Aetiology

All germ cell tumours are thought to develop secondary to a tumourigenic event in utero and progress through a non-invasive stage of intratubular germ cell neoplasia.[19] The pathogenetic World Health Organization (WHO) classification term, germ cell neoplasia in situ (GCNIS), is now recommended.[20]​ Genetic effects contribute to testicular cancer and individuals with a family history have an increased risk.[21] The most common genomic alterations found in testicular germ cell tumours include gains in chromosome 12p and mutations in KIT, KRAS, and NRAS, particularly in seminomas.[22]​ Nonetheless, over 90% of men with testicular cancer have no family history of the disease.[23]​ 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 aetiological factor for testicular cancer.[24] 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.[24]

Pathophysiology

The malignant transformation of germ cell neoplasia in situ is characterised 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 tumour embolisation through lymphatico-venous communications. This accounts for most regional treatment failures despite radical orchiectomy and retroperitoneal surgical clearance.

Non-seminoma doubling time ranges from 10 to 30 days. This is reflected by alterations in the serum tumour 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.[25][26]​ 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.[27]

Classification

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

A significant change in testicular tumour classification in the 2016 World Health Organization (WHO) classification of urogenital tumours 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 tumours, and testicular germ cell tumours 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:

  • Non-invasive germ cell neoplasia

    • GCNIS

    • Specific forms of intratubular germ cell neoplasia

    • Gonadoblastoma

  • The germinoma family of tumours

    • Seminoma

  • Non-seminomatous germ cell tumours

    • Embryonal carcinoma

    • Yolk sac tumour, postpubertal-type

    • Choriocarcinoma

    • Placental site trophoblastic tumour

    • Epithelioid trophoblastic tumour

    • Cystic trophoblastic tumour

    • Teratoma, postpubertal-type

    • Teratoma with somatic-type malignancy

  • Mixed germ cell tumours of the testis

    • Mixed germ cell tumours

  • Germ cell tumours of unknown type

    • Regressed germ cell tumours

Unrelated to GCNIS:

  • Spermatocytic tumour

  • Yolk sac tumour, prepubertal-type

  • Teratoma, prepubertal-type

  • Testicular neuroendocrine tumour, prepubertal-type

  • Mixed teratoma and yolk sac tumour, prepubertal-type

Sex cord-stromal tumours:

  • Leydig cell tumours

  • Sertoli cell tumours

  • Granulosa cell tumours

  • Tumours in the fibroma-thecoma group

  • Mixed and unclassified sex cord-stromal tumours

  • 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 tumour (T), with the American Joint Committee on Cancer staging system further subdividing T1 by size (T1a tumour <3 cm; T1b tumour ≥3 cm)

  • Regional lymph node involvement (N)

  • Presence or absence of distant metastases (M)

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

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