Cytopathology Case 14

Final Diagnosis & Discussions:

FINAL DIAGNOSIS: Bladder washing: High grade keratinizing dysplasia. Bladder biopsy: High grade dysplasia (Squamous cell carcinoma in situ) with extensive squamous metaplasia of the surrounding urothelium.


Bladder cancer ranks fifth in cancer incidence in the Western Hemisphere and is the leading cause of cancer-related death from the genitourinary tract. The most common histological type of bladder cancer is urothelial carcinoma, accounting for 90 percent to 95 percent of bladder cancer in the United States. Squamous differentiation is frequently observed in urothelial carcinomas and its frequency increases with grade and stage. However, pure squamous cell carcinoma (SCC) of the bladder is much less frequent. In the 2004 World Health Organization (WHO) classification, the diagnosis of squamous cell carcinoma is restricted to those bladder carcinomas that are composed of pure squamous cell phenotype. According to this classification it constitutes about 1.3 percent of bladder tumors in males and 3.4 percent in females.

Risk factors associated with the development of bladder squamous cell carcinoma include long-term catheterization, a nonfunctioning bladder and urinary tract calculi. Another well-known association, reported from Egypt, Sudan, and other countries, is chronic infection with Schistosoma hematobium. In addition, morphologic changes that may herald the ultimate development of bladder squamous cell carcinoma have been reported to include keratinizing squamous metaplasia, verrucous squamous hyperplasia, condyloma acuminatum, and squamous cell carcinoma in situ.

Squamous cell carcinoma of the urinary bladder is likely to arise through a process of squamous metaplasia of the urothelium, in which the normal urothelium is replaced by squamous epithelium. Squamous metaplasia can be generally categorized into 2 subtypes, nonkeratinizing and keratinizing. Nonkeratinizing glycogenated squamous metaplasia is common in the bladder from women, particularly in the trigone area. In the absence of cellular atypia, this type of squamous metaplasia, if limited to the trigone area, is regarded as an anatomic epithelial variant occurring under hormonal influence and bearing no clinical significance. However, keratinizing squamous metaplasia, clinically known as leukoplakia, is a pathologic response to chronic inflammatory stimulation from infection, indwelling catheters, stones, or parasite eggs (in the event of a Schistosoma infection). Keratinizing squamous metaplasia is more common in men; although in our case the patient is a woman. When persistent, it represents a risk factor for squamous cell carcinoma.

The diagnosis of squamous cell carcinoma should be reserved for those tumors that are purely or almost entirely squamous throughout. If an identifiable urothelial component (including urothelial carcinoma in situ) is found, the tumor should be classified as urothelial carcinoma with squamous differentiation. The presence of keratinizing squamous metaplasia in the adjacent flat epithelium, especially if associated with dysplasia, supports a diagnosis of squamous carcinoma.

The tumor may be in situ or invasive. Squamous cell carcinoma in situ of the urinary bladder is often associated with subsequent or concurrent invasive carcinoma with squamous differentiation. The invasive tumors may be well-differentiated with islands of squamous cells demonstrating keratinization, prominent intercellular bridges, and minimal nuclear pleomorphism. They may also be poorly differentiated showing marked nuclear pleomorphism with only focal evidence of squamous differentiation.

In women, the presence of atypical squamous cells in the sediment of voided urine may indicate the presence of a neoplastic lesion from a number of areas within the female genital tract, including the uterine cervix, vagina, or vulva. Thus, when atypical squamous cells are present in a voided urine from a female the pathologist should raise the possibility of a neoplastic process involving the genital tract, in addition to a neoplastic process stemming from the bladder. In the case presented here, the atypical cells can be definitively construed as arising from the bladder urothelium given that the specimen was obtained during cystoscopy as a bladder washing.

The expected findings on a bladder washing specimen is a pure population of urothelial cells, both in clusters and as single cells, with a low nuclear to cytoplasmic ratio and uniform round nuclei with fine chromatin. The cytology of this case revealed atypical cells showing both dysplastic nuclear features (enlargement, hyperchromasia, irregular nuclear membranes, and chromatin clumping) and squamous differentiation (dense, uniform cytoplasm with some cells showing cytoplasmic orangeophilia consistent with keratinization) is the expected urinary cytology from cases of keratinizing dysplasia of the bladder. The dysplasia can be categorized as being high grade if a subset of the atypical cells have a nuclear to cytoplasmic ration greater than 50%. Similar to lesions of the cervix diagnosed by the Pap test, an invasive squamous cell carcinoma can be suggested if nuclear pleomorphism beyond the scale of dysplasia is present, or if nucleoli become prominent in the atypical cell population.


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