Etiology

All germ cell tumors are thought to develop secondary to a tumorigenic event in utero and progress through a noninvasive stage of intratubular germ cell neoplasia.[18] The pathogenetic World Health Organization (WHO) classification term, germ cell neoplasia in situ (GCNIS), is now recommended.[19]​ Genetic effects contribute to testicular cancer and individuals with a family history have an increased risk.[20] The most common genomic alterations found in testicular germ cell tumors include gains in chromosome 12p and mutations in KIT, KRAS, and NRAS, particularly in seminomas.[21]​ Nonetheless, over 90% of men with testicular cancer have no family history of the disease.[22]​ Congenital abnormalities (e.g., cryptorchidism) leading to distorted differentiation of germ cells and arrest of normal development of the primordial germ cell are considered to be an important etiologic factor for testicular cancer.[23] Perinatal factors (e.g., low birth weight), hormone-disrupting chemical exposure, and endogenous hormones, may also play a role in the development of the disease.[23]

Pathophysiology

The malignant transformation of germ cell neoplasia in situ is characterized by growth beyond the basement membrane, eventually replacing most of the testicular parenchyma. Spontaneous regression is rare; therefore, any growth of the testis should be regarded as malignant and managed accordingly. The tunica albugenia is a natural barrier to local metastasis so it should not be compromised by direct diagnostic scrotal needle biopsy.

Lymphatic spread is the most common cause of metastasis and often occurs through spermatic cord lymphatics to the retroperitoneal lymph node chain. One exception is pure choriocarcinoma, which frequently disseminates through vascular invasion. On rare occasions a direct communication exists between testicular lymphatics and the thoracic duct, causing a thoracic (sternal) metastasis without retroperitoneal involvement. Scrotal invasion may present with inguinal metastasis. Germ cell cancers may also present with extranodal distant metastasis following direct vascular invasion or tumor embolization through lymphatico-venous communications. This accounts for most regional treatment failures despite radical orchiectomy and retroperitoneal surgical clearance.

Nonseminoma doubling time ranges from 10 to 30 days. This is reflected by alterations in the serum tumor markers. Most treatment failure cases followed by mortality occur within the first 2 to 3 years of diagnosis. Seminoma usually has a much slower doubling time and may recur 2 to 10 years after initial treatment because of its indolent course.[24][25]​ Based on the natural history of the disease, cure after multimodality treatment is often declared after 5 years. However, relapse has been reported 10 or more years after treatment.[26]

Classification

World Health Organization classification of tumors of the testis​[3]

A significant change in testicular tumor classification in the 2016 World Health Organization (WHO) classification of urogenital tumors was the distinction between groups based on pathogenic origin. The WHO recommends the term germ cell neoplasia in situ (GCNIS) of the testis for precursor lesions of invasive germ cell tumors, and testicular germ cell tumors are now divided into those derived from GCNIS and those unrelated to GCNIS.[4]​ This schema has been retained in the 2022 classification.[5]

Derived from GCNIS:

  • Noninvasive germ cell neoplasia

    • GCNIS

    • Specific forms of intratubular germ cell neoplasia

    • Gonadoblastoma

  • The germinoma family of tumors

    • Seminoma

  • Nonseminomatous germ cell tumors

    • Embryonal carcinoma

    • Yolk sac tumor, postpubertal-type

    • Choriocarcinoma

    • Placental site trophoblastic tumor

    • Epithelioid trophoblastic tumor

    • Cystic trophoblastic tumor

    • Teratoma, postpubertal-type

    • Teratoma with somatic-type malignancy

  • Mixed germ cell tumors of the testis

    • Mixed germ cell tumors

  • Germ cell tumors of unknown type

    • Regressed germ cell tumors

Unrelated to GCNIS:

  • Spermatocytic tumor

  • Yolk sac tumor, prepubertal-type

  • Teratoma, prepubertal-type

  • Testicular neuroendocrine tumor, prepubertal-type

  • Mixed teratoma and yolk sac tumor, prepubertal-type

Sex cord-stromal tumors:

  • Leydig cell tumors

  • Sertoli cell tumors

  • Granulosa cell tumors

  • Tumors in the fibroma-thecoma group

  • Mixed and unclassified sex cord-stromal tumors

  • Gonadoblastoma

TNMS classification for testicular cancer[6][7]

The TNMS classification describes the extent of disease based on the following anatomic factors:

  • Size and extent of the primary tumor (T), with the American Joint Committee on Cancer staging system further subdividing T1 by size (T1a tumor <3 cm; T1b tumor ≥3 cm)

  • Regional lymph node involvement (N)

  • Presence or absence of distant metastases (M)

  • Postorchiectomy nadir serum tumor marker levels (S): lactate dehydrogenase, human chorionic gonadotropin, and alpha-fetoprotein. A worse prognosis is noted with high tumor marker levels.[6][7]

Use of this content is subject to our disclaimer