Chapter 39: Testicular Cancer

Testicular germ cell tumors (GCTs) account for the majority of testicular cancers and are highly curable. This chapter primarily discusses GCTs arising in the testicle, dividing this category into seminoma versus nonseminoma germ cell tumors (NSGCTs). Then, the rare entity of extragonadal GCTs, which can arise in the mediastinum, retroperitoneum, or pineal body, is described.

Epidemiology

The GCTs are the most common new cancer diagnosis in young men. Roughly an estimated 8,430 new cases were expected to be diagnosed in 2015 (¹). Highlighting the high curability of this cancer, GCTs only claimed approximately 380 lives in 2015 (¹) and carry a 5-year overall survival (OS) rate of approximately 95% (^2,3). The GCTs have a bimodal age distribution, with most men diagnosed between ages 15 and 25. There is a second peak of diagnosis around age 60, which largely represents seminoma histology and a lower mortality risk. Lifetime risk for the development of GCTs is approximately 0.5% or 1 in 200 (⁴).

Worldwide, GCTs are six times more common in developed countries, with the largest incidence reported in Denmark and Switzerland and the lowest in Japan, Finland, and Israel (⁴). In the United States, the overall incidence of GCTs appears to be gradually increasing. The incidence has specifically increased among African Americans, with the greatest increase in seminoma histology. This does not appear to be related to screening or earlier diagnosis (⁵). Caucasian men, although still representing the group most likely to be diagnosed, are more likely to be identified at an earlier stage than in the past (⁶).

Risk Factors

Cryptorchidism is one of the few identifiable risk factors for the development of GCTs, although representing at most about 10% of cases. When present, cryptorchidism imparts a relative risk between 2.5 and 17.1 (^7,8). This increased risk includes the contralateral testicle, even if descended normally or via orchiopexy. It is unclear if orchiopexy reduces the lifetime risk of GCTs, although data showing increased incidence even in the contralateral testicle support the theory that the etiology of GCTs lies in abnormal gonadal development rather than anatomic malposition (^9,10). Men with a prior history of GCTs also have an increased risk of GCTs in the contralateral testicle, suggesting a genetic predisposition, although men with a family history of GCTs account for only 1.5% of patients with new diagnosis (¹¹). A personal history of GCT carries an increased lifetime risk of secondary cancers, irrespective of histologic type (¹²).

Tumor Biology

The most common genetic abnormality found in GCTs is an isochromosome of the short arm of chromosome 12, which has been identified in approximately 80% of GCTs (¹³). This abnormality can be found in all histologic subtypes except spermatocytic seminoma (^14,15). Overexpression of c-kit is seen in seminoma (¹⁶). Of note, p53 is rarely altered in GCTs, and single-gene mutations in general are uncommon (¹⁷).

Carcinoma in situ (CIS), or intratubular germ cell neoplasia (ITGCN), has been identified as the precursor lesion in most GCTs. It is histologically described as atypical germ cells in the seminiferous tubules. Such changes are found adjacent to most invasive GCTs, with the notable exception of spermatocytic seminoma. The ITGCN cells express numerous proto-oncogenic proteins that play a role in tumorigenesis, including the receptor tyrosine kinase CD-117 or c-kit, a protein normally involved in germ cell migration and early differentiation (^18,19).

Histologic Classification

The main histologies encountered in GCTs are seminoma, embryonal carcinoma, endodermal sinus tumor (EST, also known as yolk sac tumor), choriocarcinoma, and teratoma. The last can be further classified as mature, immature, or teratoma with malignant transformation. It is common to see more than one histologic subtype within a tumor. Importantly, the clinical course can be largely inferred from the histology. The GCTs that show exclusively the seminoma histology constitute pure seminomas, while those containing any other histologic pattern are classified as NSGCTs, even if the dominant histologic pattern is seminoma. Thus, the term seminoma is used in two very different ways: as a histologic pattern and as a main subdivision of GCTs. The biology and clinical expression are dominated by the nonseminoma component, and thus the presence of any histologic component other than seminoma places the tumor in the category of NSGCT.

Clinical Presentation

Most patients with GCTs present with painless testicular swelling or a nodule. In some cases, testicular swelling can be accompanied by pain secondary to bleeding or infarction within the tumor. In the presence of pain or a history of injury, an appropriate differential diagnosis would include testicular torsion, epididymitis, orchitis, hydrocele, spermatocele, and hematoma. It is extremely important that regardless of pain or other associated symptoms, all scrotal masses should be approached as if they were malignant. In patients who present with gynecomastia, especially bilateral, GCTs should be considered (²⁰). Other symptoms can include fever, weight loss, back pain, and hemoptysis (most often seen in patients presenting with high-volume disease).

Diagnosis

The importance of prompt diagnosis and treatment cannot be stressed enough because the extent of disease at presentation predicts overall prognosis. Awareness of GCT prevalence among young men is important for both general practitioners and the general public. Radiographic evaluation of a suspected primary should include high-resolution, trans-scrotal ultrasonography with color Doppler of both testicles, and any suspicious lesion should be definitively evaluated with radical orchiectomy.

Trans-scrotal biopsy is contraindicated in the diagnostic workup of a suspected testicular neoplasm, as this procedure can disrupt regional lymphatics, potentially altering the otherwise-predictable nodal spread. Because the diagnosis of GCTs is rarely in question, the preferred diagnostic and therapeutic procedure for a testicular mass is radical inguinal orchiectomy. If a tissue diagnosis is felt to be necessary prior to orchiectomy, an open biopsy should be performed via an inguinal incision to allow for proper examination and tissue sampling with minimal risk of inguinal or scrotal contamination.

Serum Tumor Markers

Serum markers, specifically human chorionic gonadotropin (hCG), α-fetoprotein (AFP) and lactate dehydrogenase (LDH), have unique diagnostic and prognostic significance in GCTs. These markers enable the clinician to infer clinical behavior, monitor therapy, decide when to apply surgical consolidation, and detect residual or recurrent disease.

Elevated in pregnancy, hCG is not normally detectable in males except in the setting of GCTs. With a half-life of 18 to 36 hours, hCG can also be markedly elevated in gestational trophoblastic disease and occasionally in epithelial cancers (²¹). It is composed of two subunits, α and β, which exist in multiple isoforms. The α subunit has sequence similarity to the α subunit of thyroid-stimulating hormone (TSH), follicle-stimulating hormone (FSH), and luteinizing hormone (LH), which leads to “cross-talk” between these hormones and hCG. For this reason, hCG assays measure the β subunit. This “cross talk” can be clinically significant in high-volume disease accompanied by high levels of hCG, where hCG causes hyperthyroidism by binding to the TSH receptor. Extreme elevation of hCG in males should be considered pathognomonic for GCTs and, in selected cases of threatening disease, justifies initiation of therapy even before tissue confirmation.

Normally produced by the fetal yolk sac, AFP also exists in multiple isoforms. It is elevated in GCT cells derived from the embryological yolk sac, including endodermal sinus tumor and embryonal carcinoma. It has also been found to be elevated in other neoplasms, such as hepatocellular carcinoma and pancreatic, gastric, and lung cancer, and has a serum half-life of approximately 5 days (²²). Seminoma does not produce AFP, and in the setting of GCT, an elevated AFP implies a nonseminomatous histology (²³).

Lactate dehydrogenase is neither cancer specific nor germ cell specific. Of the LDH isoforms, LDH-1 is most specific for GCTs; however, there is no established routine use for the fractionation of LDH and precise measurement of LDH-1. Total LDH can be used to estimate the prognosis in advanced NSGCT at the time of diagnosis or to detect recurrent disease (²⁴).

Anatomic Progression

The GCTs follow a distinct pattern of spread and metastasis. The lymphatic drainage from the testicle reflects embryologic origin, and thus the right testicle drains to the interaortocaval lymph nodes, and the left testicle drains to the left para-aortic lymph nodes. These initial nodes of spread are termed the “landing zone.” Epididymal lymphatics drain via the external iliac chain and scrotal lymphatics via the pelvic chain; therefore, locally advanced disease (involving the epididymis and scrotum) can present with involvement of these nodal basins. Distant metastasis involves the lungs principally, followed by the liver, brain, and bones.

Table 39-1 shows the American Joint Commission on Cancer (AJCC) TNM staging of testicular cancer (²⁵). This system is based on the anatomic characteristics of the tumor, the presence of elevated tumor markers, and the presence of distant disease. These well-defined risk factors are used to group patients into stages I-III. In general, stage I disease is confined to the testis, stage II disease has nodal metastases confined to the retroperitoneum with markers in the good prognosis range (S1), and stage III disease includes nodes that extend beyond the retroperitoneum, extranodal metastases, or elevation of tumor markers to the intermediate- or poor-prognosis range (S2-S3).

Fertility Considerations

Of particular importance to men with GCTs is the preservation of fertility. Both the diagnosis and treatment of GCTs are associated with impaired fertility. It is recommended that, if clinically feasible, the patient be counseled about and offered the opportunity to pursue sperm banking prior to starting chemotherapy. It is not recommended to delay chemotherapy in symptomatic poor-risk patients, as poor physical condition often makes sperm donation difficult or even impossible (²⁶).

Histology

Under microscopic visualization, classic seminoma has a “fried-egg” appearance, defined as a monotonous proliferation of large, rounded cells arranged in sheets or cords with large centralized nuclei and nucleoli. These tumors can be difficult to distinguish from lymphoma if there is a background of lymphocytic infiltration. Further confirmation (ie, negativity for lymphocyte markers such as common leukocyte antigen) is often required. Although not specific, seminomas stain positive for placental alkaline phosphatase (PLAP) and are routinely negative for AFP and hCG. Figure 39-1 shows the histological appearance of classic seminoma.

On pathologic examination of the testis, seminoma tends to be a semisolid tumor that readily oozes onto the gross examination table. This makes the presence of malignant cells on the surface of the spermatic cord and at the margins of resection a ubiquitous finding. Thus, the clinician must be careful not to be unduly influenced by reports of “margin positivity” and “involvement of the spermatic cord” in the pathology report (²⁷). Figure 39-2 shows the typical gross appearance of seminoma.

Even in the presence of significant metastatic disease, it is not uncommon to find only a scar in the testicle. This phenomenon is known as “burned-out” seminoma and can also occur in NSGCT. The biological basis for this spontaneous regression of the primary is not known. Seminomas are typically associated with significant inflammatory infiltration, and metastatic deposits characteristically leave a dense desmoplastic residual mass after treatment, often making them difficult to resect.

Clinical Features

Pure seminoma is the most common GCT of the testicle, accounting for approximately 50% of GCTs. By definition, seminomas have no evidence of a nonseminoma component and do not produce AFP but may have modest elevation of β-hCG. Spermatocytic seminomas, a rare variant comprising only 10% of seminomas, are not associated with ITGCN. These tumors typically occur in men over 50 years old, in stage I disease, and have a low metastatic rate. This subtype portends an excellent prognosis with resection alone (with or without radiotherapy) (²⁸). Seminomas tend to spread via lymphatics initially, with late hematogenous spread, and are more likely to spread locally, as evidenced by positive margins and involvement of the spermatic cord on histology. The most common hematogenous spread is to the lungs, and metastatic seminomas rarely metastasize to the brain. Remarkably, bulky tumors rapidly respond, with dramatic loss of tumor bulk, but tumor lysis syndrome is never encountered.

Prognosis

The International Germ Cell Cancer Collaborative Group (IGCCCG) established a standard risk classification for both seminomas and NSGCTs (Table 39-2). Patients with metastatic seminoma are divided into either good- or intermediate-risk categories, with no definable “poor-risk” seminoma. The one characteristic that predicted worse outcome for seminoma was the presence of nonpulmonary visceral metastases (intermediate prognosis). The prechemotherapy tumor markers do not predict prognosis (unlike in NSGCTs, discussed further in the chapter). Ninety percent of patients with seminoma fall into the good-prognosis category, with a 5-year OS of 86%. Patients with seminoma in the intermediate-prognosis category have a 5-year OS of 72% (²).

Management of Clinical Stage I Seminoma

Patients with clinical stage I seminoma, representing 70% of patients at diagnosis, have disease confined to the testicle with no evidence of nodal or distant metastasis. Most patients will be cured by radical orchiectomy alone, but approximately 20% recur without adjuvant intervention. The disease-specific survival is nearly 100% with or without adjuvant treatment because patients who recur on surveillance are readily salvaged with standard treatment.

Active Surveillance

The benefits of surveillance include avoidance of unnecessary treatment in patients who are likely to be already cured by orchiectomy. Warde et al reported data on 638 patients with clinical stage I seminoma managed with surveillance with a median follow-up of 7 years. Patients with a primary tumor less than 4 cm maximum dimension and without invasion of rete testis had 5-year risk of relapse of only 12%. Patients with both risk factors had a risk of recurrence of 32%, while one of the two risk factors portends a 16% risk of relapse (²⁹). Because of excellent outcomes of patients later treated for recurrent disease, active surveillance is considered a reasonable option for most patients, including those with both risk factors.

Radiotherapy

The recurrence rate after prophylactic radiotherapy for clinical stage I seminoma is about 4%, and most of those patients who recur after radiation survive with additional treatment (chemotherapy). Treatment of para-aortic lymph nodes to a dose of 20 Gy was associated with excellent local control approaching 100%. A randomized trial of 20 Gy versus 30 Gy showed no difference in rate of recurrence. Omission of ipsilateral iliac lymph nodes from the treatment field resulted in less toxicity (infertility, gastrointestinal effects) and minimal loss of efficacy. Radiotherapy is contraindicated for patients with horseshoe kidney or inflammatory bowel disease.

Radiotherapy was once viewed favorably because it reduced the number of computed tomographic (CT) scans that were necessary for follow-up, with a net reduction in the cost of treatment. There is, however, a risk of second malignant neoplasms related to treatment. Studies of testicular cancer survivors 25 or more years after treatment have revealed an increase in midline cancers, such as gastrointestinal and genitourinary malignancies. This added risk has brought about a reassessment of whether radiotherapy is warranted, especially considering that 80% of patients with clinical stage I seminoma will be treated unnecessarily, and that there is no survival benefit. At MD Anderson Cancer Center (MDACC), we no longer offer prophylactic radiation to men with stage I testicular seminoma.

Chemotherapy

A randomized controlled trial was conducted to compare a single infusion of carboplatin, with dose based on area under the curve (AUC) of 7, versus radiotherapy for the adjuvant treatment of clinical stage I seminoma (³⁰). Median follow-up was 4 years, and the relapse-free survival was similar in both treatment arms, 96.7% and 97.7%, respectively, showing noninferiority of the one-cycle, single-agent carboplatin. There are limited data comparing the long-term safety of carboplatin to that of radiotherapy, leading many practitioners to adopt surveillance as the preferred option. Figure 39-3 outlines an approach to therapy for stage I seminoma.

Management of Nonbulky, Good-Risk Seminoma (Stages IIA/IIB)

Patients with stage II seminoma are often divided into nonbulky versus bulky disease for treatment discussion. In general, nonbulky disease is defined as nodes less than 5 cm in cross-sectional dimension on CT or magnetic resonance imaging (MRI) at MDACC. The primary mode of therapy for patients in this category is radiotherapy unless the patient has a contraindication or is unable to tolerate radiation treatment.

Radiotherapy

It is no longer recommended that patients with stages IIA and IIB seminoma receive high-dose radiation (30-35 Gy), mediastinal radiation, or left supraclavicular radiation. At MDACC, our current approach is to give 20 Gy to the para-aortic and ipsilateral iliac nodal fields with a 6-Gy boost to the para-aortic lymph nodes (³¹). Occasionally, radiographic evidence for residual disease is present postradiotherapy, but if the abnormality is less than 3 cm, observation is recommended.

Alternatives to Radiotherapy

A subset of patients exists who will not be able to receive radiation therapy for various reasons. These reasons may include patient refusal, inflammatory bowel disease, horseshoe or pelvic kidney, and history of abdominal surgery. In this setting, systemic chemotherapy could be offered. In a series published by Xiao et al (³²), patients with good-prognosis seminoma were included in the analysis and were treated with four cycles of etoposide and cisplatin (EP). Although this does not represent the standard of care for stages IIA and IIB seminoma, it is a reasonable alternative for patients who absolutely cannot receive radiation therapy.

Management of Advanced, Good-Risk Seminoma (Stages IIC/III)

This treatment group includes patients with stage II with bulky lymphadenopathy (≥5 cm) and patients with stage III with good-risk disease. In this group of patients, the risk of recurrence remains high despite local therapy; therefore, the primary treatment recommendation is systemic chemotherapy. It is also in this category of patients that the role of positron emission tomographic (PET) scan may be introduced in its limited role for GCTs.

Chemotherapy

The recommended systemic chemotherapy regimen for patients with good-risk advanced seminoma (stage IIC or IIIA) is three cycles of bleomycin, etoposide, and cisplatin (BEP) or its equivalent. The evidence for use of three cycles of BEP versus four cycles was presented by de Wit et al (³³). These investigators showed that three cycles of BEP are equivalent to four cycles, with 2-year progression-free survival (PFS) of 90.4% and 89.4%, respectively (³³). Alternatively, patients who are unable or refuse to receive bleomycin or are older than 50 years can be successfully treated with four cycles of EP.

Residual Disease After Chemotherapy and the Role of Positron Emission Tomography

After completion of chemotherapy, restaging CT scans are performed. If a patient is found to have residual mass measuring 3 cm or less in size with normal tumor markers, active surveillance should be pursued. After chemotherapy, residual disease measuring greater than 3 cm can be further evaluated by PET imaging. Evidence for the role of PET imaging in the setting of residual disease greater than 3 cm was presented by De Santis et al (³⁴). In this evaluation of 33 patients with follow-up time of 23 months, the positive predictive value of fluorodeoxyglucose (FDG) PET was 100%, with specificity and sensitivity of 100% and 89%, respectively, for the identification of residual disease in lesions larger than 3 cm. Although encouraging, the role of PET imaging in this setting is being reexamined because several false-positive cases from our institution have been recently identified (³⁵).

Positron Emission Tomography–Negative Disease Postchemotherapy

If there is no evidence of avid uptake on PET after chemotherapy, the patient enters the active surveillance strategy. If the patient is unable to have PET imaging, surgical biopsy can be considered for those patients with residual disease measuring greater than 3 cm.

Positron Emission Tomography–Positive Disease Postchemotherapy

At MD Anderson, a positive PET scan requires a confirmatory biopsy. If residual disease is confirmed, several options can be considered. First, salvage radiation therapy to the residual mass can be offered, but this does not provide long-term control. Second, the patient can be offered salvage chemotherapy. Finally, the patient may undergo high-dose chemotherapy with autologous stem cell transplantation. See Fig. 39-3 for the algorithm of our management strategy.

Management of Advanced, Intermediate-Risk Seminoma

Patients with advanced, intermediate-risk seminoma have nonpulmonary visceral metastasis. The most common sites of disease are the liver and bone. These rare patients are offered systemic chemotherapy on presentation (see Fig. 39-3). The chemotherapy regimens commonly used are four cycles of BEP, four cycles of etoposide, ifosfamide, cisplatin (VIP), or four cycles of paclitaxel, ifosfamide, cisplatin (TIP) (³⁶).

Salvage Therapy for Refractory/Recurrent Seminoma

The primary treatment for recurrence after radiotherapy is salvage chemotherapy. For patients with lung metastasis (good-risk category), the standard of care is administration of either three cycles of BEP or four cycles of EP. In patients with bone or liver metastasis (intermediate-risk category), salvage chemotherapy is pursued with four cycles of BEP, TIP, or VIP. Bleomycin should be avoided in men older than 50 years.

Clinical signs of chemotherapy-refractory disease should be approached with an aggressive change of strategy, including the option of high-dose chemotherapy and stem cell transplantation. Usually reserved for BEP failures, the role of stem cell transplantation in refractory/recurrent advanced seminoma was addressed by Einhorn et al (³⁷). Nineteen percent of a series of 184 patients were patients with metastatic testicular seminoma. At a median follow-up of 48 months, 26 of 35 patients with seminoma treated were in complete remission. Patients in this category should be considered for referral to transplant centers if possible.

Histology

Embryonal Carcinoma

Embryonal carcinoma is the second most common pure presentation of GCT. It is rarely seen at the extremes of age, most commonly presenting in the 20- to 30-year age group, and presents with metastasis in one-third of cases. Microscopically, embryonal carcinoma cells are the most undifferentiated of the GCT types and are characterized by microscopically varied cells with indistinct borders and scant cytoplasm, giving the appearance of overlapping nuclei. Tumor cells can be seen in sheets or arranged as papillary or tubular structures with a high mitotic rate. There is a propensity for vascular invasion. Phenotypic characterization can reveal positivity for cytokeratin, CD30, PLAP, AFP, and hCG. Modest elevations of both AFP and hCG are typical, but importantly, pure embryonal cancers can be marker negative in the serum. Figure 39-5 shows the typical histologic appearance of embryonal carcinoma.

Endodermal Sinus Tumors (or Yolk Sac Tumors)

Pure yolk sac tumors are extremely rare in the adult patient but account for the majority of childhood GCTs. In adults, EST or yolk sac elements are commonly seen as a component of mixed NSGCTs. Microscopically, EST can manifest as macrocystic, papillary, solid, or a glandular/alveolar pattern with perivascular arrangements of epithelial cells known as glomeruloid or Schiller-Duval bodies. Very high serum AFP levels generally reflect the presence of an EST component, and serum levels of AFP immediately prior to the start of chemotherapy are important prognostically in the classification of good- (AFP <5,000 ng/mL), intermediate- (5,000-10,000 ng/mL), and poor-risk (>10,000 ng/mL) metastatic NSGCTs. Figure 39-6 shows the typical histological appearance of an EST carcinoma.

Choriocarcinoma

Also rare in the pure form in the adult population, choriocarcinoma frequently presents as a component of mixed NSGCTs. Choriocarcinomas comprise both syncytiotrophoblasts and cytotrophoblasts, typically arranged in sheets or nests. Choriocarcinomas generally make copious amounts of hCG, and the level of this marker is also an indication of prognosis in metastatic NSGCTs. Levels of hCG greater than 50,000 mIU/mL are a marker of poor-prognosis NSGCT and are typical of metastatic choriocarcinoma. Half of choriocarcinomas are PLAP positive. Choriocarcinoma elements tend to dominate the clinical course and frequently metastasize to the brain. Symptoms of hyperthyroidism are common, owing to stimulation of the TSH receptor by hCG, and treatment such as a β-blocker is indicated while chemotherapy is initiated. Figure 39-7 shows the typical histological appearance of choriocarcinoma.

Teratoma

Teratomas possess somatic cells from at least two germ cell layers (ectoderm, endoderm, and mesoderm). Variable degrees of differentiation allow for the subclassification of mature and immature forms. A mature teratoma consists of terminally differentiated tissues and can form cystic structures. Although histologically bland, this low-grade malignancy can grow to a threatening dimension and become unresectable. Only about 2% to 3% of all GCTs show mature teratoma as the only histologic component, but teratoma is commonly present as an element of a mixed GCT. An adult man presenting with teratoma as the only histologic pattern should be presumed to have a mixed GCT and be treated as such. An immature teratoma is less differentiated, although this distinction has no known clinical significance.

One of the unfortunate manifestations is the development of somatic (non-GCT) malignancy within a teratoma. Sometimes known as “teratoma with malignant transformation,” this entity typically displays the biology of whatever histology develops and can range from leukemias to sarcomas to carcinomas. In general, transformation to somatic malignancy carries a poor prognosis, and the best prevention is to surgically remove all residual teratoma whenever possible (³⁸). Figures 39-8 and 39-9 represent the typical histological and gross appearance of teratoma, respectively.

Clinical Features

As described previously, approximately half of testicular GCTs show histologic elements other than seminoma or produce serum elevation of AFP indicating nonseminoma. These cancers are collectively known as mixed GCTs or NSGCTs, and they form a group of histologically and clinically diverse cancers (³⁹). The NSGCTs are more likely to spread hematogenously with increased risk of distant metastasis when compared to seminomas. Because of the unique and heterogeneous nature of NSGCTs, there are several clinical presentations that warrant further discussion because of their significance to patient care and prognosis.

Growing Teratoma Syndrome

Residual teratoma is a low-grade, slow-growing malignancy that can be fatal by inexorable growth. This can take 10 or even 20 years to become threatening and thus can be missed without dedicated lifelong follow-up of patients with NSGCTs. One of the most remarkable and clinically important features of teratomas is that they are often “pushing” and rarely invasive. Thus, at surgery, even very large masses are sometimes removed far more easily than would be expected on the basis of the preoperative imaging. It is important to consult a center where sufficient surgical experience is available before concluding that a residual teratoma is “unresectable” (⁴⁰).

Choriocarcinoma Syndrome

As the name implies, choriocarcinoma syndrome is seen in the setting of high-volume NSGCT that shows predominantly choriocarcinoma histology and is associated with very high (in some cases over 1 million mIU/mL) levels of β-hCG. This syndrome is characterized by prominent constitutional symptoms that represent the effects of both a bulky cancer and secondary hyperthyroidism caused by cross-reaction of hCG with TSH receptors. Typically, patients are rapidly losing weight, tachycardic, anxious, and diaphoretic and have tender gynecomastia from secondary hyperprolactinemia. In addition, most patients have high-volume lung metastases with impending respiratory compromise from the burden of pulmonary metastasis. This is a medical emergency, and treatment should not be delayed for histologic confirmation because this is a pathognomonic constellation in a young man. Metastatic choriocarcinoma has a propensity for brain metastasis, although this is not always apparent on baseline imaging.

Prognosis

As described for seminoma, the IGCCCG developed a prognostic staging system for NSGCTs, with extrapulmonary visceral metastasis found as a major factor in prognosis. Unlike seminoma, prechemotherapy tumor markers were identified as significant in the prognosis of these patients. The prognostic categories are outlined in Table 39-2. In general, patients with mediastinal primary, nonpulmonary visceral metastasis and “poor-risk markers” as defined in the table are considered to have a poor prognosis and have a 5-year OS of 48% with standard treatment. Patients with testis or retroperitoneal primary and no extrapulmonary visceral metastasis are placed in the good-prognosis category based on tumor marker levels as described in the table. Patients with a good prognosis have a 5-year OS of 92%. All others are placed in the intermediate-risk group and have a 5-year OS of 80% (²). Van Dijk et al (³) updated the 5-year OS data for NSGCTs in a pooled meta-analysis. The authors reported a 5-year OS of 94% for good prognosis, 83% for intermediate prognosis, and 71% for poor prognosis. This illustrates the improving survival rates in the high-risk group.

Management of Clinical Stage I Nonseminoma Germ Cell Tumors

In general, individuals with clinical stage I NSGCT include patients with normal markers postorchiectomy and no evidence of disease outside the resected testis, epididymis, or cord. As with seminoma, radical inguinal orchiectomy is the initial therapy for early-stage NSGCT. Appropriate surgery will cure approximately 70% of patients in clinical stage I. The two identified risk factors in these patients include percentage of embryonal histology and presence of lymphovascular invasion (LVI), with LVI the most predictive (⁴¹). Patients are considered low risk for recurrence postorchiectomy if there is less than 50% embryonal component in the tumor and no evidence of LVI. The role of percentage of embryonal component is debatable, as it is often seen together with LVI. In fact, European guidelines utilize only absence of LVI for determination of “low risk” for recommendation of observation (⁴²).

Observation

Observation is a reasonable strategy for the reliable low-risk patient, which in practice can be those with absence of LVI. The active surveillance schedule as outlined by the National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology recommends that patients should have a physical examination and tumor marker measurements every 2 months during the first year, every 3 months during the second year, and every 4 to 6 months during the third year. Chest x-ray is recommended at 4 and 12 months, then annually. Abdominal and pelvic CT is recommended approximately every 4 months during the first year and annually for years 2 and 3 (⁴³).

Observation is also acceptable for high-risk patients. The NCCN guidelines recommend more frequent imaging, with chest x-ray every 2 months in the first year, every 3 months in the second year, and every 4 to 6 months in the third year. Also recommended are abdominal and pelvic CT every 4 months in the first year, every 4 to 6 months in the second year, and every 6 months in the third year.

Retroperitoneal Lymph Node Dissection

Retroperitoneal lymph node dissection (RPLND) is a surgical removal of the “landing zone” lymph nodes and is an accurate staging strategy. However, its role in primary prevention of recurrence in patients with stage I NSGCT is controversial. Morbidity of RPLND includes sympathetic nerve damage that may lead to failure of ejaculation and infertility; however, use of a modified surgical template is a nerve-sparing approach that can preserve the sympathetic nerves and may facilitate anterograde ejaculation in 90% or more patients. Stephenson et al (⁴⁴) reported that RPLND in patients with clinical stage I yielded a 4-year progression-free probability of 96% and is an option for therapy in this patient population. Higher failure rates have been reported for patients with high-risk clinical stage I NSGCT. Patients who do not undergo prophylactic RPLND must undergo periodic CT scanning of the abdomen to rule out growing teratoma in the retroperitoneum. At MDACC, we have abandoned prophylactic RPLND for stage I NSGCT in favor of active surveillance.

Chemotherapy

Adjuvant chemotherapy for clinical stage I NSGCT consists of one or two cycles of BEP. In a randomized controlled trial, Albers et al (⁴⁵) compared RPLND to one cycle of BEP in 382 patients with a median follow-up of 4.7 years. The 2-year recurrence-free survival was 99.46% in the chemotherapy group and 91.87% in the RPLND group, suggesting an advantage of one cycle of BEP chemotherapy. Tandstad et al (⁴⁶), in the Swedish and Norwegian Testicular Cancer Project (SWENOTECA) study, reported that one cycle of BEP reduced the risk of recurrence by 90% in patients with or without LVI. In practice, adjuvant chemotherapy should only be offered to patients with either LVI, embryonal carcinoma-predominant tumor, or both. Our algorithm for management of nonseminoma testicular cancer is shown in Fig. 39-10.

Management of Good-Risk Clinical Stages IIA and IIB Nonseminoma Germ Cell Tumors

Patients with tumor marker—negative stages IIA or IIB NSGCTs—present a unique clinical situation. At our institution, these patients are divided into groups by CT evidence of disease greater than or less than 3 cm. If patients have negative tumor markers with a retroperitoneal mass less than 3 cm after orchiectomy, the options are close follow-up or primary RPLND. Patients with elevated serum tumor markers or retroperitonal mass larger than 3 cm are treated with primary chemotherapy with three cycles BEP or four cycles EP. If residual mass greater than 1cm is detected on follow-up staging, surgical resection is recommended.

Management of Good-Risk Stages IIC and III Nonseminoma Germ Cell Tumors

Patients with bulky retroperitoneal disease of greater than 5 cm or pulmonary metastasis with relatively low serum markers constitute those with advanced disease, but still with favorable prognosis. These patients may be either stage IIC or IIIA according to the AJCC criteria and are considered together in this discussion. The primary mode of treatment in this patient population is systemic chemotherapy. This may be administered before or after radical orchiectomy as long as surgical resection of the primary is performed after completion of therapy. Once again, three cycles of BEP chemotherapy are considered standard of care, and four cycles of EP are considered a reasonable alternative for patients with a contraindication to receive bleomycin. Resection of residual disease present on restaging should be performed.

Pathology of the resected tumor after salvage chemotherapy is different from after primary chemotherapy. Following primary chemotherapy, viable GCT, fibrosis, and teratoma are found in approximately 20%, 40%, and 40% of pathological specimens, respectively, compared to 50%, 10%, and 40% following salvage chemotherapy, respectively. Patients with greater than 10% viable GCT in the residual pathology specimen after primary chemotherapy should receive an additional two cycles of platinum-based chemotherapy (see Fig. 39-10).

Management of Intermediate- and Poor-Risk Advanced-Stage IIIB and IIIC Nonseminoma Germ Cell Tumors

Patients with advanced NSGCTs who present with intermediate- or poor-risk features are managed with systemic chemotherapy consisting of four cycles of BEP or its equivalent (VIP or TIP). In selected cases, the treatment may be started based on clinical diagnosis prior to radical orchiectomy. Patients with persistent elevation of tumor markers after four courses of first-line chemotherapy in most cases should go on to receive salvage chemotherapy or high-dose chemotherapy with autologous stem cell transplantation.

Personalized Strategy Based on Tumor Marker Decline

Failure of either AFP or hCG to normalize is a well-recognized feature of chemotherapy resistance (⁴⁷). The rate of tumor marker decline has also been studied as a predictor of poor outcome. For patients presenting with stage IIIC NSGCT, it is possible to identify a subgroup of about 25% who, based on favorable marker decline, will do comparatively well and a larger group of about 75% whose outcome with standard therapy is poor (⁴⁸). This observation led to a phase III clinical trial in which patients with stage IIIC NSGCT received BEP in the first cycle, and at completion of the first cycle, those with normalization or favorable decline in both tumor markers remained on BEP (four courses total) and the rest were randomized (1:1) to BEP or an intensified regimen. Final results of this study confirmed superior PFS and OS in the group with favorable decline compared to unfavorable decline (treated with BEP) and demonstrated a statistically significant improvement in 3-year PFS for patients randomized to intensified treatment versus BEP (⁴⁹).

Management of Recurrent and Refractory Nonseminoma Germ Cell Tumors

Several chemotherapy regimens with clinical activity in the salvage setting have been reported, and these include VIP, TIP, VeIP (vinblastine, ifosfamide, cisplatin), or gemcitabine/oxaliplatin. In general, many patients respond and some are even cured with salvage chemotherapy and surgical consolidation, especially those with a small or moderate volume of disease.

High-Dose Chemotherapy

High-dose induction chemotherapy with autologous peripheral blood stem cell transplantation has been studied in first recurrence and later recurrence of GCT. Einhorn et al (³⁷) retrospectively reviewed 184 patients (149 patients with advanced NSGCT) with a median follow-up of 48 months. Ninety of the 149 patients (60%) with NSGCT treated with high-dose chemotherapy and subsequent autologous stem cell transplantation were disease free at follow-up. The authors advocated the use of this aggressive treatment as second-line therapy, suggesting that it is more advantageous than when it is used in the third-line setting. Based on this study and despite the absence of a randomized trial, patients with recurrent or refractory advanced-stage NSGCT may be considered for this aggressive, yet effective, treatment strategy.

Special Considerations

Pitfalls in Tumor Marker Elevation

Mild elevation of β-hCG (usually <20 mIU/mL) may occur secondary to hypogonadism or marijuana use and therefore should not always be attributed to residual or recurrent tumor. Modest elevation of AFP may be present with residual teratoma and will normalize following surgical resection, but it may also be constitutionally elevated or indicate the presence of liver disease. In addition, elevated tumor markers may indicate unidentified central nervous system disease or residual primary testicular tumor.

Role of Desperation Surgery

There are patients with NSGCTs who have rising tumor markers despite optimal systemic therapy. In these instances, “desperation surgery” to resect all visible disease may be the only option. It is estimated that up to 20% of patients who fit these criteria can be cured with surgical resection. Patients with isolated retroperitoneal lymph node disease, those with AFP-only elevation, and those who undergo a complete resection of residual disease have the most favorable outcome. Referral to a center with high surgical expertise in this setting is recommended, as potentially large en bloc resections may be required to achieve the desired outcome of complete resection.

Treatment of Late Relapse

Late relapse is defined as disease recurrence after 24 months from chemotherapy treatment. Teratoma and EST are the most common histologies in this setting, with pure teratoma conferring a better prognosis. Surgery is the preferred initial treatment in these cases if the tumor is anatomically resectable.

Late Complications of Therapy

Although rare, there are specific complications associated with treatment of GCTs that are especially important in this patient population because curability may lead to a normal life expectancy. Secondary leukemias occur in fewer than 0.5% of patients and are associated with use of etoposide. Bleomycin toxicity can appear early and is most associated with dose greater than 200 IU. Patients may also have increased risk of vascular side effects, including Raynaud’s syndrome and hypertension. Up to 25% of patients may develop the metabolic syndrome. Additional complications include renal insufficiency, chemotherapy-induced peripheral neurotoxicity, sensorineural hearing loss, chronic electrolyte abnormalities, and neuropsychiatric abnormalities.

Patients with pure seminoma arising in the mediastinum have similar prognosis as patients with testicular seminomas and are treated with four cycles of EP at our institution, provided they do not have extrapulmonary visceral metastasis. Nonseminomatous extragonadal GCTs represent a distinct subset of GCTs and carry a poor prognosis. The most common origin is the mediastinum, but they can also arise in the retroperitoneum or pineal region. Rare cases involve the vagina, prostate, liver, and orbit.

Mediastinal extra-gonadal germ cell tumors (EGCT) appear as large anterior masses on radiographs. This subset is characterized by prominence of EST and teratoma histology compared to primary testicular GCTs (⁵⁰). Initial diagnosis may be aided by elevations of AFP or hCG. Klinefelter syndrome is associated with increased risk of primary mediastinal NSGCTs (⁵¹). Additional associations include acute megakaryoblastic leukemia, acute myeloid leukemia, myelodysplastic syndrome, and malignant histiocytosis. Some of these cases represent malignant transformation of immature teratoma elements.

Mediastinal NSGCTs are classified as poor-prognosis GCTs (²), and data suggest that long-term survival is approximately 50% (^52,53,54). The aggressive nature of this entity is coupled with the surgical difficulty of resection of residual disease after therapy. Early diagnosis and aggressive resection of mediastinal NSGCTs may improve the outcome. At our institution, the treatment strategy for this rare entity includes presurgical chemotherapy to optimum response and then consolidation surgery.

The GCTs represent the paradigm of curable solid tumors. Optimal management of patients with GCTs requires a multidisciplinary approach, integrating chemotherapy and surgery, to achieve the highest cure rates. Patients who pose a unique diagnostic or therapeutic challenge should be considered for early referral to a large tertiary care center.