Extracranial germ cell tumors

This chapter will review extracranial germ cell tumors (GCTs). Please see Chapter 22 , Central nervous system tumors, for a discussion of intracranial GCTs.

Epidemiology

Tumors of germ cell origin display a bimodal distribution, with a peak seen in young children between 0 and 4 years. During childhood, GCTs account for 3.5% of childhood malignancies. In the United States the age-adjusted incidence of GCT in children 0–14 years is 0.4 per 100,000 in males and 0.6 per 100,000 in females.

A second peak in older children and adolescents starts at 9 years of age in females and at 11 years of age in males and correlates with sex-specific onset of puberty. In patients between age 15 and 19 years, GCTs account for 13.9% of malignancies making GCT one of the most common malignancies in this age group. The incidence of GCT significantly increases to a maximum rate of 11.4 per 100,000 in adolescent males and only a slight increase to 1 per 100,000 in adolescent females.

Biology

GCTs are neoplasms that arise from early germline progenitors: the primordial germ cells of the human embryo. These primordial germ cells originate in the yolk sac endoderm of the embryo and migrate around the hindgut to the gonads. Due to their cell of origin, GCTs are biologically heterogeneous tumors resulting in a spectrum of benign and malignant diseases. The Teilum hypothesis of tumorigenesis postulates oncogenic events occurring at different stages of differentiation give rise to different histological types in GCT. Fig. 28.1 depicts the histogenesis of tumors of germ cell origin. Germinomas/seminomas arise from undifferentiated primordial cells. Embryonal carcinomas (ECs) originate from cells with early embryonic differentiation and, therefore, can differentiate into teratomas. Finally, primordial cells that have extraembryonic differentiation give rise to yolk sac tumors (YSTs) or choriocarcinomas (CCs). Importantly, the biological characteristics of these tumors correlate with the age at presentation of GCT, suggesting that GCT may comprise two related but distinct entities.

Figure 28.1, Germ Cell Development. Abbreviations: GC , Germ cell; GCT , germ cell tumor.

Histology

A summary of histological characteristics is presented in Table 28.1 . Histologically, GCTs are classified into two major types.

Table 28.1

Pathology of germ cell tumors and associated markers.

Histologic variant	Morphological characteristics	Common sites of origin	AFP	β-hCG	PLAP
Mature teratoma	Mature tissue derived from: Ectoderm: squamous epithelium, neuronal tissue Mesoderm: muscle, teeth, cartilage, and 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 (340) field and not more than one such field in any slide Grade 2: immaturity and neuroepithelium present but do 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	−	−	−
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	−	−	+
Yolk sac tumor	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	+	−	−
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)	−	±	±
Choriocarcinoma	Two types of cells are seen microscopically: Cytotrophoblasts: with classic appearance of closely packed nests of uniform, medium-size cells with clear cytoplasm and distinct cell margins Syncytiotrophoblast: multinucleate syncytial trophoblastic cells with strong positive β-hCG staining	Testis (young adult) Infants (maternal Mets)	−	+	−

Abbreviations: β-hCG , Beta-subunit of human chorionic gonadotropin; AFP , α-fetoprotein; PLAP , Placental Alkaline Phosphatase.

Germinomatous/seminomatous GCTs : Characterized by the presence of undifferentiated germ cells histologically resembling early precursors of spermatogonia or oogonia. These tumors are termed seminoma if located in the testis, dysgerminoma if located in the ovary, or germinoma if located in extragonadal sites.

Nongerminomatous/nonseminomatous GCTs (NGGCTs) : Comprise different benign and malignant histological subtypes.

Teratomas are differentiated tumors characterized by the presence of mature cells from all three germ layers (ectoderm, endoderm, and mesoderm). In some cases, teratomas can acquire a unique neural differentiation state and termed immature teratoma .
YSTs or endodermal sinus tumors are histologically characterized by a complex endodermal morphology resembling embryonic and extraembryonic structures.
EC is an undifferentiated tumor and histologically resemble embryonic cells from the blastocyst.
CC is a rare histological subtype with characteristic trophoblastic differentiation.
Neoplasms that contain two or more malignant germ cell elements are known as mixed malignant GCTs.

Molecular characteristics

Increasing evidence has emerged of the different biology driving prepubertal and postpubertal GCTs. Genomic studies have identified characteristic alterations in childhood GCT. In particular, chromosomal gains in 1q, 11q, 20q, and 22, as well as loss of 1p, 6q, and 16q are more prevalent in younger patients. In adult GCT the most frequent chromosomal aberrations are the amplification of chromosome 12p, usually as isochromosome 12 and present in 80% of adult testicular GCT. Although not exclusive of adult-like GCT, this alteration has only been identified in 29% of patients younger than 5 years with GCT.

Specific methylation patterns have helped elucidate different cells of origin in childhood and adult-type GCT. Adult-type GCTs demonstrate a widespread hypermethylation of tumor suppressor genes and secondary silencing of proapoptotic genes. The most common genes involved in this process include alterations in adenomatous polyposis coli (APC) , Ras Association Domain Family 1 isoform A (RASSF1A) , and Hypermethylated In Cancer 1(HIC1). These mechanisms may explain the higher aggressiveness of GCT in adolescents as the biology resembles adult-like disease.

Eight main miRNAs miR-371–373 and miR302a/302d are overexpressed in all malignant GCT and can be measured in serum, across age groups, histological types, and anatomical sites. Moreover, cisplatin resistance in GCT has been associated with miR-371–373 upregulation along with the downregulation of tumor suppressor miRNA miR-99a and miR-100; therefore miRNAs could be useful identifying therapeutic susceptibilities. The clinical role of these molecules was evaluated in adults with testicular GCT and demonstrated clinical usefulness in the diagnosis and recurrence monitoring. Similarly, miRNAs are currently being validated in pediatric trials.

Clinical features

Extracranial GCTs present in gonadal and extragonadal sites. The most common childhood extragonadal site is the sacrococcygeal region (42%) followed by mediastinum (7%) and retroperitoneum (4%). Gonadal tumors [ovaries (24%) and testes (9%)] account for one-third of patients diagnosed with GCT in childhood. Although GCTs are a diverse group histologically, distant metastatic disease is present at diagnosis in approximately 20% of patients. The pattern of spread is similar, irrespective of the primary site: lungs, liver, regional nodes, central nervous system (CNS), and bone and bone marrow.

The signs and symptoms of GCTs are dependent on the site of origin. Table 28.2 lists the clinical features of GCTs at different sites. In addition, certain histologic variants may have associated clinical findings, as listed in Table 28.3 .

Table 28.2

Clinical features of germ cell tumors.

	Age median (year)		Frequency (%)		Clinical features
Tumor type	Female	Male	Female	Male	Female	Male
Mature/immature teratoma	13	3	41	24	Abdominal pain, abdominal mass. 10% bilateral. Gliomatosis peritonei does not affect prognosis	Nontender scrotal mass. Excellent survival with surgery alone in prepubertal males
Dysgerminoma/seminoma	16	30	24	<1	Rapidly developed intraabdominal mass. 20% bilateral. 14–25% mixed with other germ cell elements	Virtually not seen in children, most common testicular tumor in adult males. Most patients present in their 30s
YST	18	2	16	26	Most common malignant histology. 75% stage I	Most common malignant histology, most pediatric tumors are pure YST. 85% stage I
Embryonal carcinoma	14	17	6	20	Associated with precocious puberty, amenorrhea, and hirsutism	Higher incidence of metastatic disease at presentation, patients can present with retroperitoneal mass
Choriocarcinoma	N/A	N/A	<1	16	Rare in children, when present in infants related to maternal metastatic disease	Frequent pulmonary metastatic disease at presentation, patients can present with hemoptysis due to MetS hemorrhage
Gonadoblastoma	9	7	1	<1	Associated with gonadal dysgenesis. Presents mostly in phenotypical females with a Y chromosome	Very rare

Abbreviations: N/A , Not applicable; YST , yolk sac tumor.

Table 28.3

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

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, and creatinine
5.
α-Fetoprotein (AFP)
6.
Beta-subunit of human chorionic gonadotropin (β-hCG)
7.
Lactic dehydrogenase (LDH) isoenzyme 1
8.
Cross-sectional 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.
  Sacrococcygeal—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.
  Positron emission tomography scan or bone scan

Tumor markers

Certain histologic variants of GCT secrete tumor markers that can be measured in serum and aid in the diagnosis and management of these patients. AFP is a major serum protein of the human fetus. It is produced in the embryonic liver, in the yolk sac, and, in smaller amounts, in the gastrointestinal tract. Elevated levels of AFP in an infant must be interpreted with caution and using age-adjusted values.

Serum AFP is highly elevated in YSTs and a slight to intermediate elevation seen in EC. AFP is elevated in approximately 70% of NGGCT of childhood. In adults, serum levels of AFP at diagnosis can be predictive of outcome and is part of the risk stratification criteria. Furthermore, the rate of AFP decline has been shown to be prognostic in adolescents and adults.

The β-hCG is elevated in the presence of syncytiotrophoblastic components in the tumor. High levels of β-hCG are found in CCs and slight elevations can be observed in ECs and germinomas. It is thought that 20% of germinomas have β-hCG elevation. Sudden increases of β-hCG after starting chemotherapy can be seen due to cell lysis. Additionally, it can be elevated with malignancies of the liver, pancreas, Gastrointestinal tract, breast, lung, and bladder.

Pure teratomas are not associated with AFP or β-hCG production; the elevation of either marker in association with teratoma indicates the presence of malignant germ cell elements and requires review of the histologic material.

Staging and risk stratification

Historically, staging classifications for GCT differed depending on the site of origin and the age of the patient. Children’s Oncology Group (COG) classification has been used for staging in the pediatric population. The International Germ Cell Consensus Classification (IGCCC) has been used to risk stratify adolescent males with testicular tumors and the International Federation of Gynecology and Obstetrics (FIGO) system has been used to stage adolescent females with ovarian tumors.

The Malignant Germ Cell International Consortium (MaGIC) was created to bring together pediatric, gynecologic, and testicular cancer specialists to promote research initiatives and provide evidence-based approaches in the management of GCTs across different age groups. In 2015 MaGIC developed a common risk stratification system by merging 25 years of clinical trial data from COG in the United States and Children’s Cancer and Leukaemia Group in the United Kingdom. The MaGIC risk stratification system incorporates the IGCCC classification and is, thus, applicable to all pediatric and adolescent patients. Table 28.4 provides an overview of different staging classification systems and the MaGIC risk stratification system.

Table 28.4

Different Staging and Risk Stratification Systems Used in Germ Cell Tumors.

Stage	Testis	Ovarian	Extragonadal
I	Complete resection: high inguinal or high ligation scrotal orchiectomy and negative nodes	Limited to ovary (peritoneal evaluation negative), no clinical, histological, or radiological evidence of disease outside the ovary ^b	Complete resection at any site with negative margins, or coccygectomy for sacrococcygeal teratoma
II	Transscrotal biopsy, microscopic disease in the scrotum or cord, or failure of serum markers to normalize	Microscopic residual, peritoneal evaluation negative, failure of serum tumor markers to normalize	Microscopic residual, with lymph nodes negative
III	Retroperitoneal lymph node involvement, but no visceral or extraabdominal involvement	Lymph node involvement, metastatic nodule, gross residual disease, or biopsy only, contiguous visceral involvement (omentum, intestine, and bladder), peritoneal evaluation positive for malignancy	Lymph node involvement, gross residual disease, or biopsy only
IV	Distant metastasis, including liver	Distant metastasis, including liver	Distant metastasis, including liver

FIGO ovarian staging ^c	Stage	FIGO
	I	Tumor confined to ovary
	IA	Limited to one ovary, capsule intact, no tumor on surface, negative washings
	IB	Both ovaries, otherwise like IA
	IC1	Surgical spill
	IC2	Capsule rupture before surgery, or tumor on ovarian surface
	IC3	Malignant cell in ascites or peritoneal washings
	II	Both ovaries or extension lower than pelvic rim or peritoneal primary
	IIA	Extension and/or implant on uterus and/or fallopian tubes
	IIB	Extension to other pelvic intraperitoneal structures
	III	Positive RP LN and/or microscopic metastasis beyond pelvis
	IIIA1	Positive RP LN only (IIIA1i 10 mm) (IIIA1ii 10 mm)
	IIIA2	Microscopic, extrapelvic (higher than pelvic brim), peritoneal involvement with or without positive RP LN
	IIIB	Macroscopic, extrapelvic peritoneal metastasis 2 cm with or without RP LN includes extension to capsule of liver/spleen
	IIIC	Macroscopic, extrapelvic peritoneal metastasis 2 cm with or without RP LN includes extension to capsule of liver/spleen
	IV	Distant metastasis
	IVA	Pleural effusion with positive cytologic features
	IVB	Metastasis to liver/spleen parenchyma and extraabdominal organs (including inguinal LN and outside abdominal cavity)

Histologic feature	Good	Intermediate	Poor
Seminoma	The absence of nonpulmonary visceral metastasis ^e	The presence of nonpulmonary visceral metastasis ^e	Not applicable
Nonseminoma	Meets all the next criteria:	Meets all the next criteria	Meets all the next criteria
	Gonadal or RP primary site	Gonadal or RP primary site	Mediastinal primary site
	The absence of nonpulmonary visceral metastasis	The absence of nonpulmonary visceral metastasis	The presence of nonpulmonary visceral metastasis
	(S0) or S1 STM	S2 STM	S3 STM
	HCG<5000 IU/mL	HCG≥5000 and ≤50,000 IU/mL L	HCG>50,000 IU/mL
	AFP <1000 ng/mL	AFP≥1000 and ≤10,000 ng/mL	AFP >10,000 ng/mL
	LDH<1.5×ULN	LDH≥1.5×ULN and ≤10 ULN	LDH>10×ULN

Risk group	Site	COG stage	Age (years)
Low risk	Testis	I	Any
	Ovary	I	Any
	Extragonadal	I	Any
Standard risk 1	Testis	II–IV	<11
	Ovary	II–IV	<11
	Extragonadal	II–IV	<11
Standard risk 2	Testis (IGCCC good risk)	II–IV	>11
	Ovary	II–IV	>11
	Extragonadal	II	>11
Poor risk	Testis (IGCCC intermediate/poor risk)	II–IV	>11
	Ovary	IV	>11
	Extragonadal	III–IV	>11

Abbreviations: AFP , Alpha-fetoprotein; COG , Children’s Oncology Group; FIGO , International Federation of Gynecology and Obstetrics; HCG , human chorionic gonadotropin; IGCCC , International Germ Cell Consensus Classification; LDH , lactate dehydrogenase; LN , lymph node; MaGIC , Malignant Germ Cell Tumor International Consortium; RP , retroperitoneal; S0 , normal marker; S1, S2, S3 , range listed above; STM , serum tumor marker; ULN , upper limit of normal.

a Adapted from Olson et al. (2015) .

b The presence of gliomatosis peritonei does not result in a stage change.

c Adapted from .

d Adapted from the .

e Nonpulmonary visceral metastasis refers to metastasis involving organs other than lung (lymph nodes do not count).

f Adapted from .

Treatment

Due to the heterogeneity in the biology of GCTs, the therapeutic strategies are stratified to address the different biological behaviors. The management of teratomas, germinomas, and nongerminomatous GCT differs and, thus, will be presented separately.

Benign germ cell tumors

Teratoma

Pathologically, teratomas can be divided into two main groups:

Mature teratoma

These tumors contain mature tissue, and the treatment is surgical excision, irrespective of the site. It is critically important that multiple histologic sections be examined to exclude the presence of focal immature tissue and malignant germ cell elements.

Immature teratoma

These tumors contain elements of immature tissue and are graded histologically ( Table 28.5 ). The treatment of choice is surgical resection. Most immature teratomas in prepubertal children do not respond to chemotherapy. However, if AFP is increased, a malignant germ cell component is present and in addition to surgery, chemotherapy should be administered.

Table 28.5

Histologic grading of teratoma.

Grade	Description
0	All tissue mature; no embryonal tissue
1	Rare foci of embryonal tissue not exceeding 1 low-power field per slide
2	Moderate quantity of embryonal tissue and some atypia but not exceeding 3 lower power fields per slide
3	Large quantity of immature tissue exceeding 3 lower power fields per slide, with abundant mitoses and cellular atypia

Teratoma with malignant germ cell elements

These tumors contain foci of frankly malignant tissue usually EC, YST, or CC. These lesions should be treated in an aggressive multimodal fashion. Chemotherapy improves local and metastatic control. The benign teratomatous portion will not respond to chemotherapy or radiation therapy and must be treated surgically. See the section on the treatment of malignant GCT.

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