Germ Cell Tumors

INTRODUCTION

Background: Germ cell tumors (GCTs) are a morphologically distinct group of neoplasms with varied clinical presentation. Ninety-five percent of tumors arising in the testes are GCTs, indicating that they originate from the primordial germ cells. More than 90% of patients with newly diagnosed GCT are cured. A delay in diagnosis correlates with a higher stage at presentation and, consequently, a lower cure rate from treatment. The success in treating germ cell tumors in the past 2 decades is largely attributed to the effectiveness of cisplatin-containing combination chemotherapy to cure advanced disease.

Pathophysiology:

Biology

Recent studies of GCTs have suggested that cyclin D2 is overexpressed in malignant germ cells and is oncogenic.

GCT differentiation may be influenced by several interacting pathways, such as regulators of germ-cell totipotentiality, embryonic development, and genomic imprinting. Sensitivity and resistance to chemotherapy may be based in part on a p53-dependent apoptotic pathway.

Mechanism of germ cell transformation

Almost 100% of tumors show increased copy number of 12p. This chromosomal marker has been noted in carcinoma in situ (CIS), suggesting that it is one of the early changes associated with the origin of GCT. CIS is considered to be a precursor of all GCTs. Two models have been proposed to explain the origin of CIS cells, as follows:

Model 1: Fetal gonocytes that escape normal development into spermatogonia undergo abnormal cell division and proliferation. These gonocytes are prone to invasive growth, mediated by postnatal and pubertal gonadotrophin stimulation.

Model 2: Increased 12p copy number, cyclin D2 expression, consistent near triploid-tetraploid chromosome numbers, and increased expression of wild-type p53 result in tumorigenesis. Abnormal chromatid exchanges during meiotic crossing over leads to increased 12p copy number and cyclin D2 overexpression. In cells containing unrepaired DNA strand breaks, cyclin D2 can block p53-dependent apoptosis and leads to re-initiation of cell cycle and genomic instability.

Frequency:
　

• In the US: More than 7,000 cases of GCTs are diagnosed in the US each year.

• Internationally: For unknown reasons, worldwide incidence has more than doubled in the past 40 years. The incidence of GCT varies based on the geographic area. The highest incidence is in Scandinavia, Germany, and New Zealand. It is lower in the US and lowest in Asia and Africa.

Mortality/Morbidity: For all patients with GCT, the 5-year survival rate is about 95%. Cure rates are highest for early-stage disease and lower for advanced disease.

Race: Germ cell tumors are seen predominantly in whites and rarely in African Americans. The incidence ratio of whites to African Americans is approximately 5:1.

CLINICAL

History:

• Approximately 95% of GCTs occur in the gonads, and the rest occur in extragonadal tissues.

• A painless testicular mass is the most common presentation in patients with testicular cancer. However, about 20-40% of patients with primary testicular cancer present with pain, swelling, hardness, or a combination of these symptoms. It is reasonable to treat patients without palpable mass using a trial of antibiotics, as infectious epididymitis or orchitis is more common than tumor. A testicular ultrasound examination is indicated if symptoms and signs are not controlled or do not revert in 2 weeks.

• Testicular pain may be associated with epididymitis, torsion of the testes, tumor, or bleeding or infarction in the tumor. Flank pain, back pain, or abdominal pain can occur from metastatic disease.

• Gynecomastia occurs in patients with tumors that produce human chorionic gonadotropin (HCG), such as choriocarcinoma

• Pulmonary symptoms such as shortness of breath, chest pain, and hemoptysis, although rare, can occur in patients with advanced pulmonary disease or primary mediastinal GCT.

• Symptoms due to central nervous system metastasis or to bone metastases are rare.

Physical:

• Physical examination of the testicles is performed by fully palpating all areas of the testicle between thumb and fingers. Testicular mass with or without pain is a finding that requires immediate attention.

• Other areas of emphasis include examination for the following:

• Left supraclavicular lymphadenopathy
• Hepatomegaly
• Bone tenderness
• Gynecomastia
• Abdominal mass

• Seminoma, a GCT subtype, has the following clinical features:

• This usually presents in the fourth decade of life. Seminoma is confined to the testes in about 70% of cases and metastasizes to the lymph nodes in about 25% of cases. Distant metastasis occurs in 5% of cases at presentation. These testicular primary tumors are usually homogenous and large.

• Spermatocytic seminoma occurs in the sixth decade of life. It presents bilaterally more often than seminoma and is an indolent tumor that rarely metastasizes. Spermatocytic seminoma is not associated with CIS.

• Nonseminomatous germ cell tumor (NSGCT) has the following forms:

• Embryonal carcinoma is characterized by rapid and bulky growth and by spread via lymphatic and hematogenous routes to distant viscera (eg, lungs, liver). More than 60% of patients have metastases at the time of presentation. Pain is a common feature in these patients.

• Teratoma is found commonly in residual or recurrent masses. It is the least aggressive form, but approximately 30% of patients with clinical stage 1 disease have relapse after orchiectomy.

• Choriocarcinoma is the most aggressive of the NSGCTs. It disseminates hematogenously to lungs, liver, brain, and other viscera very early on in the disease process.

• Yolk sac tumors typically present as a large primary tumor.

Causes: No environmental exposures have been proven to lead to GCTs. However, a few congenital developmental defects are related to the development of GCTs.

• Cryptorchidism: Risk of developing GCT in the cryptorchid testis is 10- to- 40-fold higher. About 5-20% of patients with history of cryptorchid testis develop tumors in the normally descended testis. The risk of developing GCT when a cryptorchid testis is intra-abdominal is about 5%. The risk falls to 1% if retained in the inguinal canal and decreases further when the undescended testis is surgically placed in the scrotum when patients are younger than 6 years.

• Diethylstilbestrol: No clear association is seen between diethylstilbestrol and development of GCT.

• Klinefelter syndrome: Patients with Klinefelter syndrome have an increased incidence of mediastinal GCT.

WORKUP

Lab Studies:
　

• Tumor markers alpha-fetoprotein (AFP), beta-human chorionic gonadotrophin (beta-HCG) and lactate dehydrogenase (LDH) are vital in the evaluation and management of patients with GCTs. They are used for diagnosis, staging, prognosis, and response to therapy. It is mandatory to obtain levels of AFP, beta-HCG, and LDH in patients suspected of having GCTs prior to treatment and to follow their levels during and after treatment.

• Alpha-fetoprotein

• Secretion is restricted to GCT of nonseminomatous histology.

• Normal adult concentration is <10 ng/mL.

• Serum half-life is 5-7 days.

• In patients with pure seminoma, increased AFP levels indicate an undetected nonseminomatous tumor component.

• Beta-human chorionic gonadotrophin

• Increased levels of beta-HCG are found in seminomas and in nonseminomas.

• Serum half-life is 18-36 hours.

• Lactate dehydrogenase

• LDH has independent prognostic significance. Increased levels reflect tumor burden, growth rate, and cellular proliferation.

• Increased LDH levels are found in about 60% of advanced NSGCTs and in 80% of advanced seminomas.

Imaging Studies:
　

• Testicular ultrasound can reliably detect testicular masses and also distinguish a testicular mass from an extratesticular mass. Seminomatous tumors appear as hypoechoic lesions and nonseminomatous tumors as hyperechoic lesions.

• CT scans of the chest, abdomen, and pelvis are required. Lymph nodes in the retroperitoneum measuring 10-20 mm are involved in GCTs 70% of the time, and lymph nodes measuring 4-10 mm are involved 50% of the time.

• Chest x-ray

• CT scan or MRI of the brain is performed if patients have neurologic symptoms or signs.

Procedures:
　

• Patients with testicular mass, abnormal ultrasound, or both should undergo a unilateral radical transinguinal orchiectomy with ligation of spermatic cord at the inguinal ring. Orchiectomy is the definitive procedure for both pathologic diagnosis and local control of the primary tumor. It should be undertaken even in patients with disseminated GCT, because the testes are a sanctuary site for chemotherapy.

• Testicular biopsy of a suspicious lesion is not recommended.

• Trans-scrotal orchiectomies are contraindicated, as they have been associated with local recurrence and spread to inguinal lymph nodes.

Histologic Findings: GCTs are classified based on their histology into seminomas and nonseminomas. Seminomas account for about 40% of GCTs, of which classic and anaplastic cell types comprise the majority. The rest are classified as spermatocytic. Seminomas, both classic and anaplastic, occur in people aged 25-45 years, whereas spermatocytic seminoma occurs in men aged 65 years on average.

• Nonseminomas account for about 60% of GCTs.

  　

  • The majority of these are embryonal with or without seminoma and teratoma with embryonal carcinoma, choriocarcinoma or both.
  • Teratomas with or without seminoma account for a minority of tumors.
  • Pure choriocarcinoma and pure yolk sac tumors are extremely rare.
  • Nonseminomas occur in patients aged 15-35 years.
  • Lymphatic and vascular invasion are associated with a higher rate of relapse and predict occult nodal metastases.

Staging:

• Stage I - Limited to the testis, epididymis, and spermatic cord

• Stage II - Limited to retroperitoneal lymph nodes

• Stage IIA - Nodes less than 2 cm in maximal diameter

• Stage IIB - Nodes 2-5 cm in diameter

• Stage IIC - Nodes greater than 5 cm in diameter

• Stage III - Metastatic to supradiaphragmatic nodal or visceral sites

TREATMENT

Medical Care:

• Management of clinical stage I disease

  　

  • Seminoma: Surgical care of seminomas consists of inguinal orchiectomy. Adjuvant radiotherapy to paraaortic and ipsilateral pelvic lymph nodes is the treatment of choice. Recent studies have shown that about 15% of patients with clinical stage I disease have occult retroperitoneal disease.

    　

  • Nonseminoma: Surgical care consists of inguinal orchiectomy alone and is curative in 60-80% of patients. Retroperitoneal lymph node dissection (RPLND) has diagnostic as well as therapeutic utility. Occult metastases can be found in about 30% of patients with clinical stage I disease and are classified as pathological stage IIA. RPLND is accomplished through a thoracoabdominal approach.

    Nerve-sparing surgical technique can preserve ejaculatory capacity. Some patients choose surveillance over RPLND, with chemotherapy used at the time of recurrence. Patient compliance is absolutely vital for a surveillance strategy. A physical examination, chest x-ray, and determinations of AFP and beta-HCG levels are required at monthly intervals in the first year, every other month for the second year, every 3 months in the third year, and less frequently thereafter. An abdominal CT scan is required every 3 months in the first year, every 4 months in the second year, and every 6 months in the third year. Office visits and evaluations should be annual in the fifth year and later.

• Management of clinical stage II disease

• Seminoma (low tumor burden): The cure rate is 85-95%. This figure includes patients with retroperitoneal metastases that measure less than 5 cm in maximum transverse diameter. Radiation treatment is the treatment of choice for most patients with stage II disease, with a relapse rate of less than 5%. Patients with horseshoe kidney or inflammatory bowel disease should not receive radiation. In these situations, a discussion with an experienced radiation oncologist is indicated. Primary chemotherapy is the treatment of choice if a decision is made not to administer radiation treatment. Chemotherapeutic agents used are bleomycin, etoposide, and cisplatin (BEP).

  　

• NSGCTs(low tumor burden): RPLND is a standard surgical therapeutic approach in patients with clinical stage IIA and stage IIB disease and with normal tumor markers. If patients with stage IIA and stage II B disease have elevated serum tumor markers, then systemic disease is present and should be treated with cisplatin-containing chemotherapy regimens. Two cycles of cisplatin-containing adjuvant chemotherapy is recommended if (1) more than 6 lymph nodes were involved, (2) any of the nodes are larger than 2 cm, or (3) extranodal extension is present. Observation is a treatment choice for patients with fewer than6 lymph nodes involved and none greater than 2 cm. However, close monitoring is required. At the time of relapse, 3-4 cycles of cisplatin-based therapy are administered.

• Management of clinical stage II and III

• Seminoma (high tumor burden): This includes all patients with extensive, bulky, retroperitoneal, visceral metastases or supradiaphragmatic nodal disease, including patients with stage IIC seminomas. Cisplatin-based systemic chemotherapy cures 70-80% of these patients.

  　

  • Good prognosis GCTs: These patients have a high likelihood of cure, and response ranges from 88-95%. Treatment regimens are 4 cycles of etoposide and cisplatin or 3 cycles of BEP.

    　

  • Poor risk GCTs: In patients at intermediate risk, the response rate is 75%, and in patients considered poor risks, the response rate is about 40%. Treatment consists of 4 cycles of BEP.

  　

• NSGCTs: Radiation is used in patients with metastatic NSGCT to the brain. Postchemotherapy resection is performed on patients with persistent radiographic abnormality with normal serum tumor markers 4-6 weeks following chemotherapy. If there is evidence of persistence carcinoma, then 2 additional cycles of chemotherapy are indicated. Residual intrathoracic disease should be resected as well as all sites of residual disease.

• Management of relapse after chemotherapy: About 20-30% of patients have a relapse or do not achieve a complete response to cisplatin-based chemotherapy. Treatment regimens for first-time salvage therapy consist of ifosfamide, mesna, and cisplatin plus either vinblastine or etoposide. The response rate for salvage chemotherapy is 25-35%.

MEDICATION

The goals of pharmacotherapy are to induce remission, reduce morbidity, and prevent complications.
　

Drug Category: Antineoplastic agents -- Cancer chemotherapy is based on an understanding of tumor cell growth and of how drugs affect this growth. After cells divide, they enter a period of growth (phase G1), followed by DNA synthesis (phase S). The next phase is a premitotic phase (G2), and the final phase involves mitotic cell division (phase M).

The cell division rate varies for different tumors. The majority of common cancers increase very slowly in size compared to normal tissues, and the rate may decrease further in large tumors. This difference allows normal cells to recover more quickly from chemotherapy than malignant ones and is the rationale for current cyclic dosage schedules. Dosage cycles are determined by cancer stage and tolerance of adverse effects.

Antineoplastic agents interfere with cell reproduction. Some agents are cell-cycle specific, while others (eg, alkylating agents, anthracyclines, cisplatin) are not. Cellular apoptosis (programmed cell death) is also a potential mechanism of many antineoplastic agents.

Drug Category: Uroprotective antidote -- Mesna is a prophylactic detoxifying agent used to inhibit hemorrhagic cystitis caused by ifosfamide and cyclophosphamide. In the kidney, mesna disulfide is reduced to free mesna. Free mesna has thiol groups that react with acrolein, the ifosfamide and cyclophosphamide metabolite considered responsible for urotoxicity.

FOLLOW-UP

Further Outpatient Care:
　

• Observation

• Patients with clinical stage I NSGCT who prefer surveillance instead of RPLND should have a physical examination, chest x-ray, and measurement of AFP and HCG levels on a monthly basis for the first year, every 2 months in the second year, every 3 months in the third year, and less often subsequently.

• An abdominal CT scan is required every 3 months in the first year, every 4 months in the second year, and every 6 months in the third year.

• Office visits and evaluations should be every year in the fifth year and beyond.

• For patients with clinical stage I, IIA and IIB seminoma, and for clinical stage I NSCGT after RPLND without adjuvant chemotherapy

• After radiation therapy, perform a chest x-ray, determine AFP and HCG levels, and perform a physical examination every 6-12 weeks in the first year, every 3-4 months in the second year, and less often thereafter.

• An abdominal CT scan should be performed at the conclusion of radiation therapy.

• Following RPLND, a chest x-ray, AFP and HCG tumor markers, and a physical examination are required every 4-8 weeks in the first year, every 8-12 weeks in the second year, and less frequently in the third year and beyond, with yearly visits to detect late relapse and second primary tumors after the fifth year.

Complications:
　

• Secondary malignancies

• Metachronous GCT appears in the contralateral testis in 2-3% of patients.

• Etoposide causes secondary leukemia after a latent period of 2-4 years in 0.8-1.3% of patients.

• GI malignancies can occur secondary to radiation therapy, chemotherapy, or both. Relative risk increases with time and is greater after 10 years. Stomach cancer is of the most concern.

• Soft tissue sarcoma, melanoma, and genitourinary cancers also can occur.

• Chemotherapy related toxicities

• Acute

  　

  • Nausea and vomiting may occur. Postcisplatin delayed emesis is treated by oral administration for 2-4 days of metoclopramide, benzodiazepine, and dexamethasone.
  • A certain degree of cisplatin-related nephrotoxicity is almost always present and is cumulative. Hypomagnesemia is common.

• Subacute

  　

  • Toxicities related to vinblastine are arthralgias, myalgias, peripheral neuropathy, and paralytic ileus. Auditory toxicity with reduced high-tone hearing may be seen after cisplatin. Hearing aids are rarely required.
  • Neutropenic fever and severe thrombocytopenia are relatively uncommon with etoposide and cisplatin (EP) as first-line chemotherapy. The addition of bleomycin and salvage chemotherapy results in significant increase of these complications (50%), requiring the prophylactic use of hematopoietic growth factors after the first episode of neutropenic fever.
  • Pulmonary toxicity from bleomycin is unpredictable and rare (10% of treated patients) and dose- and age-dependent (higher in patients >70 y and after a cumulative dose >1200 IU or 400 mg). The progression to pulmonary fibrosis is uncommon and occasionally fatal (1%). Although carbon monoxide diffusing capacity may not predict clinically significant lung damage, its use was recommended along with chest x-ray as a screening test in patients treated with bleomycin. If radiographic changes or a decrease of diffusing capacity of lung for carbon monoxide (DLCO) greater than 30% are detected, discontinue the drug.

    　

  • Raynaud phenomenon and, to a lesser degree, stroke and myocardial infarction were reported after use of bleomycin.
  • Accelerated coronary artery disease is a well-recognized complication of mediastinal radiotherapy.
  • Infertility is seen in as many as 50% of patients after chemotherapy. Standard bilateral RPLND almost always is associated with retrograde ejaculation. Nerve-dissecting, nerve-avoiding, and posterior approaches decrease, but do not abolish, this complication.
  • The frequency of etoposide-related secondary leukemia is dose-dependent. It is seen in less than 0.5% of patients who receive a total dose less than 2000 mg/m² and in about 6% of those who receive more than 3000 mg/m². Abnormalities of band 11q23 are very common in this setting. The latency period varies from 2-4 years. The incidence of gastrointestinal malignancies, especially gastric cancers and soft tissue sarcomas, is increased slightly after combined radiation and chemotherapy. The latency period is about 10 years or more.

    　

  • A high rate of thromboembolic events (8.4%) is seen during chemotherapy in patients with GCTs. Liver metastases and high-dose corticosteroids were identified as risk factors for these complications.

Prognosis:
　

• GCT risk classification, international consensus: The management of GCTs is determined by the clinical stage, size, serum-marker elevation, and histologic features.

• Seminoma
  • Good prognosis - No nonpulmonary visceral metastases
  • Intermediate prognosis - Nonpulmonary visceral metastasis present

• Nonseminoma
  • Good prognosis (all of the following): (1) AFP less than 1000 ng/ mL, (2) HCG less than 5000 IU/L, (3) LDH less than 1.5 X upper limit of normal, (4) no nonmediastinal primary, and (5) nonpulmonary visceral metastasis
  • Intermediate prognosis (all of the following): (1) AFP = 1000-10,000 mg/mL, (2) HCG = 5000-50,000 IU/L, or LDH = 1.5-10 X normal limit, (3) nonmediastinal primary site, (4) no nonpulmonary visceral metastasis
  • Poor prognosis (any of the following) (1) AFP higher than 10,000 mg/mL (2) HCG >50,000 IU/L, or LDH 10 X normal limit (3) Mediastinal primary site (4) Nonpulmonary visceral metastasis present