Testicular Cancer

Testicular cancer is the most common solid malignancy affecting men 15–35 years of age. Most of the testicular cancers are of the germ cell tumor type, and they can be classified as seminomas and nonseminomas. The most common presentation of testicular cancer is a painless testicular mass. Diagnosis is via physical exam, testicular ultrasonography, and serum tumor markers Serum Tumor Markers Serum tumor markers are proteins or carbohydrates produced by cancer cells that are associated with a malignancy of a specific origin (e.g., thyroglobulin in thyroid cancer). Genetic changes in a malignancy, such as gene mutations or patterns of gene expression, are also being used as tumor markers, and are often referred to as "cellular tumor markers." Serum Tumor Markers. Additional imaging helps with staging Staging Cancer is the 2nd leading cause of death in the US after cardiovascular disease. Many malignancies are treatable or curable, but some may recur. Thus, all malignancies must be assigned a grade and stage in order to guide management and determine prognosis. Grading, Staging, and Metastasis and assessment of metastasis. Treatment consists of surgical inguinal orchiectomy, and further adjuvant therapy is based on disease pathology and stage. Subsequent strategies include disease surveillance, radiotherapy, and chemotherapy. Disease prognosis is excellent, as testicular cancer is one of the most curable solid neoplasms.

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Overview

Epidemiology

  • Testicular neoplasms are the most common tumor in men 15–35 years of age:
    • Germ cell tumors (GCTs) comprise 95% of all testicular cancers.
    • Most commonly presents as localized seminoma in about 50% of cases 
    • Only 10%–30% of patients will have metastatic disease. 
  • Annual incidence in the United States: 6 in 100,000 men:
    • Incidence is highest among non-Hispanic Whites.
    • Lowest incidence among African Americans 

Risk factors

  • History of a GCT or germ cell neoplasia in situ (GCNIS)
  • History of cryptorchidism Cryptorchidism Cryptorchidism is one of the most common congenital anomalies in young boys. Typically, this asymptomatic condition presents during a routine well-child examination where 1 or both testicles are not palpable in the scrotum. Cryptorchidism (relative risk increase of 4–6 times) 
  • Family history of testicular cancer
  • HIV
  • Klinefelter syndrome Klinefelter syndrome Klinefelter syndrome is a chromosomal aneuploidy characterized by the presence of 1 or more extra X chromosomes in a male karyotype, most commonly leading to karyotype 47,XXY. Klinefelter syndrome is associated with decreased levels of testosterone and is the most common cause of congenital hypogonadism. Klinefelter Syndrome, Down syndrome Down syndrome Down syndrome, or trisomy 21, is the most common chromosomal aberration and the most frequent genetic cause of developmental delay. Both boys and girls are affected and have characteristic craniofacial and musculoskeletal features, as well as multiple medical anomalies involving the cardiac, gastrointestinal, ocular, and auditory systems. Down Syndrome
  • Peutz-Jeghers syndrome Peutz-Jeghers Syndrome Peutz-Jeghers syndrome (PJS) is an autosomal-dominant inherited disorder characterized by GI polyps and mucocutaneous-pigmented macules. Peutz-Jeghers syndrome is 1 of the polyposis syndromes, a group of inherited or acquired conditions characterized by the growth of polyps in the GI tract and associated with other extracolonic features. Peutz-Jeghers Syndrome
  • Carney complex
  • Infertility Infertility Infertility is the inability to conceive in the context of regular intercourse. The most common causes of infertility in women are related to ovulatory dysfunction or tubal obstruction, whereas, in men, abnormal sperm is a common cause. Infertility
  • Testicular dysgenesis
  • Hypospadias

Classification

  • GCTs (95%):
    • Seminoma
    • Nonseminoma GCT (NSGCT):
      • Embryonal carcinoma
      • Yolk sac
      • Choriocarcinoma
      • Teratoma
      • Mixed germ cell tumors
  • Non-GCTs (5%):
    • Leydig cell tumors
    • Sertoli cell tumors
    • Lymphoma

Pathophysiology

The mechanisms are not fully known, but different factors appear to play a role in the development of testicular cancer.

Testicular dysgenesis syndrome

  • Environmental factors (i.e., in utero exposures) and genetic mutations affect the germ cell during early development.
  • Disturbed function leads to different phenotypes, ranging from cryptorchidism Cryptorchidism Cryptorchidism is one of the most common congenital anomalies in young boys. Typically, this asymptomatic condition presents during a routine well-child examination where 1 or both testicles are not palpable in the scrotum. Cryptorchidism, hypospadias, and other genital malformations to GCTs/testicular cancer. 

Genetic factors

  • 4× higher risk in sons of affected individuals
  • 8–10× higher risk in brothers of affected individuals
  •  KITLG (KIT ligand) locus on chromosome 12 has a strong association with GCT risk in the testicles Testicles The testicles, also known as the testes or the male gonads, are a pair of egg-shaped glands suspended within the scrotum. The testicles have multiple layers: an outer tunica vaginalis, an intermediate tunica albuginea, and an innermost tunica vasculosa. The testicles are composed of testicular lobules and seminiferous tubules. Testicles.

Clinical Presentation

Classic findings

  • Genital:
    • Painless testicular mass is the most common presentation.
    • Some men may present with testicular swelling, pain Pain Pain has accompanied humans since they first existed, first lamented as the curse of existence and later understood as an adaptive mechanism that ensures survival. Pain is the most common symptomatic complaint and the main reason why people seek medical care. Physiology of Pain, or discomfort.
    • Heaviness or dull ache
    • Scrotal erythema, pain Pain Pain has accompanied humans since they first existed, first lamented as the curse of existence and later understood as an adaptive mechanism that ensures survival. Pain is the most common symptomatic complaint and the main reason why people seek medical care. Physiology of Pain, and swelling (resemble symptoms of acute epididymitis Epididymitis Epididymitis and orchitis are characterized by acute inflammation of the epididymis and the testicle, respectively, due to viral or bacterial infections. Patients typically present with gradually worsening testicular pain and scrotal swelling along with systemic symptoms such as fever, depending on severity. Epididymitis and Orchitis)
  • Metastatic disease can be associated with abdominal pain Pain Pain has accompanied humans since they first existed, first lamented as the curse of existence and later understood as an adaptive mechanism that ensures survival. Pain is the most common symptomatic complaint and the main reason why people seek medical care. Physiology of Pain, back pain Back pain Back pain is a common complaint among the general population and is mostly self-limiting. Back pain can be classified as acute, subacute, or chronic depending on the duration of symptoms. The wide variety of potential etiologies include degenerative, mechanical, malignant, infectious, rheumatologic, and extraspinal causes. Back Pain, and shortness of breath.
  • Seminomas: commonly metastasize through the lymphatic system → present with signs of disseminated disease
  • On exam: negative transillumination test

Histologic subtypes

Table: Germ cell tumors (GCTs)
Type Subtype Characteristics
Seminoma
  • Most common testicular tumor
  • Average age at presentation: 40 years
  • Causes homogeneous testicular enlargement
  • Large cells in lobules with a fried-egg appearance
  • Serum markers: ↑ β-hCG
  • ↑ Placental ALP
  • Prognosis:
    • Excellent
    • Late lymphatic metastasis and radiosensitivity
Nonseminoma Yolk sac or testicular endodermal sinus tumor
  • Common in boys < 3 years old
  • Morphology: Schiller-Duval bodies are present.
  • Serum markers: ↑ AFP (highly characteristic)
  • Aggressive
Choriocarcinoma
  • Early hematogenous spread; can include the brain
  • Alteration of the trophoblastic cells
  • Serum markers: ↑ β-hCG, no AFP production
  • Most aggressive; poor prognosis
  • Might cause gynecomastia Gynecomastia Gynecomastia is a benign proliferation of male breast glandular ductal tissue, usually bilateral, caused by increased estrogen activity, decreased testosterone activity, or medications. The condition is common and physiological in neonates, adolescent boys, and elderly men. Gynecomastia or symptoms of hyperthyroidism Hyperthyroidism Thyrotoxicosis refers to the classic physiologic manifestations of excess thyroid hormones and is not synonymous with hyperthyroidism, which is caused by sustained overproduction and release of T3 and/or T4. Graves' disease is the most common cause of primary hyperthyroidism, followed by toxic multinodular goiter and toxic adenoma. Thyrotoxicosis and Hyperthyroidism
Embryonal carcinoma
  • Average age at presentation: 30 years
  • Clusters and sheets of cells with atypia
  • Locally aggressive
  • Serum marker: may have ↑ β-hCG
Teratoma
  • Involves tissues from ≥ 1 of the 3 germinal layers
  • Those with malignant transformation are chemotherapy-resistant.
  • Benign in children
Mixed GCT
  • Composed of > 1 type
  • About 30% of GCTs
AFP: alpha-fetoprotein
ALP: alkaline phosphatase
Table: Non–germ cells tumors
Type Characteristics
Leydig cell tumor
  • Golden brown color in gross appearance
  • Contains Reinke crystals
  • Produces androgens Androgens Androgens are naturally occurring steroid hormones responsible for development and maintenance of the male sex characteristics, including penile, scrotal, and clitoral growth, development of sexual hair, deepening of the voice, and musculoskeletal growth. Androgens and Antiandrogens or estrogens → gynecomastia Gynecomastia Gynecomastia is a benign proliferation of male breast glandular ductal tissue, usually bilateral, caused by increased estrogen activity, decreased testosterone activity, or medications. The condition is common and physiological in neonates, adolescent boys, and elderly men. Gynecomastia in men and precocious puberty Precocious puberty Precocious puberty (PP) is the appearance of secondary sexual characteristics due to elevated sex hormones before the age of 6-8 in girls and 9 in boys. Excess hormone secretion may occur only at the level of the sex hormone or may involve the whole hypothalamic-pituitary-gonadal axis. Precocious Puberty in boys
  • In some, can produce corticosteroids
Sertoli cell tumor
  • Testicular mass (hormonally silent)
  • Cell arrangement: form cords and tubules
Testicular lymphoma
  • Most common testicular cancer in older men (> 60 years)
  • Not a primary cancer
  • Arises from metastatic lymphoma to testes
Retroperitoneal mass biopsy consistent with classic seminoma

H&E stain of biopsy sample of retroperitoneal mass consistent with classic seminoma

Image: “Testicular seminoma presenting with duodenal perforation: a case report” by Miocinovic R, Abaza R. License: CC BY 2.0, cropped by Lecturio.

Diagnosis

Physical examination

Focused genitourinary exam:

  • Testicular exam palpating for masses:
    • Gently palpate testicle, epididymis, and scrotum.
    • Assess for masses, lesions, and nodules.
  • General abdominal exam to palpate for masses 
  • Chest exam to assess for gynecomastia Gynecomastia Gynecomastia is a benign proliferation of male breast glandular ductal tissue, usually bilateral, caused by increased estrogen activity, decreased testosterone activity, or medications. The condition is common and physiological in neonates, adolescent boys, and elderly men. Gynecomastia 
  • Inguinal exam to palpate for enlarged inguinal lymph nodes 
Bilateral gynecomastia

Bilateral gynecomastia Gynecomastia Gynecomastia is a benign proliferation of male breast glandular ductal tissue, usually bilateral, caused by increased estrogen activity, decreased testosterone activity, or medications. The condition is common and physiological in neonates, adolescent boys, and elderly men. Gynecomastia in a patient

Image: “Finasteride induced Gynecomastia: Case report and Review of the Literature” by Ramot Y, Czarnowicki T, Zlotogorski A. License: CC BY 2.0

Laboratory tests

Obtain tumor markers: 

  • Alpha-fetoprotein (AFP): 
    • Half-life: 5–7 days 
    • Elevated in about 50%–80% of NSGCT 
    • AFP may also be elevated in liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver disease and abdominal cancers such as hepatocellular carcinoma Hepatocellular carcinoma Hepatocellular carcinoma (HCC) typically arises in a chronically diseased or cirrhotic liver and is the most common primary liver cancer. Diagnosis may include ultrasound, CT, MRI, biopsy (if inconclusive imaging), and/or biomarkers. Hepatocellular Carcinoma (HCC) and Liver Metastases
    • Infants will have temporary elevation of AFP that will normalize. 
  • β-hCG: 
    • Half-life: 24–36 hours 
    • Elevated in 20%–60% NSGCT and 15% of seminomas 
    • May see false elevations with marijuana use 
    • Hypogonadism may cause low levels of β-hCG.
  • LDH: 
    • Half-life: 24 hours 
    • Most common isoenzyme elevated in GCTs 
    • Used as a surrogate for disease burden, bulky tumor

Imaging

  • Ultrasonography:
    • Seminomas: solid hypoechoic testicular lesions (no cystic component)
    • Nonseminomas: lesions with calcifications and cystic areas
  • Chest X-ray to rule out pulmonary metastasis 
  • Abdominal and pelvic CT scans: helpful in staging Staging Cancer is the 2nd leading cause of death in the US after cardiovascular disease. Many malignancies are treatable or curable, but some may recur. Thus, all malignancies must be assigned a grade and stage in order to guide management and determine prognosis. Grading, Staging, and Metastasis the disease
  • Other imaging (e.g., brain CT): assess metastasis

Staging

Testicular cancer is staged according to the TNM Staging System of the American Joint Committee on Cancer and the Union for International Cancer Control (UICC).

  • Staging components: 
    • Primary tumor pathology 
    • Staging imaging studies 
    • Postorchiectomy serum tumor markers Serum Tumor Markers Serum tumor markers are proteins or carbohydrates produced by cancer cells that are associated with a malignancy of a specific origin (e.g., thyroglobulin in thyroid cancer). Genetic changes in a malignancy, such as gene mutations or patterns of gene expression, are also being used as tumor markers, and are often referred to as "cellular tumor markers." Serum Tumor Markers 
  • Tumor (T):
    • pTx: cannot be assessed
    • pT0: no evidence of primary tumor
    • pTis: intratubular germ cell neoplasia 
    • pT1: tumor limited to the testis and epididymis without lymphovascular invasion; may invade tunica albuginea but not tunica vaginalis 
    • pT2: tumor limited to the testis and epididymis with lymphovascular invasion or tumor involving the tunica vaginalis 
    • pT3: tumor invasion of the spermatic cord with or without lymphovascular invasion 
    • pT4: tumor invasion of the scrotum with or without lymphovascular invasion
  • Node (N):
    • Nx: cannot be assessed 
    • N0: no regional lymph node metastasis 
    • N1–3: lymph node metastasis (number and size of lymph nodes vary)
  • Metastasis (M):
    • Mx: cannot be assessed
    • M0: no distant metastasis
    • M1: metastasis
  • Serum tumor markers (S):
    • Sx: tumor markers not available or not assessed
    • S0: normal tumor markers
    • S1–3: increasing levels of LDH, AFP, and β-hCG
Table: Staging of testicular cancer
Stage Description
I Limited to testis, no lymph nodes, no metastasis
II Testis + lymph nodes, no metastasis:
  • IIA: 1–5 lymph nodes, all node masses < 2 cm in size
  • IIB: lymph nodes 2–5 cm or > 5 lymph nodes (all ≤ 5 cm)
  • IIIC: lymph nodes > 5 cm
III Distant metastasis, significantly elevated tumor markers
Aua guideline algorithm

Overview of the diagnostic and initial management of testicular cancer:
AFP: alpha-fetoprotein
AUA: American Urological Association

Image by Lecturio. License: CC BY-NC-SA 4.0

Management

Treatment of seminomas

Fertility preservation (i.e., sperm banking) should be discussed extensively with men of reproductive age before any treatment. Primary treatment is radical inguinal orchiectomy, followed by therapy, depending on the stage:

  • Stage I seminomas (high cure rate): primary treatment is inguinal orchiectomy, followed by: 
    • Postorchiectomy surveillance with serial physical exams, serum tumor markers Serum Tumor Markers Serum tumor markers are proteins or carbohydrates produced by cancer cells that are associated with a malignancy of a specific origin (e.g., thyroglobulin in thyroid cancer). Genetic changes in a malignancy, such as gene mutations or patterns of gene expression, are also being used as tumor markers, and are often referred to as "cellular tumor markers." Serum Tumor Markers, abdominopelvic imaging as indicated 
    • Radiation therapy (RT): for patients unable to adhere to surveillance measures; low therapeutic dose needed, as seminoma is very radiosensitive.
    • Single-agent carboplatin: also an option for those who refuse surveillance
  • Stage II seminomas:
    • IIA: 
      • RT 
      • Chemotherapy for relapse
    • IIB or IIC: 
      • Chemotherapy with bleomycin, etoposide, and cisplatin (BEP), or 
      • Etoposide and cisplatin alone (EP)
      • Bleomycin: associated with dose-related pulmonary toxicity 
      • Chemotherapy also associated with short-term thrombocytopenia Thrombocytopenia Thrombocytopenia occurs when the platelet count is < 150,000 per microliter. The normal range for platelets is usually 150,000-450,000/µL of whole blood. Thrombocytopenia can be a result of decreased production, increased destruction, or splenic sequestration of platelets. Patients are often asymptomatic until platelet counts are < 50,000/µL. Thrombocytopenia and GI complications
  • Stage III (pulmonary or nonpulmonary metastatic seminomas): chemotherapy with BEP or EP

Treatment of nonseminomas

Fertility preservation (i.e., sperm banking) should be discussed extensively with men of reproductive age before any treatment. Primary treatment is inguinal orchiectomy, followed by therapy depending on the stage:

  • Stage I nonseminomas
    • Postorchiectomy surveillance with serial physical exams, serum tumor markers Serum Tumor Markers Serum tumor markers are proteins or carbohydrates produced by cancer cells that are associated with a malignancy of a specific origin (e.g., thyroglobulin in thyroid cancer). Genetic changes in a malignancy, such as gene mutations or patterns of gene expression, are also being used as tumor markers, and are often referred to as "cellular tumor markers." Serum Tumor Markers, abdominopelvic imaging as indicated 
    • Retroperitoneal lymph node dissection: for men with high-risk pathologic features and high risk of disease recurrence 
    • Adjuvant chemotherapy: BEP 
  • Stage IIA and IIB nonseminomas:
    • Chemotherapy with BEP or EP or 
    • Primary retroperitoneal lymph node dissection
  • Stage IIC and III nonseminomas: standard regimens for advanced tumors (includes BEP or EP)

Prognosis

  • Testicular GCTs: 5-year survival rates of approximately 95%
  • About 1%–2% present with brain metastasis.
  • Relapse is rare after 2 years.
  • Hypogonadism is a potential complication (can be associated with sexual dysfunction and infertility).
  • There is risk of a 2nd malignancy in those treated with RT and chemotherapy.

Differential Diagnosis

  • Varicocele: dilatation of the pampiniform venous plexus. Varicocele presents without pain Pain Pain has accompanied humans since they first existed, first lamented as the curse of existence and later understood as an adaptive mechanism that ensures survival. Pain is the most common symptomatic complaint and the main reason why people seek medical care. Physiology of Pain, like testicular cancer. Varicoceles have the characteristic “bag of worms” appearance on exam. Ultrasound shows negative transillumination and dilated venous complex with retrograde blood flow. 
  • Spermatocele: presents as an epididymal cyst, commonly arising from the head of the epididymis. Like testicular cancer, spermatocele is also a painless mass often found incidentally. Furthermore, on imaging, cystic lesions are noted, and on color Doppler, there is a characteristic “falling snow” appearance/sign (movement of internal echoes away from transducer, indicating solid particles). Spermatocele requires conservative management.
  • Hydrocele: represents extra fluid in the tunica vaginalis leading to a swollen scrotum. The condition arises from different fluid and anatomic factors. Findings include a painless scrotal mass that can be increasing in size or progressive heaviness or aching in the scrotum. Compared to testicular cancer, a hydrocele will have a positive illumination test on ultrasonography.
  • Indirect inguinal hernia: congenital inguinal hernia occurs when the processus vaginalis fails to close after the testis has descended. Indirect inguinal hernia allows abdominal contents to pass through. In contrast with testicular cancer, the hernia presents as a bulge in the groin that can reach the scrotum, which becomes more prominent with increased intraabdominal pressure (straining, coughing). Management is surgical repair.

References

  1. Gaddam, S., Chesnut, G. (2021). Testicle cancer. StatPearls. Retrieved May 21, 2021, from https://www.ncbi.nlm.nih.gov/books/NBK563159/
  2. Oh, W. (2021). Overview of the treatment of testicular germ cell tumors. UpToDate. Retrieved May 21, 2021, from https://www.uptodate.com/contents/overview-of-the-treatment-of-testicular-germ-cell-tumors
  3. Rose, T. (2021). Testis neoplasms. AUA Core Curriculum. Retrieved May 22, 2021, from https://auau.auanet.org/core 
  4. Steele, G. (2021). Clinical manifestations, diagnosis, and staging Staging Cancer is the 2nd leading cause of death in the US after cardiovascular disease. Many malignancies are treatable or curable, but some may recur. Thus, all malignancies must be assigned a grade and stage in order to guide management and determine prognosis. Grading, Staging, and Metastasis of testicular germ cell tumors. UpToDate. Retrieved May 21, 2021, from https://www.uptodate.com/contents/clinical-manifestations-diagnosis-and-staging-of-testicular-germ-cell-tumors
  5. Rajpert-De Meyts, E., Skakkebaek, N.E., Toppari, J. (2018). Testicular Cancer Pathogenesis, Diagnosis and Endocrine Aspects. Feingold, K.R., et al. (Ed.). Endotext. South Dartmouth (MA): MDText.com, Inc. https://www.ncbi.nlm.nih.gov/books/NBK278992/

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