Management of testicular seminoma has benefited from numerous advances in imaging, radiotherapy, and chemotherapy over the last 50 years leading to nearly 100% disease-specific survival for low-stage seminoma. This article examines the evaluation and management of low-stage testicular seminoma, which includes clinical stage I and IIA disease. Excellent outcomes for stage I seminoma are achieved with active surveillance, adjuvant radiotherapy, and adjuvant single-agent carboplatin. Current areas of research focus on optimizing surveillance regimens and minimizing the morbidity and long-term complications of adjuvant treatment. Radiotherapy continues to be the primary treatment option for patients with clinical stage IIa disease.
Key points
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Initial staging evaluation of seminoma after orchiectomy with serum tumor markers and imaging of chest, abdomen, and pelvis is critical.
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Disease-specific survival approaching 100% achieved for low-stage seminoma with active surveillance, adjuvant radiotherapy, or adjuvant single-agent carboplatin.
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Patient selection depends on specific patient and cancer characteristics.
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Risk of unnecessary treatment and sequelae of adjuvant therapy must be weighed against pitfalls of active surveillance such as poor compliance.
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Further research is needed to guide patient selection for adjuvant therapy and to optimize active surveillance protocols.
Introduction
Epidemiology
Although testicular cancer is the most commonly diagnosed cancer among men aged 14 to 44 years worldwide, it is a rare disease accounting for only 1% to 2% of malignancies. Over the last 40 years, for unknown reasons, the global incidence of testicular cancer has doubled. In the United States, there will be an estimated 8820 new cases of testicular cancer in 2014, accounting for 380 deaths. Testicular cancers are classified as seminomatous or nonseminomatous, with a nearly 1:1 incidence ratio. Among testicular cancer diagnoses, seminoma accounts for 46% to 60%.
Histologic Subtypes
Classic or typical seminoma accounts for 95% of seminomas. Gross pathology reveals a white or tan tumor with lobulations. Microscopic examination demonstrates large uniform cells in a sheetlike distribution with a characteristic “fried egg” appearance. Syncytiotrophoblasts may be present, which accounts for the 10% to 15% of seminomas that produce abnormally high levels of human chorionic gonadotropin (hCG). Immunohistochemistry plays a limited role in the diagnosis of seminoma, but nearly all seminomas stain strongly positive for placental alkaline phosphatase (87%–100% of cases). However, placental alkaline phosphatase staining is not specific for seminoma.
Histologic variants of seminoma include tubular seminoma, which histologically mimics Sertoli cell tumor, and anaplastic seminoma. Anaplastic seminoma is a subtype of historical significance referring to seminomas with high mitotic activity. Both tubular and anaplastic seminomas have a similar prognosis and clinical management strategy as classic seminoma.
Spermatocytic seminoma is rare (<1% of germ cell tumors [GCTs]), originates from more mature germ cells compared with classic seminoma, and has entirely different genetic and morphologic signatures. These tumors are also unique because cryptorchidism is not a risk factor and they typically present in older men (mean age at diagnosis, 54 years). Microscopy shows 3 distinct cell types (small, medium, and large) with round nuclei and no placental alkaline phosphatase expression. Spermatocytic seminomas have very low malignant potential and are usually cured with radical orchiectomy followed by surveillance, with the exception of rare cases containing sarcomatous differentiation.
Patterns of Spread
Classic seminoma metastasizes via lymphatic spread to the retroperitoneum if lymphatic flow has not been altered, such as after previous inguinal or scrotal surgery. The primary landing zone for right-sided tumors is the interaortocaval retroperitoneal nodes, compared with left-sided tumors, which typically spread initially to the left paraaortic (PA) nodes. Lymphatic spread within the retroperitoneum tends to be from right to left. Although rare, advanced seminoma presents with supradiaphragmatic lymphadenopathy or visceral metastases in the lung, liver, brain, and other sites. Even advanced seminoma has a relatively favorable prognosis and only liver and brain metastasis have been associated with an adverse prognosis.
Introduction
Epidemiology
Although testicular cancer is the most commonly diagnosed cancer among men aged 14 to 44 years worldwide, it is a rare disease accounting for only 1% to 2% of malignancies. Over the last 40 years, for unknown reasons, the global incidence of testicular cancer has doubled. In the United States, there will be an estimated 8820 new cases of testicular cancer in 2014, accounting for 380 deaths. Testicular cancers are classified as seminomatous or nonseminomatous, with a nearly 1:1 incidence ratio. Among testicular cancer diagnoses, seminoma accounts for 46% to 60%.
Histologic Subtypes
Classic or typical seminoma accounts for 95% of seminomas. Gross pathology reveals a white or tan tumor with lobulations. Microscopic examination demonstrates large uniform cells in a sheetlike distribution with a characteristic “fried egg” appearance. Syncytiotrophoblasts may be present, which accounts for the 10% to 15% of seminomas that produce abnormally high levels of human chorionic gonadotropin (hCG). Immunohistochemistry plays a limited role in the diagnosis of seminoma, but nearly all seminomas stain strongly positive for placental alkaline phosphatase (87%–100% of cases). However, placental alkaline phosphatase staining is not specific for seminoma.
Histologic variants of seminoma include tubular seminoma, which histologically mimics Sertoli cell tumor, and anaplastic seminoma. Anaplastic seminoma is a subtype of historical significance referring to seminomas with high mitotic activity. Both tubular and anaplastic seminomas have a similar prognosis and clinical management strategy as classic seminoma.
Spermatocytic seminoma is rare (<1% of germ cell tumors [GCTs]), originates from more mature germ cells compared with classic seminoma, and has entirely different genetic and morphologic signatures. These tumors are also unique because cryptorchidism is not a risk factor and they typically present in older men (mean age at diagnosis, 54 years). Microscopy shows 3 distinct cell types (small, medium, and large) with round nuclei and no placental alkaline phosphatase expression. Spermatocytic seminomas have very low malignant potential and are usually cured with radical orchiectomy followed by surveillance, with the exception of rare cases containing sarcomatous differentiation.
Patterns of Spread
Classic seminoma metastasizes via lymphatic spread to the retroperitoneum if lymphatic flow has not been altered, such as after previous inguinal or scrotal surgery. The primary landing zone for right-sided tumors is the interaortocaval retroperitoneal nodes, compared with left-sided tumors, which typically spread initially to the left paraaortic (PA) nodes. Lymphatic spread within the retroperitoneum tends to be from right to left. Although rare, advanced seminoma presents with supradiaphragmatic lymphadenopathy or visceral metastases in the lung, liver, brain, and other sites. Even advanced seminoma has a relatively favorable prognosis and only liver and brain metastasis have been associated with an adverse prognosis.
Clinical evaluation
Presentation and Initial Evaluation
Seminoma incidence peaks between 34 and 45 years, approximately 10 years later than other GCTs. Most patients with testicular cancer will present with a painless mass. If present, pain may be owing to rapid growth of the tumor, hemorrhage, or infarction. Symptoms are observed more commonly with nonseminomatous GCTs compared with seminomas, because seminomas tend to have a more indolent disease course. Gynecomastia and infertility can rarely be presenting symptoms. Additionally, a small percentage of cases present with symptoms of metastatic disease, such as abdominal or flank pain, back pain, palpable mass of the abdomen or neck, lower extremity swelling, or a unilateral right-sided varicocele. There is a well-recognized diagnostic delay between the onset of symptoms and diagnosis of seminoma, with a mean delay of 4.9 months.
Clinicians should assess for GCT risk factors when taking a history from patients with a testicular mass. A history of undescended testicle is the most significant risk factor for testicular GCT with a relative risk of between 2.7 and 8. Prepubertal orchiopexy seems to result in a significant reduction in the relative risk of testicular GCTs. Orchiopexy seems to reduce specifically the risk of seminoma, evidenced by a 74% incidence of seminoma among malignant tumors arising from uncorrected cryptorchid testicles compared with a 29% incidence of seminoma among GCTs arising after orchiopexy. Other established risk factors that should be assessed include a family history of testicular cancer, personal history of testicular cancer, presence of intratubular germ cell neoplasia, or a history of other urogenital abnormalities such as hypospadias.
The initial evaluation of a patient presenting with a testicular mass should routinely involve scrotal ultrasonography as an extension of the physical examination. Both testes should be examined. Ultrasonography will usually reveal a solitary, hypoechoic lesion. Seminomas tend to have a more homogenous appearance compared with nonseminomatous GCTs. They can also seem to be lobulated or multinodular with cystic spaces.
Serum Tumor Markers
Before radical orchiectomy, serum tumor markers such as α-fetoprotein (AFP), hCG, and lactate dehydrogenase should be obtained. The presence of syncytiotrophoblastic elements in approximately 10% to 15% of classical seminomas account for the increased hCG level in this subset of seminomatous GCTs. When hCG is increased, it is typically less than 500 IU/mL. Although increased tumor markers do play a role in the staging of testis cancer ( Table 1 ), patients with hCG-producing seminomas do not have a worse prognosis compared with nonsecretors. In contrast with nonseminomatous GCTs, tumor markers are not utilized in the International Germ Cell Cancer Collaborative Group risk stratification schema ( Table 2 ) for seminomas. Detection of lactate dehydrogenase does not aid in the differential diagnosis of seminomatous or nonseminomatous GCTs, although levels may reflect overall disease burden. Pure seminoma never secretes AFP; therefore, an increased AFP level indicates a nonseminomatous component or the presence of liver metastases, even when the primary tumor is pure seminoma on final histology. Several recent studies have investigated the role of serum microRNAs as a novel class of tumor markers for the management of testicular GCTs, but further prospective evaluation is needed.
| Stage | AFP (μg/L) | hCG (IU/L) | LDH |
|---|---|---|---|
| S0 | Normal | Normal | Normal |
| S1 | <1000 | <5000 | <1.5 × NL a |
| S2 | 1000–10,000 | 5000–50,000 | 1.5–10 × NL a |
| S3 | >10,000 | >50,000 | >10 × NL a |
| Stage and Risk Category | Primary Tumor | N Stage | Clinical M Stage | Post-Orchiectomy Tumor Markers |
|---|---|---|---|---|
| IA | pT1 (no involvement of tunica vaginalis or spermatic cord, no LVI) | N0 | M0 | S0 |
| IB | pT2 (involvement of tunica vaginalis or spermatic cord, +LVI) | N0 | M0 | S0 |
| IS | Any pT stage | N0 | M0 | S1 or greater |
| IIA | Any pT stage | N1 (<5 retroperitoneal nodes and each ≤ 2 cm) | M0 | S1 |
| IIB | Any pT stage | N2 (>5 retroperitoneal nodes or ≥1 node 2–5 cm) | M0 | S1 |
| IIC | Any pT stage | N3 (retroperitoneal lymph node > 5 cm) | M0 | S1 |
| IIIA | Any pT stage | Any N stage | M1a (distant lymph nodes or lungs) | S0 or S1 |
| IIIB | Any pT stage | Any N stage | M0 or M1a | S2 |
| IIIC | Any pT stage | Any N stage | M0 or M1a | S3 |
| Any pT stage | Any N stage | M1b (N on pulmonary visceral) metastases) | Any S | |
| Low risk | Any primary site | Any N stage | No nonpulmonary visceral metastases | Any S (normal AFP required) |
| Intermediate risk | Any primary site | Any N stage | Nonpulmonary visceral metastases | Any S (normal AFP required) |
As stated, serum tumor markers should be measured before radical orchiectomy, after radical orchiectomy, and later as part of surveillance protocols or during treatment of metastatic disease. Declining serum tumor markers at a rate consistent with the marker’s well-established half-life is expected after radical orchiectomy. Persistent markers or a decline slower than expected typically indicates the presence of metastatic disease.
Orchiectomy
After scrotal ultrasonography and serum tumor markers, the next step in management of a solid testicular mass usually involves a radical inguinal orchiectomy. Important surgical principles include high ligation of the spermatic cord using nonabsorbable suture to allow future identification if retroperitoneal lymph node dissection is required subsequently. Testis-sparing surgery has been used as a treatment option for patients with bilateral tumors or a testicular mass in a solitary testicle. A number of studies have demonstrated acceptable oncologic outcomes and preservation of hormonal function and fertility with this approach, although local recurrence rates may be as high as 27% if adjuvant radiation therapy (RT) to the testicle is not used.
Radical orchiectomy provides excellent local oncologic control in addition to establishing the histologic type, grade, and stage of the primary tumor. Pathologic review by an experienced genitourinary pathologist is strongly encouraged because tumors can be reclassified—for example, from seminoma to nonseminoma—in approximately 4% of cases and discrepancies in staging of the primary based on the presence or absence of lymphovascular invasion occur in 10% of cases. Distinguishing the exact histologic type and stage of the primary tumor is critical for finalizing management options for low-stage testicular cancer.
Imaging
Complete diagnostic and staging evaluations of testicular cancer involve imaging of the retroperitoneum and lungs. Imaging of the lungs can include a CT scan or plain chest radiograph, depending on the level of suspicion. Contrast-enhanced CT of the abdomen and pelvis remains the imaging modality of choice for evaluating the retroperitoneum. Using a size criterion of 8 mm or larger in the maximum axial dimension achieves 100% specificity but only 47% sensitivity for detection of retroperitoneal lymph node metastases. Other studies have shown that 25% to 30% of patients harbor occult metastases that cannot be detected on CT. Efforts to improve the accuracy of clinical staging have examined other imaging modalities, including MRI and fluorodeoxyglucose PET. Fluorodeoxyglucose PET has demonstrated clinical utility in differentiating benign inflammation and granulation tissue from recurrent disease in retroperitoneal masses, but does not improve staging in clinical stage I disease compared with CT. Although MRI offers the advantage of avoiding radiation, it is time consuming and costly. The use of lymphotrophic, nanoparticle-based contrast agents with MRI showed promising early results, with improved sensitivity and specificity for detection of nodal metastases compared with MRI alone; however, additional larger, prospective evaluation is needed.
Staging and Risk Stratification
Patients are assigned a stage based on the primary tumor’s final pathology, nodal and metastatic stage from imaging studies, and postorchiectomy serum tumor marker status (see Table 2 ). Approximately 80% of seminoma patients are clinical stage I and 15% clinical stage II, with the majority being stage IIA or IIB. Patients with advanced disease can be further categorized as either “good risk” or “intermediate risk” based on the International Germ Cell Cancer Collaborative Group (IGCCCG) prognostic factor based staging system (see Table 2 ). Notably, in contrast with nonseminoma, there is no “poor risk” advanced seminoma.
Management of clinical stage I seminoma
Men presenting with clinical stage I seminoma, who represent 80% of incident cases, can achieve long-term cure rates approaching 100%, regardless of management approach. The primary options include adjuvant radiotherapy, chemotherapy or surveillance ( Table 3 ). Owing to the exquisite radiosensitivity and chemosensitivity of seminoma, even relapse after adjuvant treatment is highly curable. In recent years, research has focused on minimizing unnecessary treatment and reducing treatment-related morbidity, while maintaining uniform cure rates. Consideration must also be given to the cost of various treatment strategies.
| Management | Frequency of Use | Risks | Benefits |
|---|---|---|---|
| Surveillance | 55% | Relapse Compliance Radiation exposure Cost | Only treat the minority of patients who recur Treatment of relapse is almost always curative |
| Radiotherapy | 28% | Acute toxicity Secondary malignancy Cardiovascular morbidity Unnecessary in 80%–85% of patients | Disease-specific survival near 100% Low overall recurrence rate (3%–5%) Lower cost vs surveillance |
| Adjuvant carboplatin | 17% | Acute toxicity Long-term risk unknown Unnecessary treatment | Disease-specific survival near 100% Low overall recurrence rate (4%–7%) |
Surveillance
Active surveillance has been extensively validated in numerous large institutional and population-based studies and now represents the preferred management approach in most guidelines for clinical stage I seminoma. The most recent National Comprehensive Cancer Network (NCCN) guidelines for CS IA and IB seminoma (see Table 2 ) support active surveillance as the preferred management strategy for patients with a horseshoe/pelvic kidney, inflammatory bowel disease, or a prior history of radiation. Surveillance is also an appropriate option for the remainder of CS IA/IB patients. According to data from the National Cancer Database, active surveillance is now the most common treatment modality for clinical stage I seminoma in the United States, with utilization increasing from 25% in 1998% to 56% in 2011.
Outcomes
Disease-specific survival for active surveillance has consistently approached 100% in multiple trials. Relapse rates for patients with stage I seminoma managed with surveillance are between 13% and 19%. A recent, large, multiinstitutional study of active surveillance in 1344 patients with clinical stage I seminoma showed that 99% of relapses exhibit good-risk features. All of these relapses were cured with standard chemotherapy.
Surveillance protocols
Typical active surveillance protocols for seminoma involve periodic physical examination, serum tumor markers (AFP and hCG, with or without lactate dehydrogenase), chest radiographs, and abdominal imaging with CT or MRI ( Table 4 for examples of surveillance protocols). Despite the widespread use of active surveillance, there are few data regarding the optimum extent and timing of diagnostic testing. More than 90% of relapses occur during the first 3 years of active surveillance; therefore, most schedules concentrate diagnostic testing during that time period. Relapses are detected on abdominal CT and tumor markers 87% and 3% of cases, respectively. The added value of the physical examination and chest x-ray is very limited, and future guidelines may further reduce the number of chest x-rays. The natural history of relapses after active surveillance was recently used to propose an evidence-based surveillance protocol for stage I seminoma. Table 4 compares this evidence-based surveillance protocol with current NCCN guidelines.
| Guideline | Years of Follow-Up | ||||
|---|---|---|---|---|---|
| 1 | 2 | 3 | 4 | 5 | |
| Kollmannsberger et al | |||||
| Physical examination | Every 2 mo | Every 3 mo | Every 6 mo | Every 6 mo | Every 6 mo |
| Tumor markers | Every 2 mo | Every 3 mo | Every 6 mo | Every 6 mo | Every 6 mo |
| Chest x-ray | Every 4 mo | 18 and 24 mo | — | — | — |
| CT/MRI a abdomen | Every 4 mo | 18 and 24 mo | 36 mo | — | 60 mo |
| NCCN guidelines b | |||||
| Physical examination c | Every 3–6 mo | Every 6–12 mo | Every 6–12 mo | Annually | Annually |
| Tumor markers | Optional | Optional | Optional | Optional | Optional |
| Chest x-ray | As clinically indicated; consider chest CT in symptomatic patients | ||||
| CT abdomen and pelvis | At 3,6, and 12 mo | Every 6–12 mo | Every 6–12 mo | Every 12–24 mo | |
Related posts:
Epidemiology and Diagnosis of Testis Cancer
Intratubular Germ Cell Neoplasia of the Testis, Bilateral Testicular Cancer, and Aberrant Histologies
Management of Stage I Nonseminomatous Germ Cell Tumors
Chemotherapy for Good-Risk Nonseminomatous Germ Cell Tumors
Desperation Postchemotherapy Retroperitoneal Lymph Node Dissection for Metastatic Germ Cell Tumors
Late Relapse of Testicular Germ Cell Tumors
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