Testicular Cancer – 8 Interesting Facts

Interesting Facts

1. Testicular cancer is a relatively rare malignancy, typically occurring in younger men; with proper treatment, disease is highly curable, even if metastatic
2. Germ cell tumors comprise 95% of malignant testicular tumors ¹
   • Broadly categorized as seminomas and nonseminomas
3. Painless testicular mass is most common presentation; about 20% of patients present with pain ²
4. Diagnosis is suspected based on history, physical examination, and transscrotal ultrasonogram findings
   • More than 95% of intratesticular masses are malignant ³
5. Radical inguinal orchiectomy (removal of testis and spermatic cord) is generally performed to make final diagnosis and provide staging information
   • Serum tumor markers (α-fetoprotein, β-hCG, and lactate dehydrogenase) are informative for diagnosis, staging, and prognosis
6. Management of testicular cancer consists of orchiectomy and may include chemotherapy, radiation therapy, or other surgery, depending on stage and tumor type
   • Most commonly presents at early stage and is highly curable with radical orchiectomy
   • More advanced stages are curable with multimodality treatment approach
7. Main complications include chemotherapy-related toxicities, infertility, secondary malignancies, cardiovascular disease, hypogonadism, and peripheral neuropathy
8. 5-year survival rate for testicular cancer is 95.3%; for localized cancer confined to primary site (67.9% diagnosed at this stage), 5-year survival rate is 99.2% ⁴
   • Long-term survival for men with metastatic germ cell tumor is 80% to 90% ⁵

Pitfalls

• Correct diagnosis must be established in all cases of intrascrotal mass; more than 95% of intratesticular masses are malignant ³
• To avoid diagnostic delay, consider diagnosis of testicular cancer in any male aged 15 to 50 years with a firm testis mass, midline retroperitoneal mass, or mass in left supraclavicular fossa ⁵
• Do not perform transscrotal biopsies; violating scrotum can seed cancer and complicate management

Urgent Action

• Promptly refer patient to urologist for any solid testicular mass found on physical examination and confirmed on scrotal ultrasonogram

Terminology

Clinical Clarification

• Testicular cancer is a relatively rare malignancy, accounting for 1% to 2% of all male malignancies, ^1 5 typically occurring in younger men; incidence is increasing worldwide
• With proper treatment, disease is highly curable, even if metastatic

Classification of Testicular cancer

• By cell type
  • Germ cell tumors ¹
    • Comprise 95% of testicular malignant tumors; ¹ as such, the terms testicular cancer and germ cell tumor are typically synonymous ³
      • Occasionally arise in extragonadal sites (eg, retroperitoneum, anterior mediastinum)
    • Broadly categorized as:
      • Seminoma
        • One-half of germ cell tumors are seminomas, and 80% to 85% are stage I at diagnosis ⁶
        • Most common testicular cancer in adults and in patients with cryptorchidism ³
      • Nonseminoma
        • More clinically aggressive with often faster growth rate; consists of multiple cell types, including:
          • Embryonal carcinoma
          • Choriocarcinoma
          • Yolk sac tumor
          • Teratoma
  • Non–germ cell tumors are rare and include: ⁵
    • Sex-cord stromal tumors
    • Lymphoid and hematopoietic tumors
    • Tumors of collecting duct, rete testis, and testicular adnexa
• TNM staging of Testicular cancer ⁷
  • American Joint Committee on Cancer staging system, 8th edition (2018) ⁷
    • Primary tumor (T)
      • Clinical (cT)
        • cTX: primary tumor cannot be assessed
        • cT0: no evidence of primary tumor
        • cTis: germ cell neoplasia in situ
        • cT4: tumor invades scrotum with or without vascular/lymphatic invasion
      • Pathologic (pT)
        • pTX: primary tumor cannot be assessed
        • pT0: no evidence of primary tumor
        • pTis: germ cell neoplasia in situ
        • pT1: tumor limited to testis (including rete testis invasion) without lymphovascular invasion
          • pT1a: tumor smaller than 3 cm (applies only to pure seminoma)
          • pT1b: tumor is 3 cm or larger (applies only to pure seminoma)
        • pT2:
          • Tumor limited to testis (including rete testis invasion) with lymphovascular invasion, or
          • Tumor invading hilar soft tissue or epididymis or penetrating visceral mesothelial layer covering external surface of tunica albuginea with or without lymphovascular invasion
        • pT3: tumor invades spermatic cord with or without lymphovascular invasion
        • pT4: tumor invades scrotum with or without lymphovascular invasion
    • Regional lymph node (N)
      • Clinical (cN)
        • cNX: regional lymph nodes cannot be assessed
        • cN0: no regional lymph node metastasis
        • cN1:
          • Metastases with a lymph node mass 2 cm or smaller in greatest dimension, or
          • In cases of multiple lymph nodes, none larger than 2 cm in greatest dimension
        • cN2:
          • Metastasis with a lymph node mass larger than 2 cm but not larger than 5 cm in greatest dimension, or
          • In cases of multiple lymph nodes, any 1 mass larger than 2 cm but not larger than 5 cm in greatest dimension
        • cN3: metastasis with a lymph node mass larger than 5 cm in greatest dimension
      • Pathologic (pN)
        • pNX: regional lymph nodes cannot be assessed
        • pN0: no regional lymph node metastasis
        • pN1: metastasis with a lymph node mass 2 cm or smaller in greatest dimension and 5 or fewer positive nodes, none larger than 2 cm in greatest dimension
        • pN2:
          • Metastasis with a lymph node mass larger than 2 cm but not larger than 5 cm in greatest dimension, or
          • More than 5 positive nodes, none larger than 5 cm, or
          • Evidence of extranodal extension of tumor
        • pN3: metastasis with a lymph node mass larger than 5 cm in greatest dimension
    • Distant metastasis (M)
      • M0: no distant metastases
      • M1: distant metastases
        • M1a: nonretroperitoneal nodal or pulmonary metastases
        • M1b: nonpulmonary visceral metastases
    • Serum markers (S)
      • SX: marker studies not available or not performed
      • S0: marker study levels within reference range
      • S1:
        • Lactate dehydrogenase level less than 1.5 times upper limit of reference range, and
        • β-hCG level less than 5000 milliunits/mL, and
        • α-fetoprotein level less than 1000 ng/mL
      • S2:
        • Lactate dehydrogenase level 1.5 to 10 times upper limit of reference range, or
        • β–hCG level of 5000 to 50,000 milliunits/mL, or
        • α-fetoprotein level of 1000 to 10,000 ng/mL
      • S3:
        • Lactate dehydrogenase level greater than 10 times upper limit of reference range, or
        • β-hCG level greater than 50,000 milliunits/mL, or
        • α-fetoprotein level greater than 10,000 ng/mL
  • Prognostic stage groups (American Joint Committee on Cancer staging system, 8th edition) ⁷
    • Stage 0: pTisN0M0S0
    • Stage I: pT1-4, N0, M0, SX
    • Stage IA: pT1N0M0S0
    • Stage 1B:
      • pT2N0M0S0
      • pT3N0M0S0
      • pT4N0M0S0
    • Stage IS: any pT/TX, N0, M0, S1-3
    • Stage II: any pT/TX, N1-3, M0, SX
    • Stage IIA: any pT/TX, N1, M0, S0-1
    • Stage IIB: any pT/TX, N2, M0, S0-1
    • Stage IIC: any pT/TX, N3, M0, S0-1
    • Stage III: any pT/TX, any N, M1, SX
    • Stage IIIA: any pT/TX, any N, M1a, S0-1
    • Stage IIIB
      • Any pT/TX, N1-3, M0, S2
      • Any pT/TX, any N, M1a, S2
    • Stage IIIC
      • Any pT/TX, N1-3, M0, S3
      • Any pT/TX, any N, M1a, S3
      • Any pT/TX, any N, M1b, any S
• International Germ Cell Cancer Collaborative Group risk classification for advanced disease of Testicular cancer ⁸
  • Seminoma
    • Good risk (90% of cases)
      • All of the following:
        • Any primary site
        • No nonpulmonary visceral metastasis
        • α-fetoprotein level within reference range, any β-hCG level, and any lactate dehydrogenase level
    • Intermediate risk (10% of cases)
      • All of the following:
        • Any primary site
        • Nonpulmonary visceral metastasis
        • α-fetoprotein level within reference range, any β-hCG level, and any lactate dehydrogenase level
    • Poor risk
      • No patients classified as poor risk
  • Nonseminoma
    • Good risk (56% of cases)
      • All of the following:
        • Testicular or retroperitoneal primary tumor
        • No nonpulmonary visceral metastasis
        • All postorchiectomy markers: α-fetoprotein level less than 1000 ng/mL; β-hCG level less than 5000 milliunits/mL; and lactate dehydrogenase level less than 1.5 times upper limit of reference range
    • Intermediate risk (28% of cases)
      • All of the following:
        • Testicular or retroperitoneal primary tumor
        • No nonpulmonary visceral metastasis
        • Any postorchiectomy markers: α-fetoprotein level of 1000 to 10,000 ng/mL; β-hCG level of 5000 to 50,000 milliunits/mL; or lactate dehydrogenase level 1.5 to 10 times upper limit of reference range
    • Poor risk (16% of cases)
      • Any of the following:
        • Mediastinal primary tumor
        • Nonpulmonary visceral metastasis
        • Any postorchiectomy markers: α-fetoprotein level greater than 10,000 ng/mL; β-hCG level greater than 50,000 milliunits/mL; or lactate dehydrogenase level 10 times upper limit of reference range

Diagnosis

Clinical Presentation

History

• Usually presents as painless or painful unilateral testicular nodule, mass, enlargement, or hardening (induration) ¹
• Painless testicular mass is most common presentation ^3 5
  • Detected by patient or partner
  • Incidental radiologic finding
• May present with testicular pain, discomfort, or swelling
  • Pain may be first symptom in 20% of cases ²
  • Acute testis pain can be caused by rapid expansion of testis secondary to intratumor bleeding or infarction from rapid tumor growth
    • Pain is more common with nonseminomas; they are typically more vascular and exhibit faster growth than seminomas ⁵
  • Vague discomfort, dull ache, or heaviness in testis or abdomen is also reported
  • Patient may report history of trauma
    • Incidental trauma may bring testis mass to patient’s attention
• Symptoms related to metastatic disease are presenting complaint in 10% to 20% of patients ⁵
  • Bulky retroperitoneal metastasis may cause:
    • Palpable mass
    • Abdominal pain
    • Flank pain from ureteral obstruction
    • Back pain (involvement of psoas muscle or nerve roots)
    • Lower extremity swelling from vena caval compression
    • Gastrointestinal symptoms
  • Pulmonary metastasis may manifest with respiratory symptoms such as cough, dyspnea, chest pain, or hemoptysis
  • Supraclavicular lymph node metastasis can present as lower neck or upper chest masses
• Gynecomastia may occasionally be presenting symptom
  • Related to tumor production of β-hCG; more common in nonseminomas ⁹

Physical examination

• Both affected and unaffected testes are examined, noting their relative size and consistency, and palpating for masses (testicular or extratesticular)
  • Anatomically normal testis is 3.5 to 5 cm in length, smooth, homogeneous, detached from epididymis, and freely mobile ⁶
  • Abnormal findings include hard, firm, or fixed areas within or adjacent to testes
    • Any firm area within the testis should be considered suggestive of malignancy and prompt further investigation, including scrotal ultrasonography ⁵
  • Atrophy of either testicle may be noted, especially in patients with history of cryptorchidism
• Pain and swelling may suggest epididymitis or orchitis ¹
  • Persistent tenderness, swelling, or palpable abnormality after a trial of antibiotics requires further evaluation
• Findings suggestive of distant metastasis include:
  • Supraclavicular and inguinal nodes
  • Abdominal mass or pain elicited by examination
  • Gynecomastia
  • Abnormal auscultation of chest may raise suspicion for intrathoracic disease

Causes and Risk Factors

Causes

• Carcinogenesis of testicular cancer is not well understood
• Prevailing hypothesis is that risk is largely determined in utero ¹⁰
• Genetic factors are thought to have a causative role in less than 5% of men diagnosed with testicular cancer ³
• Most testicular cancers arise from a precursor lesion: intratubular germ cell neoplasia (carcinoma in situ) ⁵
  • Intratubular germ cell neoplasia appears to develop from arrested primordial germ cells or gonocytes that failed to differentiate into prespermatogonia; may lay dormant until stimulated by testosterone after puberty
  • Seminomas are thought to originate from a unipotential cell line; nonseminomas considered to arise from a totipotential cell line that may undergo varying degrees of differentiation into embryonal, teratoma, yolk sac, or choriocarcinoma components ¹¹
• Increased copies of genetic material from short arm of chromosome 12 is a universal finding in testicular and extragonadal germ cell tumors ⁵
  • 70% to 80% of germ cell tumors have extra copy of chromosome 12 in form of isochromosome 12p (i[12p])
• Emerging evidence suggests exposure to risk factors in adolescence and adulthood might also promote testicular cancer (eg, certain pesticides, employment in occupations such as firefighting or aircraft maintenance) ¹⁰

Risk factors and/or associations

Age

• Can affect men of all ages, but most frequently diagnosed among men aged 20 to 34 years ⁴
  • Mean age at diagnosis is 33 years
• Most common solid malignancy in men aged 20 to 40 years ⁵
• Second most common cancer (after leukemia) in adolescent males aged 15 to 19 years ⁵

Genetics

• Family history of testicular cancer
  • Having a brother or father with testicular cancer increases risk by 8- to 10-fold or 4- to 6-fold, respectively ³
• Some genetic disorders (eg, Down syndrome, testicular dysgenesis syndrome) are associated with increased risk of testicular cancer ³

Ethnicity/race

• In the United States, incidence in white men is 5 times higher than in black men, 4 times higher than in Asian men, and 78% higher than in Hispanic men ⁵
• Rates are highest in Scandinavia, Western Europe, and Australia/New Zealand; intermediate in United States and United Kingdom; and lowest in Africa and Asia ⁵

Other risk factors/associations

• Well-established risk factors include: ⁵
  • Personal history of testicular cancer
    • Men with a history of testicular cancer have a 12-fold increased risk of developing malignancy in the contralateral testis; however, the 15-year cumulative incidence is only 2%
    • Occurs bilaterally in 2% of men; typically metachronous (develops at intervals) ⁵
  • Cryptorchidism (undescended testicle)
    • Increases relative risk 4 to 6 times in affected gonad; risk decreases to 2 to 3 times if orchiopexy performed before puberty ⁵
      • Contralateral descended testis at slightly increased risk
    • More commonly right-sided; as a result, right-sided testicular cancer is more common ³
  • Family history of testicular cancer
    • Men with a first-degree relative with testicular cancer have substantially increased risk; appears to be stronger link with brothers than with fathers ¹²
    • May be confounded by result of shared environmental exposures ¹²
  • Intratubular germ cell neoplasia
    • Often associated with cryptorchid testes and in contralateral testes of men with history of testicular cancer ¹²
• Environmental factors play a role in germ cell tumor carcinogenesis ⁵
  • Exposures that may be associated include heat, polyvinylchloride, nonionizing radiation, heavy metals, agricultural work, pesticides and polychlorinated biphenyls, and marijuana use ¹⁰
• Testicular microlithiasis
  • Calcifications in seminiferous tubules found in about 5% of men aged 18 to 35 years ^3 13
  • Association with testicular cancer not clearly defined
    • Some data suggest association between testicular microlithiasis and testicular cancer in patients with history of testicular cancer ^3 14
    • In a 5-year follow-up study, testicular cancer did not develop in most men (98.4%) in general population with testicular microlithiasis ¹³
• Infertile men have higher incidence of testicular cancer ¹²
  • Male factor infertility increases risk of developing testicular cancer by nearly 3-fold

Diagnostic Procedures

Primary diagnostic tools

• Suspected testicular cancer diagnosis based on history and physical examination
  • Perform transscrotal ultrasonography expeditiously on all patients with suspected testicular cancer ^1 9
    • Ultrasonography of both testes is cornerstone primary imaging study in patients with testicular tumor ²
    • More than 95% of intratesticular masses are malignant ³
  • If ultrasonographic findings of a mass are concerning for malignancy:
    • Promptly refer to urologist if any solid mass is found on physical examination and subsequently confirmed by scrotal ultrasonogram ³
      • Do not perform transscrotal biopsies; violating scrotum can seed cancer and complicate management ¹
    • Obtain serum tumor marker levels of α-fetoprotein, β-hCG, and lactate dehydrogenase ¹
    • Other basic laboratory studies often include CBC, creatinine level, electrolytes, and liver enzymes
  • Radical inguinal orchiectomy is generally performed to make final diagnosis ¹
• Postorchiectomy work-up/subsequent staging
  • After formal diagnosis of testicular cancer is made, complete staging evaluation with additional testing as follows:
    • Imaging
      • Perform CT of abdomen and pelvis with IV contrast material and chest radiography (these may be done before or after orchiectomy) ¹
        • To assess state of retroperitoneal, mediastinal, and supraclavicular lymph nodes and evaluate for metastatic disease
        • Obtain CT of chest if abdominal CT or chest radiographic findings are abnormal ¹
      • Brain MRI may be indicated in select patients with clinical suspicion for brain metastases
    • Repeat serum measurement of tumor markers (α-fetoprotein, β-hCG, and lactate dehydrogenase) after orchiectomy; postorchiectomy levels are critical for precise staging ^1 9
      • Generally obtained after appropriate number of half-lives (typically 5 half-lives) of the marker have passed; allows markers to normalize or reach new baseline level ¹²
        • β-hCG half-life is 1 to 3 days, lactate dehydrogenase-1 is 4 to 4.5 days, and α-fetoprotein is 5 to 7 days
      • European Association of Urology recommends obtaining levels 5 to 7 days after orchiectomy ⁹
  • Classify patients based on interpretation of serum tumor marker levels alongside imaging findings; TNM staging system for testicular cancer is commonly used ^1 9
    • Patients with metastatic disease are classified according to International Germ Cell Cancer Collaborative Group staging ⁸

Laboratory

• Serum tumor markers are valuable for diagnosis (before orchiectomy), as well as for staging and prognosis (after orchiectomy); increased levels are found in approximately 50% of patients with testicular cancer ⁹
  • Serum β-hCG (quantitative)
    • Most commonly elevated tumor marker in testicular cancer; present in both seminomatous and nonseminomatous tumors ¹
      • Increased in 40% to 60% of patients with nonseminoma ⁹
        • Levels above 1000 milliunits/mL generally suggest nonseminoma ¹
      • Up to 30% of seminomas can present or develop an elevated β-hCG level ⁹
    • Other causes of β-hCG elevations to consider include: ¹
      • Minor elevations (generally less than 20 milliunits/mL) include hypogonadism, hyperthyroidism, and marijuana use
      • More significant elevations (above 400 milliunits/mL) have been reported from heterophile antibodies
        • Consider repeating test using different assay if false-positive finding is suspected (eg, radiographic absence of disease)
  • Serum α-fetoprotein
    • Produced by yolk sac cells
    • Elevated levels are associated with nonseminomatous tumors, especially embryonal or yolk sac carcinomas; ¹ by definition, pure seminoma will not have increased α-fetoprotein level ¹²
      • Increased level in 50% to 70% of patients with nonseminoma; ⁹ may be seen at any disease stage
    • If elevation is caused by metastasis, a steadily rising α-fetoprotein level may be seen ¹
      • Chronically elevated levels may be seen in a small number of men; use caution when beginning treatment of mildly elevated (less than 20 ng/mL) but stable levels ¹
    • Other causes for elevated α-fetoprotein level include hepatocellular carcinoma, as well as other gastrointestinal cancers (eg, stomach, pancreas, biliary tract, lung)
  • Serum lactate dehydrogenase
    • Less specific marker for testicular cancer than α-fetoprotein or β-hCG; however, levels are elevated in about 50% of men with advanced testicular cancer ¹
      • Be aware that lactate dehydrogenase levels may be elevated in wide variety of diseases ¹²
    • Treatment decisions are not typically based on lactate dehydrogenase levels alone
      • Primary use is to risk-stratify patients with disseminated nonseminomas on first day of first line chemotherapy ¹

Imaging

• Scrotal ultrasonography
  • Used to confirm presence of testicular mass, determine location (intra- or extratesticular), and explore contralateral testis ¹
    • Intratesticular masses are more commonly malignant; extratesticular masses are more frequently benign ¹¹
    • Intratesticular solid masses are often malignant; intratesticular cystic lesions are usually benign ¹¹
      • Solid masses with internal vascularity suggest testicular tumor, in appropriate clinical setting
      • Cystic lesions may include tubular ectasia of the rete testis, simple cysts, and tunica albuginea cysts
  • 92% to 98% sensitivity and 95% to 99.8% specificity for testicular malignancy ¹¹
  • Imaging characteristics
    • Testicular cancers are typically heterogenous and hypoechoic ¹
    • Histologic sonographic generalizations ¹¹
      • Seminomas are often hypoechoic and homogeneous; they infrequently demonstrate calcifications or cystic spaces
      • Nonseminomas are more commonly heterogeneous in echotexture, with most demonstrating cystic spaces; calcifications are seen much more frequently than in seminomas
    • Microlithiasis is characterized by multiple small, echogenic foci noted within testicular parenchyma ¹¹
      • Association with testicular cancer is not clearly defined; finding alone should not prompt further evaluation ¹³
• CT of abdomen or pelvis
  • Most common study to assess retroperitoneum for presence of metastatic disease
  • Staging
    • Lymph node (N) stage refers to presence or absence of disease in regional lymph nodes ¹¹
      • Abdominal retroperitoneal lymph nodes are considered regional lymph nodes
        • Tumors involving left testis usually spread first to left para-aortic lymph nodes just below left renal vein; tumors involving right testis typically spread first to paracaval, precaval, and retrocaval lymph nodes
      • Lymph nodes larger than 1 cm in short axis are highly suggestive of metastatic disease, especially when located in kidney hilar regions or in para-aortic or caval areas
      • Sensitivity and specificity of CT in determining nodal metastases varies depending on size criteria used; CT cannot detect metastatic disease in normal-sized lymph nodes
        • Sensitivity varies from 65% to 96% and specificity ranges from 81% to 100% ¹⁵
    • Metastasis (M) stage refers to presence or absence of distant metastatic disease
      • Distant lymph nodes (eg, found in chest, pelvis, and supraclavicular regions) are considered metastatic disease
      • Most common sites of solid organ metastatic disease are lungs, liver, and brain; metastasis to bone may also occur
• Chest radiograph
  • Satisfactory in initial staging process to evaluate for pulmonary metastases ¹⁵
• Chest CT
  • Indicated in patients with positive abdominal or pelvic CT findings or abnormal chest radiograph findings
    • When ordered alone (not with abdominal or pelvic CT), non–contrast enhanced is preferred ¹⁵
  • Guideline from the European Association of Urology recommends chest CT as primary staging tool; ⁹ when combined with abdominal or pelvic CT for staging, IV contrast material is used ¹⁵
• Brain MRI
  • May be indicated in select patients, including those with: ¹
    • Neurologic symptoms concerning for brain metastasis
    • Postorchiectomy serum β-hCG greater than 5000 milliunits/L
    • Extensive lung metastases
    • Choriocarcinoma tumor (more likely to metastasize to brain) ¹¹

Procedures

Radical inguinal orchiectomy

General explanation

• Provides diagnostic and staging information, as well as potential treatment ¹²
  • Allows for histologic subtyping of tumor
  • Evaluates extent of primary tumor and assigns T-stage of tumor based on presence or absence of lymphovascular invasion and depth of tumor invasion
  • Provides definitive/curative therapy in almost 80% of men with low-stage seminomas and about 60% to 70% of men with nonseminomas ¹²

Differential Diagnosis

Most common

• Scrotal mass
  • Epididymo-orchitis
    • Inflammation of epididymis often coexists with inflammation of testes; frequently caused by infection, but has noninfectious causes as well
    • Typically causes gradual onset (over few days) of scrotal pain with or without swelling
      • Affects similar age group; most common in men aged 18 to 35 years
    • On physical examination, scrotal swelling and tenderness of epididymis (located posterior to testis)
      • Pain may be alleviated by elevating scrotum (Prehn sign)
      • May be associated with fever, chills, and symptoms of urinary tract infection or urethritis
    • Diagnosis is based on history, clinical findings, and laboratory analysis of urethral discharge or urine sample showing evidence of inflammation
      • Patients with presumptive diagnosis of epididymo-orchitis should be re-evaluated within 2 to 4 weeks of completing course of appropriate antibiotics; ⁵ diagnosis of testicular cancer is delayed in around 10% of cases that mimic epididymo-orchitis ⁹
  • Hydrocele
    • Serous fluid collection within tunica vaginalis testis or along spermatic cord
    • Can present as mass in scrotum and is typically painless
      • May accompany testicular cancer and impair examiner’s ability to evaluate testis ⁵
    • Fluid may transilluminate on examination
    • Ultrasonography can confirm diagnosis
  • Varicocele
    • Dilation of venous pampiniform plexus of spermatic cord
    • Typically painless mass in scrotum; may cause discomfort or pain
    • Often described as feeling like “bag of worms” on palpation, which increases with Valsalva maneuver
    • Generally can be diagnosed with careful physical examination; imaging studies (eg, scrotal color duplex ultrasonography) can be used for confirmation ¹⁶
  • Inguinal hernia
    • Indirect (lateral) inguinal hernia in males may manifest as scrotal swelling with or without discomfort or pain
      • Incarcerated inguinal hernia typically causes sudden increase in pain
    • Inguinal hernias can be palpated separately from the testicle
    • Diagnosis can be made by history and physical examination in most patients; imaging studies (typically ultrasonography) may be used for indeterminate physical examination findings
  • Testicular torsion
    • Acute twisting of spermatic cord and its contents, resulting in disruption of blood supply to testis and causing scrotal pain and swelling
    • Pain onset is typically sudden and severe; associated with nausea and vomiting, high-riding testis (may have horizontal lie), and absent cremasteric reflex
    • Diagnosis can often be made based on history and physical examination; ultrasonography or surgical exploration confirm diagnosis
      • Any patient presenting with acute scrotal pain and mass or swelling should be evaluated urgently for testicular torsion by ultrasonography or surgical exploration ¹⁷

Treatment

Goals

• Complete cure
  • Most patients have potential for cure
• Minimize treatment-related toxicity, including secondary cancers, without compromising curability ²

Disposition

Admission criteria

• Admit patients to hospital for surgery (initial orchiectomy)

Recommendations for specialist referral

• Refer promptly to urologist for any solid testicular mass found on physical examination and confirmed on scrotal ultrasonogram ³
• When possible, refer patients with testicular cancer to high-volume center ^1 2 5
  • Relatively rare disease; general urologists and oncologists do not typically treat a large volume of these patients
  • Treatment algorithms are complex and nuanced
  • Retroperitoneal lymph node dissection should be performed by surgeons experienced with this operation
• Refer patients expressing interest in (or ambivalent about) fertility preservation (eg, sperm cryotherapy) to reproductive specialist ¹⁸
  • Refer patients to psychosocial providers when they are distressed about potential infertility
• Encourage participation in clinical trials, when possible

Treatment Options

Expeditious application of appropriate treatment is important for best outcomes ⁵

• Germ cell tumors have potential for rapid growth

Discuss sperm banking (semen cryopreservation) with patients of reproductive age ^1 18

• Address possibility of infertility as early as possible after cancer diagnosis; can occur simultaneously with staging and formulation of a treatment plan ¹⁸
  • Advise men of a potentially higher risk of genetic damage in sperm collected after therapy begins
  • Document these discussions in the medical record ¹⁸
• Sperm banking may be done before or after orchiectomy, but definitely before subsequent therapy ¹

Radical inguinal orchiectomy (removal of testis and spermatic cord) is the primary treatment for most patients with testicular mass suggestive of malignancy on ultrasonogram ¹

• Orchiectomy and pathologic examination of testis confirms diagnosis and defines local extension (pT category) ⁹
  • Partial orchiectomy is not typically recommended and is only performed in extenuating circumstances (eg, patient with solitary testis, synchronous bilateral cancers) ³
• Consider open inguinal biopsy of contralateral testicle if: ¹
  • Ultrasonogram shows intratesticular mass concerning for cancer (does not include presence of microcalcifications)
  • Testis undescended (cryptorchid testis)
  • Shows marked atrophy
  • Suspicious mass
• Discuss option of placing testicular prosthesis during procedure if desired by patient
• In rare situations (eg, rapidly increasing tumor marker levels, symptoms related to metastasis), chemotherapy may be initiated immediately, before orchiectomy and tissue diagnosis ^1 9

Treatment after orchiectomy is based on histology, staging, and prognosis, in addition to discussion with patient regarding benefits and harms of management options ^2 6

• Management of germ cell carcinomas is guided by potential for rapid growth and cure in essentially all patients ⁵
• Fully inform patient regarding all management options, including surveillance or adjuvant chemotherapy after orchiectomy, as well as treatment-specific recurrence rates and acute and long-term adverse effects ⁹
• Primary medical treatment (after orchiectomy)
  • Seminoma (pure)
    • Diagnosis of seminoma is restricted to pure seminoma histology and serum α-fetoprotein level within reference range; may have elevated β-hCG level ¹
      • When elements of both seminoma and nonseminoma are present, follow management for nonseminoma as it is more clinically aggressive ¹
    • Stage IA and IB
      • Most patients with stage I pure seminoma are cured by orchiectomy alone ¹
      • National Comprehensive Cancer Network guidelines recommend using American Joint Committee on Cancer staging (8th edition) for subclassifying and making treatment decisions for stage I tumors ¹
      • Standard management options after orchiectomy include: ¹
        • Active surveillance for pT1-3 (preferred)
        • Chemotherapy with 1 or 2 cycles of single-agent carboplatin
        • Radiation therapy
          • European Association of Urology guideline does not recommend radiation therapy for stage I seminomas, especially in younger patients, because of higher risk of radiation-induced secondary malignancies ⁹
    • Stage IS ¹
      • Uncommon; requires persistent elevation of serum tumor marker levels after orchiectomy
      • Repeat serum tumor marker measurements and assess with chest, abdominal, and/or pelvic CT to scan for metastatic disease
        • Elevated tumor marker levels increase risk of disease outside peritoneum; chemotherapy for nonseminomas is encouraged
    • Stage IIA and IIB ¹
      • Clinical evidence of metastatic disease to lymph nodes
      • Options include:
        • Radiation therapy (to include para-aortic and ipsilateral iliac lymph nodes)
          • In stage IIB disease, often reserved for patients with nonbulky (3 cm or less) tumors
        • Chemotherapy: bleomycin-etoposide-cisplatin for 3 cycles or etoposide-cisplatin for 4 cycles
          • Preferred for stage IIB
    • Stage IIC and III ¹⁹
      • More extensive metastases; classified by International Germ Cell Cancer Consensus Group as either good or intermediate risk
        • Good risk
          • Chemotherapy: bleomycin-etoposide-cisplatin for 3 cycles or etoposide-cisplatin for 4 cycles
        • Intermediate risk (metastasis to organs other than lungs)
          • Chemotherapy: bleomycin-etoposide-cisplatin for 4 cycles or etoposide, ifosfamide, and cisplatin for 4 cycles
    • After primary treatment for all stages, CT imaging and serum tumor marker levels are followed for restaging to determine further management (eg, surveillance, surgical resection of residual masses, additional chemotherapy)
  • Nonseminoma
    • Includes nonseminoma, mixed tumor (nonseminoma and seminoma), and seminoma with elevated α-fetoprotein level
      • Mildly elevated α-fetoprotein level may not indicate germ cell tumor; treatment decisions should not be made on levels below 20 ng/mL ¹
    • National Comprehensive Cancer Network guidelines recommend using American Joint Committee on Cancer staging for subclassifying and making treatment decisions for stage I tumors ¹⁹
      • Stage IA
        • 3 treatment options after orchiectomy:
          • Surveillance (preferred)
          • Chemotherapy: bleomycin-etoposide-cisplatin for 1 cycle
          • Nerve-sparing retroperitoneal lymph node dissection
      • Stage IB
        • Postorchiectomy options:
          • Nerve-sparing retroperitoneal lymph node dissection
          • Chemotherapy: bleomycin-etoposide-cisplatin for 1 cycle
      • Stage IS
        • Chemotherapy: bleomycin-etoposide-cisplatin for 3 cycles or etoposide-cisplatin for 4 cycles
      • Stage IIA
        • Depends on postorchiectomy serum tumor marker levels
          • Negative tumor marker findings
            • Nerve-sparing retroperitoneal lymph node dissection
            • Chemotherapy: bleomycin-etoposide-cisplatin for 3 cycles or etoposide-cisplatin for 4 cycles
          • Positive tumor marker findings (persistent elevation): bleomycin-etoposide-cisplatin for 3 cycles or etoposide-cisplatin for 4 cycles
      • Stage IIB
        • Depends on postorchiectomy serum tumor marker levels and radiographic findings
        • Negative tumor marker findings
          • Lymph node metastasis limited to drainage sites within retroperitoneum. Options include:
            • Chemotherapy: bleomycin-etoposide-cisplatin for 3 cycles or etoposide-cisplatin for 4 cycles
            • Nerve-sparing retroperitoneal lymph node dissection (in highly selected cases)
          • Multifocal, symptomatic, or lymph node metastases with aberrant lymphatic drainage
            • Chemotherapy: bleomycin-etoposide-cisplatin for 3 cycles or etoposide-cisplatin for 4 cycles
        • Positive tumor marker findings (persistent elevation): bleomycin-etoposide-cisplatin for 3 cycles or etoposide-cisplatin for 4 cycles
    • Primary chemotherapy for advanced metastatic nonseminoma is based on International Germ Cell Cancer Consensus Group risk classification
      • Good risk: stage IIC and IIIA
        • Bleomycin-etoposide-cisplatin for 3 cycles or etoposide-cisplatin for 4 cycles
      • Intermediate risk: stage IIIB
        • Bleomycin-etoposide-cisplatin for 4 cycles or etoposide-ifosfamide-cisplatin for 4 cycles
      • Poor risk: stage IIIC
        • Bleomycin-etoposide-cisplatin for 4 cycles or etoposide-ifosfamide-cisplatin for 4 cycles (in selected patients)
    • After primary treatment, CT imaging and serum tumor marker levels are followed for restaging to determine further management (eg, surgical resection of residual masses, surveillance, retroperitoneal lymph node dissection, additional chemotherapy)

Rationale for treatment plans

• Orchiectomy
  • Most patients with stage I pure seminoma are cured with orchiectomy alone, though 15% to 20% of patients have recurrence ¹
    • In men with stage I disease, more than 80% with seminoma and almost 70% with nonseminoma are cured by radical orchiectomy ³
• Surveillance
  • Preferred for most stage I seminoma and nonseminoma as risk of recurrence is low compared with potential harms of adjuvant therapy ¹
    • Requires adherence to more intensive follow-up and serial CT imaging
• Chemotherapy
  • Institution of platinum-based chemotherapy has improved survival for patients with metastatic testicular cancer; most testicular tumors are sensitive to its effects
    • Seminomas are very sensitive to platinum-based chemotherapy compared with nonseminomas ³
  • Disadvantages include short-term toxicity (eg, myelosuppression, infertility, fatigue); long-term effects are poorly defined
• Radiation therapy
  • Patients with stage I seminoma who undergo radiation therapy require less intensive follow-up with CT imaging ³
    • Disadvantages includes overtreatment and increased risk of cardiac disease and secondary malignancy in treatment fields
  • Not generally used in treatment of nonseminomas
• Retroperitoneal lymph node dissection
  • Surgery performed on primary lymphatic drainage site of germ cell tumor; standard approach to surgical management of nonseminomas in both primary and postchemotherapy settings ¹
    • Nerve-sparing retroperitoneal lymph node dissection should be performed by expert surgeons in specialized center ⁹
  • Indications include adjuvant treatment (in stage I disease) to minimize risk of recurrence by clearing retroperitoneum of micrometastatic disease, or primary treatment of stage II disease in certain patients
  • Can be performed in traditional open transperitoneal approach (typically midline incision from xiphoid to pubis), or less commonly via open extraperitoneal or minimally invasive approach
  • Surgical resection is the only treatment for teratoma (potential component of nonseminomatous germ cell tumors) as these tumors are not sensitive to radiation or chemotherapy

Outcomes (cure rates and survival data relative to specific treatments)

• Seminomas
  • Stage I disease: disease-specific survival is 99%, regardless of management strategy used ¹
  • Stage IIA and IIB disease: adjuvant therapy using either radiation therapy or cisplatin-based chemotherapy regimen after orchiectomy yields overall survival rates of 98% and 99%, respectively, over 6 years of follow-up ²⁰
  • Stage IIC and III disease: after chemotherapy (with regimen determined by International Germ Cell Cancer Consensus Group risk), complete radiographic responses are reported in 70% to 90% of patients; 5-year overall survival is 91% ⁵
• Nonseminomas
  • Stage IA: overall survival rate managed with surveillance, chemotherapy, or nerve-sparing retroperitoneal lymph node dissection exceeds 98% ¹
    • High rate for surveillance depends on adherence to follow-up protocols and subsequent treatment, if required
    • Surveillance is associated with highest quality-adjusted survival when estimated risk of relapse is less than 33% to 37%; however, active treatment (retroperitoneal lymph node dissection or primary chemotherapy) is associated with more favorable outcomes when risk of relapse is greater than 46% to 54% ⁵
  • Stage IIA and IIB
    • No randomized trials have compared retroperitoneal lymph node dissection (with or without adjuvant chemotherapy) and induction chemotherapy
    • 1 prospective, multicenter, nonrandomized trial comparing retroperitoneal lymph node dissection plus 2 cycles of adjuvant chemotherapy versus induction chemotherapy alone found no significant differences in recurrence (7% for retroperitoneal lymph node dissection versus 11% for chemotherapy) or overall survival ²¹
  • Stage IIC and III
    • Induction chemotherapy with cisplatin-based regimens is the initial approach used
    • Cisplatin-based regimens have similar cure rates, but bleomycin-etoposide-cisplatin chemotherapy regimens are preferred owing to lower risks of neurotoxicity ²²
    • Cure rates with bleomycin-etoposide-cisplatin regimens depend on International Germ Cell Cancer Consensus Group risk classification ¹
      • Good risk: approximately 90% cure rate
      • Intermediate risk: approximately 70% cure rate
      • Poor risk: approximately 50% durable response rate

Recurrence is treated according to extent of disease at relapse ¹

Drug therapy

• Primary chemotherapy regimens may include:
  • Single-agent carboplatin
    • Seminoma: stages IA and IB
  • Bleomycin-etoposide-cisplatin
    • Seminoma: stages II and III
    • Nonseminoma: stages I, II, and III
  • Etoposide-cisplatin
    • Seminoma: stages II and III
    • Nonseminoma: stages IS, IIA, IIB, IIC, and IIIA
  • Etoposide-ifosfamide-cisplatin
    • Seminoma: stages IIC and III (intermediate risk)
    • Nonseminoma: stages IIIB (intermediate risk) and IIIC (poor risk)

Nondrug and supportive care

Semen cryopreservation

• Sperm freezing and storage can be used to preserve reproductive capability in men undergoing cancer therapy ¹⁸
  • Most modern sperm storage banks use nitrogen vapor
• Malignancy itself can be an indication for sperm banking; testicular cancer confers higher risk of male infertility compared with other tumor types ²³
• Treatment (eg, surgery, radiation therapy, chemotherapy) may compromise fertility
  • Retroperitoneal lymph node dissection can result in ejaculatory dysfunction owing to sympathetic nerve injury
  • Spermatogenesis can recover in many patients after cancer therapy
    • Patients receiving radiation therapy may take 2 to 3 years to recover spermatogenesis ³
    • After chemotherapy, almost all patients become azoospermic; however: ³
      • 50% of patients return to preoperative sperm counts after 2 years
      • 80% of patients return to preoperative sperm counts within 5 years
• Health care providers should discuss sperm banking with postpubertal males receiving cancer treatment
  • Before beginning any treatment that may compromise fertility, patient may require guidance whether to retain their frozen pretreatment sperm if concerns exist regarding quality of their posttreatment ejaculated sperm
  • Advise patients of a potentially higher risk of genetic damage in sperm collected after initiation of therapy ¹⁸

Radiation therapy

• Seminoma is extremely sensitive to radiation therapy and substantially lower doses are required compared with other solid tumors ⁵
  • Treatment is typically delivered to the retroperitoneum
    • Most testicular cancers spread via predictable lymphatic channels (rather than hematogenous route), typically to the retroperitoneal lymph nodes ¹²
      • Right-sided tumors generally spread to interaortocaval nodes; left-sided tumors commonly spread to left para-aortic nodes
  • Standard treatment option for clinical stage I, IIA, and IIB seminoma
• No role in treatment of nonseminoma (except for brain metastasis)

Procedures

Radical inguinal orchiectomy

General explanation ³

• Establishes histologic diagnosis and primary T stage, provides important prognostic information from tumor histology, and is curative in most clinical stage I disease ⁵
• Performed via inguinal incision and involves removal of testicle and spermatic cord at the level of the inguinal ring
  • Spermatic cord is ligated high (at peritoneal reflection) with permanent suture, which allows future identification if retroperitoneal lymph node dissection is subsequently required
• If desired, testicular prosthesis may be inserted at time of orchiectomy or at later date

Indication

• Initial treatment of suspected testicular neoplasm

Special populations

• Pediatric and adolescent males
  • Accounts for 0.5% of pediatric malignancies and 14% of adolescent malignancies (most common solid tumor in this age group) ²⁴
    • Young boys have primarily pure teratoma and pure yolk sac histology (mostly benign); adolescent histology is typically mixed nonseminomatous germ cell tumor ²⁵
  • As tumor histology differs between prepubertal and postpubertal males, staging and treatment also differ ^24 25
    • Prepubertal
      • Children’s Oncology Group staging system is used ²⁶
      • Usually less aggressive; therefore, treatment is also less aggressive
        • Mostly benign pathology; if serum tumor markers are negative, most patients undergo testicle-sparing surgery
        • Children’s Oncology Group protocols recommend surveillance for all local disease and reduced, pediatric-specific chemotherapeutic dosing for metastatic disease
    • Postpubertal
      • Best managed using the same algorithms as those for adult men (TNM system and International Germ Cell Cancer Consensus Group system for metastatic disease)
      • Adolescents are treated per adult protocols because of similarities in tumor biology
  • Lower event-free survival has been observed in adolescent patients with germ cell tumors than in children or adults ²⁷
    • Patients aged 13 to 19 years have a 3-year event-free survival of 60%, significantly worse than patients aged younger than 13 years (87%) and patients aged older than 19 years (80%) ²⁷
    • Reasons are considered multifactorial, including delayed presentation and diagnosis, transition between pediatric and adult providers, decreased research/clinical trials for adolescents, and lack of awareness in this age group ²⁴
  • Long-term sequelae of treatments are important to consider, as this age group has longer life expectancy ²⁴
    • Guidelines are available for adolescent and young adult oncology patients ²⁸

Monitoring

• Follow-up
  • Follow all patients for at least 5 years after primary treatment to monitor for recurrence; may be extended at physician’s discretion ^1 6
  • Recommendations vary with tumor type, stage, and treatment modality. Components include: ¹
    • History and physical examinations; testicular ultrasonography for any equivocal examination
    • Elevated serum tumor marker levels may signify early relapse; useful in monitoring stage II and III seminomas and all stages of nonseminomas ¹
      • α-fetoprotein and β-hCG levels are determined throughout follow-up period
        • β-hCG level greater than 5000 milliunits/L in postorchiectomy patient is associated with increased risk of brain metastasis; perform brain MRI ¹
      • Lactate dehydrogenase level can be used to monitor for relapse, but is nonspecific with a high false-positive rate
    • Abdominal or pelvic CT is performed at specified time intervals to evaluate for recurrence
    • Chest radiography
      • Sufficient for routine follow-up, but chest CT is preferred in presence of thoracic symptoms ¹
    • Chest CT with contrast enhancement
      • Preferred imaging study in presence of thoracic symptoms and in patients with supradiaphragmatic disease present at diagnosis ¹
  • Perform reassessment of disease activity in patients with new or worsening signs or symptoms of disease, regardless of time since previous studies ¹
• For men with testicular microlithiasis, routine testicular self-examination is reasonable surveillance strategy ^3 14

Complications and Prognosis

Complications ⁶

• Can arise secondary to both disease process and treatment
  • Treatment-related sequelae (varies with individual course)
    • Early ⁵
      • Cisplatin-based chemotherapy is associated with many early complications/adverse effects including fatigue, myelosuppression, infection, peripheral neuropathy, hearing loss, decreased renal function, and death
      • Radiation therapy is associated with fatigue, nausea and vomiting, leukopenia, and dyspepsia
      • Both chemotherapy and radiation therapy negatively impact spermatogenesis
    • Long-term ^3 6
      • Most concerning late complications are secondary malignancies and cardiovascular disease
        • Secondary malignancies
          • Incidence of secondary malignant neoplasms is 60% to 100% higher in survivors treated with cisplatin-based chemotherapy or radiation therapy (200% higher in patients who receive both), compared with the general population ⁵
            • Frequent use of CT imaging for surveillance may also increase risk of secondary malignancies
          • Radiation therapy to the abdomen or pelvis confers 3-fold higher risk of leukemia among survivors; cisplatin and etoposide therapies increase risk as well ⁶
          • Radiation therapy and chemotherapy increase risk of solid cancers beginning 5 years after treatment ⁶
            • In order of decreasing risk, sites include: stomach, pancreas, pleura, bladder, colon, and esophagus
            • Other potential secondary malignancies include melanoma, thyroid, kidney, and connective tissues
        • Cardiovascular disease
          • Cause is uncertain, but contributing factors include radiation- or chemotherapy-induced vascular injury and chemotherapy-induced cardiac injury and metabolic syndrome ⁵
      • Pulmonary toxicity after bleomycin treatment may result in restrictive lung disease ⁶
      • Infertility
        • Orchiectomy, chemotherapy, and radiation can increase risk of infertility
        • Retroperitoneal lymph node dissection may induce retrograde ejaculation or anejaculation (reduced risk with advanced surgical techniques) ⁶
      • Hypogonadism
        • Cause is likely multifactorial, including orchiectomy, chemotherapy, radiation effects, and testicular dysgenesis
      • Peripheral neuropathy
      • Hearing loss resulting from cisplatin-based chemotherapy
        • Reported in up to 20% to 40% of men ³
  • Testicular cancer alone can affect fertility ⁶
    • Up to 50% of patients have semen abnormalities before orchiectomy ⁶

Prognosis

• Long-term survival for men with metastatic germ cell tumor is 80% to 90% ⁵
  • Testicular cancer is 1 of the few cancers where long-term survival is possible, even with distant metastatic spread (stage III disease) ¹²
• 5-year survival rate for testicular cancer is 95.3% ⁴
  • Survival by stage (5-year overall) ⁴
    • Localized (confined to primary site): 99.2%
      • 67.9% of cases are diagnosed at local stage
    • Regional (spread to regional lymph nodes): 96%
    • Distant (metastasis): 73.7%
    • Unknown (unstaged): 79.7%
• Survival of advanced germ cell tumors by risk group (International Germ Cell Cancer Collaborative Group) ⁸
  • Seminoma
    • Good risk: 5-year progression-free survival: 82%; 5-year overall survival: 86%
    • Intermediate risk: 5-year progression-free survival: 67%; 5-year overall survival: 72%
    • Poor risk: no patients classified as poor risk
  • Nonseminoma
    • Good risk: 5-year progression-free survival: 89%; 5-year overall survival: 92%
    • Intermediate risk: 5-year progression-free survival: 75%; 5-year overall survival: 80%
    • Poor risk: 5-year progression-free survival: 41%; 5-year overall survival: 48%

Screening and Prevention

Screening

At-risk populations

• No recommended guidelines currently exist for testicular screening in healthy, asymptomatic men
• US Preventive Services Task Force recommends against screening for testicular cancer in adolescent or adult men ²⁹
  • Unlikely to offer meaningful health benefits, given very low incidence and high cure rate of even advanced testicular cancer; potential harms include false-positive results, anxiety, and harms from diagnostic tests or procedures
• Consider targeted screening for men with higher risk factors for developing testicular cancer (eg, cryptorchidism, personal or family history of germ cell tumor) ¹²
  • European Association of Urology guidelines recommend advising patients with a familial history of testicular cancer, as well as their family members, to perform regular self-examination of testes ⁹

Screening tests

• Testicular self-examination ³⁰
  • Easiest to examine after warm bath or shower
  • Hold penis away from body and observe each testicle for lumps or swelling
  • Roll each testicle gently between thumb and forefinger in its entirety
    • Feel for lumps, swelling, or discomfort
    • Anatomically normal testicle is egg-shaped and feels firm, smooth, and not tender. Spermatic cord is felt as firm, spaghettilike cord at back of testicle
  • Examine groin area between abdomen and upper thighs bilaterally
    • Palpate for tender swelling or lymphadenopathy
• Educate patients who perform self-examinations to contact health care provider in the following situations:
  • Bumps or lumps (eg, small, hard, pea-sized lump)
  • Swelling, pain, or soreness
  • Any other changes in testicles

Sources

National Comprehensive Cancer Network: NCCN Clinical Practice Guidelines in Oncology: Testicular Cancer. Version 1.2019. NCCN website. Updated October 22, 2018. Accessed January 2, 2019. https://www.nccn.org/

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