan (may be reserved for patients with pure choriocarcinoma or known Stage IV disease).