Nonseminomatous Testicular Tumors

Etiology

The risk factors for the development of testicular cancer are generally associated with testicular dysgenesis syndrome. The list of risk factors for testicular cancer includes cryptorchidism, hypospadias, decreased spermatogenesis evidenced by subfertility or infertility, a positive familial history of testicular tumors in first-degree relatives, childhood inguinal hernias, pediatric atrophic testis, germ cell neoplasia in situ (GCNIS), and a history of a contralateral testicular malignancy.[8][9] 

The single greatest risk factor is heredity, with the relative risk of finding testicular cancer 6 to 10 times higher in first-degree blood relatives (brothers and sons) of men with germ cell malignancies.[10][11][12] Studies in families and twins suggest that testicular cancers may be inheritable in up to about 50% of closely related relatives, making testicular germ cell tumors more likely to be inherited than breast, colorectal or ovarian cancers.[13]

Germ cell neoplasia in situ or GCNIS, formerly called intratubular germ cell neoplasia, is generally considered the primary premalignant precursor lesion for almost all testicular germ cell tumors (90%), except for spermatocytic seminomas, yolk sac tumors, and mature teratomas. About 50% of the patients known to have GCNIS will develop testicular cancer at some point during the next 5 years.[14]

GCNIS gets its origin from transformed primordial germ cells that develop in utero or early infancy, which lay dormant until puberty when stimulated by increased serum luteinizing hormone (LH) and/or testosterone levels.[15] The precise pathogenesis of GCNIS and testicular neoplasm is vaguely understood. The increasing incidence of testicular tumors and other male reproductive disorders (e.g., infertility, hypospadias) suggests that germ cell tumors arise from "testicular dysgenesis," which results from the mixture of environmental and lifestyle factors in combination with genetic susceptibility. Other risk factors include intersex individuals, androgen insensitivity syndromes, mixed gonadal dysgenesis, Klinefelter's syndrome, and Down syndrome. 

The clustering of germ cell tumors further supports genetic factors in some families, the extreme difference in the incidence of testicular cancers between black and white Americans, and the finding of susceptibility loci on chromosomes 5, 6, and 12.[16] Also, polymorphisms of certain genes (like gene encoding c-KIT ligand) are associated with a known increased risk of testicular cancer.[17]

There appears to be some good evidence for an association between testicular cancer and long-term marijuana use for more than 10 years.[18][19]

Estrogenic effects during pregnancy, such as from the use of diethylstilbestrol (DES) and increased levels of organochlorine pesticides (which bind estrogen receptors), have been proposed as possible etiological factors for testicular cancers. Still, studies looking at this connection are inconclusive.[20]

Testicular microlithiasis is more commonly found in men with germ cell cancers than in the general population, but the incidence of microlithiasis is almost 1000 times more common than gonadal malignancies.[21] This makes testicular microlithiasis essentially useless as a marker or screening tool for germ cell tumors.[22][23][24]

Epidemiology

Testicular cancer is the most common solid malignancy among young men. The incidence is highest among White race individuals, lowest among African-Americans, and most rapidly increasing in Hispanic populations.[25] The incidence in the White race is roughly 4 times higher than in African-Americans.[26] Age-adjusted incidence has nearly doubled over the last 4 decades, from 3.7 per 100,000 in 1975 to 6.4 per 100,000 in 2014. The reason for this significant increase is unknown but may represent a more toxic environment.  A stage migration of germ cell tumors has also been observed, presumably due to increased awareness and earlier diagnosis. Between 1973 and 2014, the percentage of testicular tumors diagnosed at a localized stage increased from 55% to 68% in the US. At present, less than 15% of men present with stage III disease (with metastasis to the pulmonary, non-pulmonary, or non-regional lymph nodes). The risk of developing invasive germ cell cancers in men with GCNIS is approximately 50% within 5 years.[27] 

Cryptorchidism increases the risk of developing testicular cancer in the affected testicle from four to sixfold. Still, the relative risk falls two to threefold while orchiopexy is performed before puberty.[28][29] A meta-analysis of cryptorchidism studies showed only a slightly increased risk of developing cancer in the contralateral, fully descended testis. (Relative Risk [RR] 1.74; 95% Confidence Interval [CI], 1.01 to 2.98).[30] The risk of developing testicular cancer among men with a first-degree relative with a germ cell malignancy is higher and at an earlier age than in the general population.[1] The incidence of a new testicular cancer in the contralateral testis in men with a personal history of testis cancer is about 12 times greater than in the general population. However, the 15-year cumulative incidence is only 2%.[31]

The worldwide incidence of testicular cancer is increasing, with the highest rate in Scandinavia (Norway and Denmark), Germany, Switzerland, and New Zealand.[32] The fastest rates of increase are found in Southern Europe and South America. While the incidence of testicular cancers is growing in the US, this increase is beginning to slow.[33] The current overall risk of testicular cancer in the US is about 6 per 100,000 men, and the yearly rate of increase is averaging about 0.8%.[34]

Pathophysiology

The tumor pathogenesis of testicular germ cell tumors is only vaguely understood.[35] It arises from a precursor lesion, germ cell neoplasia in situ (GCNIS), which develops from arrested spermatocytes that failed to differentiate.[36] In mothers during pregnancy, higher estrogen exposure, increased serum levels of polychlorinated biphenyls (other organic pollutants), exposure to organochloride pesticides, firefighting, and aircraft maintenance occupations are hypothesized as risk factors, but this remains controversial.[37] An increased number of genetic material copies from the short arm of chromosome 12 is a universal finding in postpubertal testicular and extragonadal germ cell tumors except for spermatocytic cancers.[6]

Non-seminomatous germ cell tumors tend to spread lymphatically, with the exception of choriocarcinoma, which metastasizes hematogenously. Right and left-sided tumors tend to stay on their respective sides initially but may overlap when they become bulky.[38] Right-sided tumors are more likely to develop contralateral nodal metastases due to the higher right-to-left lymphatic flow. Lymphatic drainage from the right testicle is directly into the interaortocaval node at the L2 level, while the lymph drainage from the left testicle empties into the left paraaortic lymph nodes.

Histopathology

Non-Seminomatous Germ Cell Tumors (NSGCT) are broadly classified into two classes according to histology: seminomas and non-seminomatous germ cell tumors. Non-seminomatous germ cell tumors (NSGCT) are further classified into four types: choriocarcinoma, embryonal carcinoma, teratoma, and yolk cell carcinoma. Mixed histology tumors are common, and even seminomatous elements may be included in NSGCT malignancies. When mixed, the treatment and overall prognosis are generally that of the most aggressive of the NSGCT elements.

Choriocarcinoma

Choriocarcinoma is a rare and very aggressive testicular cancer that is typically seen with extremely highly elevated serum human chorionic gonadotropin (HCG) levels and metastatic disease. Pure choriocarcinomas are rare at only 1% of all testicular malignancies, but they may be found as a component in up to 15% of all mixed germ cell tumors.[39] They are typically poor-risk (stage IIIC) at the time of diagnosis with high serum HCG levels and non-pulmonary organ metastases.[40] Unlike other non-seminomatous germ cell tumors, choriocarcinoma can spread hematogenously with common sites of metastases, including the lungs, liver, and brain.[40][41] 

Microscopically, the tumor is composed of both syncytiotrophoblasts and cytotrophoblasts, with the former staining positively for HCG. In fact, the HCG levels may become quite high, resulting in male gynecomastia. Testicular choriocarcinomas are highly vascular and prone to hemorrhage, often spontaneously and sometimes immediately after chemotherapy is initiated. This hemorrhaging can be catastrophic, especially when the bleeding is significant and occurs in the lungs or brain. Elevated HCG levels are usually associated only with seminomas, except for choriocarcinoma and sometimes embryonal carcinoma. 

Embryonal Carcinoma

Embryonal carcinoma consists of undifferentiated malignant cells resembling primitive epithelial cells from early-stage embryos with crowded pleomorphic nuclei.[42] Embryonal carcinoma is relatively aggressive and appears in about 40% of all mixed germ cell testicular malignancies. It can produce both alpha-fetoprotein (AFP) and HCG. Grossly, embryonal carcinoma is a tan to a yellow neoplasm that often exhibits large areas of hemorrhage and necrosis. The microscopic appearance of these tumors varies considerably as they may grow in solid sheets or papillary, glandular-alveolar, or tubular patterns.

Teratoma

These tumors contain well or poorly differentiated elements of at least two of the three germ cell layers: endoderm, mesoderm, and ectoderm. All components derived from these three germ layers are characteristically intermixed. Mature teratomas are defined as well-differentiated tumors, whereas those that are poorly differentiated are called immature teratomas. In adolescent and adult men, histopathologists do not distinguish between the two entities, and its distinction is clinically insignificant.[42]

Mature teratomas may include mature bone, cartilage, teeth, hair, and squamous epithelium. Due to these findings, teratomas are roughly called “monster tumors” in Greek. The gross appearance largely depends on the elements within it. Most of these tumors have two physical components, i.e., solid and cystic areas. They are typically associated with normal serum tumor markers (LDH, alpha-fetoprotein (AFP), and human chorionic gonadotropin (HCG)), but they may cause slightly elevated serum AFP levels. Approximately 47% of adult mixed germ cell tumors contain teratomatous elements, but pure teratomas are uncommon. Mature teratoma often constitutes the remnant of non-seminomatous germ cell tumors after treatment with chemo or radiation therapy, as they are relatively resistant to both. Treatment often requires surgery.

Yolk Sac Tumor

Pure yolk sac tumors (sometimes called endodermal sinus tumors) constitute a very small percentage of adult primary testicular and retroperitoneal germ cell tumors. They are most commonly found in mediastinal locations and the pediatric age group. They are the most common testicular malignancy in male children 3 years of age and younger, comprising about 30% of all testicular cancers in this age group.[42] 

The median age at diagnosis is 18 months. Yolk sac tumors typically grow in a glandular, papillary, or micro-cystic pattern and often make alpha-fetoprotein. Children usually have pure yolk sac tumors, while in adults, it is found as part of a mixed germ cell malignancy. Most yolk sac tumors, up to 75%, will demonstrate Schiller-Duvall bodies which resemble glomeruli with a fibro-vascular core. If present, these are pathognomic for yolk sac tumors.  Prognosis is usually good with treatment, especially in children.[43]

History and Physical

The evaluation for testicular non-seminomatous germ cell tumors begins by getting a detailed history and performing a thorough physical examination. Physicians should inquire about clinical features such as anything unusual with either testicle. It is important to ask about antenatal maternal and neonatal history regarding undescended testes and orchiopexy. A family history of testicular cancer in the father, brothers, and male blood relatives should be elicited. A solid, firm intra-testicular mass felt on physical examination should be considered a testicular tumor unless proven otherwise. A complete general physical examination is necessary to identify any signs of systemic spread.

Non-seminomatous germ cell tumors are associated with male infertility due to low sperm counts, reduced sperm motility, and increased abnormal morphology. This is thought to be due to spermatogenesis abnormalities and has been reported in up to 35% of patients with NSGCT.[44][45] Therefore, a careful examination of the testes in male infertility patients should also screen for possible testicular masses.

Patients with the localized disease will typically present with a painless nodule, lump, mass, or swelling in one of the testes. It might also present with dull scrotal or testicular pain. Ten percent of the affected individuals will experience acute testicular pain. Testicular cancer is not associated with trauma, but the presentation in the ER with scrotal or testicular trauma may elicit an examination or imaging of the testes resulting in the final diagnosis. A careful testicular examination will allow the examiner to detect a firm intra-testicular lesion.

To differentiate intra-testicular from extra-testicular lesions, each testis should be gently held and rolled between the fingers. It is important to examine the contralateral testis completely. Sometimes, due to a hydrocele presence, the testis cannot be adequately examined or palpated, and the presence or absence of a testicular lesion should be confirmed with ultrasonography (which is an extension of the physical examination in such situations). It is unusual for patients to present with symptoms or signs of disseminated disease.[46] However, male gynecomastia is found in about 5% of men with testicular cancer, presumably from elevated HCG levels. Therefore, all men with gynecomastia should have a careful examination of the testicles, and patients with testicular masses should be checked for gynecomastia.

Patients with a significantly enlarged or swollen testicle are most likely to have epididymo-orchitis, especially if the testicle is erythematous or painful. An apparent epididymo-orchitis that is painless or does not respond to antibiotics should be considered suspicious for a testicular malignancy.

Systemic symptoms include anorexia, malaise, and weight loss. The patients with pulmonary spread might present with cough, hemoptysis, or shortness of breath. Cervical or supraclavicular lymphadenopathy can be palpated in the lymphatic spread. In patients with retroperitoneal spread, it can present with back pain, varicocele, or lower limb edema due to testicular vasculature compression. Patients who are having retro-duodenal spread can present with nausea, vomiting, or gastrointestinal hemorrhage. Early diagnosis and immediate treatment are pivotal since testicular NSGCT has excellent cure rates due to its extreme sensitivity to cisplatin-based chemotherapy and radiation when properly combined with orchiectomy or retroperitoneal lymph node dissection.

Evaluation

Tumor Markers: alpha-fetoprotein (AFP), human chorionic gonadotropin (HCG), and lactic dehydrogenase (LDH).

Serum tumor markers (AFP, HCG, and LDH) should be checked before any intervention, including orchiectomy, as these may be elevated in non-seminomatous testicular germ cell tumors (NSGCT).

Alpha-fetoprotein is elevated in 50% to 70% of all patients with NSGCT.  Pure seminomas do not make alpha-fetoprotein, so if it's elevated in a patient diagnosed only with seminoma, it means that NSGCT elements were missed. The patient should be treated as having a mixed germ cell malignancy. Syncytiotrophoblasts manufacture human chorionic gonadotropins in seminomas and a few non-seminomatous germ cell tumors such as choriocarcinoma and embryonal carcinomas. LDH is generally a nonspecific tumor marker that is elevated in 20% to 60% of patients with NSGCT and is generally considered an indicator of bulky disease. Alpha-fetoprotein has a half-life of about 6 days, while the half-life of HCG is 24 to 48 hours.  In practical terms, HCG should begin to return to normal about 1 week after orchiectomy, while alpha-fetoprotein will take a minimum of 5 weeks. AFP and β-hCG are also elevated in various lung, liver, gut, bone, and live tumors.[47][48] There are new markers to diagnose and evaluate germ cell tumors, like levels of circulating microRNAs, especially miR-371a-3p. However, their precise role in the management of testicular tumors is yet to be determined.[49]

Ultrasonography of both testes is the primary initial imaging modality recommended to identify testicular cancer when suspected on physical examination.[50] Ultrasonography findings, when combined with the physical examination, provide nearly 100% sensitivity in the diagnosis of testicular cancer.[51] A hypoechoic, solid, vascularized intra-testicular lesion would be a typical finding suspicious for a testicular malignancy on ultrasound imaging. The patient should be properly counseled regarding the disease behavior, its management plan, the possibility of infertility, and the placement of a testicular prosthesis if desired. He should be counseled for sperm banking in bilateral testicular pathology cases or if either chemotherapy or retroperitoneal lymph node dissection surgery is planned.[50] 

For tissue diagnosis, a radical inguinal orchiectomy should be performed to serve both diagnostic and therapeutic (in stage I disease) purposes. Testicular biopsy can diagnose malignancy, but it may also cause upstaging of the disease in some cases. Testicular cancer spread is generally along well-known lymphatic chains except for choriocarcinoma,s which can spread hematogenously.[52][53] For NSGCT cancers arising in the right testis, the primary metastatic landing zone is the infrarenal inter-aortocaval lymph nodes, followed by the para-caval and para-aortic lymph nodes. Tumors arising from the left testis spread initially to the para-aortic lymph nodes, followed by the inter-aortocaval nodes. Retroperitoneal crossover from the right to the left side is common due to the natural pathway of lymphatics towards the cisterna chyle, but crossover from the left to the right side is rare unless it is associated with bulky nodal disease.[53] Contrast-enhanced CT imaging of the abdomen and pelvis is important to identify retroperitoneal lymph node disease arising from primary testicular cancer.  A chest CT is preferred over a simple chest X-ray to evaluate possible pulmonary metastases in NSGCT patients.[50]

All patients with testicular non-seminomatous germ cell tumors should undergo contrast-enhanced computed tomography of the abdomen and pelvis.[50] Patients with high levels of β-hCG should undergo cross-sectional CT imaging of the brain to identify possible metastatic lesions. Post-orchiectomy levels of serum tumor markers are necessary to help check the response to initial treatment and surveillance. Higher LDH levels can suggest a greater tumor burden. AFP and β-hCG evaluations are seen in many germ cell tumors.[54] β-hCG is produced by the syncytiotrophoblast component within germ cell tumors and is most closely associated with seminomas, although it can present in both seminomatous and non-seminomatous malignancies. β-hCG is commonly expressed by the syncytiotrophoblasts found in choriocarcinoma and approximately 15% of seminomas. Yolk sac tumors, embryonal cell carcinomas, and some teratomas secrete alpha-fetoprotein (AFP).[55]

There is no clinical role or justification for a percutaneous needle biopsy of a possible testicular malignancy. It would expose new lymphatic channels to possible metastatic spread of cancer, resulting in atypical metastases. In those rare situations where a biopsy is needed instead of a radical orchiectomy, it can be done through an inguinal incision with full control of the spermatic cord vascular supply to the testis. In such cases, usually, a frozen section is obtained with the expectation that a radical orchiectomy will be done if the preliminary diagnosis is cancer.  There is also no current clinical role for routine MRI or positron emission tomography at the current time.

Treatment / Management

Treatment of the Primary Tumor

Radical orchiectomy through the inguinal approach is the primary surgical standard treatment for testicular cancer with normal contralateral testes. It will allow exact histopathological diagnoses and T staging of the tumor. In stage I disease, it is the curative treatment in 75% of cases. Only an inguinal approach should be used for testicular surgery whenever there is a suspicion of possible cancer. This is because lymphatic drainage from the scrotum is different from the testis, and therefore, scrotal lymph channels should not be exposed to possible tumor cell contamination. Non-absorbable sutures with a longer tail are recommended for tying off the spermatic cord in suspected or confirmed cases of testicular cancer. This is to make it easier to find in the event that a retroperitoneal lymph node dissection might be needed at some point in the future. 

The patient should be counseled for a possible biopsy of the contralateral testes when appropriate. This would include patients with risk factors for GCNIS, like a history of undescended testes or cryptorchidism.[56] The expected incidence of GCNIS in the contralateral testis in such cases is about 5%.[57](A1)

Intra-testicular lesions require meticulous investigation, and the diagnosis should be made through both imaging modalities and histopathological techniques. Orchiectomy is overtreatment in cases of obvious benign disease and solitary testes. Low volume malignant lesions can often be managed by organ-sparing surgery.[58]  Sperm banking should be encouraged early, before any chemotherapy or RPLND surgery. 

Active Surveillance

Active surveillance implies delayed therapy for relapse after orchiectomy. Relapse occurs in 35% of patients, but cause-specific survival is 98%.[59] Relapse is usually due to undetectable micrometastases to the regional retroperitoneal lymph nodes at the time of the orchiectomy. The risk of micrometastases increases with a higher AFP level, embryonal carcinoma, and with the presence of vascular or significant local invasion on examination of the orchiectomy tumor specimen. Active surveillance involves different regimens of serial clinical examinations, blood tests, and radiological imaging studies after radical orchiectomy. Surveillance is intended to avoid the toxicity of radio-chemotherapy in the majority of patients with limited/localized disease. Active surveillance as a management option for stage I NSGCT after Peckham first reported orchiectomy in 1982.[60] (A1)

A combination of concurrent factors served as the impetus for this management strategy. The factors that can help select surveillance for stage I NSGCT are greater accuracy of clinical staging by CT and serological studies of tumor markers, correct identification of risk stratification criteria by AJCC, and confidence that chemotherapy can be given in cases of recurrences as salvage therapy. Most relapses are detected simultaneously by more than one modality, with an abdominal/pelvic CT scan being the predominant modality indicating disease recurrence. The use of tumor markers alone is not an adequate indicator of recurrent disease, which still requires periodic CT scans.[61] 

It is expected that patients who are candidates for active surveillance will have their tumor markers return to normal after surgery and be able to maintain frequent, typically monthly, office visits with routine tumor markers, chest x-rays, and abdominal CT scans. This routine is recommended every 3 to 4 months for the first year, then periodically over the next 4 years with gradually decreasing office visit frequency. Overall, 65% of patients will not demonstrate any recurrence, relapse, or metastasis over the subsequent 5 years. For those who do, surgery (retroperitoneal lymph node dissection) and/or chemotherapy offer a cure rate greater than 90%. Using CT scans at 3 months post-op and again at 12 months proved to be a reasonable and safe protocol in selected low-risk patients.[62](A1)

Supraclavicular or inguinal adenopathy presents as a palpable disease. Inguinal lymph node involvement usually happens only after a surgical scrotal violation. In patients who adopted active surveillance, the risk of developing testicular tumors in the contralateral testis is only 1 to 2%, but these malignancies should be considered separate primary tumors. The factors which should be considered in the initial recurrence of NSGCT are the site of recurrence, the recurrence detecting modality, and documented time of recurrence. The majority of NSGCT progression and recurrence are detected in the first year during surveillance.

Neo-adjuvant Chemotherapy

Non-seminomatous germ cell tumors are the most sensitive testicular cancers to cisplatin-based chemotherapy. Patients with elevated markers are typically given 3-4 cycles of bleomycin, etoposide, and cisplatin (BEP) chemotherapy. After completion of chemotherapy, tumor markers are repeated to see the decline in values, along with a contrast-enhanced CT scan to evaluate for any residual mass. If a mass is present with normal tumor markers, this is considered an indication for RPLND. In patients who developed pulmonary fibrosis or with a history of significant pre-existing pulmonary disease, bleomycin would be contraindicated. If the patient still has elevated markers, second-line chemotherapy, including vincristine, ifosfamide, and cisplatin (VIP), should be considered. Other second and third-line agents include gemcitabine, etoposide, paclitaxel, and oxaliplatin. Chemotherapy causes azoospermia in most patients for at least 2 to 3 years after treatment. Cisplatin and similar alkylating agents are the most injurious to spermatogenesis, with Sertoli cells being relatively sensitive but Leydig cells being relatively resistant. Sertoli cells are also very radiosensitive. Overall, fertility is reduced by an average of 30% after chemotherapy treatment for NSGCT.[45][63][64](B2)

Other potential side effects of chemotherapy include peripheral neuropathy, renal failure, myelosuppression, loss of hearing, increased cardiovascular disorders, and hypogonadism. 

Primary Retroperitoneal Lymphadenectomy

Retroperitoneal lymph node dissection (RPLND) with adjuvant chemotherapy is the mainstay of managing low-stage non-seminomatous germ cell tumors (NSGCT) in the United States. RPLND is a staging, diagnostic and therapeutic procedure for patients with NSGCT. One of the benefits of RPLND surgery is that it helps identify those patients who might benefit from postoperative chemotherapy. Also, men with NSGCT who do not undergo RPLND will require more intensive surveillance protocols even for stage I disease than similar patients who may only need routine tumor markers and chest x-rays after RPLND surgery, retroperitoneal relapse rate drops to <1%.[58] Some centers will tend to recommend RPLND in stage I disease over active surveillance or chemotherapy if they have histological risk factors (evidence of vascular invasion in the original testicular malignancy or a significant component of embryonal carcinoma).

The retroperitoneal lymph nodes are the primary nodal sites involved in the spread of NSGCT. Removal of these draining lymph nodes results in a high cure rate for testicular tumors. The cure rate for stage I NSGCT is about 93-95% with RPLND alone. It is generally 3-4 hours of surgery with a mortality rate of less than 1%. It involves the dissection of the retroperitoneal lymph nodes with the resulting possibility of retrograde ejaculation, loss of fertility, and incontinence due to disruption of pelvic nerves during the dissection. It is still the gold standard for stage I NSGCT for staging and therapeutic purposes. RPLND may also be used for stage IIA, but for stage IIB and higher. Initial chemotherapy is the standard of care. In general, patients with residual lymph nodes 1 cm or larger after definitive chemotherapy are candidates for RPLND. 

Modern modifications include a nerve-sparing approach to save the nerves supplying the bladder neck to preserve ejaculatory function and continence.[65] This approach uses a template-based right and left-sided dissection, which preserves sexual function and fertility in over 90% of patients.[66] Other complications from RPLND surgery include wound infection, bowel ileus, pulmonary embolism, lymphocele, lymphedema, chylous ascites, and hydronephrosis.[58] RPLND is traditionally done as an open surgical procedure with a large midline abdominal incision. Removal of residual masses with RPLND after chemotherapy is a much more complicated and technically difficult procedure but provides excellent survival in high-risk/high tumor volume cases. Disease-specific survival has been reported as 81%, with 70% having no progression of their cancers.[67][68] Laparoscopic RPLND has been reported in several series with good results, even when performed after chemotherapy.[67][68] (B2)

Complications of RPLND, even in experienced hands, are relatively common at 18% as the surgery is technically demanding and often complicated by patient comorbidities.[69] Postoperative ejaculatory problems are common.[70][71][72] Erectile dysfunction (ED) is reported in up to 15% with current nerve-sparing techniques.[72][73] Some patients may require resection of the inferior vena cava or aortic tube grafts to replace aortic segments.[74][75] Referral to tertiary care centers with surgeons experienced in RPLND surgery is recommended when this procedure is required, as in experienced hands, the outcomes are significantly better.[50][76] (An experienced RPLND surgeon has been defined as one who performs 24 or more of these procedures a year.) (B2)

Relapses after RPLND are typically pulmonary, with a reported incidence of 10% for those with negative nodes and 28% for patients with positive nodal disease.[77] Fortunately, such recurrences are usually curable with systemic chemotherapy.

Adjuvant Chemotherapy

In clinical stage I of non-seminomatous germ cell tumors, the relapse rate is about 64%. Relapsed cases are generally considered high-risk for metastatic disease. In the United States, RPLND is offered to re-confirm the pathological stage as well as for curative treatment. However, in European countries, patients are usually offered adjuvant treatment consisting of two cycles of BEP, which is generally reserved for NSGCT with high-risk features, such as vascular invasion. After treatment, 95-97% of patients remain relapse-free, with a cure rate approaching 100%. Adjuvant chemotherapy with two cycles of BEP in the high-risk group can provide a long-term progression-free survival rate of 97%.[78] 

Summary of Treatment Options by Stage:

Clinical Stage I NSGCT would include those cases where serum markers are normal or return to normal after radical orchiectomy. CT scans are negative for lymphatic or organ spread of disease, and the CXR is also negative. This stage represents about 70% of all cases of NSGCT. However, it should be noted that about 30% of these patients will have undetectable micrometastases at the time of their orchiectomy. For most patients with stage I disease, radical orchiectomy alone is curative. For those that do relapse, curative treatment is likely with long-term disease-specific survival exceeding 99%.[79] Adjuvant chemotherapy with one to two cycles of BEP is optional. While it reduces the recurrence rate, it also causes side effects and toxicity. One cycle of BEP is suggested for patients who decline surveillance or are likely to be non-compliant.[50] 

Patients whose primary testicular tumors contain a significant proportion of teratoma may benefit the most from an RPLND. Active Surveillance is a reasonable and recommended choice for Clinical Stage IA NSGCT which is a primary tumor less than 3 cm in diameter that is confined to the testis. Initial treatment with RPLND is also reasonable and provides optimal staging information, and possibly cures early metastatic disease. However, this may represent overly aggressive surgical treatment for most stage IA patients, even though the overall cure rate with RPLND is about 90%. For Clinical Stage IB (initial tumor larger than 3 cm) or where there is a high-risk disease (such as a large percentage of embryonal carcinoma or evidence of vascular or lymphatic invasion in the primary tumor as these patients face a much higher risk of micrometastases and delayed retroperitoneal metastases), RPLND may be preferred. Tumors with both lymphovascular invasion and a predominance of embryonal carcinoma have relapse rates of over 50%.[69][80][81] Another option in high-risk disease is cisplatin-based chemotherapy, with a reported cure rate of 90% to 100%.(B2)

Clinical Stage IIA NSGCT includes patients where the CT scan indicates enlarged retroperitoneal lymph nodes but smaller than 2 cm in diameter. In Stage IIB, the lymph nodes are between 2 cm and 5 cm in diameter. Treatment is usually with initial RPLND or primary chemotherapy. Patients who have a larger volume of disease tend to have higher relapse rates, and adjuvant chemotherapy should be considered. The American Urological Association Guidelines on Early Stage (Stage I - IIB) Testicular Cancer can be found at https://www.auanet.org/guidelines/testicular-cancer-guideline.[50]

Clinical Stage IIC NSGCT (Bulky Metastatic Disease) is usually treated with primary chemotherapy as the initial recommended treatment. Initial RPLND has a very high relapse rate in such cases. RPLND can be done after chemotherapy for any remaining retroperitoneal lymphatic disease.

Clinical Stage III NSGCT (Metastatic Disease Above Diaphragm) patients are usually classified into low, intermediate, and high-risk groups with 5-year overall survival is 92%, 80%, and 48%, respectively. The risk stratification is based on their tumor marker levels, histology, size of metastatic deposits, presence of cervical lymph node enlargement, and the size as well as the number of pulmonary metastases. (Patients with persistently elevated levels of tumor markers after radical orchiectomy without any evidence of metastatic disease radiographically are also considered clinical stage III.)

Surveillance After Definitive Therapy

The median time to relapse in NSGCT patients is 7 months. The majority (90%) of NSGCT patients who develop a recurrence will experience it within the first 2 years after definitive therapy. Therefore, the recommended surveillance schedule is relatively intense for the first 2 years. For most patients, this means a physical examination of the remaining testicle, a chest x-ray, CT scan, and serum marker levels every 2 months. Late relapses after the first 2 years are relatively uncommon at only 2% to 4%. When present, such recurrences are typically found in the retroperitoneum.[82] However, rare instances of very late relapses have been reported up to 24 years after initial definitive therapy.[83]

A more liberal monitoring plan has been suggested for low-risk patients with clinical stage I disease who may be able to avoid most of the routine surveillance CT scans, just performing them at 3 and 12 months rather than the standard scan every 2 months.[62] While promising, this is not yet the standard, accepted, or recommended protocol. (A1)

Complete, detailed, and comprehensive reviews of the most recent recommended surveillance guidelines can be found on the NCCN website under "Guidelines for Testicular Cancer" or the American Urological Association Guidelines on Early Stage (Stage I - IIB) Testicular Cancer.[50] 

Primary Extragonadal Mediastinal and Retroperitoneal Non-Seminomatous Germ Cell Tumors

Extragonadal tumors are those where there is no evidence of a primary testicular malignancy. They are relatively rare. Their pathogenesis is not clearly understood, but there are two theories. 1) They develop from primordial germ cells that fail to normally migrate along the urogenital ridge due to a defect in the microenvironment or an abnormal germ cell. 2) They develop from germ cells in the testis but undergo reverse migration. There is current evidence supporting both theories. 

For mediastinal tumors, the initial diagnosis is usually by chest X-ray or CT scan. Initial symptoms (in decreasing order of frequency) include chest pain, dyspnea, cough, weight loss, superior vena cava syndrome, fever, and nausea. Gynecomastia may be present if HCG is elevated. Most patients are symptomatic at presentation. A definitive diagnosis is made from an open or percutaneous biopsy. Patients with Klinefelter syndrome have an increased risk of mediastinal germ cell tumors. All patients should have tumor markers drawn and testicular ultrasound. Extragonadal non-seminomatous germ cell tumors will demonstrate elevated alpha-fetoprotein and/or HCG in 85% of cases. Typically, primary mediastinal NSGCTs are more likely to have an elevated AFP compared to similar tumors of the retroperitoneum or testicles.[84](B2)

Anterior mediastinal germ cell tumors are more likely to be primary cancers as metastatic germ cell testicular malignancies rarely metastasize to the anterior mediastinum. Any poorly differentiated cancer of the retroperitoneum or anterior mediastinum should be considered a possible germ cell tumor, especially if the AFP is elevated. Among extragonadal non-seminomatous germ cell malignancies, yolk sac tumors are quite common (60%), with choriocarcinoma also being seen relatively frequently (12%) while embryonal carcinoma is relatively rare (6%).[85](B3)

Treatment is based on the underlying pathology but is usually chemotherapy followed by surgery to remove any residual tumor. Overall prognosis is guarded, with 5-year survival at only 40 to 45%.[86] All primary mediastinal non-seminomatous germ cell tumors are considered high risk as treatment of local recurrences carries a grim prognosis, with most cases not responding well to salvage chemotherapy. Long-term survival in such patients is typically <10%.[84][87][88][89](B2)

Primary retroperitoneal tumors are typically quite bulky at the time of diagnosis. They are initially diagnosed based on symptoms or noted on imaging. Initial therapy is usually cisplatin-based chemotherapy such as BEP, the same as for testicular NSGCT. Residual masses after chemotherapy should be surgically removed when feasible. Prognosis: Typically, patients can expect a 5-year progression-free survival rate of 42% and an overall survival rate of 65%.[84](B2)

Differential Diagnosis

• Epididymo-orchitis
• Hematocoele
• Hernia
• Hydrocoele
• Orchitis
• Spermatocele
• Syphilitic gumma
• Testicular seminoma
• Testicular torsion
• Varicocoele

Pertinent Studies and Ongoing Trials

Researchers recently initiated a study; A Prospective Phase II Trial of Cabazitaxel in Male Patients With Chemotherapy Pre-treated Metastatic Non-seminomatous Germ-cell Tumors. Cabazitaxel is a new generation taxane with a high capacity for blood-brain barrier crossing and limited peripheral neurotoxicity, two major potential advantages in patients with advanced NSGCTs. Cabazitaxel has a broader in vitro spectrum of activity than docetaxel. Taxanes have demonstrated activity in pre-treated GCTs and are now part of standard treatment, but cabazitaxel has not yet been tested in patients with NSGCT.

A risk-adapted strategy of using dose-dense chemotherapy in patients with poor-prognosis disseminated non-seminomatous germ cell tumors is a randomized phase III trial that compares two different combination chemotherapy regimens to see how well they work in treating patients with stage II or stage III non-seminomatous germ cell tumors.

Toxicity and Adverse Effect Management

More than 50% of patients considered high-risk due to vascular involvement are over-treated; hence long-term toxicity assessment is crucial. There is a high rate of unfavorable changes in body mass index and blood pressure, which consecutively results in an increased risk of cardiovascular disease in patients after chemotherapy for testis cancer.[90] Only a handful number of studies of two cycles of adjuvant chemotherapy have evaluated long-term toxicities. Nephrotoxicity, neurotoxicity, vascular toxicity, and high serum triglyceride levels have been reported at different doses. Thus, valid conclusions on the impact of long-term toxicity of adjuvant chemotherapy cannot be drawn.

Etoposide has been reported with secondary leukemia. Secondary malignancies have been reported with radiotherapy and chemotherapy. There is a relative risk of 2.9 to develop solid malignancy like esophageal carcinoma, carcinomas of the lungs, bladder, colon, and pancreas. Studies have shown no effects on long-term fertility. However, no good long-term data on fertility is available after adjuvant chemotherapy, and hence cryopreservation is recommended before chemotherapy. In summary, long-term studies with advanced disease have indicated only some long-term toxicity of chemotherapy. Extrapolation of data suggests no significant long-term toxicities of two cycles of PEB.

Management of infertility in patients with NSGCT can be challenging. There may be pre-existing infertility before the discovery of the testicular malignancy. All of the definitive treatments for NSGCT, with the possible exception of the initial radical orchiectomy, are likely to have a deleterious effect on male fertility due to ejaculatory dysfunction, interference with spermatogenesis, or disruption of pituitary hormones in men who receive radiation for brain metastasis. The reported pregnancy rate from cryopreservation of sperm in such situations is 18% to 50%. If semen preservation is not done, sperm can still be retrieved directly from the remaining testicle via testicular sperm aspiration and similar techniques, followed by intracytoplasmic sperm injection (ICSI). This technique has a reported successful pregnancy rate of up to 31%.[91][92]

Staging

According to the American Joint Committee on Cancers (AJCC), the Staging of NSGCT is:

Prognosis

Patients who have received chemotherapy, radiation therapy or both are at increased risk of cardiovascular disorders as well as secondary malignancies.  They should also be monitored for possible hypogonadism.[50] 

The histology, presence or absence of visceral metastasis, and serum tumor marker levels (following orchiectomy) are used to classify patients with testicular germ cell tumors into low, intermediate, and high-risk groups with significantly different progression-free and overall survival rates.[93]

A low-risk prognosis is associated with a good outcome. Fifty-six percent of non-seminomatous germ cell tumors have a good prognosis with a 5-year progression-free survival of 89% and 5-year overall survival of 92%. The low risk would be defined as limited testicular or retroperitoneal primary disease without non-pulmonary visceral metastases and with low tumor markers such as the following:

• AFP < 1000 ng/mL and
• HCG < 5,000 IU/L (1,000 ng/mL) and
• LDH < 1.5 x upper limit of normal). 

Intermediate risk malignancies constitute 28% of all non-seminomas germ cell tumors. They will have a 5-year progression-free survival of 75% and 5-year overall survival of 80%. Intermediate risk tumors are defined as having a testicular or retroperitoneal primary without non-pulmonary visceral metastases and intermediate markers such as any of the following:

• AFP≥ 1,000 and ≤ 10,000 ng/mL or
• HCG ≥ 5,000 IU/L and ≤ 50,000 IU/L or
• LDH ≥ 1.5 x N and ≤ 10 x normal).

High-risk tumors are associated with a poor prognosis. Sixteen percent of non-seminomas have a poor prognosis with a 5-year progression-free survival rate of only 41% and 5-year overall survival of only 48%. The definition of a high-risk tumor is one that is associated with a mediastinal primary without non-pulmonary visceral metastases or poor tumor markers such as any of the following:

• (AFP > 10,000 ng/mL or
• HCG > 50,000 IU/L (10,000 ng/mL) or
• LDH > 10 x upper limit of normal). 

Survival Statistics by Stage

Stage I disease: 5-year disease-free survival - 98%.

Stage IIA and IIB disease: 5-year disease-free survival - 92%.

Stage IIC disease: 5-year overall survival - 92%.

Stage III disease:

• Low risk: 5-year overall survival - 92%
• Intermediate risk: 5-year overall survival - 80%
• High risk: 5-year overall survival - 48%

Complications

Complications are usually associated with the spread of NSGCT to the retroperitoneum and distant tissues. Treatment-related complications are already described in the text above. These are retrograde ejaculation, bladder neck incontinence, infertility, and mass effects. Other complications are according to the organs involved.