PATHOLOGY

Noninvasive urothelial carcinoma of the bladder with glandular differentiation: report of 24 cases
Miller JS, Epstein JI
Departments of Pathology, Urology and Oncology, The Johns Hopkins Hospital, Baltimore, MD, USA
Am J Surg Pathol. 2009; 13 [Epub ahead of print]

• Noninvasive urothelial carcinoma (UC) with glandular differentiation in the absence of infiltrating carcinoma is a rare entity that has not been well characterized. We retrieved 24 cases of noninvasive UC of the bladder with glandular differentiation on biopsy (n = 20) or transurethral resection (n = 4) without an associated invasive component. The cases were identified from the consult files of one of the authors between 1992 and 2008. Mean patient age at diagnosis was 70 years (range: 48 to 87 y) and 75% were male. Half of the cases were pure noninvasive UC with glandular differentiation; half were associated with either carcinoma in situ or high-grade noninvasive papillary carcinoma. The glandular component consisted of 1 or more patterns: papillary (46% of cases), glandular (42%), cribriform (33%), and flat (25%). Mitoses, apoptosis, and necrosis were identified in 83%, 67%, and 17% of the biopsies, respectively. One case was a recent diagnosis, and 5 patients either refused treatment or were lost to follow-up. Of the 18 patients with available follow-up information, 9 (50%) did not develop invasive carcinoma; the remaining 9 (50%) eventually developed an invasive bladder tumor. Of these, 2 were small cell carcinoma, 3 were poorly-differentiated UC (2 of these developed widespread metastases), and 4 were UC, not otherwise specified. In both instances of eventual small cell carcinoma, and in 2 of the 3 cases of poorly-differentiated UC, the initial biopsy consisted of pure noninvasive UC with glandular differentiation without carcinoma in situ or noninvasive papillary carcinoma. Of note, none of the patients in the study developed invasive adenocarcinoma.
  
  
• Editorial Comment
  Divergent differentiation is a very peculiar capacity of urothelial tumors (1). Squamous differentiation, defined by the presence of intercellular bridges or keratinization, occurs in up to 20% of urothelial carcinomas (2,3). Glandular differentiation is less common than squamous differentiation (4,5). The findings of squamous and/or glandular phenotype in urothelial carcinoma of the bladder is a marker of invasiness and consequently of a more aggressive behavior. In a study in our institution squamous and/or glandular differentiation was seen in 12/165 (7.27%) transurethral resections of the bladder. All 12 cases were infiltrative (pT1 or pT2 stage) at clinical presentation (6). In the study by Miller and Epstein of noninvasive urothelial carcinoma with glandular differentiation on clinical presentation, of the 18 patients with available follow-up information, 9(50%) developed an invasive bladder tumor.

References
1. Grignon DJ: Neoplasms of the urinary bladder. In: Bostwick DG, Eble JN, (ed.), Urologic Surgical Pathology. St.Louis, Mosby, 1997: pp. 214-305.
2. Sakamoto N, Tsuneyoshi M, Enjoji M: Urinary bladder carcinoma with a neoplastic squamous component: a mapping study of 31 cases. Histopathology. 1992; 21: 135-41.
3. Martin JE, Jenkins BJ, Zuk RJ, Blandy JP, Baithun SI: Clinical importance of squamous metaplasia in invasive transitional cell carcinoma of the bladder. J Clin Pathol. 1989; 42: 250-3.
4. Grace DA, Winter CC: Mixed differentiation of primary carcinoma of the urinary bladder. Cancer. 1968; 21: 1239-43.
5. Fegen JP, Albert DJ, Persky L: Adenocarcinoma and transitional cell carcinoma occurring simultaneously in the urinary bladder (mixed tumor). J Surg Oncol. 1971; 3: 387-92.
6. Billis A, Schenka AA, Ramos CC, Carneiro LT, Araujo V: Squamous and/or glandular differentiation in urothelial carcinoma: prevalence and significance in transurethral resections of the bladder. Int Urol Nephrol. 2001; 33: 631-3.

Dr. Athanase Billis
Full-Professor of Pathology
State University of Campinas, Unicamp
Campinas, São Paulo, Brazil
E-mail: athanase@fcm.unicamp.br