Case 2 -

Plasmacytoid Transitional Cell Carcinoma Jae Y. Ro Asan Medical Center Ulsan University, Seoul, Korea

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Clinical History A 79 year-old man presented with gross hematuria of 1 month's duration. His past medical history was remarkable for diabetes and hypertension for 10 years, but his family history was unremarkable. Urinalysis demonstrated RBC 3+ with no protein or sugar. Other laboratory tests were within normal limits except for slight elevation of PSA level (6.0 ng/ml) and fasting glucose of 131 mg/dl. Chest x-ray was normal. Abdominal CT showed an intraluminal protruding mass in the right anterior wall of the urinary bladder with wall thickening (Figure 1). No enlarged lymph nodes were identified. On cystoscopy, two nodular masses (3 cm and 1.5 cm in diameter) were found in the right antero-posterior wall of the bladder (Figure 2). Under the clinical diagnosis of T1 invasive transitional carcinoma, transurethral resection of the bladder tumor (TURBT) was performed. Microscopically the tumor (Figures 3, 4 and 5) and mucosa adjacent to invasive tumor (Figure 6) are illustrated. Figures 7 and 8 are CK7 and CK20 in neoplastic cells, respectively. After TURBT, the patient received intravesical mitomycin C for 6 times. Follow-up urine cytology 3 months after the diagnosis demonstrated a few malignant cells. The patient is alive with disease. Case 2 - Figure 1 - CT scan finding Case 2 - Figure 2 - Cystoscopic finding Case 2 - Figure 3 - Low-power H&E finding of tumor Case 2 - Figure 4 - High-power H&E finding of tumor Case 2 - Figure 5 - High-power H&E finding of tumor Case 2 - Figure 6 - Bladder mucosa adjacent to invasive tumor Case 2 - Figure 7 - CK7 immunostainings in tumor cells Case 2 - Figure 8 - CK20 immunostainings in tumor cells Diagnosis: Plasmacytoid Transitional Cell Carcinoma Discussion TURBT specimen consisted of multiple fragments of soft, tan to yellowish brown tissue, measuring 4.5 x 3.0 x 2.2 cm in aggregate. The tissue revealed a diffusely infiltrating tumor within edematous lamina propria. In areas, the tumor was composed of dyscohesive oval to round tumor cells with abundant densely eosinophilic and rarely vacuolated cytoplasm. The nuclei were eccentric, hyperchromatic, and displayed inconspicuous nucleoli. Mitoses were frequently observed. In addition, other areas of the tumor exhibited invasive high-grade urothelial carcinoma. The contiguous uninvolved mucosa showed foci of high-grade urothelial dysplasia/carcinoma in situ. There was no evidence of vascular invasion. In this biopsy, small amounts of muscle proper were present with no tumor invasion. Alcian blue and mucicarmine stains were negative for intracytoplasmic mucin in both plasmacytoid and vacuolated cells. Immunohistochemically, the tumor cells were positive for cytokeratin (CK), CK7, and CK20, but negative for vimentin, LCA, CD138 (Mum1), synaptophysin and chromogranin. Most of the tumor cells were positive for p53 and about 40% of the tumor cells were positive for Ki-67. Electron microscopic examination revealed dyscohesive groups of tumor cells with eccentric nuclei and abundant cytoplasm. The cytoplasm contained abundant endoplasmic reticuli and dense bodies. Cell junctions were occasionally evident. Based on the light microscopic, immunohistochemical and electron microscopic findings, this tumor was diagnosed as plasmacytoid transitional cell carcinoma. Bladder cancer is one of the most common tumors treated by urologists. According to American Cancer Society's data in 2004, 60,240 new cases of bladder cancers will be diagnosed both in men (44,640 for men) and women (15,600 for women) and 12,710 will die of their disease (8,780 for men and 3,930 for women). [1] More than 90% of bladder cancers are transitional cell (urothelial) carcinoma (TCC). TCCs are broadly divided into two large categories, TCC not otherwise specified and TCC, histologic variants. WHO classification includes the following types under histologic variants: Table 1: WHO classification of infiltrating bladder TCC [2] TCC NOS Variants TCC with squamous differentiation TCC with glandular differentiation TCC with trophoblastic differentiation Nested Microcystic Micropapillary Lymphoepithelioma-like Lymphoma-like Plasmacytoid Sarcomatoid Giant cell Undifferentiated TCC, transitional cell carcinoma; NOS, not otherwise specified Neoplasms of urothelial derivatives are capable of exhibiting a wide range of morphologic differentiation. Among the divergent differentiation, squamous differentiation is the most common followed by glandular differentiation. Sahin et al first reported plasmacytoid TCC in 1991. [3] They described a previously undescribed morphologic variant of TCC of the bladder in a 63-year-old man. The patient initially presented with multiple lytic bony metastases in the ribs and skull. Aspiration biopsy of the one of the skull lesions showed tumor cells with a striking plasmacytoid appearance, similar to the plasma cells seen in myeloma, leading to the outside diagnosis of multiple myeloma. A subsequent bladder biopsy revealed a tumor with the same cytomorphologic features to the skull lesion. Immunohistochemical and ultrastructural studies performed on the aspirated material and on the bladder biopsy specimen established the epithelial nature of the tumor and the tumor was diagnosed as plasmacytoid TCC. Zukerberg et al [4] in 1991 reported five cases of carcinoma of the urinary bladder simulating malignant lymphoma and two of them showed plasmacytoid differentiation. Since then only a handful of cases of plasmacytoid TCC have been reported, including one case diagnosed from urine cytology. [5] Two relatively large series of plasmacytoid TCC have been appeared in the literature as abstract forms. One of these, from Tamboli et al, [6] described clinicopathologic features of six cases collected from five institutions. There were four males and two females with an age range from 54 to 73 years. Initial biopsy (4/6) or TURBT (2/6) in all patients consisted exclusively of tumor cells with eccentrically placed nuclei resembling plasma cells. One case was associated with foci of sarcomatoid differentiation. None of these showed typical areas of TCC in the initial biopsy or TURBT specimens. Radical resection specimens in 4 cases showed areas of typical TCC with foci of sarcomatoid carcinoma in one case. Of the remaining two patients, one demonstrated no residual tumor, and the other patient did not undergo any further resection. All tumors were positive for CK, CK7 and CK20, and negative for LCA. One each was TNM stage II and III, and the remaining four patients were TNM IV. Four patients died of disease (mean survival, 23 months), one died of post-operative complications, and one patient (TNM stage II) is alive and well at 23 months. Based on the findings, the authors concluded that awareness of plasmacytoid histology in urothelial carcinoma has therapeutic and prognostic implications as 1) it may be mistaken fro plasmacytoma or lymphoma, and 2) it is associated with a poor prognosis. Lee et al from Korea, [7] reported in abstract form, seven patients with plasmacytoid TCC accrued from three institutions. All seven patients were males and their ages ranged from 46 to 81 years with a mean of 62 years. Six patients presented with gross hematuria and one with urgency and microhematuria. Cystoscopic findings in four patients revealed a single solid mass surrounded by a diffuse papillary lesion, and multiple mass-like lesions in other three patients. Initial diagnosis was made on TURBT in six cases and on cystoscopic biopsy in one case. Radical cystectomy with chemotherapy was performed in two patients, radical cystectomy alone in another two patients, chemotherapy alone in one and intravesical mitomycin instillation in one patient. The last patient did not receive any further therapy. Microscopically, the tumors were composed of plasmacytoid cells with eccentrically located nuclei and abundant eosinophilic cytoplasm in variable amounts. The plasmacytoid tumor component ranged from 30% to 100%. Four cases were TNM stage I, two TNM stage II and one TNM stage III. In five cases, high grade (grade 3) invasive TCC or TCIS was variably associated. Immunostaining demonstrated positivity for CK7 and CK20 in both plasmacytoid and conventional TCC components in all patients. P53 expression was low (5 to 10%) except for one patient where it was high (80%). Ki-67 labeling index was from 10 to 40%. Vimentin, CD138 and LCA were negative in neoplastic cells. Six patients were alive with no evidence of disease between 2 to 23 months after the diagnosis was made (mean 10.6 months). One patient was lost to follow-up. Based on these findings, they concluded that when the bladder tumors have extensive plasmacytoid component, a careful search for associated invasive TCC or TCIS should be made for the proper diagnosis of plasmacytoid TCC. Immunohistochemical studies should be performed for differential diagnoses from plasmacytoma, lymphoma, malignant melanoma and embryonal rhabdomyosarcoma. Plasmacytoid TCC appears to be a morphologic variant of TCC, however, clinical follow-up on these patients was too short to meaningfully evaluate biologic behavior. Plasmacytoid cellular morphology can be seen in a variety of bladder neoplasms including lymphomas, plasmacytomas, malignant melanomas, paraganglioma, neuroendocrine carcinomas and rhabdomyosarcomas. In fact, a plasmacytoid appearance was originally thought to be diagnostic of B-cell lymphomas and plasmacytomas, but it is now apparent that the cells of non-B-cell hematopoietic neoplasms and a variety of nonhematopoietic neoplasms including epithelial, neuroendocrine, myoepithelial, myogenic and melanocytic derivatives can have a plasmacytoid appearance. Rhabdoid cells and signet ring cells may resemble plasma cells, because of eccentric localization of nucleus. Table 2: Cells with eccentric nuclei   Plasmacytoid cells Rhabdoid cells Signet ring cells Nuclear shape round round indented Nucleolus +/- + -/+ Cytoplasm eosino/ampho eosino ampho/clear CK + + + Vimentin - + - EM RER/amorphous intermediate filaments mucin eosino = eosinophilic ampho = amphophilic CK = cytokeratin EM = electron microscope RER = rough endoplasmic reticulum Therefore, the differential diagnosis of plasmacytoid TCC of the bladder requires the above-mentioned tumors. Lymphomas and plasmacytomas rarely occur in the bladder as a primary tumor, but more commonly involve the bladder secondarily. Malignant melanoma also may occur in the urinary bladder as a primary or, more commonly, as metastatic tumor. The tumor cells of these tumors may have prominent plasmacytoid features. Paragangliomas, neuroendocrine carcinomas, rhabdomyosarcomas, rhabdoid tumors and signet ring cell carcinomas occur in the bladder and may have tumor cells with eccentrically located nucleus, creating plasmacytoid appearance. However, they can be excluded by presence of urothelial carcinoma in situ in the surrounding mucosa areas of cohesive growth typical of carcinoma immunohiostochemical staining reactions with positive CK, CK7, and CK20 and negative for vimentin, lymphoma markers, CD138, neuroendocrine markers, S-100 protein, desmin, and SMA Mucin stains are negative in plasmacytoid TCC, which is different from signet ring cell carcinoma. Chronic inflammation containing plasma cells may be confused with plasmacytoid TCC, but the cytologic features of plasmacytoid TCC are distinctly malignant and relatively easily differentiated from chronic inflammation. Salient differential diagnostic features are summarized in Table 3: Table 3: Differential features of tumors containing plasmacytoid cells   TCC lymph/plasma paragang/NE ca melanoma Rhabd Associated TCC/TCIS + - - - - CK + -/+ -/+ -/+ -/+ CK7 + - -/+ - - CK20 + - - - - S100 - - + + - LCA - + - - - Vimentin - + + + + HMB45 - - - + - CD138 - + - - - Desmin - - - - + TCC = transitional cell carcinoma TCIS = transitional cell carcinoma in situ lymph/plasma = lymphoma/plasmacytoma paragang/NE ca = paraganglioma/neuroendocrine carcinoma Rhabd = rhabdomyosarcoma CK = cytokeratin LCA = leukocyte common antigen In summary, caution should be exercised in the evaluation of neoplasms with plasmacytoid morphology; ancillary studies, such as immunohistochemical and electron microscopic studies are needed to document the cell of origin. Furthermore, plasmacytoid TCCs have therapeutic and prognostic implications. Although advanced stage at presentation for plasmacytoid TCC indicates an aggressive behavior, the reported cases are too few and clinical follow-up has been too short to meaningfully conclude on prognosis of this variant of TCC. References Jemal A, Tiwari R C, Murray T: Cancer statistics, 2004.CA A Cancer Journal for Clinicians 54: 8-29, 2004. Eble J N, Sauter G, Epstein J I: Pathology and genetics: Tumours of the urinary system and male genital organs. WHO classification of tumors. Lyon: IARC press, 2004. Sahin AA, Myhre M, Ro JY, Sneige N, Dekmezian RH, Ayala AG: Plasmacytoid transitional cell carcinoma: report of a case with initial presentation mimicking multiple myeloma. Acta Cytol 35:277-280, 1991. Zukerberg LR, Harris NH, Young RH: Carcinomas of the urinary bladder simulating malignant lymphoma: a report of five cases. Am J Surg Pathol 15:569-576, 1991. Zhang X, Elhosseiny A, Melamed MR: Plasmacytoid urothelial carcinoma of the bladder. Acta Cytol 46:412-416, 2002. Tamboli P, Amin MB, Mohsin SK, Ben-Dor D, Lopez-Beltran A: Plasmacytoid variant of non-papillary urothelial carcinoma. Mod Pathol 13:107A, 2000 (abstract 618). Lee HI, Jung SJ, Lee S, Ro JY: Plasmacytoid transitional cell carcinoma (P-TCC) of urinary bladder: a clinicopathologic study in 7 patients. Mod Pathol 15: 2005 (abstract).