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.
Histological 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.
Histological appearance of EST carcinoma.
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.
Histological appearance of choriocarcinoma.
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.
Histological appearance of teratoma.
Gross appearance of teratoma.
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).
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.
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 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.
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 testicular cancer (nonseminoma).
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 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.
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.
Case 39-2: BEP/TIP Failure
A 24-year-old man presented with lower back pain, anorexia, night sweats, and weight loss. Imaging studies revealed extensive retroperitoneal lymphadenopathy, a right testicular mass, and bilateral lung nodules. Tumor markers were hCG 33,261, AFP 4.1, and LDH 1,847. A fine-needle aspiration of the retroperitoneal mass revealed embryonal carcinoma. Chemotherapy with BEP was initiated. The kinetics of decline of serum hCG levels were as shown next for the first three of four planned cycles:
s/p cycle 1: 1,507
s/p cycle 2: 279
s/p cycle 3: 323
Salvage chemotherapy commenced after the third cycle of BEP. The patient received four cycles of TIP, with decrease in adenopathy and decline of serum hCG to an undetectable level. The patient was then referred for RPLND and right radical orchiectomy. Pathology revealed no viable tumor. Two months postoperatively, serum hCG rose to 161. He received one cycle of irinotecan, paclitaxel, and oxaliplatin with tumor marker normalization. He then underwent tandem peripheral blood stem cell transplantation with high-dose Ifosfamide, Carboplatin and Etoposide (ICE). He remains disease free 3.5 years later.
Comments: For symptomatic patients with intermediate- or poor-risk GCTs, chemotherapy can be initiated before orchiectomy. Rising tumor markers during BEP chemotherapy signal BEP failure and dictate a change of therapy. The best results are achieved with high-dose chemotherapy and stem cell transplantation.
Case 39-3: The Challenge of Managing Intercurrent Illness
A 35-year-old man who was a heavy smoker and marijuana user underwent a left orchiectomy for a 3.5-cm mixed NSGCT and presented 2 months later to MDACC with left groin pain and left thigh numbness. Tumor markers were AFP 6,575, hCG 1,059, and LDH 2,441. Computed tomographic scans revealed bilateral lung nodules, a large (14.7-cm) retroperitoneal mass, left hydronephrosis, and multiple other enlarged abdominal and pelvic lymph nodes. During the first BEP chemotherapy cycle, he suffered an inferior myocardial infarction (MI) secondary to an occluding atherosclerotic plaque in the right coronary artery. After coronary stenting and optimal medical therapy, the patient was able to complete four cycles of BEP on schedule and at full dose, without delay or significant complications, except for moderate peripheral neuropathy. His tumor markers declined as follows:
s/p cycle 1 AFP = 3,853, hCG = 34.7
s/p cycle 2 AFP = 542, hCG = 5.2
s/p cycle 3 AFP = 88.1, hCG = 4.6
s/p cycle 4 AFP = 42, hCG = 4.7
The patient received intramuscular testosterone injection for a low serum testosterone level, and 3 weeks later serum hCG was <1.0. Six months after his MI, the patient had resection of the large left retroperitoneal mass, the left kidney, and left adrenal gland; RPLND; and segmental resection of the left psoas muscle. Pathology of the specimen revealed 98% necrosis and only two microscopic foci of residual viable EST in transition to adenocarcinoma. The patient has been recurrence free for 3 years.
Comments: This case illustrates three points. The first is the importance of pursuing chemotherapy while managing an intercurrent illness. The second point is to remember that there are causes of elevated tumor markers other than tumor. The third point is that we do not treat foci of Malignant transformation of Teratoma (MTT).
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.