Brett S. Carver, MD
BASICS
DESCRIPTION
• Choriocarcinoma is a type of germ cell tumor (GCT) composed of syncytiotrophoblastic, cytotrophoblastic, and other trophoblastic cells.
• Histologic cell type for nonseminomatous GCTs.
• Pure choriocarcinomas are commonly associated with metastatic disease and high levels of β-hCG at the time of presentation
EPIDEMIOLOGY
Incidence
• It is projected that in US, 8,820 new cases of testicular cancer would be diagnosed and 380 men would die of this disease in 2014.
• Pure choriocarcinoma compromises <1% of testicular GCT.
• Choriocarcinoma is a histologic cell type in ∼10% of nonseminomas.
Prevalence
N/A
RISK FACTORS
• Risk factors associated with the development of testicular cancer include:
– Cryptorchidism, family history, testicular atrophy, infertility.
Genetics
Identification of isochromosome 12p amplification.
PATHOPHYSIOLOGY
• Choriocarcinoma is a histologic subtype of nonseminomatous GCTs composed primarily of syncytiotrophoblasts and cytotrophoblasts.
• Syncytiotrophoblastic cells produce human chorionic gonadotropin (HCG) which may be detected by immunohistochemistry or measurement of serum levels.
• Pure choriocarcinoma is associated with significantly elevated levels of serum HCG. Choriocarcinoma represents a germ cell transformed through extraembryonic differentiation.
• Relationship between size of primary tumor and metastatic disease may seem paradoxical, with widespread disease associated with a relatively small primary tumor.
• Route of metastatic spread is variable compared to other GCTs, which are often stepwise and predictable. Choriocarcinoma is associated with a greater propensity for hematogenous dissemination.
• β-hCG is produced by syncytiotrophoblasts and is elevated in 100% of choriocarcinomas. The serum half-life of β-hCG is 24–36 hr.
– Elevated serum levels of β-hCG are also noted in 40–60% of embryonal carcinomas and 5–10% of pure seminomas.
ASSOCIATED CONDITIONS
• Infertility
• Cryptorchidism
• Gynecomastia
GENERAL PREVENTION
Conflicting data if early orchiopexy reduces testis cancer risk in cryptorchidism
DIAGNOSIS
HISTORY
• Past medical history focusing on history of cryptorchidism
• The most common symptom at the time of diagnosis is painless swelling or enlargement of the testis.
– Acute testicular pain is reported to occur in ∼10% of patients with testicular cancer and often represents infarction or hemorrhage within the tumor.
• At initial presentation, symptoms manifesting secondary to metastatic disease occur in ∼20% of patients and include, a mass in the left neck, pulmonary complaints such as hemoptysis or dyspnea, an abdominal mass, or back pain that can often be disabling.
– Patients with choriocarcinoma may present with gynecomastia or tenderness of the breast secondary to elevated serum HCG.
• Neurologic symptoms related to brain metastases may be present in patients with advanced pure choriocarcinoma.
PHYSICAL EXAM
• The most common finding on physical exam is a solid intratesticular mass or swelling.
• Thorough exam of both gonads
– Careful palpation of surrounding spermatic cord structures on involved side to evaluate extent of disease
– Transillumination of scrotal contents if hydrocele is associated or suspected.
• Exam for metastatic disease including inguinal, abdominal, thoracic, neurologic exams.
– Cervical lymph nodes (lymphadenopathy), breasts (gynecomastia), abdomen (retroperitoneal masses/lymphadenopathy, liver masses)
• Gynecomastia can be noted in ∼5% of patients with GCT:
– β-hCG can stimulate estrogen production from Leydig cells, leading to breast enlargement and tenderness, and the contralateral testis (bilateral testicular tumors).
DIAGNOSTIC TESTS & INTERPRETATION
Lab
• Serum tumor markers (AFP, HCG, LDH) should be obtained prior to and following radical orchiectomy. The serum tumor markers are necessary for diagnosis, staging, and risk classification. While normal postorchiectomy serum tumor markers does not preclude the finding of metastatic disease, an elevation of either AFP or HCG does signify the presence of metastasis.
• Pure choriocarcinomas are often associated with significantly high levels of serum HCG.
Imaging
• Testicular ultrasonography is the initial imaging modality of choice with a >95% sensitivity and specificity in identifying intratesticular lesions.
• Testicular ultrasonography often reveals a solid hypoechoic mass present within the testis.
• The initial staging evaluation should include a CT scan of the chest, abdomen, and pelvis. CT is the most effective radiographic technique for identifying metastatic disease both above and below the diaphragm.
• MRI of the brain should be performed to evaluate for metastases in patients with pure choriocarcinoma.
Diagnostic Procedures/Surgery
A radical orchiectomy with high ligation of the spermatic cord at the level of the inguinal ring provides histopathologic diagnosis, primary tumor staging, and excellent local control of the tumor, with minimal morbidity and no mortality.
Pathologic Findings
• Choriocarcinoma may be associated with other nonseminomatous germ cell histologies, as well as seminomatous histologies.
• Histology revealing syncytiotrophoblasts and cytotrophoblasts.
– Macroscopically, tumors are often hemorrhagic with areas of necrosis, and can be associated with areas of fibrosis and tumor regression. Hemorrhage is usually central with viable tumor located peripherally.
• Mix of mononuclear cells with lightly staining cytoplasm (cytotrophoblasts) combined with multinucleated cells with smudged/degenerating nuclei and densely eosinophilic cytoplasm (syncytiotrophoblasts)
• Multiple fields need to be examined to clearly identify the cytotrophoblasts. Syncytiotrophoblasts stain strongly with HCG
• Pathologic and clinical staging follows the TNM classification and risk assessment if performed using the IGCCCG risk classification.
DIFFERENTIAL DIAGNOSIS
• These are a delineation of testicular masses only. For a complete listing of intrascrotal and testicular masses see Section I: “Scrotum and Testicle Mass”:
• Benign lesions
– Epididymitis/orchitis: Bacterial, STD, mumps, TB
Often delayed testicular cancer diagnosis due to treatment of presumed epididymitis
– Testicular trauma: Usually blunt; contusion, rupture; usually associated hematocele
– Torsion (testicle or appendages)
– Incarcerated/strangulated hernia
– Cysts (simple, tunica albuginea, epidermoid)
– Adrenal rest tumors: In general benign, but can contribute to infertility in patients with congenital adrenal hyperplasia
– Fibrous pseudotumor of the tunica albuginea: Painless fibrous mass often associated with prior history of trauma or infection
– Adenomatoid tumor of testis or epididymis
– Other rare benign lesions: Angioma, fibroma, leiomyoma, hamartoma, carcinoid, neurofibroma
• Malignant lesions
– Testicular primary tumors (seminoma and nonseminomatous GCT, stromal and mixed as discussed above)
– Leukemia involving testis—testis can be a site of solitary recurrence of leukemia posttreatment (sanctuary site). Biopsy can be utilized to confirm diagnosis in a patient with history of leukemia.
Treatment can be testis-sparing with radiation, though contralateral testis should be treated as bilateral disease can be present.
– Lymphoma involving testis—usually represents extension from extratesticular sites, rarely can represent a primary lymphoma site (1% of lymphoma cases); can present bilaterally one-third of the time; mostly involves older men >60 yr; constitutional symptoms commonly present (fever, chills, night sweats, weight loss).
– Metastatic solid tumors: More common—prostate, lung, GI tract; more rare—kidney, malignant melanoma, pancreas, bladder, and thyroid
– Adenocarcinoma of the rete testis: Arises in the testis collecting system, high-stage presentation, poor response to chemotherapy and radiation, with median survival of 1 yr.
– Mesothelioma of tunica vaginalis: Rare, similar to the more common pleural histology, associated with asbestos exposure
– Paratesticular sarcomas: Rhabdomyosarcoma, malignant fibrous histiocytoma (most common soft tissue sarcoma in late adult life)
TREATMENT
GENERAL MEASURES (1)
• Inguinal radical orchiectomy with high ligation of the spermatic cord is diagnostic and therapeutic.
• Treatment options are based on clinical staging. Staging following removal of the primary tumor is similar to all GCT and is based on physical exam, radiographic studies, serum tumor markers, and histologic tumor features according the TNMS staging system.
MEDICATION
First Line (2)
• Regardless of histology, patients with advanced GCTs (cIIB–cIII) and those with persistently elevated tumor markers following radical orchiectomy (cIS), are initially treated with platinum-based chemotherapy according to the International Germ Cell Cancer Collaborative Group (IGCCCG) risk stratification.
– Patients with good-risk disease are treated with 3 cycles of bleomycin, etoposide, and cisplatin (BEP) or 4 cycles of etoposide and cisplatin (EP).
– While patients with intermediate-risk or high-risk disease receive 4 cycles of BEP.
• Choriocarcinomas are often associated with hemorrhage, neurologic and pulmonary monitoring is critical following chemotherapy.
Second Line
Second-line chemotherapy is reserved for patients with advanced testicular cancer in whom serum tumor markers do not normalize following initial chemotherapy regimen.
SURGERY/OTHER PROCEDURES
• Radical orchiectomy should be performed for diagnosis and treatment of the primary tumor.
• In US, the preferred management for patients at high risk for relapse in the retroperitoneum, ie, predominant embryonal carcinoma, lymphovascular invasion, or extension into the tunica or scrotum, is primary RPLND if serum tumor markers have normalized.
• Postchemotherapy RPLND (PC-RPLND) and resection of residual masses are an integral component in the management of advanced nonseminoma.
ADDITIONAL TREATMENT
Radiation Therapy
Occasionally radiation therapy for cerebral metastases is utilized, but systemic therapy remains the initial treatment of choice for the management of metastatic disease including cerebral metastasis.
Additional Therapies
N/A
Complementary & Alternative Therapies
N/A
ONGOING CARE
PROGNOSIS
• The multidisciplinary approach to the management of GCTs of the testis has resulted in survival rates of >90% overall.
• The prognosis for patients with testicular cancer including choriocarcinoma depends on stage, risk stratification, and histology.
• Prognosis for patients with metastatic disease estimated using the IGCCC system for NSGCT:
– Good prognosis: Testis or retroperitoneal primary, no nonpulmonary visceral metastases, AFP <1,000, β-hCG <5,000, and LDH <1.5 for upper limit of normal (ULN)
– Intermediate prognosis: Testis or retroperitoneal primary, no nonpulmonary visceral metastases, AFP 1,000–10,000, β-hCG 5,000–50,000, or LDH 1.5–10 ULN
– Poor prognosis: Mediastinal primary, nonpulmonary visceral metastases, AFP >10,000, β-hCG >50,000, or LDH >10 ULN
COMPLICATIONS
• The complications of radical orchiectomy include: Wound infection, scrotal hematoma, and retroperitoneal hematoma.
• Complications of RPLND: Wound infection, pancreatitis, venous thrombosis, chylous ascites, anejaculation, and small-bowel obstruction.
• Complications of chemotherapy: Neutropenia, gastrointestinal symptoms, alopecia, pulmonary fibrosis, and cardiovascular events; propensity for choriocarcinomas to hemorrhage
FOLLOW-UP
Patient Monitoring
Following management of GCTs, patients should be followed with history and physical exam, serum tumor markers, chest x-ray, and periodic CT imaging of the chest, abdomen, and pelvis for life. Follow-up protocols should be followed according to guidelines established by the National Comprehensive Cancer Network.
Patient Resources
American Cancer Society: http://www.cancer.org/cancer/testicularcancer/index
REFERENCES
1. Bosl G, Bajorin D, Sheinfeld J, et al. Cancer of the testis. In: DeVita VT, Hellman S, Rosenberg SA, eds. Cancer: Principles and Practice of Oncology. Philadelphia: PA, JB Lippincott; 2000:1491–1518.
2. Carver BS, Sheinfeld J. Germ cell tumors of the testis. Ann Surg Oncol. 2005;12(11):871–880.
ADDITIONAL READING
NCCN Guidelines for the Treatment of Testis Cancer (www.nccn.org)
See Also (Topic, Algorithm, Media)
• International Germ Cell Cancer Collaborative Group (IGCCCG)
• Reference Tables: TNM: Testis Cancer
• Testis Cancer, Adult General Considerations
• Testis Cancer, Choriocarcinoma Image 
• Testis Cancer, Nonseminomatous Germ Cell Tumors, General
• Testis Cancer, Pediatric, General Considerations
CODES
ICD9
• 186.9 Malignant neoplasm of other and unspecified testis
• 608.3 Atrophy of testis
• 752.51 Undescended testis
ICD10
• C62.90 Malig neoplasm of unsp testis, unsp descended or undescended
• N50.0 Atrophy of testis
• Q53.9 Undescended testicle, unspecified
CLINICAL/SURGICAL PEARLS
• All intratesticular masses should be assumed to be testicular cancer until proven otherwise.
• Choriocarcinomas are associated with production of HCG.
• Choriocarcinomas have a predilection for brain metastases.
• Inguinal radical orchiectomy with high ligation of the spermatic cord is the initial treatment.