Section 3 -

Other carcinomas of the urinary bladder Antonio Lopez-Beltran Cordoba University Medical School Cordoba, Spain

Primary adenocarcinoma A malignant neoplasm derived from the urothelium showing histologically pure glandular phenotype [1, 2, 3, 4]. It accounts for 0.5-2% of all malignant bladder tumors and two major categories have been recognized, 1) those arising in the bladder proper and 2) those arising from the urachal remnants. Adenocarcinoma of the urinary bladder occurs more commonly in males than in females with a peak incidence in the sixth decade of life. Hematuria is common. Adenocarcinoma of the bladder may show different patterns of growth. These include: 1) enteric (colonic) type, 2) adenocarcinoma not otherwise specified (NOS), 3) signet ring cell, 4) mucinous (colloid), 5) clear cell, 6) hepatoid, and 7) mixed forms [1, 2, 3] . The NOS type consists of an adenocarcinoma with a non-specific glandular growth. The enteric type closely resembles adenocarcinoma of the colon. Tumors that show abundant mucin with tumor cells floating within the mucin are classified as mucinous or colloid type. The signet ring cell variant may be diffuse or mixed, can have a monocytoid or plasmacytoid phenotype. An extremely rare variant of adenocarcinoma is the clear cell type (mesonephric), which consists of papillary structures with cells that exhibit a hob-nail appearance. The hepatoid type is also rare and consists of large cells with eosinophilic cytoplasm that are reactive for alpha-Fetoprotein [3]. Finally, it is not uncommon to find a mixture of these growth patterns. Adenocarcinoma in situ may be found in the urinary bladder alone or in combination with an invasive adenocarcinoma. There is no generally accepted grading system ascribed to adenocarcinoma of the bladder. The immunohistochemical profile of these tumours that has been reported in the literature is variable and closely matches that of colonic adenocarcinomas including its neuroendocrine differentiation [4]. Reports of CK 7 positivity are variable, while CK-20 is reported to be positive in most bladder adenocarcinomas. Villin has recently been reported to be positive in enteric type adenocarcinomas of the urinary bladder and Beta-catenin has been reported to be of help in distinguishing primary adenocarcinoma of the bladder from metastatic colonic adenocarcinoma. Stage is the most important prognostic factor. It is important to distinguish between urachal and non-urachal adenocarcinomas especially for treatment purposes. Among histologic types of adenocarcinoma, pure signet ring cell carcinoma carries the worst prognosis [2]. Squamous cell carcinoma A malignant neoplasm derived from the urothelium showing histologically pure squamous cell phenotype [5, 6]. Schistosomiasis and chronic urinary tract infection are conditions associated with the development of squamous cell carcinoma. If an identifiable urothelial element 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 cell carcinoma. The invasive tumors may be well differentiated with well-defined islands of squamous cells with keratinization, prominent intercellular bridges, and minimal nuclear pleomorphism. They may also be poorly differentiated, with marked nuclear pleomorphism and only focal evidence of squamous differentiation. The verrucous form of squamous cell carcinoma is an uncommon variant that occurs most frequently in patients with schistosomiasis, accounting for 3% to 4.6% of bladder cancers in such a setting; but isolated cases have been described in the literature from non-endemic areas. A basaloid pattern of squamous cell carcinoma has been reported, and a clear cell pattern of squamous cell carcinoma of the bladder is under discussion [5, 6]. T-stage, lymph node involvement and tumor grade have been shown to be of independent prognostic value. Patients undergoing radical surgery appear to have an improved survival as compared to radiation therapy and/or chemotherapy. Small cell carcinoma Small cell carcinoma is a malignant neuroendocrine neoplasm derived from the urothelium which histologically mimics its pulmonary counterpart [7, 8, 9]. In a recent series of 64 cases of small cell carcinoma of the urinary bladder all the patients except one had muscle-invasive disease at presentation. Thirty-eight patients (59%) underwent cystectomy and 66% of patients had lymph node metastasis at the time of cystectomy with regional lymph nodes, bone, liver and lung being the most common locations. Twenty cases (32%) were pure small cell carcinoma; 44 cases (68%) cases consisted of small cell carcinoma with other histological types (urothelial carcinoma, 35 cases; adenocarcinoma, 4 cases; sarcomatoid urothelial carcinoma, 2 cases; and 3 cases with both adenocarcinoma and urothelial carcinoma). Patients with organ-confined cancers had marginally better survival than those with non organ-confined cancer (P=0.06). At histology, they consist of small, rather uniform cells, with nuclear molding, scant cytoplasm and nuclei containing finely stippled chromatin and inconspicuous nucleoli. Mitoses are present and may be frequent. Necrosis is common and there may be DNA encrustation of blood vessels walls (Azzopardi phenomenon). Most cases have areas of urothelial carcinoma sometimes in the form of flat urothelial carcinoma in situ and exceptionally, squamous cell carcinoma, adenocarcinoma or sarcomatoid carcinoma. The immunohistochemical profile reveals neuronal-specific enolase in 87% of cases, and chromogranin A only in a third of cases. Some cases are also reactive against synaptophysin, PGP 9.5, thyroid transcription factor-1 (TTF-1), p53 (DO7), and Ki67 (MIB-1). The recent finding of c-kit and c-erbB2 expression by immunohistochemistry opens new possibilities for therapy in small cell carcinoma of the bladder [7, 8, 9]. References Bentley G and Grignon D. Non-transitional epithelial tumors. In: Foster and Ross (eds.) Pathology of the urinary bladder. MPP 42 series. Saunders, Philadelphia 2004 Ayala, AG, et al. Adenocarcinoma. In: Eble JN Sauter G, Epstein JI, Sesterhenn I, (eds.) World Health Organization Classification of Tumors. Pathology and Gentics of Tumors of the Urinary System and Male Genital Organs. Lyon: IARC; 2004. Lopez-Beltran A, Luque RJ, Quintero A, Requena MJ, Montironi R. Hepatoid adenocarcinoma of the urinary bladder. Virchows Arch. 2003;442(4):381-7. Bollito ER, Pacchioni D, Lopez-Beltran A, Volante M, Terrone C, Casetta G, Mari M, DePompa R, Cappia S, Papotti M. Immunohistochemical study of neuroendocrine differentiation in primary glandular lesions and tumors of the urinary bladder. Anal Quant Cytol Histol. 2005;27(4):218-24. Grignon D, et al. Squamous cell carcinoma. In: Eble JN Sauter G, Epstein JI, Sesterhenn I, (eds.) World Health Organization Classification of Tumors. Pathology and Gentics of Tumors of the Urinary System and Male Genital Organs. Lyon: IARC; 2004. Grignon D and El-Bolkainy MN. Verrucous Squamous cell carcinoma. In: Eble JN Sauter G, Epstein JI, Sesterhenn I, editors. World Health Organization Classification of Tumors. Pathology and Gentics of Tumors of the Urinary System and Male Genital Organs. Lyon: IARC; 2004. Small cell carcinoma of the urinary bladder: a clinicopathologic analysis of 64 patients. Cancer. 2004;101(5):957-62 Cheng L, Jones TD, McCarthy RP, Lopez-Beltran A, et al. Molecular genetic evidence for a common clonal origin of urinary bladder small cell carcinoma and co-existing urothelial carcinoma. Am J Pathol 2005;166:1533-9 Pan CX, Yang XJ, Lopez-Beltran A, et al. c-kit expression in small cell carcinoma of the urinary bladder: prognostic and therapeutic implications. Mod Pathol 2005;18:320-3