Testicular Choriocarcinoma

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Practice Essentials

Testicular choriocarcinoma is one of the histologic types of nonseminomatous germ cell tumors (NSGCTs), which along with testicular seminoma constitute the two major histologic groups of testicular cancers. Pure choriocarcinoma of the testis is the exception to most of the rules established for testicular seminoma and all other forms of NSGCTs.

Like other germ cell tumors (GCTs), choriocarcinoma typically affects younger men. Unlike other such cancers, choriocarcinoma metastasizes hematogenously, with the testicular primary tumor often small or even "burned-out." In most reports, the tumor responds poorly to radiation and chemotherapy and carries a high mortality rate. Surgery is usually limited to radical orchiectomy for tissue diagnosis.[1]  Chemotherapy for disseminated disease is principally with cisplatin-based regimens, particularly combination chemotherapy with bleomycin, etoposide, and cisplatin.[2]  

For patient education information, see Men's Health, as well as Testicular Cancer and Testicular Self-Exam.

Pathophysiology and Etiology

Choriocarcinoma recapitulates placental tissue development. For unknown reasons, it metastasizes early via hematogenous routes to the lung, liver, and brain, among others.[1, 3]

Patients with a history of cryptorchidism are at a greatly increased risk of testis cancer (by a factor of 10-40 times). Abdominal undescended testis is associated with a greater risk than the inguinal form. An abdominal testis cancer is more likely to be seminoma, while cancer in a testis that was surgically brought to the scrotum via orchiopexy is more likely to be an NSGCT. Orchiopexy allows for earlier detection by physical examination but does not alter the risk of GCT. Ten percent of patients with a GCT have a history of cryptorchidism. In a series of 125 patients with a history or clinical evidence of cryptorchidism and testis tumor, 3 (2%) were pure choriocarcinoma, which is similar to the overall incidence of choriocarcinoma among GCTs.[4]

Genetic changes in the form of amplifications and deletions are observed predominantly in the 12p11.2-p12.1 chromosomal region. Gain of 12p sequences is associated with invasive growth of seminomas and nonseminomas. In contrast, spermatocytic seminoma shows a gain of chromosome 9, and most infantile yolk sac tumors and teratomas show no chromosomal changes.[5]

Other risks include the following:

Epidemiology

United States

Testicular GCTs are rare, representing only 1%-2% of all malignancies in males and occurring in 1 of 250 men by age 65 years. However, these tumors represent the most common malignancy in males aged 15-35 years. The incidence rates are 3.7 cases and 0.9 cases per 100,000 per year in white males and black males, respectively. Subtypes and frequencies of GCTs include the following:

International

The incidence of testis cancer increased worldwide from the early 1960s to the mid 1980s. The malignancy is more common in whites than in nonwhites. The highest rates are in Denmark (8.4 cases per 100,000 per y) and Switzerland (6.2-8.8 cases per 100,000 per y), and the frequency varies across Europe. In a histologic review of 1010 orchiectomies from 1999 to 2011 from a single Mexican oncology institution, 0.6% were pure choriocarcinomas and 0.9% were mixed germ cell tumors with a predominant choriocarcinoma component.[6]

Age

In a literature review of 10,000 cases of germinal testicular cell tumors, Ramon y Cajal et al found 54 (0.5%) cases of pure choriocarcinoma. Most patients were aged 20-30 years; the oldest patient with a pure choriocarcinoma was 63 years old.[7]  The patient died of aspiration shortly after initiation of chemotherapy, so a determination of treatment efficacy in this age group was impossible. In a 2008 review of GCTs in 50 men older than 60 years, only one was found to have a component of choriocarcinoma.[8]

Prognosis

In most reports, choriocarcinoma carries a dismal prognosis due to its early hematogenous spread. 

Batata et al (1980) reported a 5-year survival rate of 0% (0 of 20 patients)[9]

Requena et al (1991) reported a case of pure choriocarcinoma with metastases to the skin (rare), lung, and brain; this patient was treated with a 4000-rad dose to the skull and a multi-agent chemotherapy regimen, including platinum, vinblastine, and bleomycin (PVB) and lomustine, VP-16, and VePesid; the patient's beta-hCG level normalized, and he was disease-free at 2 years[10]

Lepidini et al (1997) reported a patient treated with multi-agent chemotherapy who was disease-free at 43 months of follow-up[11]

In five cases of pure choriocarcinoma with brain metastases, all patients died, and median survival was 1 month despite treatment with multi-agent chemotherapy[12]

In a 9-year review of patients treated in multi-agent chemotherapy trials at Memorial Sloan-Kettering Cancer Center, Bosl et al (1983) reported five cases of pure choriocarcinoma and two long-term survivors[13]

A review of survival after a diagnosis of testicular germ cell cancers in Germany and the United States from 2002-2006 found that 5-year relative survival was lowest with choriocarcinomas: 80.1% in Germany and 79.6% in the US; this compared with survival rates of 93.3% and 91.0% with nonseminomas generally[14]

A review by Alvarado-Cabrero et al (2014) found that of six patients with pure testicular choriocarcinoma, all died of their disease after a median of 9.5 months; of eight patients with predominant choriocarcinoma, five died of the disease after a median of 27 months, one was alive with disease, and two were alive with no evidence of disease at 60 and 72 months of follow-up, respectively; the latter two patients were the only ones with M1a disease on presentation[6]

History

Unlike classic seminoma or mixed germ cell tumors (GCTs), pure choriocarcinoma of the testis is less likely to produce localized findings and more likely to manifest with signs and symptoms of metastatic disease—in particular, brain metastases. In male patients with metastatic foci from an unknown primary, the possibility of testicular choriocarcinoma should be kept in the differential diagnosis.[15]

The most frequent sites of metastases are lung, liver, brain, gastrointestinal tract, spleen, and adrenal glands. Although rare, cutaneous metastasis of testicular choriocarcinomas have been reported as angiomas, pyogenic granulomalike tumors, hemorrhagic nodules, or nontender subcutaneous nodules. In one report, the initial presentation of pure testicular choriocarcinoma was a hemorrhagic nodule on the lip, and the diagnosis was made only after histologic examination.[16]

The local tumor itself may be small and may not cause symptoms.

Choriocarcinoma syndrome is a rare complication that occurs in patients with metastatic choriocarcinoma and markedly elevated levels of beta–human chorionic gonadotropin (beta-hCG).[17, 18]  The syndrome most often develops shortly after the initiation of chemotherapy, but cases of choriocarcinoma syndrome as the initial presentation of testicular cancer have been reported.[19] The syndrome is characterized by hemorrhage from metastases and is characterized by acute hemorrhage from metastates. Any site may be involved but bleeding from lung metastases is typical; patients may present with dry cough or hemoptysis, which may progress to acute respiratory failure. The syndrome is life-threatening and requires immediate treatment.[20, 21]

 

 

 

Physical Examination

The local tumor in choriocarcinoma may be small or nonpalpable, whereas most testicular GCTs cause scrotal swelling and a palpable mass. Testicular pain, with or without radiating pain to the groin and abdomen, is possible but is more consistent with epididymitis.

Widely metastatic testicular GCTs, including choriocarcinoma, may also manifest as a "burned-out" local testis lesion that consists of fibrous scar with absent or minute amounts of viable tumor.

Physical examination findings from lung, liver, and/or brain metastases may be more pronounced than an abnormal finding on testicular examination.

Laboratory Studies

The workup for testicular choriocarcinoma should include assays of the following:

AFP is secreted by yolk sac elements; elevated levels of AFP are consistent with nonseminomatous germ cell tumors (NSGCTs). Choriocarcinoma could be a component of such a tumor, but AFP is within the reference range in pure choriocarcinoma. AFP has a serum half-life of between 5 and 7 days.

Human chorionic gonadotropin is a glycoprotein with the same alpha unit as thyroid-stimulating hormone (TSH), follicle-stimulating hormone (FSH), and luteinizing hormone (LH). Therefore, the beta subunit must be assayed. Beta-hCG has a 24- to 36-hour half-life and is secreted by syncytiotrophoblast cells within the tumor. Beta-hCG levels are usually markedly elevated in pure choriocarcinoma. Persistently elevation of beta-hCG levels is defined as continued elevation of the tumor marker above the predicted levels based on serum half-life of 24-36 hours.[22] This can also be applied to AFP, in which levels above that expected for the zero order kinetics of a 5- to 7-day expected half-life represent persistent elevation. From a clinical perspective, persistent tumor marker elevation represents residual disease. As such, more advanced treatment modalities (eg, chemotherapeutic) may be required.

The liver enzyme profile should include lactate dehydrogenase (LDH). Elevated levels of LDH may indicate bulky or advanced disease; however, the sensitivity and specificity are limited compared with beta-hCG and AFP. Rising levels after treatment may indicate relapse. Elevation of the remaining liver function tests may correlate with metastatic liver disease.

Placental alkaline phosphatase (PLAP) levels are elevated in some patients with seminoma and advanced disease; however, smoking and several other tumors also cause elevations. Therefore, this marker not commonly used.

Research has identified a number of molecular biomarkers for testicular germ cell tumors, including microRNAs. In addition to diagnosis, these hold the potential for use in treatment selection and establishing prognosis.[23, 24]

Imaging Studies

Scrotal ultrasonography

Any male with a palpable testicular mass should undergo scrotal ultrasonography. Other indications for ultrasonography may include acute scrotal pain, hydrocele, or other nonspecific scrotal pain, swelling, or mass.

Choriocarcinoma is associated with hemorrhage and necrosis and may appear more cystic, inhomogeneous, and calcified than a seminoma.[25]

Abdominal CT scanning of the abdomen and pelvis with intravenous and oral contrast

In all other forms of testis GCT, CT scanning can be used to most commonly identify metastatic disease to the retroperitoneal lymph nodes, and it understages approximately 15%-20% of patients thought to have stage I.

In patients with pure choriocarcinoma, metastatic disease via hematogenous routes may skip the retroperitoneal lymphatics.

CT scanning of the brain

Choriocarcinoma is associated with brain metastases. In a review of 242 patients with metastatic germ cell testis cancer undergoing treatment with a multi-agent chemotherapy protocol, Vugrin et al (1979) found 38 cases of brain metastases.[12] Among patients with pure embryonal carcinomas, 13% had brain metastases, compared to 83% of patients with pure choriocarcinomas. Furthermore, choriocarcinomas tended to have multiple brain metastatic sites with cerebellar involvement.

In almost all cases, pulmonary metastases preceded or coincided with brain metastases.

Chest radiography/chest CT scanning

Chest CT scan is indicated only for an abnormal finding on chest radiography; however, choriocarcinoma has a high metastatic rate, and CT scanning of the chest is usually indicated.

Bone scan

In an autopsy study by Bredael et al (1982), GCTs had bony metastases at autopsy, including seminoma (56%), mixed choriocarcinoma (35%), teratocarcinoma (30%), and embryonal carcinoma (24%); however, 0 of 6 cases of pure choriocarcinoma metastasized to the bone.[26]

In pure choriocarcinoma, a bone scan can probably be omitted in the absence of bone pain.

Histologic Findings

Gross findings include a small hemorrhagic nodule with some grayish-white viable tumor at the periphery. Histology shows that choriocarcinoma contains both syncytiotrophoblastic cells and cytotrophoblastic cells in intimate association (see image below).



View Image

Testicular choriocarcinoma has multinucleated syncytiotrophoblastic cells that drape over smaller cytotrophoblastic cells, which together appear to fo....

Syncytiotrophoblastic cells are responsible for beta-HCG production.

Staging

American Joint Committee on Cancer and the International Union Against Cancer staging systems are described below.[27]  

Primary tumor (T)

Pathologic

Regional lymph nodes (N)

Clinical

Pathologic

Distant metastases (M)

Distant metastases

Table 1. Serum Tumor Markers (S)



View Table

See Table

Table 2. Stage Grouping



View Table

See Table

Approach Considerations

The treatment of choriocarcinoma includes orchidectomy, chemotherapy, and retroperitoneal lymph node dissection.[15]  As most cases of choriocarcinoma have poor risk features, primary chemotherapy is followed by radiographic reassessment and staging. Most radical orchiectomies are performed in the same day or in 23-hour observation settings. This surgery is comparable to an inguinal herniorrhaphy, and the patient can expect limited physical activity for a brief period following surgery. Following orchiectomy, a short course of pain management medication may be required.

High-dose chemotherapy with autologous stem cell rescue has been used in patients with incomplete responses to initial therapy.[28] A multimodal approach involving the urologist and hematologist/oncologist is essential in the treatment of advanced nonseminomatous germ cell tumors.

 

Medical Care

Metastatic nonseminomatous germ cell tumors (NSGCTs) are highly sensitive to cisplatin-based chemotherapy, with cure rates of approximately 80% for advanced disease and nearly 100% for early-stage disease. Furthermore, numerous randomized clinical trials conducted for NSGCT have identified effective chemotherapy regimens that reduce toxicity. Risk-adapted protocols are also available to tailor treatment regimens for patients with good, moderate, or poor risk factors.

Standard chemotherapy for good-to-poor–risk NSGCT is with bleomycin, etoposide, and cisplatin (BEP) for four cycles. Alternative regimens include etoposide and cisplatin (EP) for four cycles only for patients with good risk disease; etoposide, mesna, ifosfamide, and cisplatin (VIP) for four cycles for intermediate and poor risk disease.[29]

Pure choriocarcinoma, an extremely rare variant comprising less than 1% of NSGCT cases, is not as sensitive to chemotherapy as mixed NSGCT. The authors' exhaustive search of major textbooks and the literature revealed no clear guidelines as to how to treat these patients. Most case reports describe patients presenting with advanced metastatic disease, with varying responses to chemotherapy. In general, standard chemotherapy for poor-risk NSGCT is the initial therapy. However, these patients may require salvage regimens and may benefit from referral to a major cancer center to be treated under protocols that can involve cyclical regimens or dose escalation with growth factor/stem cell support. Cases responsive to chemotherapy may require additional surgical debulking.

 

Surgical Care

Radical inguinal orchiectomy

Preoperative details are as follows:

Intraoperative details are as follows:

Postoperative details are as follows:

Complications are rare but may include the following:

Consultations

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Complications

Choriocarcinoma syndrome, which was first described in 1984 by Logothetis et al, is a rare complication that typically occurs shortly after the initiation of chemotherapy in patients with metastatic germ cell tumors and a beta–human chorionic gonadotropin level over 50,000 IU/L. The syndrome results from the tendency of choriocarcinoma to invade small blood vessels and is characterized by acute hemorrhage from metastases. Any site may be involved but bleeding from lung metastases is typical and can result in acute respiratory failure. Early recognition and prompt therapy is critical as such cases have a high mortality rate.[17, 19]

Choriocarcinoma syndrome is most likely to occur in patients with pure choriocarcinoma who have widespread lung metastases and a high beta-hCG level. The optimal therapeutic approach in these patients remains uncertain, but evidence suggests that risk can be reduced by using either a reduced or shortened course of induction chemotherapy before the progressing to the full-dose chemotherapeutical regimen. In addition, the best treatment results in these “superhigh-risk” patients appear to be obtained in high-volume reference centers.[19]

 

 

Prevention

Prior to diagnosis, testicular self-examination on a monthly basis should begin at puberty.

Following diagnosis of testicular carcinoma, a mutual understanding between the patient and his treating physician in terms of strict adherence to follow-up regimens must be discussed. Early on, the follow-up regimens are frequent, as tumors can dramatically advance within short periods.

Medication Summary

Metastatic pure choriocarcinoma is treated with the same multi-agent chemotherapy regimens used in nonseminomatous germ cell tumors (NSGCTs), which are discussed in a separate article (see Nonseminomatous Testicular Tumors).

Standard chemotherapy for poor-risk patients and some good-to-moderate–risk patients includes 4 cycles of BEP (ie, bleomycin, etoposide, cisplatin). Additional agents in some regimens or for salvage include vinblastine and ifosfamide.

Most case reports show a poor response to chemotherapy, and the literature offers no clear treatment guidelines.[7, 18, 31, 10, 32]

Bleomycin (Blenoxane)

Clinical Context:  Composed of cytotoxic glycopeptide antibiotics, which appear to inhibit DNA synthesis, with some evidence of RNA and protein synthesis inhibition to a lesser degree. Used in the management of several neoplasms as a palliative measure; however, it is an important part of curative regimens for testicular cancer.

Etoposide (Toposar, VePesid)

Clinical Context:  Arrests cells in the G2 portion of the cell cycle and induces DNA strand breaks by interacting with DNA topoisomerase II and forming free radicals.

Cisplatin (Platinol, Platinol-AQ)

Clinical Context:  Inorganic metal complex thought to act analogously to alkylating agents. Kills cells in all stages of cell cycle and inhibits DNA biosynthesis.

Ifosfamide (Ifex)

Clinical Context:  Related to nitrogen mustards and a synthetic analog of cyclophosphamide.

Vinblastine (Alkaban-AQ, Velban)

Clinical Context:  Alkaloid derivative that causes depolymerization of microtubules important to the mitotic spindle and cytoskeleton.

Class Summary

These agents inhibit cell growth and proliferation.

Author

Michael B Williams, MD, MS, Assistant Professor, Department of Urology, Leroy T Canoles, Jr, Cancer Research Center, Eastern Virginia Medical School

Disclosure: Nothing to disclose.

Coauthor(s)

Paul F Schellhammer, MD, Professor of Urology, Eastern Virginia Medical School; Urologist, Urology of Virginia, PC

Disclosure: Nothing to disclose.

Specialty Editors

Francisco Talavera, PharmD, PhD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Received salary from Medscape for employment. for: Medscape.

Chief Editor

Bradley Fields Schwartz, DO, FACS, Professor of Urology, Director, Center for Laparoscopy and Endourology, Department of Surgery, Southern Illinois University School of Medicine

Disclosure: Serve(d) as a director, officer, partner, employee, advisor, consultant or trustee for: AUA Journal of Urology<br/>Serve(d) as a speaker or a member of a speakers bureau for: Cook Medical; Olympus, .

Additional Contributors

Leonard Gabriel Gomella, MD, FACS, The Bernard W Godwin Professor of Prostate Cancer Chairman, Department of Urology, Associate Director of Clinical Affairs, Kimmel Cancer Center, Jefferson Medical College of Thomas Jefferson University

Disclosure: Received consulting fee from GSK for consulting; Received honoraria from Astra Zeneca for speaking and teaching; Received consulting fee from Watson Pharmaceuticals for consulting.

Acknowledgements

John W Davis, MD Assistant Professor, Department of Urology, University of Texas MD Anderson Cancer Center

John W Davis, MD is a member of the following medical societies: American College of Surgeons and American Urological Association

Disclosure: Nothing to disclose.

Dan Theodorescu, MD, PhD Paul A Bunn Professor of Cancer Research, Professor of Surgery and Pharmacology, Director, University of Colorado Comprehensive Cancer Center

Dan Theodorescu, MD, PhD is a member of the following medical societies: American Cancer Society, American College of Surgeons, American Urological Association, Medical Society of Virginia, Society for Basic Urologic Research, and Society of Urologic Oncology

Disclosure: Key Genomics Ownership interest Co-Founder-50% Stock Ownership; KromaTiD, Inc Stock Options Board membership

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Testicular choriocarcinoma has multinucleated syncytiotrophoblastic cells that drape over smaller cytotrophoblastic cells, which together appear to form a border along a blood-filled villouslike space (upper right). Used with permission from Ernstoff MS, Heaney JA, and Peschel RE, eds. Testicular and Penile Cancer. Malden, Mass: Blackwell Science, Inc; 1998:20.

Testicular choriocarcinoma has multinucleated syncytiotrophoblastic cells that drape over smaller cytotrophoblastic cells, which together appear to form a border along a blood-filled villouslike space (upper right). Used with permission from Ernstoff MS, Heaney JA, and Peschel RE, eds. Testicular and Penile Cancer. Malden, Mass: Blackwell Science, Inc; 1998:20.

S LDH HCG (mIU/mL) AFP (ng/mL)
SxNot assessedNot assessedNot assessed
S0NormalandNormalandNormal
S1< 1.5 x Nand< 5000and< 1000
S21.5-10 x Nor5000-50,000or1000-10,000
S3>10 x Nor>50,000or>10,000
*N=upper limit of reference range for the LDH assay
Stage grouping T N M S
Stage 0pTisN0M0S0
Stage IpT1-T4N0M0Sx
Stage IApT1N0M0S0
Stage IBpT2-4N0M0S0
Stage ISAny pT/TXN0M0S1-S3
Stage IIAny pT/TXN1-3M0Sx
Stage IIAAny pT/TXN1M0S0-S1
Stage IIBAny pT/TXN2M0S0-S1
Stage IICAny pT/TXN3M0S0-S1
Stage IIIAny pT/TXAny NM1Sx
Stage IIIAAny pT/TXAny NM1aS0-S1
Stage IIIBAny pT/TXN1-3M0S2
Any pT/TXAny NM1aS2
Stage IIICAny pT/TXN1-3M0S3
Any pT/TXAny NM1aS3
Any pT/TXAny NM1bAny S