Germ cell tumors

Germ cell tumors are tumors that develop in germ cells (fetal cells that give rise to sperm and eggs) in the ovaries (in girls) and the testes (in boys). But germ cells can sometimes be left behind in other parts of the body from when you developed in the womb. So germ cell tumors can develop anywhere in your body where there are germ cells such as in the lower back (common in infancy), the abdomen, the chest, and within the brain. Germ cell tumors that form in the ovaries or testicles are called gonadal germ cell tumors. Germ cell tumors that occur in places other than the testicles and ovaries are called extragonadal germ cell tumors and they are very rare. Germ cell tumors that form in the brain or spinal column are called intracranial or intraspinal germ cell tumors. Germ cell tumors that are extracranial and extragonadal tend to form along the midline of the body, such as in the bottom of the spine, at the back of the belly, between the lungs or on the neck.

Germ cell tumors may be cancerous or noncancerous. Most germ cell tumors that are cancerous occur as cancer of the testicles (testicular cancer) or cancer of the ovaries (ovarian cancer).

Germ cell tumors can be 1 of 3 types:

1. Mature teratomas are benign tumors that are not likely to become cancerous. They usually occur in the bottom part of the spine in babies, or in the ovaries of girls when they reach puberty. These are the most common type of extracranial germ cell tumors.
2. Immature teratomas might become cancerous. They usually occur in the bottom part of the spine in babies, or in the ovaries of girls when they reach puberty. They can contain several types of cells, such as bone, hair and muscle.
3. Malignant germ cell tumors are cancerous. They are divided into germinomas and nongerminomas, depending on the type of hormone they release. Germinomas are the most common type of intracranial germ cell tumor.

Childhood germ cell tumors are rare in children younger than 15 years, accounting for approximately 3% of cancers in this age group ¹⁾. The incidence of extracranial germ cell tumors with the onset of puberty represents approximately 14% of cancers in adolescents aged 15 to 19 years. The incidence of extracranial germ cell tumors according to 5-year age group and sex is shown in Table 1.

Table 1. Incidence of extracranial germ cell tumors by age group and sex

	0–4 years	5–9 years	10–14 years	15–19 years
Males	7	0.3	1.4	31
Females	5.8	2.4	7.8	25.3

Footnote: Rates are per 1 million children from 1986 to 1995 for the nine Surveillance, Epidemiology, and End Results (SEER) regions plus Los Angeles

[Source ²⁾ ]

Based on the pathology, germ cell tumors are classified into several subtypes:

• Benign teratoma, requires no chemotherapy
• Malignant teratoma, may require chemotherapy, depending upon Stage
• Yolk sac tumor, has a high alpha-fetoprotein (AFP) blood test, which can be used to follow for recurrence
• Choriocarcinoma, has a high beta human chorionic gonadotropin (bHCG) blood test, which can be used to follow for recurrence
• Embryonal carcinoma, common in the testes of adolescent boys
• Germinoma (also called seminoma in boys or dysgerminoma in girls)

In the fetal/neonatal age group, most extracranial germ cell tumors are benign teratomas occurring at midline locations, including the head and neck, sacrococcyx, and retroperitoneum ³⁾. Despite the small percentage of malignant teratomas that occur in this age group, perinatal tumors have a high morbidity rate caused by hydrops fetalis and premature delivery ⁴⁾.

Germ cell tumors in the testes of an adolescent male commonly present as an enlarging, solid mass, which may be painful. Within the ovaries, germ cell tumors can usually be distinguished from ovarian cysts, which are much more common, using ultrasound. Germ cell tumors can spread to lymph nodes, lung, liver, and brain. Some germ cell tumors secrete hormones that can lead to changes resembling puberty. Germ cell tumors are more common, but still rare, in undescended testes that were not corrected. Abnormal ovaries or testes due to genetic syndromes (such as Turner’s or Klinefelter’s) are also at higher risk.

Germ cell tumors tend to respond to treatment and many can be cured, even when diagnosed at a late stage.

You usually have surgery to remove germ cell cancers. This might be all the treatment you need if the cancer is small and easy to remove.

You might have chemotherapy after surgery if there is a chance of the cancer coming back. Germ cell tumors generally respond very well to chemotherapy and most people are cured. Even cancers that have spread are still very treatable with chemotherapy.

Germ cell tumors in children key points

• Germ cell tumors may be cancer (malignant) or not cancer (benign).
• Germ cell tumors usually affect the ovaries or testicles. They may also affect the brain, mediastinum, retroperitoneum, sacrum, or coccyx.
• Symptoms vary depending on the size and location of the tumor. There may a lump, pain, or other symptoms.
• Germ cell tumors are diagnosed with blood tests, biopsy, and imaging tests.
• Treatment may include surgery, chemotherapy, and radiation therapy.

Figure 1.  Extracranial germ cell tumor locations

Figure 1. Extracranial germ cell tumors form in parts of the body other than the brain. This includes the testicles, ovaries, sacrococcyx (usually originating from the coccyx and including the sacrum), mediastinum, and retroperitoneum.

Germ cell tumor types

Testicular germ cell tumors

The most common germ cell tumors are teratomas or seminomas of the testicle in men. Between 40 and 45 out of every 100 testicular cancers (40 to 45%) are pure seminomas. Some testicular tumors have both seminoma cells and non seminoma cells (teratomas). Doctors usually treat these in the same way as non seminomas.

Younger men are more likely to get testicular cancer. Men in their early 30s are the most likely to get it. It then becomes less common as men get older.

• Children (aged <11 years): During early childhood, both testicular teratomas and malignant testicular germ cell tumors are identified. The malignant tumors are commonly composed of pure yolk sac tumor (also known as endodermal sinus tumor), are generally diploid or tetraploid, and up to approximately 44% contain the isochromosome of the short arm of chromosome 12 (i12p) that characterizes testicular cancer in young adults ⁵⁾. Deletions of chromosomes 1p, 4q, and 6q and gains of chromosomes 1q, 3, and 20q are reported as recurring chromosomal abnormalities for this group of tumors ⁶⁾.
• Adolescents and young adults (aged ≥11 years): Testicular germ cell tumors in the adolescent and young adult population almost always possess an i12p ⁷⁾ and are aneuploid ⁸⁾.

Ovarian germ cell tumors

Ovarian germ cell tumors occur primarily in adolescent and young adult females. Women can develop ovarian germ cell tumors. Many of these are non cancerous (benign). But some are cancerous. Only about 1 or 2% of ovarian cancers are this type.

Most ovarian germ cell tumors occur in teenagers or young women, although they also occur in women in their 60s.

Ovarian teratoma is a type of ovarian germ cell tumor. While most ovarian germ cell tumors are benign mature teratomas (dermoid cysts), a heterogeneous group of malignant germ cell tumors, including immature teratomas, dysgerminomas, yolk sac tumors, and mixed germ cell tumors, do occur in females. The malignant ovarian germ cell tumor commonly shows increased copies of the short arm of chromosome 12 ⁹⁾.

Extragonadal germ cell tumor

The medical name for germ cell tumors that develop outside of the gonads (ovaries, testicles) or the brain is extragonadal extracranial germ cell tumor. Cancers that develop from germ cells in other parts of the body are rare.

Germ cell tumors can start in:

• Germ cell tumors that form in the brain or spinal cord are called CNS (central nervous system) germ cell tumors.
• The back of the abdomen (retroperitoneal cancer)
• A part of the chest called the mediastinum (mediastinal germ cell tumors). The mediastinum is the area between the lungs, which contains the heart.

Children (aged <11 years)

Extragonadal germ cell tumors typically present at birth or during early childhood. Most of these tumors are benign teratomas occurring in the sacrococcygeal region, and thus are not included in Surveillance, Epidemiology, and End Results (SEER) data ¹⁰⁾. Malignant yolk sac tumor histology occurs in a minority of these tumors; however, they may have cytogenetic abnormalities similar to those observed for tumors occurring in the testes of young males ¹¹⁾. Mediastinal germ cell tumors in children younger than 8 years share the same genetic gains and losses as do sacrococcygeal and testicular tumors in young children ¹²⁾.

Older children, adolescents, and young adults (aged ≥11 years)

The mediastinum is the most common primary site for extragonadal germ cell tumors in older children and adolescents ¹³⁾.

Germ cell tumors pathology

Childhood extracranial germ cell tumors are broadly classified as the following:

• Teratomas
  • Mature teratoma.
  • Immature teratoma.
• Malignant germ cell tumors
  • Seminomatous germ cell tumor
    • Seminoma (testis).
    • Dysgerminoma (ovary).
    • Germinoma (brain).
  • Nonseminomatous germ cell tumor.
    • Yolk sac tumor (endodermal sinus tumor)
    • Choriocarcinoma.
    • Embryonal carcinoma.
    • Gonadoblastoma.
    • Teratoma and yolk sac tumor.
• Mixed germ cell tumor (contains at least two of the malignant histologies listed above).

The histologic properties of extracranial germ cell tumors are heterogeneous and vary by primary tumor site and the sex and age of the patient ¹⁴⁾. Histologically identical germ cell tumors that arise in younger children have different biological characteristics from those that arise in adolescents and young adults ¹⁵⁾.

Mature teratoma

Mature teratomas can occur at gonadal or at extragonadal locations. They are the most common histological subtype of childhood germ cell tumor ¹⁶⁾. Mature teratomas usually contain well-differentiated tissues from the ectodermal, mesodermal, and endodermal germ cell layers, and any tissue type may be found within the tumor.

Mature teratomas are benign, although some mature teratomas may secrete enzymes or hormones, including insulin, growth hormone, androgens, and prolactin ¹⁷⁾.

Immature teratoma

Immature teratomas contain tissues from the ectodermal, mesodermal, and endodermal germ cell layers, but immature tissues, primarily neuroepithelial, are also present. Immature teratomas are graded from 0 to 3 on the basis of the amount of immature neural tissue found in the tumor specimen ¹⁸⁾. Tumors of higher grade are more likely to have foci of yolk sac tumor ¹⁹⁾. Immature teratomas can exhibit malignant behavior and metastasize.

Immature teratomas occur primarily in young children at extragonadal sites and in the ovaries of girls near the age of puberty, but there is no correlation between tumor grade and patient age ²⁰⁾. Some immature teratomas may secrete enzymes or hormones such as vasopressin ²¹⁾.

Malignant germ cell tumors

germ cell tumors contain malignant tissues of germ cell origin and, rarely, tissues of somatic origin. Isolated malignant elements may constitute a small fraction of a predominantly mature or immature teratoma ²²⁾.

Malignant germ cell elements of children, adolescents, and young adults can be grouped broadly by location (refer to Table 2). Adolescent and young adult males present with more germinomas (testicular and mediastinal seminomas), and females present with more ovarian dysgerminomas.

Table 2. Histology of malignant germ cell tumors in children, adolescents, and young adults

Malignant Germ Cell Elements	Location
Seminoma	Testicular
Dysgerminoma	Ovarian
Germinoma	Extragonadal
Yolk sac tumor (endodermal sinus tumor)	Extragonadal, ovarian, testicular
Choriocarcinoma	Extragonadal, ovarian, testicular
Embryonal carcinoma	Extragonadal, testicular
Mixed germ cell tumors	Extragonadal, ovarian, testicular

[Source ²³⁾ ]

Germ cell tumors causes

The cause of germ cell tumors isn’t fully known. Some gene defects passed on from parents to children (inherited) may increase the risk for germ cell tumors. Some genetic syndromes can cause abnormal growth of the male and female reproductive systems. Boys born with undescended testicles (cryptorchidism) are believed to have a higher risk of germ cell tumors in the testicles.

Germ cells are special types of cells that are present as the fetus (unborn baby) develops. These cells usually become sperm in the testicles or unfertilized eggs in the ovaries as the child matures. Most germ cell tumors form in the testes or ovaries. Sometimes the germ cells travel to or from other parts of the fetus as it develops and later become germ cell tumors. Germ cell tumors arise from primordial germ cells, which migrate during embryogenesis from the yolk sac through the mesentery to the gonads ²⁴⁾. Childhood extracranial germ cell tumors can be divided into the following two types:

• Gonadal germ cell tumors
  
• Extragonadal germ cell tumors
  

Most childhood extragonadal germ cell tumors arise in midline sites (i.e., head and neck, sacrococcygeal, mediastinal, and retroperitoneal); the midline location may represent aberrant embryonic migration of the primordial germ cells.

The presence of an abdominal undescended testis (cryptorchidism) has been associated with a risk of developing testicular cancer that is 3.7 to 7.5 times higher than in those with normal testes ²⁵⁾. The presence of Y-chromosome material in an abdominal gonad, as seen in gonadal dysgenesis, also increases the risk of developing a gonadal germ cell tumor, especially gonadoblastoma ²⁶⁾.

There are few data about the potential genetic or environmental risk factors associated with childhood extragonadal extracranial germ cell tumors. Patients with the following syndromes are at an increased risk of extragonadal extracranial germ cell tumors:

• Klinefelter syndrome—increased risk of mediastinal germ cell tumors ²⁷⁾. Patients with germ cell tumors were identified from the Children’s Oncology Group (COG) Childhood Cancer Research Network. Twenty-nine patients in the study had mediastinal primary tumors, and nine patients (31%) had Klinefelter syndrome. In the Centers for Disease Control and Prevention’s large 2013 WONDER database, 3% of patients with germ cell tumors had Klinefelter syndrome (70% were mediastinal), compared with 0.2% of males in the general population with reported Klinefelter syndrome ²⁸⁾.
• Swyer syndrome—increased risk of gonadoblastomas and seminomas ²⁹⁾.
• Turner syndrome—increased risk of gonadoblastomas and dysgerminomas ³⁰⁾.

Germ cell tumors symptoms

Childhood extracranial germ cell tumors develop at many sites, including testicles, ovaries, mediastinum, retroperitoneum, sacrum, coccyx, and head and neck (see Figure 1) ³¹⁾. The clinical features at presentation are specific for each site.

Symptoms of germ cell tumors depend on where the tumor is, how big it is and whether it produces hormones.

Symptoms of germ cell tumors outside the brain may include:

• a lump in the abdomen (belly), lower back or testicle
• a solid testicular mass, with or without associated testicular pain
• abdominal (belly) pain
• fever
• constipation
• in girls, not having periods or having unusual bleeding from the vagina
• a solid ovarian mass discovered on ultrasound done for abdominal pain
• a mass visible in the lower back, near the anus, often in an infant
• respiratory distress associated with a mass inside the chest
• development of pubic hair, breast enlargement, or vaginal bleeding at a very young age

Germ cell tumors in the brain may cause symptoms such as:

• extreme thirst
• frequent urination
• headaches
• nausea or vomiting
• changes in vision
• loss of appetite
• weight loss
• tiredness
• early or late puberty.

Benign teratomas and immature teratomas can cause morbidity and mortality through obstruction (i.e., head and neck teratomas). In preterm infants and neonates, head and neck teratomas and immature teratomas can cause significant airway compromise. In a single-institutional report, airway obstruction was overcome by using the ex utero intrapartum treatment procedure ³²⁾. Complete resection of a teratoma can be achieved.

Germ cell tumors complications

A child may have complications from the tumor or from treatment. They may include:

• Damage to the brain or nervous system that causes problems with coordination, muscle strength, speech, or eyesight
• Problems after surgery, such as infection, bleeding, and problems with general anesthesia
• Infection and bleeding from chemotherapy
• Delayed growth and development
• Learning problems
• Problems with reproduction (infertility)
• Return of the cancer
• Growth of other cancers

Germ cell tumor diagnosis

Diagnostic evaluation of germ cell tumors includes imaging studies and measurement of tumor markers. In suspected cases, tumor markers can suggest the diagnosis before surgery and/or biopsy. This information can be used by the multidisciplinary team to make appropriate treatment choices.

After a careful history and physical examination, your doctor typically obtain:

• CT scan of chest, abdomen, and pelvis, with oral and intravenous contrast
• Ultrasound of the testes (if testes tumor) or abdomen (if ovarian)
• Blood tests for alpha-fetoprotein (AFP) and beta human chorionic gonadotropin (bHCG) (elevated in some germ cell tumors)
• Blood tests to measure blood counts and liver and kidney function
• A baseline hearing evaluation
• Pulmonary function tests, as a baseline lung evaluation
• A nuclear medicine glomerular filtration rate (GFR), as a baseline kidney evaluation

After completing the diagnostic evaluation, a surgical resection is planned. A testicular or ovarian malignancy will be removed along with the involved normal testes or ovary. Abdominal lymph nodes may be biopsied. Tumors arising in the lower back, the chest, or elsewhere will also be removed surgically if possible – otherwise they will be biopsied. A central line will be placed to allow chemotherapy.

Tumor markers

Yolk sac tumors produce alpha-fetoprotein (AFP), and beta-human chorionic gonadotropin (beta-hCG) is produced by all choriocarcinomas and by some germinomas (seminomas and dysgerminomas) and embryonal carcinomas, resulting in elevated serum levels of these substances. Most children with malignant germ cell tumors will have a component of yolk sac tumor and have elevations of AFP levels ³³⁾., which are serially monitored during treatment to help assess response to therapy ³⁴⁾. Benign teratomas and immature teratomas may produce small elevations of AFP and beta-hCG.

The fetal liver produces AFP, and during the first year of life, infants have elevated serum AFP levels, which are not associated with the presence of a germ cell tumor. Normal ranges have been described ³⁵⁾. The serum half-life of AFP is 5 to 7 days, and the serum half-life of beta-hCG is 1 to 2 days. Even though the data are limited, tumor markers are measured with each cycle of chemotherapy for all pediatric patients with malignant germ cell tumors. After initial chemotherapy, tumor markers may show a transient elevation ³⁶⁾. A Children’s Oncology Group study measured AFP levels in children who received chemotherapy for germ cell tumors. AFP decline was defined as automatically satisfactory if AFP normalized after two cycles of chemotherapy and was calculated satisfactory if the AFP half-life decline was less than or equal to 7 days after the start of chemotherapy. Other decline in AFP was defined as unsatisfactory. The cumulative incidence of relapse was 11% for patients with a satisfactory decline in AFP (n = 117) and 38% for patients with an unsatisfactory decline in AFP (n = 14) ³⁷⁾.

Imaging tests

Imaging tests may include the following:

• Computed tomography (CT) scan of the chest.
• CT or magnetic resonance imaging (MRI) of the primary site.
• Radionuclide bone scan, if clinically indicated.
• MRI of the brain, if clinically indicated.

Based on the results of the imaging studies and surgery, a clinical stage will be assigned:

• Stage I tumor completed resected
• Stage II tumor resected, but a small number of cells were left behind
• Stage III tumor has spread to lymph nodes
• Stage IV tumor spread to the lung or liver or other locations

Germ cell tumor staging

As with other childhood solid tumors, stage directly impacts the outcome of patients with malignant germ cell tumors ³⁸⁾. The most commonly used staging systems in the United States are as follows ³⁹⁾:

• Testicular germ cell tumor Staging (Children’s Oncology Group [COG]).
• Ovarian germ cell tumor Staging (Children’s Oncology Group).
• Ovarian germ cell tumor Staging (International Federation of Gynecology and Obstetrics [FIGO]).
• Extragonadal Extracranial germ cell tumor Staging (Children’s Oncology Group).

Testicular germ cell tumor staging from Children’s Oncology Group (Patients Aged <11 Years)

Table 3. Testicular germ cell tumor Staging From the Children’s Oncology Group AGCT1531 Trial ⁴⁰⁾

Stage	Extent of Disease
I	(1) Ovarian tumor removed without violation of the tumor capsule; (2) no evidence of partial or complete capsular penetration; (3) peritoneal cytology negative for malignant cells; (4) peritoneal surfaces and omentum documented to be free of disease in operative note or biopsied with negative histology if abnormal in appearance; (5) lymph nodes all <1 cm by short-axis diameter on multiplanar imaging or biopsy proven negative. (Note: Nodes 1–2 cm require short-interval follow-up in 4–6 weeks. If nodes are unchanged at 4–6 weeks [1–2 cm], consider biopsy or transfer to chemotherapy arm. If growing, transfer to chemotherapy arm.)
II	(1) Ovarian tumor completely removed but with preoperative biopsy, violation of tumor capsule in situ, or presence of partial or complete capsule penetration at histology; (2) tumor >10 cm removed laparoscopically; (3) tumor morcellated for removal so that capsule cannot be assessed for penetration; (4) peritoneal cytology must be negative for malignant cells; (5) lymph nodes, peritoneal surfaces, and omentum documented to be free of disease in operative note or biopsied with negative histology if abnormal in appearance.
III	(1) Lymph nodes ≥2 cm or lymph nodes >1 cm but <2 cm on short axis by multiplanar imaging CT that fail to resolve on re-imaging at 4–6 weeks; (2) ovarian tumor biopsied or removal with gross residual; (3) positive peritoneal fluid cytology for malignant cells, including immature teratoma; (4) lymph nodes positive for malignant cells, including immature teratoma; (5) peritoneal implants positive for malignant cells, including immature teratoma.
III–X	Patients otherwise stage I or II by Children’s Oncology Group criteria but with the following: (1) Failure to collect peritoneal cytology; (2) failure to biopsy lymph nodes >1 cm on short axis by multiplanar imaging; (3) failure to sample abnormal peritoneal surfaces or omentum; or (4) delayed completion of surgical staging at a second procedure for patients who had only oophorectomy at first procedure.
IV	(1) Metastatic disease to the parenchyma of the liver (surface implants are stage III) or metastases outside the peritoneal cavity to any other viscera (bone, lung, or brain) and pleural fluid with positive cytology.

Footnote: a) Males younger than 50 years are eligible for the AGCT1531 trial. b) Children’s Oncology Group trials include patients younger than 15 years with testicular germ cell tumor. Although data are scarce, patients between the ages of 11 years and 15 years might be more appropriately staged according to adult testicular guidelines.

Abbreviations: COG = Children’s Oncology Group; CT = computed tomography; GCT = germ cell tumor.

Testicular germ cell tumor staging (Patients Aged ≥11 Years)

The staging system most often used for testicular cancer is the American Joint Committee on Cancer (AJCC) TNM system, which is based on 4 key pieces of information:

• The size and extent of the main tumor (T): How large is the tumor? Has it grown into nearby structures or organs?
• The spread to nearby lymph nodes (N): Has the cancer spread to nearby lymph nodes ? How many, and how big are they?
• The spread (metastasis) to distant sites (M): Has the cancer spread to distant parts of the body? (The most common sites of spread are distant lymph nodes, the bones, the liver, and the lungs.)
• The serum (blood) levels of tumor markers (S): Are any tumor marker levels higher than normal? This includes lactate dehydrogenase (LDH), human chorionic gonadotropin (HCG), and alpha-fetoprotein (AFP).

Numbers or letters after T, N, M, and S provide more details about each of these factors. Higher numbers mean the cancer is more advanced. Once a person’s T, N, M, and S categories have been determined, this information is combined in a process called stage grouping to assign an overall stage.

The system described below is the most recent AJCC system, effective as of January 2018. It’s used for germ cell tumors (seminomas and non-seminomas) that occur after puberty, and for sex cord stromal tumors (Leydig cell tumors and Sertoli cell tumors).

Testicular cancer might be given a clinical T category (written as cT) based on the results of a physical exam, biopsy, and imaging tests (as described in Tests for Testicular Cancer). Once surgery is done, the pathologic T category (written as pT) is determined by examining tissue removed during the operation.

Retroperitoneal lymph node dissection has not been required in pediatric germ cell trials to stage disease in males younger than 15 years. Data on adolescent males with testicular germ cell tumors are limited. Retroperitoneal lymph node dissection is used for both staging and treatment in adult testicular germ cell tumor trials ⁴¹⁾.

In males older than 15 years, there are only stage I tumors and metastatic tumors. Metastatic tumors are assigned risk according to the International Germ Cell Consensus Classification ⁴²⁾.

Table 4. Stages of testicular cancer

AJCC Stage	Stage grouping	Stage description*
0	pTis N0 M0 S0	The cancer is only in the seminiferous tubules (small tubes inside each testicle). It has not grown into other parts of the testicle (pTis). It hasn’t spread to nearby lymph nodes (N0) or to distant parts of the body (M0). All tumor marker levels are within normal limits (S0).
I	pT1-pT4 N0 M0 SX	The tumor has grown beyond the seminiferous tubules, and might have grown outside the testicle and into nearby structures (pT1-pT4). The cancer has not spread to nearby lymph nodes (N0) or to distant parts of the body (M0). Tumor marker test results aren’t available, or the tests haven’t been done (SX).
IA	pT1 N0 M0 S0	The tumor has grown beyond the seminiferous tubules, but is still within the testicle, and it hasn’t grown into nearby blood vessels or lymph nodes (pT1). The cancer hasn’t spread to nearby lymph nodes (N0) or to distant parts of the body (M0). All tumor marker levels are within normal limits (S0).
IB	pT2-pT4 N0 M0 S0	The tumor has grown outside of the testicle and into nearby structures (pT2-pT4). The cancer has not spread to nearby lymph nodes (N0) or to distant parts of the body (M0). All tumor marker levels are within normal limits (S0).
IS	Any pT (or TX) N0 M0 S1-S3	The tumor might or might not have grown outside the testicle (any pT), or the extent of the tumor can’t be assessed for some reason (TX). The cancer has not spread to nearby lymph nodes (N0) or to distant parts of the body (M0). At least one tumor marker level is higher than normal (S1-S3).
II	Any pT (or TX) N1-N3 M0 SX	The tumor might or might not have grown outside the testicle (any pT), or the extent of the tumor can’t be assessed for some reason (TX). The cancer has spread to 1 or more nearby lymph nodes (N1-N3), but it hasn’t spread to distant parts of the body (M0). Tumor marker test results aren’t available, or the tests haven’t been done (SX).
IIA	Any pT (or TX) N1 M0 S0 or S1	The tumor might or might not have grown outside the testicle (any pT), or the extent of the tumor can’t be assessed for some reason (TX). The cancer has spread to at least 1 nearby lymph node (but no more than 5, if checked by surgery), and none of the lymph nodes are larger than 2 centimeters (cm) across (N1). The cancer has not spread to distant parts of the body (M0). All tumor marker levels are within normal limits (S0), or at least 1 tumor marker level is slightly higher than normal (S1).
IIB	Any pT (or TX) N2 M0 S0 or S1	The tumor might or might not have grown outside the testicle (any pT), or the extent of the tumor can’t be assessed for some reason (TX). The cancer has spread to at least 1 nearby lymph node that’s larger than 2 cm but no larger than 5 cm across, OR it has grown outside of a lymph node, OR more than 5 nodes contain cancer (found during surgery) (N2). The cancer has not spread to distant parts of the body (M0). All tumor marker levels are within normal limits (S0), or at least 1 tumor marker level is slightly higher than normal (S1).
IIC	Any pT (or TX) N3 M0 S0 or S1	The tumor might or might not have grown outside the testicle (any pT), or the extent of the tumor can’t be assessed for some reason (TX). The cancer has spread to at least 1 nearby lymph node that’s larger than 5 cm across (N3). The cancer has not spread to distant parts of the body (M0). All tumor marker levels are within normal limits (S0), or at least 1 tumor marker level is slightly higher than normal (S1).
III	Any pT (or TX) Any N M1 SX	The tumor might or might not have grown outside the testicle (any pT), or the extent of the tumor can’t be assessed for some reason (TX). The cancer might or might not have spread to nearby lymph nodes (any N). It has spread to distant parts of the body (M1). Tumor marker test results aren’t available, or the tests haven’t been done (SX).
IIIA	Any pT (or TX) Any N M1a S0 or S1	The tumor might or might not have grown outside the testicle (any pT), or the extent of the tumor can’t be assessed for some reason (TX). The cancer might or might not have spread to nearby lymph nodes (any N). It has spread to distant lymph nodes or to the lungs (M1a). All tumor marker levels are within normal limits (S0), or at least 1 tumor marker level is slightly higher than normal (S1).
IIIB	Any pT (or TX) N1-N3 M0 S2	The tumor might or might not have grown outside the testicle (any pT), or the extent of the tumor can’t be assessed for some reason (TX). The cancer has spread to 1 or more nearby lymph nodes (N1-N3), but it hasn’t spread to distant parts of the body (M0). At least 1 tumor marker level is much higher than normal (S2).
	OR
	Any pT (or TX) Any N M1a S2	The tumor might or might not have grown outside the testicle (any pT), or the extent of the tumor can’t be assessed for some reason (TX). The cancer might or might not have spread to nearby lymph nodes (any N). It has spread to distant lymph nodes or to the lungs (M1a). At least 1 tumor marker level is much higher than normal (S2).
IIIC	Any pT (or TX) N1-N3 M0 S3	The tumor might or might not have grown outside the testicle (any pT), or the extent of the tumor can’t be assessed for some reason (TX). The cancer has spread to 1 or more nearby lymph nodes (N1-N3), but it hasn’t spread to distant parts of the body (M0). At least 1 tumor marker level is very high (S3).
	OR
	Any pT (or TX) Any N M1a S3	The tumor might or might not have grown outside the testicle (any pT), or the extent of the tumor can’t be assessed for some reason (TX). The cancer might or might not have spread to nearby lymph nodes (any N). It has spread to distant lymph nodes or to the lungs (M1a). At least 1 tumor marker level is very high (S3).
	OR
	Any pT (or TX) Any N M1b Any S	The tumor might or might not have grown outside the testicle (any pT), or the extent of the tumor can’t be assessed for some reason (TX). The cancer might or might not have spread to nearby lymph nodes (any N). It has spread to distant parts of the body other than the lymph nodes or to the lungs (M1b). Tumor marker levels might or might not be higher than normal (any S).

Footnote: * The following additional category is not listed on the table above. NX = Nearby lymph nodes cannot be assessed due to lack of information.

Ovarian germ cell tumor staging from Children’s Oncology Group

Table 5 describes the ovarian germ cell tumor staging from the Children’s Oncology Group AGCT1531 (NCT03067181) trial ⁴³⁾.

Table 5. Ovarian germ cell tumor staging From the COG AGCT1531 Trial ⁴⁴⁾

Stage	Extent of Disease
I	(1) Ovarian tumor removed without violation of the tumor capsule; (2) no evidence of partial or complete capsular penetration; (3) peritoneal cytology negative for malignant cells; (4) peritoneal surfaces and omentum documented to be free of disease in operative note or biopsied with negative histology if abnormal in appearance; (5) lymph nodes all <1 cm by short-axis diameter on multiplanar imaging or biopsy proven negative. (Note: Nodes 1–2 cm require short-interval follow-up in 4–6 weeks. If nodes are unchanged at 4–6 weeks [1–2 cm], consider biopsy or transfer to chemotherapy arm. If growing, transfer to chemotherapy arm.)
II	(1) Ovarian tumor completely removed but with preoperative biopsy, violation of tumor capsule in situ, or presence of partial or complete capsule penetration at histology; (2) tumor >10 cm removed laparoscopically; (3) tumor morcellated for removal so that capsule cannot be assessed for penetration; (4) peritoneal cytology must be negative for malignant cells; (5) lymph nodes, peritoneal surfaces, and omentum documented to be free of disease in operative note or biopsied with negative histology if abnormal in appearance.
III	(1) Lymph nodes ≥2 cm or lymph nodes >1 cm but <2 cm on short axis by multiplanar imaging CT that fail to resolve on re-imaging at 4–6 weeks; (2) ovarian tumor biopsied or removal with gross residual; (3) positive peritoneal fluid cytology for malignant cells, including immature teratoma; (4) lymph nodes positive for malignant cells, including immature teratoma; (5) peritoneal implants positive for malignant cells, including immature teratoma.
III–X	Patients otherwise stage I or II by Children’s Oncology Group criteria but with the following: (1) Failure to collect peritoneal cytology; (2) failure to biopsy lymph nodes >1 cm on short axis by multiplanar imaging; (3) failure to sample abnormal peritoneal surfaces or omentum; or (4) delayed completion of surgical staging at a second procedure for patients who had only oophorectomy at first procedure.
IV	(1) Metastatic disease to the parenchyma of the liver (surface implants are stage III) or metastases outside the peritoneal cavity to any other viscera (bone, lung, or brain) and pleural fluid with positive cytology.

Footnote: a) Bilateral ovarian tumors may be any stage as long as other stage criteria are met. Tumor staged according to ovary with most advanced features.

Abbreviations: COG = Children’s Oncology Group; CT = computed tomography; GCT = germ cell tumor.

Ovarian germ cell tumor staging from International Federation of Gynecology and Obstetrics

Another ovarian germ cell tumor staging system used frequently by gynecologic oncologists is the International Federation of Gynecology and Obstetrics staging system, which is based on adequate surgical staging at the time of diagnosis ⁴⁵⁾. This system has also been used by some pediatric centers ⁴⁶⁾ and is described in Table 6.

The ovarian staging systems described below require adherence to specific guidelines. However, in a pediatric intergroup trial, guidelines were followed in only 2 of 131 patients with ovarian tumors ⁴⁷⁾. In a single-institution retrospective study, guidelines were followed in only 2 of 44 patients with ovarian tumors ⁴⁸⁾.

Table 6. International Federation of Gynecology and Obstetrics staging for carcinoma of the ovary

Stage		Description
I		Tumor confined to the ovary.
IA		Tumor limited to one ovary (capsule intact); no tumor on surface of the ovary; no malignant cells in the ascites or peritoneal washings.
IB		Tumor limited to both ovaries (capsules intact); no tumor on surface of the ovary; no malignant cells in the ascites or peritoneal washings.
IC		Tumor limited to one or both ovaries, with any of the following:
	IC1	Surgical spill.
	IC2	Capsule ruptured before surgery or tumor on the surface of the ovary.
	IC3	Malignant cells in the ascites or peritoneal washings.
II		Tumor involves one or both ovaries with pelvic extension (below pelvic brim) or primary peritoneal cancer.
IIA		Extension and/or implants on uterus and/or fallopian tubes.
IIB		Extension to other pelvic intraperitoneal tissues.
III		Tumor involves one or both ovaries or primary peritoneal cancer, with cytologically or histologically confirmed spread to the peritoneum outside the pelvis and/or metastasis to the retroperitoneal lymph nodes.
IIIA1		Positive retroperitoneal lymph nodes only (cytologically or histologically proven):
	IIIA1(i)	Lymph nodes ≤10 mm in greatest dimension.
	IIIA1(ii)	Lymph nodes >10 mm in greatest dimension.
IIIA2		Microscopic extrapelvic (above the pelvic brim) peritoneal involvement with or without positive retroperitoneal lymph nodes.
IIIB		Macroscopic peritoneal metastasis beyond the pelvis ≤2 cm in greatest dimension, with or without metastasis to the retroperitoneal lymph nodes
IIIC		Macroscopic peritoneal metastasis beyond the pelvis >2 cm in greatest dimension, with or without metastasis to the retroperitoneal lymph nodes (includes extension of tumor to capsule of liver and spleen without parenchymal involvement of either organ).
IV		Distant metastasis excluding peritoneal metastases.
IVA		Pleural effusion with positive cytology.
IVB		Parenchymal metastases and metastases to extra-abdominal organs (including inguinal lymph nodes and lymph nodes outside of the abdominal cavity).

[Source ⁴⁹⁾ ]

Extragonadal extracranial germ cell tumor staging From Children’s Oncology Group

Table 7 describes the extragonadal extracranial germ cell tumor staging from the Children’s Oncology Group AGCT1531 (NCT03067181) trial ⁵⁰⁾.

Table 7. Extragonadal Extracranial germ cell tumor staging From the Children’s Oncology Group AGCT1531 Trial

Stage	Extent of Disease
I	(1) Complete resection at any site, including coccygectomy for sacrococcygeal site; (2) must have negative tumor margins and intact capsule; (3) for any tumors involving abdominal cavity or retroperitoneum, peritoneal fluid or washings must be done for cytology and be negative for malignant cells; (4) lymph nodes ≤1 cm by imaging of abdomen, pelvis, and chest. (Note: Nodes 1–2 cm require short-interval follow-up in 4–6 weeks. If nodes are unchanged at 4–6 weeks [1–2 cm], consider biopsy or transfer to chemotherapy arm. If growing, transfer to chemotherapy arm. For any tumors involving abdominal cavity or retroperitoneum, peritoneal fluid or washings must be done for cytology and be negative for malignant cells.)
II	(1) Microscopic residual disease; (2) gross-total resection with preoperative biopsy, intraoperative biopsy, microscopic residual disease, or pathologic evidence of capsular disruption; (3) lymph nodes negative by abdomen, pelvic, and chest imaging. Peritoneal fluid negative.
III	(1) Gross residual disease or biopsy only; (2) lymph nodes positive with tumor resection. Lymph nodes ≥2 cm or lymph nodes >1 cm but <2 cm on short axis by multiplanar imaging CT that fail to resolve on re-imaging at 4–6 weeks.
IV	Distant metastases, including liver, lung, bone, and brain.

Abbreviations: COG = Children’s Oncology Group; CT = computed tomography; GCT = germ cell tumor.

Germ cell tumor treatment

Childhood extracranial germ cell tumors (germ cell tumors) are very heterogenous. The benefits and limitations of therapy are related to differences in histology. For example, pediatric germ cell tumors such as mature and immature teratomas may not respond to chemotherapy.

On the basis of clinical factors, appropriate treatment for extracranial germ cell tumors may involve one of the following:

• Surgical resection followed by careful monitoring for disease recurrence.
• Initial surgical resection followed by platinum-based chemotherapy.
• Diagnostic tumor biopsy and preoperative platinum-based chemotherapy followed by definitive tumor resection ⁵¹⁾.

To maximize the likelihood of long-term survival while minimizing the likelihood of treatment-related long-term complications (e.g., secondary leukemias, infertility, hearing loss, and renal dysfunction), children with extracranial malignant germ cell tumors need to be cared for at pediatric cancer centers with experience treating these rare tumors.

Surgery

Surgery is an essential component of treatment.

For patients with completely resected immature teratomas of all grades and at any location, and for patients with localized, completely resected (stage I) seminomatous and nonseminomatous germ cell tumors (testicular and ovarian), additional therapy may not be necessary; however, close monitoring is important ⁵²⁾. The watch-and-wait approach requires scheduled serial physical examination, tumor marker determination, and primary tumor imaging to ensure that a recurrent tumor is detected without delay.

Chemotherapy

Chemotherapy is based on tumor stage and location. Before effective chemotherapy became available, children with extracranial malignant germ cell tumors had 3-year survival rates of 15% to 20% with surgery and radiation therapy ⁵³⁾, although young boys with localized testicular tumors did well with surgical resection alone ⁵⁴⁾. Cisplatin-based chemotherapy has significantly improved outcomes for most children and adolescents with extracranial germ cell tumors; 5-year survival rates now approach 85%.

Patients are given the opportunity to enroll on Children’s Oncology Group therapy protocols or may choose to be treated off protocol with standard of care therapy as summarized below:

• Stage I testes/ovary: no chemotherapy unless recurs
• Stage II-IV testes, Stage II-III ovary, Stage I-II non-testes or ovary: Cisplatin, Etoposide, Bleomycin intravenously every 3 weeks for 3 cycles
• Stage IV ovary, Stage III or IV non-testes or ovary: Cisplatin, Etoposide, Bleomycin intravenously every 3 weeks for 4 cycles

Radiation therapy is not routinely used for initial therapy, except in some instances instead of chemotherapy for germinoma.

If there is a residual tumor present after chemotherapy, surgical resection may be recommended, and additional chemotherapy may be needed.

The cure rates are approximately 90% for Stage I, 90% for Stage II, 87% for Stage III, and 82% for Stage IV.

In the United States, the standard chemotherapy regimen for both adults and children with malignant non-seminomatous germ cell tumors includes cisplatin, etoposide, and bleomycin. Adult patients receive weekly bleomycin throughout treatment (bleomycin, etoposide, and cisplatin [BEP]) ⁵⁵⁾. U.S. pediatric trials included patients aged 15 years and younger with testicular germ cell tumors and patients aged 21 years and younger with ovarian and extragonadal germ cell tumors. Patients received bleomycin only on day 1 of each cycle (cisplatin, etoposide, and bleomycin [PEb]) ⁵⁶⁾. The combination of carboplatin, etoposide, and bleomycin (JEb) underwent clinical investigation in the United Kingdom in children younger than 16 years and was reported to have an event-free survival by site and stage similar to that of cisplatin, etoposide, and bleomycin (PEb) ⁵⁷⁾. In both adult and pediatric trials, the number of adolescent subjects was small; the optimal therapy for adolescents (aged ≥11 years) is not clear ⁵⁸⁾.

The use of carboplatin, etoposide, and bleomycin (JEb) appears to be associated with fewer otologic toxic effects and renal toxic effects than does the use of cisplatin, etoposide, and bleomycin (PEb) ⁵⁹⁾. In a retrospective meta-analysis of data from the Children’s Oncology Group (COG) and the Children’s Cancer and Leukaemia Group germ cell studies conducted contemporaneously, the multivariate cure model showed no difference in 4-year event-free survival rates. The 4-year event-free survival rate was 86% (95% confidence interval [CI], 83%–89%) for patients who received the cisplatin regimen (n = 620) and 86% for patients who received the carboplatin regimen (n = 163) ⁶⁰⁾. However, PEb and JEb have not been compared in a randomized pediatric germ cell tumor trial.

Several trials were conducted by the Children’s Oncology Group ⁶¹⁾. These trials explored the use of PEb for the treatment of localized gonadal germ cell tumor ⁶²⁾ and intensified regimens for patients with poor-risk features. The strategies included high-dose cisplatin (200 mg/m²) and cyclophosphamide or the protective agent amifostine ⁶³⁾. None of these strategies had a significant effect on survival or decreased toxicity.

Radiation therapy

Testicular and mediastinal seminomas in males and ovarian dysgerminomas in females are sensitive to radiation, but radiation therapy is rarely recommended because of the known late effects. Radiation may be used to treat germ cell tumors in the brain.

High-dose chemotherapy with a stem cell transplant

Some children with germ cell tumors in the brain may be treated using a stem cell transplant (also known as a bone marrow transplant), in combination with high-dose chemotherapy.

Clinical trials

Ask your child’s healthcare provider if there are any treatments being tested that may work well for your child.

Follow-up after treatment

The following tests and procedures may be performed at the physician’s discretion for monitoring children with extracranial germ cell tumors:

• AFP and beta-hCG. Monitor AFP and beta-hCG levels monthly for 6 months (period of highest risk) and then every 3 months, for a total of 2 years (3 years for sacrococcygeal teratoma). In a Children’s Oncology Group trial of patients with low-risk and intermediate-risk germ cell tumors, 48 patients with elevated tumor markers at diagnosis relapsed during the surveillance phase. At the time of relapse (after central review), 47 of 48 (98%) relapses were detected by tumor marker elevation ⁶⁴⁾.
• Imaging tests.
  • MRI/CT may be performed at the completion of therapy.
  • Guided imaging of the primary site may be performed every 3 months for the first year and every six months for the second year. Seminomas and dysgerminomas may recur later, so the imaging schedule may need to be extended.
  • Chest x-ray annually.

The following tests and procedures may be performed at the physician’s discretion when tumor markers are normal at diagnosis:

• Imaging tests. Ultrasonography or CT/MRI may be performed every 3 months for 2 years and then annually for 5 years for germinomas.

How can I help my child live with a germ cell tumor?

A child with a germ cell tumor needs ongoing care. Your child will be seen by oncologists and other healthcare providers to treat any late effects of treatment and to watch for signs or symptoms of the tumor returning. Your child will be checked with imaging tests and other tests. And your child may see other healthcare providers for problems from the tumor or from treatment.

You can help your child manage his or her treatment in many ways. For example:

• Your child may have trouble eating. A dietitian may be able to help.
• Your child may be very tired. He or she will need to balance rest and activity. Encourage your child to get some exercise. This is good for overall health. And it may help to lessen tiredness.
• Get emotional support for your child. Find a counselor or child support group can help.
• Make sure your child attends all follow-up appointments.

Germ cell tumor prognosis

Prognostic factors for extracranial germ cell tumors depend on many circumstances and include the following (obtained from historical national germ cell tumor trials) ⁶⁵⁾.:

• Age (e.g., young children vs. adolescents).
• Stage of disease.
• Primary site of disease.
• Tumor marker decline (AFP and beta-hCG) in response to therapy.
• Histology (e.g., seminomatous vs. nonseminomatous).
• Presence of gonadal dysgenesis.

To better identify prognostic factors, data from five U.S. trials and two U.K. trials for malignant extracranial germ cell tumors in children and adolescents were merged by the Malignant Germ Cell Tumor International Collaborative. The goal was to ascertain the important prognostic factors in 519 young patients who received chemotherapy, incorporating age at diagnosis, stage, and site of primary tumor, along with pretreatment AFP level and histology ⁶⁶⁾. In this age-focused investigation of these factors in young children and adolescents, prognostic factors included the following (refer to Table 8) ⁶⁷⁾:

• Patients aged 11 years and older with stage III or stage IV extragonadal disease or ovarian stage IV disease had a less than 70% likelihood of long-term disease-free survival, ranging from 40% (extragonadal stage IV) to 67% (ovarian stage IV).
• Boys (aged 11 years and older) with International Germ Cell Consensus Classification (IGCCC) ⁶⁸⁾ intermediate-risk or poor-risk features also had inferior outcomes.
• Preoperative AFP levels were not prognostic. AFP levels, drawn postoperatively, are prognostic in adult men ⁶⁹⁾.
• Yolk sac tumor predicted better outcome, but did not achieve statistical significance at the 0.05 level.

The presence of gonadal dysgenesis in patients with ovarian nondysgerminomatous tumors is associated with worse outcomes. In a report from the Children’s Oncology Group AGCT0132 study (https://clinicaltrials.gov/ct2/show/NCT00053352), seven patients with gonadal dysgenesis and ovarian nondysgerminoma had an estimated 3-year event-free survival rate of 67%, compared with 89% for 100 patients with nondysgerminoma ovarian tumors who did not have gonadal dysgenesis ⁷⁰⁾. These dysgenetic gonads contain Y-chromosome material, and intra-abdominal gonads with Y-chromosome material are at increased risk of tumor development ⁷¹⁾. In contrast to nondysgerminomas, gonadal dysgenesis was identified in 7 of 48 patients with ovarian dysgerminomas in a report from the French Society of Pediatric Oncology. With a medium follow-up of 14 years, all patients survived ⁷²⁾.

Although few pediatric data exist, adult studies have shown that an unsatisfactory decline of elevated tumor markers after the first cycle of chemotherapy is a poor prognostic finding ⁷³⁾.

Table 8. Predicted fraction of pediatric germ cell tumors cured by site, age, and stage using parameter estimates from cure model

[Source ⁷⁴⁾ ]