Bladder & urothelial tract

• Urothelial carcinoma with variable amounts of squamous differentiation (intracellular keratin, intercellular bridges or keratin pearls)

• ICD-O: 8120/3 - urothelial carcinoma with squamous differentiation
• ICD-10
  • C67.9 - malignant neoplasm of bladder, unspecified
  • C66.9 - malignant neoplasm of unspecified ureter
  • C68.0 - malignant neoplasm of urethra
  • C65.1 - malignant neoplasm of right renal pelvis
  • C65.2 - malignant neoplasm of left renal pelvis

• Occurs in 30 - 40% of urothelial carcinomas of bladder (J Clin Pathol 2007;60:332, Urology 2007;70:69)

• Hematuria, dysuria and frequent urination (Urology 2006;67:3)

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Contributed by Huihui Ye, M.D., M.S.

• Most commonly associated with high grade urothelial carcinoma
• By definition, must have clear cut evidence of urothelial component (invasive urothelial carcinoma)
• Squamous components are similar to typical squamous cell carcinoma: nests of squamous epithelial cells, characterized by large nuclei with abundant eosinophilic cytoplasm and evidence of keratinization (intracellular keratin, intercellular bridges or keratin pearls)
• Squamous component may show basaloid or clear cell features
• Tumor associated eosinophilia in the bladder may present (J Clin Pathol 1984;37:500)
• Presence of squamous component should be reported and providing estimation of the percentage of differentiation is strongly recommended

Contributed by Huihui Ye, M.D., M.S.

• High grade urothelial carcinoma component: high N:C ratio, nuclear pleomorphism, nuclear membrane irregularity and severe hyperchromasia
• Squamous component: keratinizing cells with high N:C ratio, large and hyperchromatic nuclei, irregular nuclear contour, polygonal cell shape, abundant eosinophilic cytoplasm or dense orangeophilic cytoplasm
• See Paris system for urothelial neoplasia

Contributed by Chunlai Zuo, M.D., M.S.


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• Squamous component
  • CK14, MAC387 (L1 antigen), CK5/6, CK5 / 14, desmoglein, desmocollins (J Clin Pathol 2007;60:332, Virchows Arch 2011;458:301)
• Caveolin-1 (Am J Clin Pathol 2003;120:93)

• Squamous component
  • Uroplakins (positive in urothelial component), CK20

• Squamous cell carcinoma:
  • Can be associated with Schistosoma haematobium
  • Must not have a urothelial carcinoma component
  • No criteria to distinguish squamous cell carcinoma with predominately well / moderately differentiated areas and focal poorly differentiated area from urothelial carcinoma with extensive squamous differentiation
• Metastatic squamous cell carcinoma secondarily involving bladder:
  • Squamous cell carcinoma arising from cervical, anal or penile origin or other locations should be excluded
  • Clinical presentation and imaging studies are crucial
  • Often HPV associated
• Keratinizing squamous metaplasia with dysplasia or squamous cell carcinoma in situ:
  • May be present in adjacent bladder mucosa in cases of bladder primary squamous cell carcinoma

Invasive urothelial carcinoma with squamous differentiation is characterized by which of the following?

1. High risk HPV in situ hybridization positive
2. Intercellular bridges or keratinization
3. No clear cut evidence of urothelial component
4. p63 positive on immunostain

B. Intercellular bridges or keratinization. The diagnosis is established based on squamous morphology characterized by intercellular bridges or keratinization on H&E stains. Answer A is incorrect because human papillomavirus (HPV) is not commonly associated with urothelial carcinoma with squamous differentiation. In contrast, high risk HPV positivity would support a secondary involvement by cervical, anal or penile squamous cell carcinoma. Answer C is incorrect because, by definition, clear cut evidence of urothelial component must be identified. Answer D is incorrect because p63 is also commonly positive in conventional urothelial carcinoma.

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Reference: Urothelial carcinoma with squamous differentiation

A 50 year old woman presented with hematuria and was found to have a mass involving the bladder posterior wall shown above. Which of the following findings is most supportive of invasive urothelial carcinoma with squamous differentiation over secondary involvement by carcinoma from the other organs?

1. Component of uroplakin II positive conventional urothelial carcinoma
2. High risk HPV ISH positive
3. Mass lesion found at lower uterine segment
4. p16 positivity with a diffuse block-like staining pattern

A. Component of uroplakin II positive conventional urothelial carcinoma. Uroplakin II is a highly specific immunohistochemical marker for urothelial differentiation. Answers B, C and D are incorrect since these findings would favor squamous cell carcinoma of cervical or uterine primary over bladder primary.

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Reference: Urothelial carcinoma with squamous differentiation