Testicular cancer pathophysiology

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Gertrude Djouka, M.D.[2], Shanshan Cen, M.D. [3]

Overview[edit | edit source]

The pathophysiology of testicular cancer depends on the histological cell subtypes and findings. Most testicular cancers derived from the lack of differentiation of primordial germ cell into spermatogonia. Germ cells testicular tumor have some genetic component while most sex cord stromal testicular cancer are hormonal dependent. Most gross pathology of testicular tumors look similar on the physical appearance. On microscopic histopathological analysis of testicular cancer, fried-egg appearance is the characteristic finding of seminoma; marked nuclear atypia is the characteristic finding of embryonal carcinoma; hyaline-type globules, and Schiller-Duval bodies are characteristic findings of yolk sac tumor  ; syncytiotrophoblasts and cytotrophoblast cells are the characteristic findings of choriocarcinoma, Polymorphism with"spirene" chromatin for spermatocytic.

Pathogenesis[edit | edit source]

Normal process of testicular germ cells[edit | edit source]

• Normal inner cell mass leads to primordial germ cell mass^[1][2]

• Primordial germ cell mass leads to gonocytes through cell proliferation
• Gonocytes differentiate into spermatogonia

Normal process of testicular sex cord stromal[edit | edit source]

Leydig cells[edit | edit source]

• Leydig cells are found in the seminiferous tubules of the testis.^[3][4]
• Leydig cells secrete testosterone hormone under the signal of luteinizing hormone.
• Leydig cells are involved in the development of male secondary sexual characteristics and spermatogenesis.

Germ cells tumors[edit | edit source]

Germ cell tumors derived from germ cell neoplasia in situ[edit | edit source]

• Lack of primordial germ cell to differentiate into spermatogonia leads to germ cell neoplasia in Situ^[2]
• Germ cell neoplasia in Situ may gain some abnormal chromosome(12), then it leads to seminomas and nonseminomas cancers.
• Seminomas and non seminotous germ cell tumors have similar pathogenesis.^[5][6]
  • Aneuploid
  • Loss of chromosomes 4,5,11,13,18, and Y
  • Gain of chromosomes 7,8,12, and X
• More than 90% of all testicular cancers are germ cell tumors. This type of cancer starts in germ cells, which are the cells that develop into sperms.
• About 50% of all germ cell tumors are seminomas, or seminomatous germ cell tumours. They grow slower than non-seminomas.
• Overrepresentation of short arm of chromosomes 12p may be related to invasive growth of seminomas and nonseminomatous testicular cancer.^[7]
• Seminomas tumors may have both genetic and immune components due to lymphocytes infiltration in HIV patients.^[8]
• Histological of seminomas tumor in HIV patients: tumor infiltrated by lymphocytes which may lead to weak immune system response.^[8]
• Familial contribution:^[9]
  • Gene on chromosome Xq27 may be related to testicular germ cell tumors
• Some proteins such as C-kit (receptor) and placental-like alkaline phosphatase (PLAP) may be excessively expressed^[10]

Germ cell tumors unrelated to germ cell neoplasia in situ[edit | edit source]

• Mutations from the proteins that may be involved in the maturation of the spermatogonia.^[11]
• Mostly located in the testis and rarely metastases.
• Mutated proteins involved: SAGE1 and SSX2-4.
• Hypothesis of gain of chromosome 9 may be involved in the process.^[12]

Testicular sex cord stromal tumors[edit | edit source]

Leydig cells tumor[edit | edit source]

• The pathogenesis of leydig cells tumors is not well understood.^[3][13]
• It is hypothesized that there is a disturbance of hypothalamic-pituitary-testicular axis which lead to excess of hormone productions.
• The G proteins in the leydig cells and the structure alteration of Luteinizing hormone receptors may play role in leydig cells tumors.

Sertoli cell tumor[edit | edit source]

• Sertoli cell arise from testicular supporting cells which regulate the spermatogenesis.
• It may due to excess production of androgen hormone.^[14]

Granulosa cell tumor[edit | edit source]

• It involved in hyperestrogenism due to an unregulated aromatase enzyme activity that leads to excessive production of hormones.^[15]

Gross and Microscopic Pathology[edit | edit source]

The gross and microscopic features of the most common tumors are described below:^{[16][17][18][19][20][21][22][19][23][24][25][26][27][3][28][29][15]}

Types	Gross pathology	Microscopic pathology	Images
Germ cell neoplasia in situ	Solid, fleshy nodules Similar to seminoma in appearance Well-circumscribed with hemorraghic and necrotic areas	Hyperchromatic nuclei Prominent nucleoli and clear cytoplasm Thickened basement menbrane Proliferation of tumor germ cell in the seminiferous tubules
Seminoma	Solid, firm without cross section Solid fleshy tan to yellow mass in homogeneous appearance Well-circumscribed with small hemorraghic and necrotic areas	Large nucleoli with clear to pale to eosinophilic cytoplasm due to the presence of glycogen Clonal proliferation of neoplastic germ cells Fried-egg appearance Prominent mitotic figures Nests and sheets of cancer cells with "squared-off" nuclei Granulomatous inflammation
Embryonal carcinoma	Poorly demarcated mass Soft gray on cut surface Large hemorraghic and necrotic foci.	Presents with mixed histological features (solid, papular, glandular) Marked nuclear atypia Marked epithelial cells with polymorphism Large nuclei with abundant amphophilic cytoplasm Prominent mitotic activities
Yolk sac tumor	Solid, lobulated, soft, mucinous on cut surface Gray and grayish yellow mass May have small hemorrhagic and necrotic foci Heterogenous mass	Hyaline-type globules Schiller-Duval bodies Multiple histological patterns such as recticular, microcystic, glandular, papillary, hepatoid, and solid Associated with myxoid stroma Variable cytologic atypia
Choriocarcinoma	Hemorrhagic and necrotic nodules May appear more cystic and calcified in homogeneous	More Hemorrhagic and necrotic Made up of mononucleated trophoblast and multinucleated syncytiotrophoblast cells Hyperchomatic cytoplasm
Teratoma, postpubertal-type	Hetereogenous, cystic and irregular calcification on appearance Solid, firm mass	Arrange in disorder fashion Cytologic atypia High mitotic activities Presence of 3 germ cells layers Presence of immature elements with primitive nuclei
Mixed germ cell tumors	Solid and cystic mass More hemorhragic and necrotic.	Microscopic findings are variable depending on the tumor type May have the component of yolk sac and choriocarcinoma
Spermatocytic tumor	Soft, gray, and gelatinous mass Well circumscribed with small hemorrhagic and necrotic foci.	Atyical mitoses activities Eosinophilic cytoplasm without glycogen Tumors cells with three different sizes (small, intermediate, and large) Polymorphism with"spirene" chromatin find in the giant cells Frequent apoptosis
Teratoma, prepubertal-type, Desmoid cyst Epidermoid cyst	Solid and firm mass	Lack of cytologic atypia No mitotic activities Absence of immature elements Desmoid cyst has polosebaceous cells Epidermoist cyst is surrounded with squamous epithelial cells
Testicular lymphoma	Soft, gray, and gelatinous mass Well circumscribed with small hemorrhagic and necrotic foci.	Vascular invasion Pleomorphic tumor cells Large irregular nuclei
Leydig cells tumor	Homogeneous and well circumscribed mass Solitary and unilateral mass White to brown to yellow on cut surface	Cells are arranged in nest, sheets polygonal fahsion Cytoplasm is eosinophilic with round nuclei and prominent nucleoli Presence of lipofuscin pigment and reinke crystal intracytoplasmic
Sertoli tumor	Homogeneous and well circumscribed mass White to grey on cut surface	Cells are arranged in cords, nests and lobulated tubules Fibrous stroma ans septa with lymphocytes Elongated spaces and microscysts Pale lipid- rich cytoplasm No prominent nucleoli
Granulosa tumor	Adult type No distint feature Juvenile type Solid, nodule yellow-orange and cystic mass	Adult type Cells are arranged in elongated, microfollicular "call-Exner bodies" Juvenile type Cells are presented in solid sheets and nodules and form the estatic space Eosinophilic cytoplasm Hyperchromatic, round to oval nuclei High mitotic activities Follicles are located on the periphery

Genetics[edit | edit source]

These are genes involved in the pathogenesis of testicular cancer:^[30][31]

• Chromosome 12p
• 12q22.2

Immunohistochemical Markers[edit | edit source]

• Germ cell neoplastic in situ:
  • +PLAP (Placenta like-alkaline phosphatase)^[32]
• Seminomas:^[21][33][34]
  • OCT3/4 transcription factors^[35]
  • C-kit
  • CD30
  • D2-40 monoclonal antibody
  • PLAP
  • NANOG transcription factor

• Embryonal carcinoma:^[33][34]
  • PLAP
  • OCT3/4^[35]
  • SOX2
  • CD30
  • +/-GpC3,keratin

• Yolk sac tumor:^[12][36]
  • +SALL4
  • +AFP
  • +GATA3
  • +Glypican3
  • +Keratin
  • +/-C-kit

• Choriocarcinoma:^[12]
  • +Ck7
  • +GATA3
  • +HCG
  • +/-SALL4

• Spermatocytic tumor:^[12]
  • +SALL4
  • +/-C-kit

• Teratoma:^[23][37][12]
  • +SALL4
  • +Cytokeratin
  • +HCG
  • +/-GATA3,SOX2,OCT4

• Testicular lymphoma:^[12]
  • +CD3
  • +CD20
  • +CD45

• Leydig cell tumor:^[3][38]
  • +Inhibin
  • +Calretinin
  • +Melan-A
  • +Vimentin

• Sertoli cell tumor:^[29][38][3]
  • +Inhibin
  • +Vimentin
  • +EMA (epithelial menbrane antigen)
  • +/-Cytokeratin

• Granulosa cell tumor:^[39][29][40]
  • +Inhibin
  • +Calretinin
  • +Vimentin

References[edit | edit source]

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