Testicular tumors

Testicular tumors most commonly occur in men between 20 and 35 years of age, and are the most common solid malignancy in this group. Most often, patients present with a painless nodule or swelling of the testis. Diagnosis is made primarily based on palpation and findings on testicular ultrasound. Diagnostic staging further includes an abdominopelvic and chest CT, determination of serologic tumor markers (AFP, HCG, LDH), and radical inguinal orchiectomy of the affected side to confirm the diagnosis and to evaluate the histopathology (seminoma vs. nonseminoma). The necessity and choice of adjuvant treatment depends on tumor pathology, staging, and prognosis. Treatment options include active surveillance, retroperitoneal radiotherapy, retroperitoneal lymph node dissection, and platinum-based chemotherapy. The overall prognosis of testicular tumors is excellent; patients can often be cured even in advanced, metastatic stages.

• Most common solid malignant tumor in young men in the US
• Peak incidence: 20–35 years; (nonseminomas peak in the third decade, seminomas in the fourth decade of life)

References:^[1]

Epidemiological data refers to the US, unless otherwise specified.

• Risk factors
  • Cryptorchidism (increased risk for germ cell tumors) ^[2]
  • Contralateral testicular cancer
  • Germ cell neoplasia in situ (GCNIS)
  • Family history of testicular cancer
  • Klinefelter syndrome; , trisomy 21 (increased risk for germ cell tumors)
  • Subfertility/infertility, hypospadia

References:^[2][3][4]

Testicular tumors are classified according to pathology.

Overview of testicular tumors
Type of tumor		Frequency	AFP	HCG	Characteristics	Pathology
Germ cell tumors of the testis (95%)
Seminoma		∼ 40%	–	–/↑	Malignant tumor that has slow growth and late metastases Good radiosensitivity Better overall prognosis compared to nonseminomas Most common testicular tumor Increased placental ALP	Comparable to ovarian dysgerminoma in women Macroscopic findings: uniform white cut section Microscopy Fried egg cell appearance Cells have an abundance of watery cytoplasm Fibrous septae divide the tumor into lobules
Nonseminoma tumors	Embryonal carcinoma	∼ 25%	–	–/↑	Pure embryonal carcinomas are rare, but are a very common element of mixed germ cell tumors. Aggressive tumor with high malignant potential and early metastases May be painful Worse prognosis than seminoma	Macroscopic findings: grey-white regressive changes with hemorrhage, necrosis, and cysts Microscopy: glandular or papillary pattern
	Teratoma	∼ 25%	–	–	Rare in adults, but common in children Typically benign but may be malignant in adults (teratocarcinoma)	Composed of tissue from different germinal layers. May be immature or may contain fully differentiated elements of muscle, cartilage, bone, teeth in mature teratomas
	Testicular choriocarcinoma	∼ 5%	–	↑↑	Highly malignant and most aggressive Early hematogenous metastasis to the lungs or brain is common.	Consist of both cytotrophoblasts and syncytiotrophoblasts multinucleated giant cells
	Yolk sac tumor	∼ 5%	↑↑	–	Most common prepubertal testicular tumor [5] Aggressive tumor with high malignant potential	Similar to ovarian yolk sac tumor Gross: yellow, mucinous cut surface Microscopy: Schiller-Duval bodies (perivascular glomeruloid structures)
	Mixed germ cell tumors	∼ 30% [6]	–/↑	–/↑	Even if seminoma component is present, it is classified and treated as a nonseminoma.	Heterogeneous cut surface with solid areas, hemorrhage, and necrosis
Non-germ cell tumors of the testis (5%)
	Leydig cell tumors	∼ 2%	–	–	Rare tumors which arise from the hormone-producing stromal cells of the testes Usually develop after the age of 4 Produce large amounts of testosterone and a small amount of estrogen, progesterone, and corticosteroids Malignant transformation is very rare.	Gross: characteristic golden brown color Microscopy: Reinke crystals (eosinophilic cytoplasmic inclusions)
	Sertoli cell tumors	< 1%	–	–	Rare sex-chord stromal tumor derived from Sertoli cells Can produce estrogen and lead to gynecomastia in affected men	Multiple Sertoli cells arranged in cords
Secondary testicular tumors	Lymphoma	Most common testicular tumor in men > 60 years of age	–	–	Usually extranodal non-Hodgkin lymphoma	Usually diffuse large B-cell lymphomas [7]

HCG is always elevated in choriocarcinoma and sometimes elevated in seminoma. AFP is always elevated in yolk sac tumors. Both AFP and HCG may be elevated in mixed germ cell tumors.

Testicular tumors metastasize early into the retroperitoneum via the lymphatic system (drain to the para-aortic lymph nodes first), with the exception of early hematogenous metastasizing choriocarcinomas.

References:^{[8][9][10][10][11]}

• Painless testicular nodule or swelling
• Negative transillumination test
• Dull lower abdominal or scrotal discomfort is more common than acute scrotal pain.
• In metastatic disease
  • Cough, shortness of breath, chest pain
  • Lower back or bone pain
• Gynecomastia
• In Leydig cell tumors
  • Androgen excess features
    • Prominent external genitalia, pubic hair growth, accelerated skeletal and muscle development, and mature masculine voice
    • May cause precocious puberty in boys
  • Occassionally, estrogen excess features: gynecomastia, breast tenderness, and gonadogenital underdevelopment.
• Paraneoplastic hyperthyroidism: alpha subunits of HCG and TSH are identical, enabling weak stimulation of the TSH receptor in tumors with HCG overproduction. ^[12]

Until proven otherwise, a firm nodule on the testis should be considered cancer!

References:^[1][12]

Extragonadal germ cell tumors

• Definition: primary germ cell tumors that arise outside of the gonads, anywhere along the body's midline from the pineal gland to the coccyx.
• Epidemiology: 5–10% of all germ cell tumors; mostly affects young males
• Location
  • Midline organs
  • Mediastinal > retroperitoneal > intracranial (pineal gland and suprasellar region)
  • Sacrococcygeal teratomas (most common in infancy or early childhood) ^[13]
• Symptoms :
  • Chest pain, dyspnea (on exertion), cough
  • Palpable abdominal mass, back pain, weight loss
  • Headache, nausea, vomiting, ataxia, change in vision
• Diagnosis
  • Testicular ultrasound: to rule out gonadal primary tumor
  • Tumor markers: alpha fetoprotein (AFP) and human chorionic gonadotropin (HCG)
  • Tumor biopsy (confirmatory) :Nonseminomas are more common than seminomas
• Therapy
  • Determined by the location, size, and histology of the tumor
  • Chemotherapy , radiation therapy , and/or surgical resection
• Prognosis: The 5-year survival is ∼ 95% for seminomas and 45–60% for nonseminomas.

References:^[14][15][16]

Suspicion of a testicular tumor is usually established based on the clinical findings and ultrasound (to localize the tumor).

• Laboratory tests
  • Tumor markers : alpha fetoprotein (AFP), human chorionic gonadotropin (HCG) (see overview of testicular tumors) and lactate dehydrogenase (LDH)
• Imaging
  • Ultrasound
    • Seminoma: hypoechoic, homogenous, sharp margins
    • Nonseminomas: variable echogenicity; , inhomogenous; , may be calcified or cystic
    • Microlithiasis: disseminated calcification as a possible precursor of carcinoma (starry sky appearance)
  • CT: Because of the descended testis, the regional lymph nodes are located retroperitoneally (e.g., para-aortocaval) beneath the diaphragm.
    • High-resolution abdominopelvic and chest CT
    • Cranial CT or MRI if distant metastasis to the brain is suspected
• Histopathological confirmation: following radical inguinal orchiectomy

If a testicular tumor is suspected, the testis should be removed and sent to pathology. Transscrotal biopsy should not be conducted because of the risk of tumor seeding!

References:^[1][17]

Differential diagnosis of painless testicular swelling
Condition	Clinical features	Ultrasound
Testicular tumor	Usually painless mass (however, may feel dull ache or "heavy" sensation in the testicle) Palpation of solid mass Negative transillumination test	Solid mass with variable echogenicity
Hydrocele testis	Fluctuant swelling of the scrotum Palpation of an elastic soft swelling Positive transillumination test	Hypoechoic mass around the testis
Varicocele testis	Usually painless ; swelling may be reduced when supine Visible or palpable strands and “bag of worms” sensation Negative transillumination test	Dilated hypoechoic pampiniform vessels
Spermatocele testis	Fluctuant swelling of the upper testicular pole Positive transillumination test	Hypoechoic dilation of epididymal duct or rete testis
Scrotal hernia	Visible groin protrusion Bowel sounds on auscultation over scrotum	Herniated bowels

References:^[18]

The differential diagnoses listed here are not exhaustive.

Surgery

• Prior to surgery: sperm cryopreservation
• Radical inguinal orchiectomy

Adjuvant radiotherapy and chemotherapy

• Adjuvant therapy is based on the clinical staging group, histology (seminoma vs. nonseminoma), and the prognosis.

Adjuvant treatment for testicular cancer
Staging according to the classification	Seminoma	Nonseminoma
Stage I	Standard: active surveillance Alternatively : chemotherapy (carboplatin) or radiation therapy of the regional lymph nodes	Active surveillance or RPLND3 ± cisplatin-based chemotherapy Chemotherapy: BEP1
Stage II	Radiation therapy or Chemotherapy:BEP1 or EP2	In patients with normal post-orchiectomy tumor markers: RPLND3 ± cisplatin-based chemotherapy In patients with elevated post-orchiectomy tumor markers: chemotherapy with BEP1or EP2
Stage III	Chemotherapy (depending on prognosis): BEP1 or EP2 followed by evaluation of any residual disease that may require resection
1BEP = chemotherapy with bleomycin, etoposide, and cisplatin, 2EP = chemotherapy with etoposide, cisplatin, 3RPLND= retroperitoneal lymph node dissection

References:^{[19][20][21][9]}

• The overall prognosis of testicular tumors is excellent, with a high cure rate and 5-year survival rates of > 95%.
• Even in advanced, metastatic stages, testicular tumors are often curable.

Testicular tumors, particularly seminomas, are one of the few cancers that can be cured even in very advanced stages with adequate treatment. Patients with nonseminomas have a significantly poorer prognosis but still an excellent overall survival rate!
References:^[22]