Robert B. Den, MD
Mark Hurwitz, MD
BASICS
DESCRIPTION
• Seminoma is a GCT (germ cell tumor) of the testicle composed of cells that are considered the malignant counterpart of gonocytes
• These tumors are generally very sensitive to both chemotherapy and radiation therapy.
• GCTs account for 95% of testicular cancer and are broadly classified as seminoma or NSGCT.
– Seminoma accounts for 50% of GCTs
– Represents 20% of mixed GCTs (combinations of seminomatous and NSGCT)
• Histologic subtypes:
– Classic seminoma (peak age 35–39)
– Spermatocytic seminoma typically found in men >50–60
– Anaplastic seminoma is no longer recognized as distinct entity.
EPIDEMIOLOGY
Incidence
• Peak incidence among men aged 20–40
• 4–5 times more common among white than African American men.
• Patients who have had 1 seminoma are at an increased risk of developing a contralateral seminoma.
Prevalence
N/A
RISK FACTORS
• Cryptorchidism; 3–14 times the normal incidence
• HIV infection
• Gonadal dysgenesis with Y chromosome
• Testicular feminization >30 yr of age
Genetics
• Genetic changes in the form of amplifications and deletions are observed mainly in the 12p11.2–p12.1 chromosomal regions (1).
• A gain of 12p sequences is associated with invasive growth of both seminomas and NSGCTs.
• In contrast, spermatocytic seminoma shows a gain of chromosome 9, whereas most infantile yolk sac tumors and teratomas show no chromosomal changes.
• p53 mutations are also seen with seminoma.
PATHOPHYSIOLOGY
• The slow growth characteristics of most seminomas result in them most commonly being diagnosed at an early stage (≥85% stage I) (2).
• Right-sided tumors tend to spread in the following sequence: Interaortocaval nodes, precaval zone, and para-aortic nodes.
• Left-sided tumors spread in the following order: The para-aortic, preaortic, and renal hilar nodes. Interaortocaval nodes are involved with typically higher-stage disease.
• Rarely presents as an extragonadal GCT in a site remote from the testicle.
• Hematogenous dissemination is much less common than in NSGCT.
• β-hCG elevation can sometimes be seen in seminoma.
• The presence of elevated AFP during evaluation usually suggests nonseminomatous elements
• Due to slower growth pattern, relapses tend to be later than with NSGCT, and many can occur 2–3 yr after therapy.
ASSOCIATED CONDITIONS
Increased risk in patients with cryptorchidism; risk is >35 times the general population
GENERAL PREVENTION
Unclear if orchidopexy reduces risk in undescended testicles
DIAGNOSIS
HISTORY
• Painless mass or swelling in the testes
• History of undescended testicle or inguinal surgical procedure as a child
PHYSICAL EXAM
• Palpate the testes bilaterally.
• Transilluminate the mass.
• Examine the groin for evidence of surgical scar (prior orchiopexy).
• Inspect for lymphedema of the groin or lower extremities.
• Lymphatic spread is not typically inguinal; however, prior scrotal surgery may change lymphatic drainage.
DIAGNOSTIC TESTS & INTERPRETATION
Lab
• CBC and chemistry
• β-hCG and AFP to rule out NSGCT:
– Seminoma never have elevated AFP.
– 10–20% may have elevated β-hCG.
• Placental alkaline phosphatase: Pulmonary and renal function tests for patients who may receive chemotherapy
Imaging (3)
• Scrotal US: Often diagnostic, characterizes solid vs. cystic lesions, flow
• Chest x-ray: To rule out metastatic lesions
• CT of chest, abdomen, and pelvis to evaluate for lymphatic spread:
– Studies suggest that in seminoma patients treated for retroperitoneal adenopathy, up to 50% will resolve on subsequent imaging.
– Bipedal lymphangiography was once the standard of care to identify retroperitoneal nodes to direct radiation planning. It is no longer routinely used.
– PET: Limited role in patients with postchemotherapy residual masses to determine the presence of viable tumor.
Diagnostic Procedures/Surgery
Biopsy not indicated. The diagnostic procedure of choice is the radical orchiectomy.
Pathologic Findings
• Classic seminoma (most common):
– Large cells or uniform size with clear cytoplasm and distinct cell borders
– Stains positive for PLAP
• Spermatocytic seminoma (up to 4%):
– Cells of varying size that resemble maturing spermatogonia (peak age >50)
– Does not stain for PLAP
• Anaplastic seminoma is no longer considered a distinct subtype of seminoma:
– Same histology as classic seminoma, with high mitotic activity and unchanged prognosis using current treatment standards
– Histologically, must differentiate from lymphoma and embryonal carcinoma
DIFFERENTIAL DIAGNOSIS
• Adult/pediatric painful mass:
– Epididymitis/orchitis; bacterial, STD, mumps, TB
– Incarcerated/strangulated hernia
– Testicular trauma: Usually blunt; contusion, rupture; usually associated hematocele
– Torsion (testicle, testicular, or epididymal appendage)
– Tumor (pain infrequent unless traumatized or rapidly growing; see below)
• Adult painless mass:
– Adenomatoid tumor of testis or epididymis
– Adrenal rest tumors
– Adenocarcinoma of the rete testis
– Chylocele: Usually associated with filariasis
– Fibrous pseudotumor of the tunica albuginea
– Hydrocele, primary or due to trauma, torsion, tumor, epididymitis; hydrocele of the cord
– Lipoma of the cord
– Mesothelioma of tunica vaginalis
– Polyorchidism
– Paratesticular sarcomas: Rhabdomyosarcoma, fibrosarcoma, leiomyosarcoma, liposarcoma
– Scrotal edema (insect bite, nephrotic syndrome, acute idiopathic scrotal edema)
– Scrotal wall: Sebaceous and inclusion cysts, idiopathic calcinosis, fat necrosis, malignancy
– Sperm granuloma following vasectomy
– Spermatocele (epididymal cyst)
– Testicular cysts (simple, tunica albuginea, epidermoid)
– Testicular tumor:
GCTs (95% of testicular malignancies): Seminoma, embryonal cell carcinoma, choriocarcinoma, yolk sac carcinoma teratoma (1–5%), teratocarcinoma
Gonadal stromal tumors: Leydig tumor, Sertoli cell, granulosa cell tumors
Metastatic tumors: Prostate, lung, and GI tract; rare kidney, malignant melanoma, pancreas, bladder, and thyroid.
Mixed germ cell and stromal tumor (gonadoblastoma)
Angioma, fibroma, leiomyoma, hamartoma, carcinoid, mesothelioma, and neurofibroma
Malignant fibrous histiocytoma (most common soft tissue sarcoma in late adult life)
Leukemia or lymphoma
– Varicocele
• Pediatric painless mass:
– Similar to adult list; most/more common are: Hydrocele, hernia, varicocele, testicular teratoma, adrenal rest tumors, rhabdomyosarcoma, endodermal sinus tumor
TREATMENT
GENERAL-MEASURES (4)
• Discuss sperm banking
• Stage IA,B: Radical orchiectomy and adjuvant RT in low stage most common treatment:
– Close surveillance with CT scanning in lieu of RT for low-stage seminoma is gaining acceptance.
– Single-agent chemotherapy (carboplatin)
• Stage IS: RT as adjuvant therapy
• Stage II: Radical orchiectomy and adjuvant therapy:
– Nonbulky retroperitoneal nodes: RT 35 Gy or chemotherapy
– Bulky lymphadenopathy (>5–7 cm nodes) or higher visceral metastasis (retroperitoneal adenopathy) and is treated with standard platinum-based chemotherapy (BEP = bleomycin/etoposide/cisplatinum or EP = etopiside/cisplatinum).
MEDICATION
First Line
• Regardless of histology, patients with advanced germ cell tumors (cIIB–cIII) and those with persistently elevated tumor markers following radical orchiectomy (cIS), are initially treated with platinum-based chemotherapy according to the IGCCCG risk stratification.
– Patients with good-risk disease are treated with 3 cycles of bleomycin, etoposide, and cisplatin (BEP) or 4 cycles of etoposide and cisplatin (EP). While patients with intermediate-risk or high-risk disease receive 4 cycles of BEP, ∼30–40% of patients with poor-risk disease fail to achieve a durable response to conventional chemotherapy.
Second Line
High-dose chemotherapy or clinical trial
SURGERY/OTHER PROCEDURES
• Radical inguinal orchiectomy
• RPLND is not usually for seminoma.
ADDITIONAL TREATMENT
Radiation Therapy
• Stage I:
– Standard RT is para-aortic field to 20–25 Gy following surgery
– If prior ipsilateral pelvic surgery, treat para-aortic and ipsilateral iliac lymph nodes.
Shield contralateral testis
• Stage II:
– Subdiaphragmatic radiation to 35 Gy to the para-aortic and ipsilateral iliac lymph nodes following radical orchiectomy (hockey stick template).
• Prophylactic mediastinal RT has generally been abandoned due to side-effect profile (cardiovascular) and failure to significantly improve outcomes. It also interferes with ability to administer salvage chemotherapy.
Additional Therapies
• Active surveillance for low-risk, early disease:
– Avoids unnecessary treatment and related side effects
– CT every 4–6 mo; reduce interval after ∼5 yr
– Traditional risk factors that increase the recurrence risk: Tumor >4 cm, invasion of the rete testis, anaplastic features, small vessel invasion
• The role of salvage chemotherapy, surgical removal, or RT of persistent masses detected by CT continues to be controversial.
Complementary & Alternative Therapies
Patients should consider sperm banking prior to treatment to aid in avoiding risk of infertility.
ONGOING CARE
PROGNOSIS
• Elevation of LDH, hCG, or both and number of metastatic sites are the most important prognostic factors in patients with GCTs
• ∼75% have localized disease (stage I) at diagnosis. ∼15% have metastatic disease to the regional lymph nodes, and 5–10% have involvement of regional nodes or visceral metastases.
• All stages have at least a 90% cure rate:
– Stage I: 98–100%
– Stage II (B1/B2 nonbulky): 98–100%
– Stage II (B3 bulky) and stage III: >90% complete response to chemotherapy and 86% durable response rate to chemotherapy
• Response rates to chemotherapy seem to be slightly better without prior radiation.
COMPLICATIONS
• Infertility, GI complications, and possible induction of secondary malignancies are a concern following adjuvant RT.
• Involvement of retroperitoneal lymph nodes may produce backache.
FOLLOW-UP
Patient Monitoring
• Surveillance:
– H&P, AFP, β-hCG, LDH:
Every 3–4 mo for years 1–2
Every 6–12 mo for years 3–4, then annually
– Abdominal/pelvic CT every 6 mo for yr 1–2, every 6–12 mo for yr 3, then annually for yr 4–5
– CXR as clinically indicated for yr 1–5
• Carboplatin:
– H&P, AFP, β-hCG, LDH:
Every 3 mo for yr 1
Every 4 mo for yr 2
Every 6 mo for yr 3, then annually
– Abdominal/pelvic CT annually for yr 1–3
– CXR as clinically indicated
• RT:
– H&P, AFP, β-hCG, LDH:
Every 4 mo for yr 1–2, then annually
Abdominal/pelvic CT annually for yr 1–3 (for patients post only para-aortic RT)
– CXR as clinically indicated
REFERENCES
1. Bosl GJ, Ilson DH, Rodriguez E, et al. Clinical relevance of the i(12p) marker chromosome in germ cell tumors. J Natl Cancer Inst. 1994;86(5):349–355.
2. Mannuel HD, Mitikiri N, Khan M, et al. Testicular germ cell tumors: Biology and clinical update. Curr Opin Oncol. 2012;24(3):266–271.
3. Chung PW, Bedard P. Stage II seminomas and nonseminomas. Hematol Oncol Clin North Am. 2011;25(3):529–541.
4. Mok G, Warde P. Management of stage I testicular seminoma. Hematol Oncol Clin North Am. 2011;25(3):503–516.
ADDITIONAL READING
• Huddart R, Kataja V; ESMO Guidelines Working Group. Testicular seminoma: ESMO clinical recommendations for diagnosis, treatment and follow-up. Ann Oncol. 2008;19(suppl 2):ii49–ii51.
• International Germ Cell Consensus Classification. A prognostic factor-based staging system for metastatic germ cell cancers. International Germ Cell Cancer Collaborative Group. J Clin Oncol.1997;15:594–603.
See Also (Topic, Algorithm, Media)
• International Germ Cell Cancer Collaborative Group (IGCCCG)
• Reference Tables: TNM: Testis Cancer
• Testis Cancer, Pediatric, General Considerations
• Testis Cancer, Nonseminomatous Germ Cell Tumors, General
• Testis Cancer, Seminoma Image 
• Testis, Teratoma, Mature and Immature
• Testis, Tumor and Mass, Adult, General Considerations
• Testis, Tumor and Mass, Pediatric, General Considerations
CODES
ICD9
• 186.9 Malignant neoplasm of other and unspecified testis
• 608.89 Other specified disorders of male genital organs
ICD10
• C62.90 Malig neoplasm of unsp testis, unsp descended or undescended
• C62.92 Malig neoplasm of left testis, unsp descended or undescended
• N50.8 Other specified disorders of male genital organs
CLINICAL/SURGICAL PEARLS
Anaplastic seminoma is no longer recognized as distinct entity.