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Plasmacytoid urothelial carcinoma of the bladder
Human Pathology (2009) 40, 1023–1028
www.elsevier.com/locate/humpath
Original contribution
Plasmacytoid urothelial carcinoma of the bladder Antonio Lopez-Beltran MD, PhD a,d,⁎, Maria J. Requena MD b , Rodolfo Montironi MD, FRCPath c , Ana Blanca PhD d , Liang Cheng MD, PhD e a
Unit of Anatomic Pathology, Department of Surgery, Faculty of Medicine, E-14004 Cordoba, Spain Urology Service, Reina Sofia University Hospital, E-14004 Cordoba, Spain c Section of Pathological Anatomy, Polytechnic University of the Marche Region, School of Medicine, I-60020 Ancona, Italy d Uro-oncology Laboratory, Biomedical Research Unit, Reina Sofia University Hospital, E-14004 Cordoba, Spain e Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA b
Received 16 September 2008; revised 2 January 2009; accepted 7 January 2009
Keywords: Urinary bladder; Carcinoma; Plasmacytoid; Cytokeratin 7 and 20; CD138; Transitional cell carcinoma variants
Summary In this report, we present the clinicopathologic features of 11 cases of the plasmacytoid variant of urothelial carcinoma. This is a rare variant of bladder cancer recognized by the current World Health Organization classification of urologic tumors. The plasmacytoid component varied from 30% to 100% of the tumor specimen; in 8 cases, the plasmacytoid component comprised greater than 50% of the tumor with 2 cases showing pure plasmacytoid carcinoma. The architectural pattern of the tumor varied from solid expansile nests with noncohesive cells to mixed solid and alveolar growth; a streaking discohesive architecture was additionally present in 2 cases (18%). At histology, the individual tumor cells had an eccentrically placed nucleus and abundant eosinophilic cytoplasm reminiscent of plasma cells. Most neoplastic cells had nuclei of low to intermediate nuclear grade with occasional nuclear pleomorphism. Seven of 9 mixed cases had concurrent conventional high-grade urothelial carcinoma, and the remaining 2 cases presented features of nested or micropapillary urothelial carcinoma. Small intracytoplasmic vacuoles were variably present in all cases. All patients had advanced stage cancer (NpT3), and 8 (73%) had lymph node metastasis. Immunohistochemical staining demonstrated that both plasmacytoid and associated conventional urothelial carcinoma were positive for cytokeratins 7, 20, and AE1/AE3 and epithelial membrane antigen; CD138 was positive in 3 cases. Follow-up information was available in all cases (range, 2-16 months; mean, 7 months). Nine of the patients died of disease from 2 to 11 months, and 2 patients were alive with disease at 8 and 16 months. In summary, plasmacytoid variant of urothelial carcinoma is an aggressive variant associated with poor prognosis that presents at an advanced clinical stage. In limited samples, it may be misdiagnosed as chronic cystitis or plasmacytoma, a pitfall further compounded by CD138 expression in some cases. Morphological distinction from other malignant neoplasms with plasmacytoid phenotype is critical for its clinical management. © 2009 Elsevier Inc. All rights reserved.
⁎ Corresponding author. Unit of Anatomical Pathology, Faculty of Medicine, E-14004 Cordoba, Spain. E-mail address: [email protected] (A. Lopez-Beltran). 0046-8177/$ – see front matter © 2009 Elsevier Inc. All rights reserved. doi:10.1016/j.humpath.2009.01.001
1024
A. Lopez-Beltran et al.
1. Introduction
2. Materials and methods
Plasmacytoid urothelial carcinoma, a rare variant of urothelial carcinoma with histologic appearance similar to plasma cells [1,2], has been recognized in the current World Health Organization (WHO) classification of urothelial neoplasms [3] and may pose a significant differential diagnostic problem, particularly if it is the predominant or exclusive pattern in a limited biopsy sample [4]. There are limited data available about the pathologic and immunohistochemical characteristics as well as the clinical behavior of this pathologic entity [1-16]. Since the initial description by Sahin et al [11] and Zukerberg et al [14], about 30 cases have been reported, mostly as single case report [1-16]. Two recent series of 7 and 9 cases [4,7] concluded that these patients have a variable clinical course with some patients dying rapidly and others experiencing prolonged survival. This probably reflects that the reported series are nonhomogeneous and that the entity is not fully well characterized. More recently, Ro et al [4] reported 9 cases of plasmacytoid urothelial carcinoma obtained from 5 different hospitals and found this tumor to be diagnosed by transurethral resection in males with hematuria. All cases in this series were immunoreactive for cytokeratins (CKs) 7 and 20; CD138 was also positive in one case [4]. The finding of some plasmacytoid urothelial carcinomas of the bladder immunoreactive for CD138, a marker of plasma cells, represents an important challenge in daily practice but has been reported to occur rarely [4,8,10]. Hence, more reports on larger series are needed to elucidate the clinical significance and differential diagnostic implications of this interesting morphological variant of bladder cancer. Herein, we present a large sequential series of 9 plasmacytoid carcinoma of the bladder supplemented with 2 additional consultation cases.
This study included resection and surgical specimens from 11 patients. Nine cases were collected in a series of 1737 (0.51%) bladder tumor specimens studied from 1998 to 2007 at the uropathology practice of one of the authors (A. LopezBeltran). Two other cases were seen in consultation. The cases spanned a period of 10 years, with the earliest case diagnosed in 1999 and the last one in 2007. Clinical information was obtained from patients' records, and an average of 12 hematoxylin and eosin slides (range, 3-29 slides) from each case were evaluated. The following pathologic parameters were evaluated: percentage of plasmacytoid carcinoma component and of conventional urothelial carcinoma, histologic type of urothelial carcinoma (based on WHO classification), and depth of invasion and clinical TNM staging. Immunostaining was performed on at least one representative paraffin section using standard protocols with a 3-step biotin-streptavidin procedure. The antibodies used on paraffin-embedded tissues included epithelial membrane antigen (EMA) (prediluted; Signet, Dedham, MA), CK AE1/AE3 (prediluted, Signet), CK7 (1:50; Dako, Glostrup, Denmark), CK20 (1:50, Dako), CD138 (prediluted, Dako), leukocyte common antigen (LCA) (prediluted, Dako), S-100 protein (prediluted, Dako), HMB45 (prediluted, Dako), vimentin (prediluted, Dako), κ light chain (prediluted, Dako), λ light chain (prediluted, Dako), p53 (1:200, Dako), and Ki-67 (1:50, Dako). For all analyses, appropriated negative and positive controls were included. When necessary, antigen retrieval was performed following standard protocols. Immunostaining was graded from 0 to 3+.
Table 1
3. Results The clinicopathologic features of the 11 patients are summarized in Table 1. In all 11 patients, there was hematuria
Clinical and pathologic features of 11 cases of plasmacytoid bladder urothelial carcinoma
Case no.
Age (y)/sex
Initial symptoms
Plasmacytoid (%)
Associated urothelial carcinoma/type of specimen
Final TNM clinical stage
Follow-up status (mo)
1 2 3 4 5 6 7 8 9 10 11
63/M 55/M 76/M 87/M 62/M 80/F 56/M 65/M 87/M 48/M 62/F
Gross hematuria Hematuria, dysuria Hematuria Hematuria, frequency, dysuria Gross hematuria, dysuria Gross hematuria, nocturia Hematuria, urgency Hematuria, frequency Gross hematuria Hematuria, frequency Gross hematuria
60 50 50 40 60 30 70 90 100 100 30
Nested + CIS/TURB HG UC + CIS/CyP HG UC/TURB HG papillary + solid UC/TURB HG UC + CIS/CyP HG papillary + solid UC/TURB Micropapillary/CyP HG UC/TURB NA/TURB NA/CyP HG UC/CyP
T4a, N1 T3a, N0, T3b, N1 T4a, N1 T4a, N1, T3b, N1 T3b, N2 T4a, N1 T3b, N0 T3b, N0 T3b, N1
DOD, 2 AWD, 8 DOD, 2 DOD, 8 DOD, 4 DOD, 11 DOD, 2 DOD, 8 DOD, 10 AWD, 16 DOD, 9
Abbreviations: CIS, carcinoma in situ; AWD, alive with disease; DOD, died of disease; NA, not applicable; F, female; M, male; CyP, cystoprostatectomy; HG, high grade, UC, urothelial carcinoma.
Plasmacytoid urothelial carcinoma with dysuria (2 patients), frequency (3 patients), or nocturia in one patient. Their ages ranged from 48 to 87 years (mean, 67 years). The initial diagnosis of plasmacytoid carcinoma of the bladder was made on transurethral resection of bladder (TURB) in 8 cases and cystoprostatectomy in 3 others. None of the 11 cases had prior history of bladder cancer. Patients received definitive therapy 2 to 16 weeks after the onset of symptoms (mean, 8 weeks); one patient (case 10) received definitive therapy after 24 weeks. Seven patients had clinical stage T3 tumors, and 4 had stage T4 disease (Table 1). Eight patients (73%) had lymph node metastasis. Follow-up data after surgery were available in all 11 cases (range, 2-16 months; mean, 7 months). Nine of the patients died of disease from 2 to 11 months (mean, 6.2 months; median, 8 months), and 2 patients were alive with metastases at 8 and 16 months. One patient (case 5) developed soon after surgery round ligament metastasis followed by peritoneal carcinomatosis. In addition, 3 patients (cases 2, 8 and 10) received adjuvant chemotherapy resulting in 2 patients alive with disease (cases 2 and 10) and one died of disease (case 8) (Table 1).
1025 At histology (Fig. 1), the individual tumor cells were small to medium sized and had an eccentrically placed nucleus and abundant amphophilic cytoplasm with an eosinophilic paranuclear hof reminiscent of plasma cells. Most neoplastic cells had nuclei of low to intermediate nuclear grade with occasional nuclear pleomorphism. Binucleation was occasionally seen in all cases. The cells were 25 μm in diameter or larger. The nuclei varied from being hyperchromatic to those with evenly distributed chromatin. Prominent nucleoli were variably present in plasmacytoid cells; small intracytoplasmic vacuoles were variably present in all cases but only rarely sufficient to mimic signet ring cells. The plasmacytoid component varied from 30% to 100% of the tumor specimens; in 8 cases, the plasmacytoid component comprised greater than 50% of the tumor in the specimen; of these, 2 cases showed pure plasmacytoid carcinoma. The architectural pattern of growth of the tumors varied from solid expansile nests with noncohesive cells (40% of cases) to mixed solid and alveolar growth (60% of the cases); a streaking discohesive architecture was additionally present
Fig. 1 Diffuse infiltration of the plasmacytoid carcinoma cells in the bladder wall with an architectural pattern of solid expansile nests (A) with noncohesive cells (B). Mixed architectural pattern of solid (C) and alveolar growth (D) showing cells with plasmacytoid appearance. Discohesive architecture (E) retaining the plasmacytoid morphology (F). Plasmacytoid carcinoma immunoreactive for CK7 (G), CK20 (H), and CD138 (I).
1026 Table 2
A. Lopez-Beltran et al. Summary of the immunostains results
Case no.
EMA
CK7
CK20
CK AE1/AE3
CD138
LCA
S-100
HMB45
Vimentin
κ light chain
λ light chain
1 2 3 4 5 6 7 8 9 10 11
+ + + + + + + + + + +
+ + + + + + + + + + +
+ + + + + + + + + + +
+ + + + + + + + + + +
− + − − − + − − − + −
− − − − − − − − − − −
− − − − − − − − − − −
− − − − − − − − − − −
− − − − − − − − − − −
− − − − − − − − − − −
− − − − − − − − − − −
in 2 cases (18%), although individual cells still retained plasmacytoid morphology in these cases (Fig. 1). Seven (78%) of 9 mixed cases were associated with conventional high-grade urothelial carcinoma, and the remaining 2 cases presented features of nested or micropapillary urothelial carcinoma. Carcinoma in situ was additionally present in 3 cases (Table 1). Immunohistochemical staining demonstrated that both plasmacytoid and associated conventional urothelial carcinoma were positive for CK7 (3+), CK20 (variable, 1+ to 2+), and CK AE1/AE3 (3+) and EMA (2+); CD138 was positive in 3 cases with variable intensity in 2 cases (1+) and 3+ in the remaining case (Fig. 1) (Table 2). LCA, S-100, HMB45, κ light chain, λ light chain, and vimentin were negative in all cases (Table 2). Ki-67 labeling index ranged form 20% to 60% (mean, 35.5%) and p53 ranged from 10% to 40% (mean, 26%).
4. Discussion More than 90% of bladder carcinomas are urothelial carcinomas [1-3]. A small group of tumors are recognized as pathologic variants of invasive bladder cancer because of their unique histologic appearance [1-3]. These uncommon variant entities are distinct enough to be recognized separately in the current WHO classification system. These variants are significant from the diagnostic, prognostic, and/ or therapeutic perspective [1-3]. The plasmacytoid variant of urothelial carcinoma has been the subject of recent interest with one well-documented series of 9 cases and few case reports [1-16]. Our series represents the largest experience to date describing in detail the architectural patterns and cellular features of this uncommon form of bladder cancer. All patients in our series had a poor outcome, reiterating the importance of accurate classification of these tumors because of the poor prognosis associated with this variant. The observed positivity for CD138, also an immunohistochemical marker for plasma cells, in 3 (27%) of our cases is in line with other recent reports [4,8,10] and highlights an important potential diagnostic pitfall because of the morphological resemblance of tumor cells to plasma cells, mainly in tumors
with pure plasmacytoid morphology or in case of chronic cystitis with predominant plasma cell infiltrate. Several tumors have the potential to demonstrate plasmacytoid morphology (Table 3), although in general, this is a rare finding [4]; myoepithelial tumors and medullary carcinoma of the thyroid, melanoma, paraganglioma, neuroendocrine carcinoma, lymphoma, myeloma, and some sarcomas are in the spectrum [4,17-27]. In the urinary bladder, the main differential diagnostic considerations of plasmacytoid urothelial carcinoma include benign conditions such as chronic cystitis with prominent plasma cell infiltrate, as well as other malignant tumors such as plasmacytoma, signet ring cell adenocarcinoma, and metastatic carcinoma from other primary sites, specifically breast and stomach [1-4,17-27]. Rarely, myofibroblastic proliferations enter the differential diagnosis because they may have a prominent plasma cell infiltrate. All these distinctions have significant therapeutic implications. The diagnostic difficulty posed by this neoplasm was first exemplified by Sahin et al [11]; these authors reported a patient presenting with a skull lesion that was diagnosed as multiple myeloma. However, further clinical workup failed to support a diagnosis of plasmacytoma. The clinical evaluation revealed a large tumor in the urinary bladder that was composed of cells with plasmacytoid morphology and was histologically similar to the skull lesion. At about the same period, Zuckerberg et al [14] reported their series of bladder tumors simulating malignant lymphoma, one of them showing malignant cells with eccentric nuclei resembling plasma cells. After these initial reports, several publications discussed the differential diagnosis of a hematolymphoid malignancy in this setting, particularly a plasmacytoma/ myeloma in the initial, frequently limited, biopsy sample [4,17-27]. Primary plasmacytoma of the bladder is rare, but in patients with a prior history of multiple myeloma, where there is no identifiable surface urothelial component, it is necessary to maintain a level of suspicion to avoid misdiagnosis of a plasmacytoma as urothelial carcinoma with plasmacytoid features [4,17-27]. There have been cases of extramedullary plasmacytoma involving the bladder in patients with no demonstrable systemic involvement by multiple myeloma;
Plasmacytoid urothelial carcinoma Table 3
1027
Main differential features of bladder tumors with plasmacytoid cells Cytologic features
Immunohistochemical features
Nuclear Shape Nucleolus Cytoplasm Pan-CK Vim CK7 CK20 S-100 LCA HMB45 Syn CD138 Desmin Plasmacytoid carcinoma Rhabdoid carcinoma Signet ring cell carcinoma Lymphoma/ plasmacytoma Paraganglioma/ neuroendocrine carcinoma Melanoma Rhabdomyosarcoma
Round
+
Round
+
Indented
+
Round
+
Round
+
Round Round/ fusiform
+ +
Eosino/ ampho Eosino Ampho/ clear Eosino/ ampho Ampho/ clear Eosino Scant/ eosino
+
−
+
+
−
−
−
−
±
−
±
+
±
+
−
−
−
−
−
−
±
−
+
+
−
−
−
−
−
−
±
+
−
−
−
+
−
−
+
−
±
+
±
−
+
−
−
±
−
−
± ±
+ +
− −
− −
+ −
− −
+ −
− +
− −
− +
Abbreviation: Ampho, amphophilic; Eosino, eosinophilic; Vim, vimentin; Syn, synaptophysin.
however, reports such as these are still rare, and most of the patients present with systemic disease [19-20]. In a clinical scenario where this is a diagnostic concern, ancillary immunohistochemical testing for CK, CD138, and κ and λ light chains may further confirm the diagnosis. Primary signet ring cell adenocarcinoma enters into the differential diagnosis because of the occasional presence of intracytoplasmic vacuoles and the noncohesive nature of the tumor cells [18,24]. Primary pure signet ring cell adenocarcinoma of the bladder is rare. The signet ring cells, the predominant component, permeate the wall of the urinary bladder in a linitis plastica type manner [18]. This was a rare and focal compelling feature in our series, similar to other recent reported series [4]. Also, carcinoma with rhabdoid phenotype that has been described to occur in the bladder should be considered in the differential diagnosis with plasmacytoid carcinoma, which is mostly based on cytoplasmic features and the presence of prominent nucleolus, unlike the plasmacytoid carcinoma in rhabdoid cells, determined by positive immunostaining for vimentin [21]. Metastatic carcinoma from the breast, stomach, and, rarely, colon may have morphology overlapping with that of plasmacytoid urothelial carcinoma. Baldwin et al [17] recently described a “discohesive” variant of urothelial carcinoma and commented on the morphological overlap with metastatic lobular carcinoma of the breast. The authors described the bladder tumors in their series to be deeply invasive into the muscular wall and composed of discohesive cells arranged in a single-file pattern reminiscent of lobular carcinoma of the breast [17]. A similar discohesive pattern in plasmacytoid urothelial carcinoma was observed recently by Ro et al [4], and in 2 cases of our series; in both situations, the discohesive cells still retained the plasmacytoid morphological features, thus, suggesting that plasmacytoid carcinoma is morphologically different to the discohesive variant reported by Baldwin et al [17]. This is also different in terms of
differential diagnosis from metastatic breast carcinoma, the compelling feature in the cases reported by Baldwin et al [17], but a rare consideration for plasmacytoid carcinoma of the bladder. The observation of an obvious urothelial carcinoma component, present in 88% of our cases and in other reported cases, is also helpful in confirming a bladder primary. An additional important feature of plasmacytoid carcinoma of the bladder is its presentation at advanced stage with poor outcome. Within a 2-year follow-up period after surgery, all of our patients had either died of cancer or had developed metastases, a finding similar to other recent reports [1-16]. In summary, urothelial carcinoma with plasmacytoid features is an important variant of bladder cancer that has diagnostic, prognostic, and therapeutic significance. It may pose diagnostic difficulties, especially in limited biopsy samples, where it may be mistaken for an inflammatory process. Attention to histologic features, together with clinical history and appropriate immunohistochemical studies, should help distinguish plasmacytoid urothelial carcinoma from its mimickers.
References [1] Lopez-Beltran A, Cheng L. Histologic variants of urothelial carcinoma: differential diagnosis and clinical implications. HUM PATHOL 2006;37:1371-88. [2] Lopez-Beltran A, Requena MJ, Cheng L, Montironi R. Pathological variants of invasive bladder cancer according to their suggested clinical significance. BJU Int 2008;101:275-81. [3] Lopez-Beltran A, Sauter G, Gasser T, et al. Infiltrating urothelial carcinoma. In: Eble JN, Sauter G, Epstein JI, Sesterhenn IA, editors. Pathology and genetics of tumours of the urinary system and male genital organs. Lyon: IARC Press; 2004. p. 93-109. [4] Ro JY, Shen SS, Lee HI, et al. Plasmacytoid transitional cell carcinoma of urinary bladder: a clinicopathologic study of 9 cases. Am J Surg Pathol 2008;32:752-7.
1028 [5] Coyne JD, Sim E. Urothelial neoplasia with plasmacytoid morphology. Histopathology 2006;48:200-1. [6] Kohno T, Kitamura M, Akai H, et al. Plasmacytoid urothelial carcinoma of the bladder. Int J Urol 2006;13:485-6. [7] Mai KT, Park PC, Yazdi HM, et al. Plasmacytoid urothelial carcinoma of the urinary bladder report of seven new cases. Eur Urol 2006;50:1111-4. [8] Mitsogiannis IC, Ioannou MG, Sinani CD, et al. Plasmacytoid transitional cell carcinoma of the urinary bladder. Urology 2005;66: 194. [9] Mokhtar GA, Yazdi H, Mai KT. Cytopathology of extramedullary plasmacytoma of the bladder: a case report. Acta Cytol 2006;50: 339-43. [10] Patriarca C, Di Pasquale M, Giunta P, et al. CD138-positive plasmacytoid urothelial carcinoma of the bladder. Int J Surg Pathol 2008;16:215-7. [11] Sahin AA, Myhre M, Ro JY, et al. Plasmacytoid transitional cell carcinoma. Report of a case with initial presentation mimicking multiple myeloma. Acta Cytol 1991;35:277-80. [12] Shimada K, Nakamura M, Ishida E, et al: Urothelial carcinoma with plasmacytoid variants producing both human chorionic gonadotropin and carbohydrate antigen 19-9. Urology 2006, 68:891 e897-810. [13] Zhang XM, Elhosseiny A, Melamed MR. Plasmacytoid urothelial carcinoma of the bladder. A case report and the first description of urinary cytology. Acta Cytol 2002;46:412-6. [14] Zukerberg LR, Harris NL, Young RH. Carcinomas of the urinary bladder simulating malignant lymphoma. A report of five cases. Am J Surg Pathol 1991;15:569-76. [15] Manousakas T, Kyroudi A, Dimophoulos MA, Moraitis E, Mitropoulos D. Plasmacytoid transitional cell carcinoma of the bladder. BJU Int 2000;86:910. [16] Soylu A, Aydin NE, Yilmaz U, Kutlu R, Gunes A. Urothelial carcinoma featuring lipid cell and plasmacytoid morphology with poor prognostic outcome. Urology 2005;65:797.
A. Lopez-Beltran et al. [17] 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. [18] Grignon DJ, Ro JY, Ayala AG, et al. Primary signet-ring cell carcinoma of the urinary bladder. Am J Clin Pathol 1991;95:13-20. [19] Ho DS, Patterson AL, Orozco RE, et al. Extramedullary plasmacytoma of the bladder: case report and review of the literature. J Urol 1993; 150:473-4. [20] Lopez A, Mendez F, Puras-Baez A. Extramedullary plasmacytoma invading the bladder: case report and review of the literature. Urol Oncol 2003;21:419-23. [21] Parwani AV, Herawi M, Volmar K, et al. Urothelial carcinoma with rhabdoid features: report of 6 cases. HUM PATHOL 2006;37:168-72. [22] Bates AW, Baithun SI. Secondary neoplasms of the bladder are histological mimics of nontransitional cell primary tumours: clinicopathological and histological features of 282 cases. Histopathology 2000;36:32-40. [23] Takahashi R, Nakano S, Namura K, et al. Plasmacytoma of the urinary bladder in a renal transplant recipient. Int J Hematol 2005; 81:255-7. [24] Wong C, Begin LR, Reid M, et al. Oliguria, an unusual presentation of primary signet ring-cell adenocarcinoma of the urinary bladder: a case report and review of the literature. J Surg Oncol 1999;70:64-7. [25] Franquemont DW, Mills SE. Plasmacytoid monomorphic adenoma of salivary glands. Am J Surg Pathol 1993;17:146-53. [26] Suzuki H, Inoue K, Fujioka Y, Ishikura H, Furuta Y, Fukada S. Myoepithelial carcinoma with predominance of plasmacytoid cells arising in a pleomorphic adenoma of the parotid gland. Histopathology 1998;32:86-7. [27] Biancari F, Lepidini G, D'Andrea V. Recurrent plasmacytoid lymphocytic lymphoma of the bladder secreting multiple monoclonal and biclonal proteins. J Urol 1998;159:985-8.
www.elsevier.com/locate/humpath
Original contribution
Plasmacytoid urothelial carcinoma of the bladder Antonio Lopez-Beltran MD, PhD a,d,⁎, Maria J. Requena MD b , Rodolfo Montironi MD, FRCPath c , Ana Blanca PhD d , Liang Cheng MD, PhD e a
Unit of Anatomic Pathology, Department of Surgery, Faculty of Medicine, E-14004 Cordoba, Spain Urology Service, Reina Sofia University Hospital, E-14004 Cordoba, Spain c Section of Pathological Anatomy, Polytechnic University of the Marche Region, School of Medicine, I-60020 Ancona, Italy d Uro-oncology Laboratory, Biomedical Research Unit, Reina Sofia University Hospital, E-14004 Cordoba, Spain e Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA b
Received 16 September 2008; revised 2 January 2009; accepted 7 January 2009
Keywords: Urinary bladder; Carcinoma; Plasmacytoid; Cytokeratin 7 and 20; CD138; Transitional cell carcinoma variants
Summary In this report, we present the clinicopathologic features of 11 cases of the plasmacytoid variant of urothelial carcinoma. This is a rare variant of bladder cancer recognized by the current World Health Organization classification of urologic tumors. The plasmacytoid component varied from 30% to 100% of the tumor specimen; in 8 cases, the plasmacytoid component comprised greater than 50% of the tumor with 2 cases showing pure plasmacytoid carcinoma. The architectural pattern of the tumor varied from solid expansile nests with noncohesive cells to mixed solid and alveolar growth; a streaking discohesive architecture was additionally present in 2 cases (18%). At histology, the individual tumor cells had an eccentrically placed nucleus and abundant eosinophilic cytoplasm reminiscent of plasma cells. Most neoplastic cells had nuclei of low to intermediate nuclear grade with occasional nuclear pleomorphism. Seven of 9 mixed cases had concurrent conventional high-grade urothelial carcinoma, and the remaining 2 cases presented features of nested or micropapillary urothelial carcinoma. Small intracytoplasmic vacuoles were variably present in all cases. All patients had advanced stage cancer (NpT3), and 8 (73%) had lymph node metastasis. Immunohistochemical staining demonstrated that both plasmacytoid and associated conventional urothelial carcinoma were positive for cytokeratins 7, 20, and AE1/AE3 and epithelial membrane antigen; CD138 was positive in 3 cases. Follow-up information was available in all cases (range, 2-16 months; mean, 7 months). Nine of the patients died of disease from 2 to 11 months, and 2 patients were alive with disease at 8 and 16 months. In summary, plasmacytoid variant of urothelial carcinoma is an aggressive variant associated with poor prognosis that presents at an advanced clinical stage. In limited samples, it may be misdiagnosed as chronic cystitis or plasmacytoma, a pitfall further compounded by CD138 expression in some cases. Morphological distinction from other malignant neoplasms with plasmacytoid phenotype is critical for its clinical management. © 2009 Elsevier Inc. All rights reserved.
⁎ Corresponding author. Unit of Anatomical Pathology, Faculty of Medicine, E-14004 Cordoba, Spain. E-mail address: [email protected] (A. Lopez-Beltran). 0046-8177/$ – see front matter © 2009 Elsevier Inc. All rights reserved. doi:10.1016/j.humpath.2009.01.001
1024
A. Lopez-Beltran et al.
1. Introduction
2. Materials and methods
Plasmacytoid urothelial carcinoma, a rare variant of urothelial carcinoma with histologic appearance similar to plasma cells [1,2], has been recognized in the current World Health Organization (WHO) classification of urothelial neoplasms [3] and may pose a significant differential diagnostic problem, particularly if it is the predominant or exclusive pattern in a limited biopsy sample [4]. There are limited data available about the pathologic and immunohistochemical characteristics as well as the clinical behavior of this pathologic entity [1-16]. Since the initial description by Sahin et al [11] and Zukerberg et al [14], about 30 cases have been reported, mostly as single case report [1-16]. Two recent series of 7 and 9 cases [4,7] concluded that these patients have a variable clinical course with some patients dying rapidly and others experiencing prolonged survival. This probably reflects that the reported series are nonhomogeneous and that the entity is not fully well characterized. More recently, Ro et al [4] reported 9 cases of plasmacytoid urothelial carcinoma obtained from 5 different hospitals and found this tumor to be diagnosed by transurethral resection in males with hematuria. All cases in this series were immunoreactive for cytokeratins (CKs) 7 and 20; CD138 was also positive in one case [4]. The finding of some plasmacytoid urothelial carcinomas of the bladder immunoreactive for CD138, a marker of plasma cells, represents an important challenge in daily practice but has been reported to occur rarely [4,8,10]. Hence, more reports on larger series are needed to elucidate the clinical significance and differential diagnostic implications of this interesting morphological variant of bladder cancer. Herein, we present a large sequential series of 9 plasmacytoid carcinoma of the bladder supplemented with 2 additional consultation cases.
This study included resection and surgical specimens from 11 patients. Nine cases were collected in a series of 1737 (0.51%) bladder tumor specimens studied from 1998 to 2007 at the uropathology practice of one of the authors (A. LopezBeltran). Two other cases were seen in consultation. The cases spanned a period of 10 years, with the earliest case diagnosed in 1999 and the last one in 2007. Clinical information was obtained from patients' records, and an average of 12 hematoxylin and eosin slides (range, 3-29 slides) from each case were evaluated. The following pathologic parameters were evaluated: percentage of plasmacytoid carcinoma component and of conventional urothelial carcinoma, histologic type of urothelial carcinoma (based on WHO classification), and depth of invasion and clinical TNM staging. Immunostaining was performed on at least one representative paraffin section using standard protocols with a 3-step biotin-streptavidin procedure. The antibodies used on paraffin-embedded tissues included epithelial membrane antigen (EMA) (prediluted; Signet, Dedham, MA), CK AE1/AE3 (prediluted, Signet), CK7 (1:50; Dako, Glostrup, Denmark), CK20 (1:50, Dako), CD138 (prediluted, Dako), leukocyte common antigen (LCA) (prediluted, Dako), S-100 protein (prediluted, Dako), HMB45 (prediluted, Dako), vimentin (prediluted, Dako), κ light chain (prediluted, Dako), λ light chain (prediluted, Dako), p53 (1:200, Dako), and Ki-67 (1:50, Dako). For all analyses, appropriated negative and positive controls were included. When necessary, antigen retrieval was performed following standard protocols. Immunostaining was graded from 0 to 3+.
Table 1
3. Results The clinicopathologic features of the 11 patients are summarized in Table 1. In all 11 patients, there was hematuria
Clinical and pathologic features of 11 cases of plasmacytoid bladder urothelial carcinoma
Case no.
Age (y)/sex
Initial symptoms
Plasmacytoid (%)
Associated urothelial carcinoma/type of specimen
Final TNM clinical stage
Follow-up status (mo)
1 2 3 4 5 6 7 8 9 10 11
63/M 55/M 76/M 87/M 62/M 80/F 56/M 65/M 87/M 48/M 62/F
Gross hematuria Hematuria, dysuria Hematuria Hematuria, frequency, dysuria Gross hematuria, dysuria Gross hematuria, nocturia Hematuria, urgency Hematuria, frequency Gross hematuria Hematuria, frequency Gross hematuria
60 50 50 40 60 30 70 90 100 100 30
Nested + CIS/TURB HG UC + CIS/CyP HG UC/TURB HG papillary + solid UC/TURB HG UC + CIS/CyP HG papillary + solid UC/TURB Micropapillary/CyP HG UC/TURB NA/TURB NA/CyP HG UC/CyP
T4a, N1 T3a, N0, T3b, N1 T4a, N1 T4a, N1, T3b, N1 T3b, N2 T4a, N1 T3b, N0 T3b, N0 T3b, N1
DOD, 2 AWD, 8 DOD, 2 DOD, 8 DOD, 4 DOD, 11 DOD, 2 DOD, 8 DOD, 10 AWD, 16 DOD, 9
Abbreviations: CIS, carcinoma in situ; AWD, alive with disease; DOD, died of disease; NA, not applicable; F, female; M, male; CyP, cystoprostatectomy; HG, high grade, UC, urothelial carcinoma.
Plasmacytoid urothelial carcinoma with dysuria (2 patients), frequency (3 patients), or nocturia in one patient. Their ages ranged from 48 to 87 years (mean, 67 years). The initial diagnosis of plasmacytoid carcinoma of the bladder was made on transurethral resection of bladder (TURB) in 8 cases and cystoprostatectomy in 3 others. None of the 11 cases had prior history of bladder cancer. Patients received definitive therapy 2 to 16 weeks after the onset of symptoms (mean, 8 weeks); one patient (case 10) received definitive therapy after 24 weeks. Seven patients had clinical stage T3 tumors, and 4 had stage T4 disease (Table 1). Eight patients (73%) had lymph node metastasis. Follow-up data after surgery were available in all 11 cases (range, 2-16 months; mean, 7 months). Nine of the patients died of disease from 2 to 11 months (mean, 6.2 months; median, 8 months), and 2 patients were alive with metastases at 8 and 16 months. One patient (case 5) developed soon after surgery round ligament metastasis followed by peritoneal carcinomatosis. In addition, 3 patients (cases 2, 8 and 10) received adjuvant chemotherapy resulting in 2 patients alive with disease (cases 2 and 10) and one died of disease (case 8) (Table 1).
1025 At histology (Fig. 1), the individual tumor cells were small to medium sized and had an eccentrically placed nucleus and abundant amphophilic cytoplasm with an eosinophilic paranuclear hof reminiscent of plasma cells. Most neoplastic cells had nuclei of low to intermediate nuclear grade with occasional nuclear pleomorphism. Binucleation was occasionally seen in all cases. The cells were 25 μm in diameter or larger. The nuclei varied from being hyperchromatic to those with evenly distributed chromatin. Prominent nucleoli were variably present in plasmacytoid cells; small intracytoplasmic vacuoles were variably present in all cases but only rarely sufficient to mimic signet ring cells. The plasmacytoid component varied from 30% to 100% of the tumor specimens; in 8 cases, the plasmacytoid component comprised greater than 50% of the tumor in the specimen; of these, 2 cases showed pure plasmacytoid carcinoma. The architectural pattern of growth of the tumors varied from solid expansile nests with noncohesive cells (40% of cases) to mixed solid and alveolar growth (60% of the cases); a streaking discohesive architecture was additionally present
Fig. 1 Diffuse infiltration of the plasmacytoid carcinoma cells in the bladder wall with an architectural pattern of solid expansile nests (A) with noncohesive cells (B). Mixed architectural pattern of solid (C) and alveolar growth (D) showing cells with plasmacytoid appearance. Discohesive architecture (E) retaining the plasmacytoid morphology (F). Plasmacytoid carcinoma immunoreactive for CK7 (G), CK20 (H), and CD138 (I).
1026 Table 2
A. Lopez-Beltran et al. Summary of the immunostains results
Case no.
EMA
CK7
CK20
CK AE1/AE3
CD138
LCA
S-100
HMB45
Vimentin
κ light chain
λ light chain
1 2 3 4 5 6 7 8 9 10 11
+ + + + + + + + + + +
+ + + + + + + + + + +
+ + + + + + + + + + +
+ + + + + + + + + + +
− + − − − + − − − + −
− − − − − − − − − − −
− − − − − − − − − − −
− − − − − − − − − − −
− − − − − − − − − − −
− − − − − − − − − − −
− − − − − − − − − − −
in 2 cases (18%), although individual cells still retained plasmacytoid morphology in these cases (Fig. 1). Seven (78%) of 9 mixed cases were associated with conventional high-grade urothelial carcinoma, and the remaining 2 cases presented features of nested or micropapillary urothelial carcinoma. Carcinoma in situ was additionally present in 3 cases (Table 1). Immunohistochemical staining demonstrated that both plasmacytoid and associated conventional urothelial carcinoma were positive for CK7 (3+), CK20 (variable, 1+ to 2+), and CK AE1/AE3 (3+) and EMA (2+); CD138 was positive in 3 cases with variable intensity in 2 cases (1+) and 3+ in the remaining case (Fig. 1) (Table 2). LCA, S-100, HMB45, κ light chain, λ light chain, and vimentin were negative in all cases (Table 2). Ki-67 labeling index ranged form 20% to 60% (mean, 35.5%) and p53 ranged from 10% to 40% (mean, 26%).
4. Discussion More than 90% of bladder carcinomas are urothelial carcinomas [1-3]. A small group of tumors are recognized as pathologic variants of invasive bladder cancer because of their unique histologic appearance [1-3]. These uncommon variant entities are distinct enough to be recognized separately in the current WHO classification system. These variants are significant from the diagnostic, prognostic, and/ or therapeutic perspective [1-3]. The plasmacytoid variant of urothelial carcinoma has been the subject of recent interest with one well-documented series of 9 cases and few case reports [1-16]. Our series represents the largest experience to date describing in detail the architectural patterns and cellular features of this uncommon form of bladder cancer. All patients in our series had a poor outcome, reiterating the importance of accurate classification of these tumors because of the poor prognosis associated with this variant. The observed positivity for CD138, also an immunohistochemical marker for plasma cells, in 3 (27%) of our cases is in line with other recent reports [4,8,10] and highlights an important potential diagnostic pitfall because of the morphological resemblance of tumor cells to plasma cells, mainly in tumors
with pure plasmacytoid morphology or in case of chronic cystitis with predominant plasma cell infiltrate. Several tumors have the potential to demonstrate plasmacytoid morphology (Table 3), although in general, this is a rare finding [4]; myoepithelial tumors and medullary carcinoma of the thyroid, melanoma, paraganglioma, neuroendocrine carcinoma, lymphoma, myeloma, and some sarcomas are in the spectrum [4,17-27]. In the urinary bladder, the main differential diagnostic considerations of plasmacytoid urothelial carcinoma include benign conditions such as chronic cystitis with prominent plasma cell infiltrate, as well as other malignant tumors such as plasmacytoma, signet ring cell adenocarcinoma, and metastatic carcinoma from other primary sites, specifically breast and stomach [1-4,17-27]. Rarely, myofibroblastic proliferations enter the differential diagnosis because they may have a prominent plasma cell infiltrate. All these distinctions have significant therapeutic implications. The diagnostic difficulty posed by this neoplasm was first exemplified by Sahin et al [11]; these authors reported a patient presenting with a skull lesion that was diagnosed as multiple myeloma. However, further clinical workup failed to support a diagnosis of plasmacytoma. The clinical evaluation revealed a large tumor in the urinary bladder that was composed of cells with plasmacytoid morphology and was histologically similar to the skull lesion. At about the same period, Zuckerberg et al [14] reported their series of bladder tumors simulating malignant lymphoma, one of them showing malignant cells with eccentric nuclei resembling plasma cells. After these initial reports, several publications discussed the differential diagnosis of a hematolymphoid malignancy in this setting, particularly a plasmacytoma/ myeloma in the initial, frequently limited, biopsy sample [4,17-27]. Primary plasmacytoma of the bladder is rare, but in patients with a prior history of multiple myeloma, where there is no identifiable surface urothelial component, it is necessary to maintain a level of suspicion to avoid misdiagnosis of a plasmacytoma as urothelial carcinoma with plasmacytoid features [4,17-27]. There have been cases of extramedullary plasmacytoma involving the bladder in patients with no demonstrable systemic involvement by multiple myeloma;
Plasmacytoid urothelial carcinoma Table 3
1027
Main differential features of bladder tumors with plasmacytoid cells Cytologic features
Immunohistochemical features
Nuclear Shape Nucleolus Cytoplasm Pan-CK Vim CK7 CK20 S-100 LCA HMB45 Syn CD138 Desmin Plasmacytoid carcinoma Rhabdoid carcinoma Signet ring cell carcinoma Lymphoma/ plasmacytoma Paraganglioma/ neuroendocrine carcinoma Melanoma Rhabdomyosarcoma
Round
+
Round
+
Indented
+
Round
+
Round
+
Round Round/ fusiform
+ +
Eosino/ ampho Eosino Ampho/ clear Eosino/ ampho Ampho/ clear Eosino Scant/ eosino
+
−
+
+
−
−
−
−
±
−
±
+
±
+
−
−
−
−
−
−
±
−
+
+
−
−
−
−
−
−
±
+
−
−
−
+
−
−
+
−
±
+
±
−
+
−
−
±
−
−
± ±
+ +
− −
− −
+ −
− −
+ −
− +
− −
− +
Abbreviation: Ampho, amphophilic; Eosino, eosinophilic; Vim, vimentin; Syn, synaptophysin.
however, reports such as these are still rare, and most of the patients present with systemic disease [19-20]. In a clinical scenario where this is a diagnostic concern, ancillary immunohistochemical testing for CK, CD138, and κ and λ light chains may further confirm the diagnosis. Primary signet ring cell adenocarcinoma enters into the differential diagnosis because of the occasional presence of intracytoplasmic vacuoles and the noncohesive nature of the tumor cells [18,24]. Primary pure signet ring cell adenocarcinoma of the bladder is rare. The signet ring cells, the predominant component, permeate the wall of the urinary bladder in a linitis plastica type manner [18]. This was a rare and focal compelling feature in our series, similar to other recent reported series [4]. Also, carcinoma with rhabdoid phenotype that has been described to occur in the bladder should be considered in the differential diagnosis with plasmacytoid carcinoma, which is mostly based on cytoplasmic features and the presence of prominent nucleolus, unlike the plasmacytoid carcinoma in rhabdoid cells, determined by positive immunostaining for vimentin [21]. Metastatic carcinoma from the breast, stomach, and, rarely, colon may have morphology overlapping with that of plasmacytoid urothelial carcinoma. Baldwin et al [17] recently described a “discohesive” variant of urothelial carcinoma and commented on the morphological overlap with metastatic lobular carcinoma of the breast. The authors described the bladder tumors in their series to be deeply invasive into the muscular wall and composed of discohesive cells arranged in a single-file pattern reminiscent of lobular carcinoma of the breast [17]. A similar discohesive pattern in plasmacytoid urothelial carcinoma was observed recently by Ro et al [4], and in 2 cases of our series; in both situations, the discohesive cells still retained the plasmacytoid morphological features, thus, suggesting that plasmacytoid carcinoma is morphologically different to the discohesive variant reported by Baldwin et al [17]. This is also different in terms of
differential diagnosis from metastatic breast carcinoma, the compelling feature in the cases reported by Baldwin et al [17], but a rare consideration for plasmacytoid carcinoma of the bladder. The observation of an obvious urothelial carcinoma component, present in 88% of our cases and in other reported cases, is also helpful in confirming a bladder primary. An additional important feature of plasmacytoid carcinoma of the bladder is its presentation at advanced stage with poor outcome. Within a 2-year follow-up period after surgery, all of our patients had either died of cancer or had developed metastases, a finding similar to other recent reports [1-16]. In summary, urothelial carcinoma with plasmacytoid features is an important variant of bladder cancer that has diagnostic, prognostic, and therapeutic significance. It may pose diagnostic difficulties, especially in limited biopsy samples, where it may be mistaken for an inflammatory process. Attention to histologic features, together with clinical history and appropriate immunohistochemical studies, should help distinguish plasmacytoid urothelial carcinoma from its mimickers.
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