Urethral cancer pathophysiology

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Vindhya BellamKonda, M.B.B.S [2], Aida Javanbakht, M.D.


Urethral cancer is a rare disease. The pathophysiology of urethral cancer depends on the histological subtypes. It could be primary from epithelial origin or secondary like from bladder cancer which is more common than primary type [1] [2].


Mucous cells in the urethra have the ability to turnover rapidly. In primary type of the urethral cancer It has been suggested that defect in "DNA repair mechanism" may cause urethral cancer.

Other etiologies for primary types are [3]:

  • Although cigarette smoking can cause bladder cancer but the role of it in causing primary urethral cancer is still unknown.

The pathogenesis is different in male and female:

  • Female: Proximal 2/3 of the urethral cancer are more primary types and distal 1/3 is usually squamous cell carcinoma.


The exact gene and mutations that cause urethral cancer are unknown. But below genetic correlation are known to be involved in the pathogenesis:

  • Overexpression of the semaphorin 3A in patients with urethral cancer has been reported [11].

Associated Conditions

  • Urethral cancers in proximal urethra have worse prognosis than those arising in the distal portion in men.

Gross Pathology

In end stage type, they may appear as an exophytic mass.

Microscopic Pathology

The microscopic view of urethral cancer is depended on the location of the cancer. The type of the cancer in the distal part of the urethra is usually squamous cell. [12]

Histology based on the types of the cancer:

  • SCC: high mitotic activity, nuclear atypia. Positive with cytoplasmic beta-catenin stain. pleomorphic tumor cells with focal or abundant keratinization, intercellular bridges. Stains: High molecular weight cytokeratin (CK903, CK5/6), p63, p16.
  • Clear Cell: clear or eosinophilic cytoplasm, vacuoles in the cytoplasm, hyperchromatic nuclei. Positive with  p53 and vimentin stain. Hobnail changes and extracellular mucoid material.


  1. Sui W, RoyChoudhury A, Wenske S, Decastro GJ, McKiernan JM, Anderson CB (February 2017). "Outcomes and Prognostic Factors of Primary Urethral Cancer". Urology. 100: 180–186. doi:10.1016/j.urology.2016.09.042. PMID 27720774.
  2. Zargar-Shoshtari K, Sexton WJ, Poch MA (November 2016). "Management of Urethral Recurrences: Urothelial and Nonurothelial". Urol. Clin. North Am. 43 (4): 515–521. doi:10.1016/j.ucl.2016.06.012. PMID 27717437.
  3. Klemann N, Toft BG, Thind P (January 2014). "[Urethral cancer is rare and difficult to diagnose]". Ugeskr. Laeg. (in Danish). 176 (4A): V07130435. PMID 25347253.
  4. Colapinto V, Evans DH (October 1977). "Primary carcinoma of the male urethra developing after urethroplasty for stricture". J. Urol. 118 (4): 581–4. PMID 916053.
  5. Browne BM, Vanni AJ (October 2017). "Management of Urethral Stricture and Bladder Neck Contracture Following Primary and Salvage Treatment of Prostate Cancer". Curr Urol Rep. 18 (10): 76. doi:10.1007/s11934-017-0729-0. PMID 28776126.
  6. Cupp MR, Malek RS, Goellner JR, Espy MJ, Smith TF (October 1996). "Detection of human papillomavirus DNA in primary squamous cell carcinoma of the male urethra". Urology. 48 (4): 551–5. doi:10.1016/S0090-4295(96)00246-4. PMID 8886059.
  7. Mohan H, Bal A, Punia RP, Bawa AS (February 2003). "Squamous cell carcinoma of the prostate". Int. J. Urol. 10 (2): 114–6. PMID 12588611.
  8. Ahmed K, Dasgupta R, Vats A, Nagpal K, Ashrafian H, Kaj B, Athanasiou T, Dasgupta P, Khan MS (June 2010). "Urethral diverticular carcinoma: an overview of current trends in diagnosis and management". Int Urol Nephrol. 42 (2): 331–41. doi:10.1007/s11255-009-9618-x. PMID 19649767.
  9. Wang X, Lopez-Beltran A, Osunkoya AO, Wang M, Zhang S, Davidson DD, Emerson RE, Williamson SR, Tan PH, Kaimakliotis HZ, Baldridge LA, MacLennan GT, Montironi R, Cheng L (April 2017). "TERT promoter mutation status in sarcomatoid urothelial carcinomas of the upper urinary tract". Future Oncol. 13 (8): 705–714. doi:10.2217/fon-2016-0414. PMID 28052688.
  10. Zhang CT, Lu R, Lin YL, Liu RL, Zhang ZH, Yang K, Dang RF, Zhang HT, Shen YG, Kong PZ, Ren HL, Li XL, Quan W, Xu Y (2012). "The significance of fragile histidine triad protein as a molecular prognostic marker of bladder urothelial carcinoma". J. Int. Med. Res. 40 (2): 507–16. doi:10.1177/147323001204000212. PMID 22613411.
  11. Vadasz Z, Rubinstein J, Bejar J, Sheffer H, Halachmi S (April 2018). "Overexpression of semaphorin 3A in patients with urothelial cancer". Urol. Oncol. 36 (4): 161.e1–161.e6. doi:10.1016/j.urolonc.2017.12.007. PMID 29288007.
  12. Grivas PD, Davenport M, Montie JE, Kunju LP, Feng F, Weizer AZ (December 2012). "Urethral cancer". Hematol. Oncol. Clin. North Am. 26 (6): 1291–314. doi:10.1016/j.hoc.2012.08.006. PMID 23116581.
  13. Cantiello F, Cicione A, Salonia A, Autorino R, Tucci L, Madeo I, Damiano R (May 2013). "Periurethral fibrosis secondary to prostatic inflammation causing lower urinary tract symptoms: a prospective cohort study". Urology. 81 (5): 1018–23. doi:10.1016/j.urology.2013.01.053. PMID 23608423.
  14. Mallya V, Mallya A, Gayathri J (2018). "Clear cell adenocarcinoma of the urethra with inguinal lymph node metastases: A rare case report and review of literature". J Cancer Res Ther. 14 (2): 468–470. doi:10.4103/0973-1482.226734. PMID 29516944.