Incidence and Epidemiology

Testicular cancer accounted for some 8090 new cases and 380 estimated deaths in 2008.² Although it represents only 1% of cancers in men it is the most common malignancy among men aged 20 to 30 years. Bilateral involvement is seen in 2% to 4% of patients. These tumors are highly curable even in advanced stage. The peak age incidence for seminoma is slightly older compared to NSGCT, with the histologic variant spermatocytic seminoma occurring in men older than age 60.³ Interestingly the worldwide incidence of testicular cancers has doubled in the past 40 years.² Although germ cell tumors can rarely occur in extragonadal sites, their management follows that of testicular germ cell tumors.

Cryptorchidism, or an undescended testis, is the most studied risk factor for developing testis cancer. The relative risk of developing testicular cancer is 3.7 to 7.5.^4,5 Orchiopexy before puberty decreases this risk.⁶ HIV as a risk factor is controversial. Although many reports show an increase in incidence,⁷ population-based studies have failed to confirm this.^8,9 Chromosomal abnormalities most commonly involve chromosome 1 and 12. Deletions are seen in both arms of chromosome 1. The most frequent, and sometimes used diagnostically, is the isochrome of the short arm of chromosome 12, denoted as i(12p), and has been reported in up to 90% of germ cell tumors.¹⁰ Testicular cancers are observed 5 times more frequently among White men than among Black men. An association with the dysplastic nevus syndrome and Klinefelter’s syndrome has also been noted.

Anatomy

The adult testicle typically measures 4 to 5 cm in length and 2.5 cm in diameter. The testicle is covered by a parietal and visceral layer of the tunica vaginalis (Fig. 46-1). When this potential space accumulates fluid, a hydrocele forms. The testicle is encased by a hard outer capsule, the tunica albuginea. On the posterior-lateral aspect of the testicle, the tunica albuginea projects inwards, creating the mediastinum testis, the point of entry of blood vessels and ducts transporting sperm. Within the testicle, approximately 300 lobules exist, containing one or more seminiferous tubules: the site of spermatogenesis as well as site of origin for germ cell tumors. Each lobule of seminiferous tubules has short straight tubes that enter the mediastinum testis which then coalesce, forming the “rete testis” which, in turn, become fewer in number and wider in caliber, forming “efferent ductules.” These exit the testis and enter the head of the epididymis and subsequently the body and tail, where they become the vas deferens. Leydig cells reside in the interstitial tissue between seminiferous tubules and are responsible for testosterone production.

FIGURE 46-1 • Diagram the anatomy of the testis. A, Testis and epididymis. B, Cross section of the testis.

(From Tanagho EA: Anatomy of the lower urinary tract. In Walsh PC, et al, eds: Campbell’s urology, ed 6, Philadelphia, 1992, WB Saunders.)

Pathology

The majority of testicular tumors are of germ cell origin. From a therapeutic perspective, these histologies are divided into two types: seminoma and NSGCTs. The histologies are listed in Table 46-1. The frequency of germ cell tumor histologies encountered is given in parentheses.

Table 46-1 Histologies of Testicular Tumors

Germ Cell Tumors (95%)

Pure seminoma (40%)

Classic Seminoma Anaplastic Seminoma Spermatocytic Seminoma

Embryonal

Teratoma

Choriocarcinoma

Mixed

Seminoma (35%)

Three histologic subtypes of pure seminoma have been described. However, stage for stage, there is no prognostic significance to any of these subtypes. Classic seminoma accounts for 85% of all seminomas and is most common in the fourth decade of life. Grossly, coalescing gray nodules are observed (Fig. 46-2). Microscopically, monotonous sheets of large cells with clear cytoplasm and densely staining nuclei are seen (Fig. 46-3). It is noteworthy that syncytiotrophoblastic elements are seen in approximately 10% to 15% of cases, an incidence that corresponds approximately to the incidence of human chorionic gonadotropin (hCG) production in seminomas.

FIGURE 46-2 • Gross pathologic specimen of a testicular seminoma.

FIGURE 46-3 • Histology of classic seminoma.

Anaplastic seminoma accounts for 5% to 10% of all seminomas. Diagnosis requires the presence of three or more mitoses per high-power field, and the cells demonstrate a higher degree of nuclear pleomorphism than the classic types. Anaplastic seminoma tends to present at a higher stage than the classic variety. When stage is taken into consideration, however, this subtype does not convey a worse prognosis.

Spermatocytic seminoma accounts for 5% to 10% of all seminomas. Microscopically, cells vary in size and are characterized by densely staining cytoplasm and round nuclei that contain condensed chromatin (Fig. 46-4). More than half the patients with spermatocytic seminoma are over the age of 50. The important clinical aspect of spermatocytic seminoma is that they do not metastasize, thus, orchiectomy is curative and no additional therapy is needed.

FIGURE 46-4 • Histology of spermatocytic seminoma.

Clinical Presentation

The classic presentation is that of a painless mass in the testes. Among the differential diagnoses are epididymitis, orchitis, and hydrocele. Trauma may lead to the discovery of an existing tumor but is not thought to be causative. Pain, though not common can be associated with presentation 40% of the time. Delay in diagnosis of greater than 3 to 6 months have been associated with worse prognosis.¹⁴ Evaluation of infertility occasionally leads to the diagnosis.^15,16 Analysis of 38,000 men from the Surveillance, Epidemiology and End Results (SEER) database revealed that infertile men with abnormal semen analyses have a 20-fold greater incidence of testicular cancer compared to the general population.¹⁵ Gynecomastia and breast tenderness may be seen in 5% of patients¹⁷ owing to the production of estradiol in response to elevated levels of hCG. Patients with metastases to lymph nodes in the retroperitoneum most commonly present with low back pain and may or may not have hydronephrosis with secondary ureteral obstruction.

Serum Tumor Markers

Germ cell tumors frequently produce proteins that can serve as tumor markers for disease burden as well as diagnosis (Table 46-2). The two most important of these are AFP and the β subunit of human chorionic gonadotropin (β-hCG). Lactate dehydrogenase (LDH) level is also used as a marker for disease burden. It should be kept in mind, however, that these proteins are not specific to germ cell tumors. The serum half-life of these tumor markers is of clinical relevance and is 4 to 6 days for AFP; for β-hCG, 1 to 2 days. After 5 half-lives a previously elevated serum marker should return to within normal levels if all tumor cells have been eradicated. In pure seminoma elevated β-hCG is present about 10% of the time, yet if present tends to be modest in magnitude (usually <100). AFP, by contrast, is never present with pure seminoma.

Table 46-2 Frequency of Serum Marker Elevation in Testicular Tumors

AFP, Alpha-feto protein; hCG, human chorionic gonadotropin.

Routes of Spread

With the exception of choriocarcinoma, which demonstrates early hematogenous spread, germ cell tumors of the testis typically spread in a stepwise fashion via lymphatic channels. Lymph nodes of the testis extend from T11 to L4 but are concentrated at the level of the renal hila due to their common embryological origin with the kidney. The right and left testes possess somewhat different lymphatic pathways of clinical relevance in designing radiation fields. The primary landing site for the right testis is the interaortocaval area at the level of the right renal hilum. Stepwise spread, in order, is to the precaval, preaortic, paracaval, right common iliac, and right external iliac lymph nodes. The primary landing site for the left testis is the periaortic area at the level of the left renal hilum. Stepwise spread, in order, is to the preaortic, left common iliac, and left external iliac lymph nodes. In the absence of disease on the left side, no crossover metastases to the right side have ever been identified. However, right-to-left crossover metastases are common.^18,19 These observations have resulted in modified surgical dissections to avoid injury to the sympathetic nervous system in select patients.

Certain factors may alter the primary drainage of a testis neoplasm. Invasion of the epididymis or spermatic cord may allow spread to the distal external iliac and obturator lymph nodes. Scrotal violation or invasion of the tunica albuginea may result in inguinal metastases.

The retroperitoneum is the site most commonly involved in metastatic disease; however, visceral metastases may be seen in advanced disease. The sites involved in decreasing frequency include lung, liver, brain, bone, kidney, adrenal glands, gastrointestinal tract, and spleen.²⁰ As mentioned, choriocarcinoma is the exception to the rule and is characterized by early hematogenous spread, especially to the lung. Choriocarcinoma also has a predilection for unusual sites of metastasis, such as the spleen.

Diagnostic Work-Up and Staging Studies

A testicular mass should be considered a tumor until proven otherwise. Work-up of a patient with a testicular mass should include an ultrasound of the both testes and tests for tumor markers, including AFP, β-hCG, and LDH. Once the diagnosis of testicular cancer has been pathologically established, one should then obtain a computed tomography (CT) scan of the abdomen and pelvis and a chest x-ray. Post-op serum markers should also be obtained, after an appropriate time interval, if they were elevated before surgery. A CT scan of the chest may be helpful to establish a baseline. Lymphangiography, although having the advantage of being able to detect nodal architecture, is now rarely used. The role of a positron-emission tomography (PET) scan in staging is controversial at this time. Its current utility lies in evaluating masses postchemotherapy to detect viable cancer cells. However, the decision to perform surgical resection of the residual mass should not be based exclusively on a positive PET image, since false-positive results appear to be common.²¹ The specificity of PET is significantly higher than that of CT when using a ≥3 cm cutoff. A negative PET scan excludes viable disease.²² Routine blood tests evaluating renal function and liver function would be required in patients with advanced disease. Counseling regarding sperm banking should be offered to all patients.

Prognostic Factors

Several prognostic factors for relapse have been identified. They include age (>30 years old), tumor size (>4 cm), presence of lymph/vascular invasion, histologic subtype (nonclassical), rete testes invasion, pT2, and preoperative levels of detectable hCG.^23,24 Warde et al.²³ demonstrated that primary tumor >4 cm was associated with a two-fold risk of relapse; the presence of rete testes invasion was associated with a 1.7-fold risk of relapse; and having both factors resulted in a 3.4-fold risk of relapse. Absence of rete testes invasion and tumor size <4 cm had a relapse rate of 12%, compared to tumor size >4 cm and absence of rete testes invasion at 17%. Patients with both rete testes invasion and tumors >4 cm had a relapse rate of 32%.²⁵ Low-risk patients such as those with small tumors without rete testes invasion would be ideal candidates for surveillance.

For patients with advanced disease, the International Germ Cell Consensus Classification (IGCCC) risk stratification²⁶ is commonly used (Table 46-3). It stratifies patients into good, intermediate, and poor risk based on the gonadal or extragonadal nature of the primary, the level of tumor markers, and sites of visceral metastases. Nonpulmonary sites of metastases have a poorer outcome. No patient with seminoma has poor risk.

Table 46-3 International Germ Cell Consensus Classification

hCG, Human chorionic gonadotropin; AFP, α-feto protein; LDH, lactate dehydrogenase.

Staging Systems

The American Joint Committee of Cancer (AJCC) TNM staging system (Table 46-4) is currently standard.²⁷ Only stage and disease burden are of clinical prognostic significance for seminomas. Neither the histologic subtype nor elevation of β-hCG has been shown to be of significant prognostic value in seminoma.

Standard Therapeutic Approaches

General Management Principles

After radical inguinal orchiectomy, the management of seminomas depends primarily upon stage and should be part of a multidisciplinary approach. Patients with stage I seminoma have a roughly 20% risk of occult disease in the retroperitoneum. Although standard adjuvant radiation therapy (RT) offers cure rates approaching 99%, the rate of overtreatment is obviously high and concern over late effects in the context of emerging alternate management options warrants further study. The evolving role of surveillance and chemotherapy for Stage I seminomas will be discussed following the presentation of what is still traditionally considered the standard of care, namely adjuvant radiotherapy.

In the rare instance of a second primary early stage seminoma after standard management for the first presentation with adjuvant radiation therapy, such patients can be considered for reirradiation provided that lateral fields are used for this second course and that cumulative doses to the kidneys are carefully calculated.

Stage I (IA, IB, and IS)

The standard management for patients with stage I seminoma includes a radical inguinal orchiectomy followed by adjuvant radiation therapy to the para-aortic and ipsilateral pelvic lymph nodes (sometimes called “dog-leg” field) (Fig. 46-5). In instances where a scrotal approach to orchiectomy is performed, such patients are generally not considered for alternative management such as surveillance or reduced radiation fields. Although thought to be at higher risk for scrotal recurrence, several studies report no increase in pelvic, abdominal, or scrotal recurrence in patients with previous scrotal surgery.²⁸

FIGURE 46-5 • Standard AP “dog-leg” field for a Stage I seminoma of the left testis. Note the inclusion of nodes in proximity to the renal hilum for this left-sided tumor. Kidneys and nodes (large vessels) are drawn from computed tomography simulation scan.

For early-stage NSGCT, a retroperitoneal lymph node dissection (RPLND) is performed, and chemotherapy follows if there is pathologic N2 involvement or for a persistence of elevated serum tumor markers. With a greater propensity for hematogenous spread, adjuvant radiation therapy has been abandoned in favor of surveillance or chemotherapy, and has a limited role in palliating residual bulky disease.

Surveillance for Stage I Seminoma

Surveillance, although commonly used in NSGCT, has only recently been considered for seminomas. In light of the high success rate of salvage chemotherapy (consisting of platinum-based regimens), the necessity of adjuvant radiation therapy after orchiectomy has been called into question. The advantage is that unnecessary treatment can be avoided in approximately 80% to 85% of patients and therefore spare these patients the toxicities of treatment. However, long surveillance follow-up of 7 to 10 years is needed and optimal patient selection is crucial to the success of these programs. However, any advantage should be weighed against the potential harm of whole-body CT scans over a 10-year surveillance period (20 scans) and the toxicities of salvage chemotherapy regimens in relapsed patients. Although it may offer some advantages in well-selected and compliant patients, the long-term benefit has yet to be proven. It is interesting to note that in recent patterns of care surveys the option of surveillance is often not discussed.²⁹

To date, several investigators have published^24,30–33 their experience with surveillance of patients with stage I seminoma (Table 46-5). With good follow-up data, the overall relapse rate varies from 15% to 20%. At relapse, these patients are offered systemic chemotherapy with excellent results. The protocol for following these patients on surveillance requires periodic exams, tumor markers, CT scans, and chest x-rays for a minimum of 7 years. The National Comprehensive Cancer Network (NCCN) guidelines recommend physical exams, markers every 3 to 4 months for years 1 to 3; every 6 months for years 4 to 7, and then annually. Abdominal and pelvic scans are recommended at each visit, and chest x-rays at every alternate visit up to 10 years.

Table 46-5 Surveillance for Stage I Seminoma

Chemotherapy for Stage I Seminoma

Multiple nonrandomized trials have been published^24,34–38 using either a single or 2 cycles of carboplatin. These trials have demonstrated the safety of this approach and have yielded low rates of relapses (Table 46-6).

Table 46-6 Chemotherapy for Stage I Seminoma

The only randomized trial was done by the UK Medical Research Council/European Organization for Research and Treatment of Cancer (MRC/EORTC); 1447 patients were randomized to receive a single dose of carboplatin with an AUC of 7 versus radiotherapy (para-aortic or dog-leg field, 30 Gy). The primary endpoint was relapse-free survival (RFS). A noninferiority design was used and median follow-up was 4 years. RFS at 3-years was similar, 95.5% and 94.8% in the radiotherapy and chemotherapy arms, respectively. New primary second testicular tumors were seen in 10 patients in the RT arm and in two patients in the chemo arm. One seminoma-related death occurred in the RT arm. Recurrences in the RT arm were above the diaphragm and in the chemotherapy group in the retroperitoneum.³⁹ In an updated follow-up presented in 2008 with a median follow-up of 6.5 years, the RFS at 5 years was 96% and 95%, respectively.

Risk-adapted approach involves selective treatment of those patients with increase risk. Such an approach was used in the Spanish Germ Cell Co-Op Group.⁴⁰ Of the 314 patients, 100 had no risk factor (i.e., size >4 cm or rete testes invasion), were given no chemotherapy, and placed on a surveillance protocol. Two hundred fourteen patients had increased risk factors and were treated with two cycles of single-agent carboplatin with an AUC of 7. Overall, a 6% relapse was seen in the surveillance arm and 3.3% in the chemotherapy arm. An overall disease-free survival rate (DFS) was 93% on surveillance and 96% on chemotherapy. This approach spared chemotherapy for 30% of patients. A similar risk-adapted approach has been reported using two cycles of cisplatin and etoposide in patients with either a tumor >4 cm or age <34 years. With a median follow-up of 60 months, no relapses were noted.⁴¹

The downsides of chemotherapy are multiple: the impact on late mortality, overtreatment, risk for secondary cancers, optimum number of cycles not defined, cardiovascular implications, and the fact that, since relapses occur in the retroperitoneum, continued surveillance with CT scans is necessary.

The long-term effects of carboplatin have been evaluated and no excess mortality was noted compared to an age- and sex-matched general UK population. Neither an increase in circulatory disease nor an increase in secondary cancers was noted.⁴²

Chemotherapy for advanced disease has been well described.⁴³ For patients with good-risk disease, three cycles of cisplatin, etoposide, and bleomycin (BEP) or two cycles of cisplatin and etoposide (EP) achieve a high cure rate.⁴⁴ For patients with intermediate risk, four cycles of BEP is considered the standard of care.

Stage II

Stage II seminomas may also be managed with adjuvant radiation therapy, provided that the retroperitoneal involvement is less than 5 cm in maximum dimension (stage IIA and IIB). Recurrence after radiation therapy is directly related to initial bulk. Stage IIC patients should receive chemotherapy. The role of radiation therapy for residual disease after chemotherapy is not well defined, and most of these patients are observed.

Stage III

For Stage III and IV seminomas, the current management is with platinum-based chemotherapy regimens (platinum, etoposide and bleomycin [PEB]), with radiation therapy reserved for persistent or recurrent disease.

Radiation Therapy, Simulation, and Treatment Planning

Late Toxicities and Critical Normal Tissues

Outcomes

Testicular cancers are highly curable and very gratifying to treat. With modern approaches to therapy, the RFS rate for stage I seminoma is greater than 95%, and the cure rate approaches 99%.⁵³ For stage II seminoma the cure rates are close to 98%.⁵⁴ For more advanced stages the long-term survival approaches 85%. For stage I NSGCT, the survival rates are close to 100% and for more advanced disease is in the range of 70% to 80%.