Section 2 -

Variants of urothelial carcinoma Antonio Lopez-Beltran Cordoba University Medical School Cordoba, Spain

Urothelial carcinoma has a propensity for divergent differentiation with the most common being squamous, followed by glandular [1]. Virtually the whole spectrum of bladder cancer variants may be seen in variable proportions accompanying otherwise typical urothelial carcinoma [2, 3]. The clinical outcome of some of these variants differs from typical urothelial carcinoma; therefore, recognition of these variants is important (Table 1) for the surgical pathologist. Table 1. Variants of urothelial carcinoma (WHO, 2004) [1] Mixed differentiation With squamous differentiation With glandular differentiation Other (specify type and %) Small cell carcinoma Nested variant Micropapillary carcinoma Microcystic carcinoma Lymphoepithelioma-like Plasmocytoid/Lymphoma-like carcinoma Inverted papilloma-like carcinoma Urothelial carcinoma with syncitiotrophoblastic giant cells Giant cell carcinoma Clear cell (glycogen-rich) urothelial carcinoma Sarcomatoid carcinoma (Carcinosarcoma) Lipoid-cell variant Undifferentiated carcinoma Urothelial carcinoma with unusual stromal reactions Pseudosarcomatous stroma Stromal osseous or cartilaginous metaplasia Osteoclast-type giant cells Prominent lymphoid infiltrate Urothelial carcinoma with mixed differentiation About 20% of urothelial carcinomas contain areas of glandular or squamous differentiation. Squamous differentiation, defined by the presence of intercellular bridges or keratinization, occurs in 21% of urothelial carcinomas of the bladder. Its frequency increases with grade and stage, and the proportion of the squamous component may vary considerably [4]. These cases may have a less favorable response to therapy than pure urothelial carcinoma. Of 91 patients with metastatic carcinoma, 83% with mixed adenocarcinoma and 46% with mixed squamous cell carcinoma experienced disease progression despite intense chemotherapy, whereas it progressed in <30% of patients with pure urothelial carcinoma. Low-grade urothelial carcinoma with focal squamous differentiation has a higher recurrence rate [4]. Tumors with any identifiable urothelial element are classified as urothelial carcinoma with squamous differentiation. Cytokeratin 14 and L1 antigen have been reported as immunohistochemical markers of squamous differentiation. Glandular differentiationis less common and may be present in about 6% of urothelial carcinomas of the bladder [2]. Glandular differentiation is defined as the presence of true glandular spaces within the tumor. These may be tubular or enteric glands with mucin secretion. A colloid-mucinous pattern characterized by nests of cells "floating" in extracellular mucin, occasionally with signet ring cells, may be present.. The expression of MUC5AC-apomucin may be useful as immunohistochemical marker of glandular differentiation in urothelial tumors. Nested variant The nested variant of urothelial carcinoma is an aggressive neoplasm with fewer than 50 reported cases [5, 6]. There is a marked male predominance, and 70% of patients died 4-40 months after diagnosis, in spite of therapy. This rare pattern of urothelial carcinoma was first described as a tumor with a "deceptively benign" appearance that closely resembles Brunn's nests infiltrating the lamina propria [5, 6]. Some nests have small tubular lumens that eventually can predominate. Nuclei generally show little or no atypia, but invariably the tumor contains foci or unequivocal cancer with cells exhibiting enlarged nucleoli and coarse nuclear chromatin. Small cell carcinoma Small cell carcinoma is a malignant neoplasm derived from the urothelium which mimics its pulmonary counterpart [7] (see the following section of this hand-out). Micropapillary carcinoma Micropapillary carcinoma is a distinct variant of urothelial carcinoma that resembles papillary serous carcinoma of the ovary, and approximately 60 cases were reported in the literature [8, 9, 10]. There is a male predominance. The first description of micropapillary carcinoma consisted of 18 patients whose ages ranged from 47 to 81 years (mean 67) with a male-to-female ratio of 5:1. Seven patients died of carcinoma [8]. The micropapillary component shows slender delicate filiform processes or small papillary clusters of tumor cells and when present in invasive carcinoma, it is composed of infiltrating tight clusters of micropapillary aggregates that are often within lacunae that are negative for endothelial markers [8, 9, 10]. Vascular and lymphatic invasion is common. Immunohistochemical studies in one large series disclosed immunoreactivity in 20 of 20 cases for EMA, Cytokeratin 7 and 20, and Leu M-1; but high molecular weight cytokeratin may be present. The presence of a surface micropapillary component in bladder biopsy specimens is an unfavorable prognostic feature, and deeper biopsies may be useful to determine muscle invasion. The prognosis seems to be related to the proportion and location of the micropapillary component.. The main differential consideration is serous micropapillary ovarian carcinoma in women or mesothelioma in both genders. In the micropapillary pattern of invasive carcinoma, the expression of MUC1 is largely limited to the basal surface of the cells in contrast to the conventional carcinomas in which MUC1 is largely apical, intracytoplasmic, or intercellular. The MUC1 expression was predominantly in the aspect of the cell clusters facing the stroma, accentuating the outlines of the micropapillary units by forming a distinct band on this surface. This observation provides support for the hypothesis that the reversal of cell polarity as an important factor in the pathogenesis of the invasive micropapillary carcinoma. Since MUC1 is known to be involved in lumen formation and has an inhibitory effect on cell-to-stroma interaction, it may play an important role in the detachment of cells from the stroma easing the spread of neoplastic cells [10]. Microcystic carcinoma The microcystic variant of invasive urothelial carcinoma is characterized by the formation of microcysts, macrocysts, or tubular structures with cysts ranging from microscopic up to 1-2 cm in diameter. The cysts and tubules may be empty or contain necrotic debris or mucin [1, 2, 3] Lymphoepithelioma-like carcinoma Carcinoma that histologically resembles lymphoepithelioma of the nasopharynx has been described in the urinary bladder, with fewer than 50 cases reported. [11] It is more common in men (mean: 69 years). Histologically, it may be pure or mixed with typical urothelial carcinoma. Glandular and squamous differentiation may be seen [11]. The tumor is composed of nests, sheets, and cords of undifferentiated cells with large pleomorphic nuclei and prominent nucleoli. The cytoplasmic borders are poorly defined, imparting a syncytial appearance. The background consists of a prominent T and B lymphocyte infiltration, plasma cells, histiocytes; neutrophils or eosinophils may be present. Epstein-Barr virus infection has not been identified in bladder cases. This tumor has been found to be responsive to chemotherapy when it is encountered in its pure form. The epithelial cells of this tumor stain with several cytokeratin markers. A relatively favorable prognosis has been reported when pure or predominant [11]. Lymphoma-like or plasmacytoma-like carcinoma In this variant, the tumor cells were medium-sized, with eosinophilic cytoplasm and eccentric nuclei producing a plasmacytoid appearance. In a series report of 6 cases, the age range was 54-73years. All cases stained positively for cytokeratin AE1/AE3 and CK 20 and 7. Five of six patients died of disease (mean survival, 23 months) [12]. Inverted papilloma-like (inverted growth) carcinoma The potential for misinterpretation of urothelial carcinoma with endophytic growth as inverted papilloma is high. By definition, this variant of urothelial carcinoma has significant nuclear pleomorphism, mitotic figures, and architectural abnormalities consistent with low- or high-grade urothelial carcinoma. Large papillary tumors with prominent endophytic growth "invade" the lamina propria with a pushing border. Unless this pattern is accompanied by true destructive stromal invasion the likelihood of metastasis is minimal, because the basement membrane is not truly breached [13]. Urothelial carcinoma with syncytiotrophoblastic giant cells Syncytiotrophoblastic giant cells are present in up to 12% of cases of urothelial carcinoma, producing substantial amounts of beta-human chorionic gonadotropin (HCG) indicative of syncytiotrophoblastic differentiation. Giant cell carcinoma High grade urothelial carcinoma may contain epithelial tumor giant cells or the tumor may appear undifferentiated, resembling giant cell carcinoma of the lung. The giant cells display cytokeratin and vimentin immunoreactivity. Clear cell (glycogen-rich) carcinoma Up to two-thirds of cases of urothelial carcinoma have foci of clear cell change resulting from abundant glycogen.This variant consisting predominantly or exclusively of cells with abundant clear cytoplasm that stains for cytokeratin 7 [14]. Sarcomatoid carcinoma with/without heterologous elements (carcinosarcoma, metaplastic carcinoma) The term sarcomatoid variant of urothelial carcinoma should be used for all biphasic malignant neoplasms exhibiting morphologic and/or immunohistochemical evidence of epithelial and mesenchymal differentiation (with the presence or absence of heterologous elements acknowledged in the report) [15]. The gross appearance is characteristically "sarcoma-like," and the tumors are often polypoid. Microscopically, sarcomatoid carcinoma is composed of urothelial, glandular or small cell component showing variable degrees of differentiation. Carcinoma in situ is present in 30% of cases and occasionally is the only apparent epithelial component.. The mesenchymal component most frequently observed is a undifferentiated high grade spindle cell neoplasm. The most common heterologous element is osteosarcoma followed by chondrosarcoma, rhabdomyosarcoma, leiomyosarcoma, liposarcoma, angiosarcoma or multiple types of heterologous differentiation may be present. By immunohistochemistry, epithelial elements react with cytokeratins , whereas stromal elements react with vimentin or specific markers corresponding to the mesenchymal differentiation. The sarcomatoid phenotype retains the epithelial nature of the cells by immunohistochemistry. Recent molecular studies strongly argue for a monoclonal origin of both components in sarcomatoid carcinoma and carcinosarcoma. Pathological stage is the best predictor of survival in sarcomatoid carcinoma [15]. Lipoid-cell variant Lipoid cell variant, is a rare neoplasm defined by the WHO (1999, 2004) [1] as an urothelial carcinoma which exhibits transition to a cell type resembling signet-ring lipoblasts [16]. It is currently considered to be an ill-defined tumor variant. Clinicopathologic features and the immunohistochemical findings in seven reported cases showed gross hematuria as the initial symptom. All patients were elderly men. The immunohistochemical results showed an epithelial phenotype characterized by diffuse staining with cytokeratins AE1/AE3. Undifferentiated carcinoma This category contains tumors that cannot be otherwise classified. Other uncommon morphologic variations in bladder cancer Baldwin et al. [17] described a series of 10 cases of urothelial carcinoma with a striking discohesive growth pattern that show morphological features that mimicked infiltrating lobular carcinoma of the breast and diffuse carcinoma of the stomach. [19] In areas the tumor cells were arranged in linear single-cell files (indian file pattern). References Lopez-Beltran A, Sauter G, Gasser T, Grignon D, et al. Urothelial tumors: Infiltrating urothelial carcinoma. In: Eble JN SG, Epstein JI, Sesterhenn I, editor. World Health Organization Classification of Tumors. Pathology and Genetics of Tumors of the Urinary System and Male Genital Organs. Lyon: IARC; 2004. Lopez-Beltran A, Cheng L. Histologic Variants of Urothelial Carcinoma: Differential Diagnosis and Clinical Implications. Hum Pathol 2006, In Press Eble JN, Young RH. Carcinoma of the urinary bladder: a review of its diverse morphology. Semin Diagn Pathol 1997;14:98-108. Lopez-Beltran A, et al. Squamous differentiation in primary urothelial carcinoma of the urinary tract as seen by Mac 387 immunohistochemistry. J Clin Pathol 2006 (Aug 1, Epub ahead of print) Murphy WM, Deana DG. The nested variant of transitional cell carcinoma: a neoplasm resembling proliferation of Brunn's nests. Mod Pathol 1992;5:240-3. Talbert ML, Young RH. Carcinomas of the urinary bladder with deceptively benign appearing foci. A report of three cases. Am J Surg Pathol 1989;13:374-81. 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 Amin MB, Ro JY, el-Sharkawy T, et al. Micropapillary variant of transitional cell carcinoma of the urinary bladder. Histologic pattern resembling ovarian papillary serous carcinoma. Am J Surg Pathol 1994;18:1224-32. Samaratunga H, Khoo K. Micropapillary variant of urothelial carcinoma of the urinary bladder; a clinicopathological and immunohistochemical study. Histopathology 2004;45:55-64. Nassar H, Pansare V, Zhang H, Grignon D, et al. Pathogenesis of invasive micropapillary carcinoma: role of MUC1 glycoprotein. Mod Pathol 2004;17:1045-50. Lopez-Beltran A, Luque RJ, Vicioso L, et al. Lymphoepithelioma-like carcinoma of the urinary bladder: a clinicopathologic study of 13 cases. Virchows Arch 2001;438:552-7. Tamboli P, Amin MB, Mohsin SK, Lopez-Beltran A, et al. Plasmocytoid variant of non-papillary urothelial carcinoma(Abstract). Mod Pathol 2000;13:107A. Amin MB, Gomez JA, Young RH. Urothelial transitional cell carcinoma with endophytic growth patterns: a discussion of patterns of invasion and problems associated with assessment of invasion in 18 cases. Am J Surg Pathol 1997;21:1057-68. Oliva E, Amin MB, Jimenez R, et al. Clear cell carcinoma of the urinary bladder: a report and comparison of four tumors of mullerian origin and nine of probable urothelial origin with discussion of histogenesis and diagnostic problems. Am J Surg Pathol 2002;26:190-7. Lopez-Beltran A, Pacelli A, Rothenberg HJ, et al. Carcinosarcoma and sarcomatoid carcinoma of the bladder: clinicopathological study of 41 cases. J Urol 1998;159:1497-503. Lopez-Beltran A, Luque RJ, Oliveira PS, et al. Urothelial carcinoma of the bladder, lipid cell variant (UCBLCV). Immunohistochemical and clinico-pathologic findings in seven cases(Abstract). Mod Pathol 2002;15:171A. Baldwin L, Lee AH, Al-Talib RK, et al. Transitional cell carcinoma of the bladder mimicking lobular carcinoma of the breast: a discohesive variant of urothelial carcinoma. Histopathology 2005;46:50-6.