BJUI Mini Reviews - Pathological Variants of Invasive Bladder Cancer According to Their Suggested Clinical Significance Show Comments
  
Thursday, 06 March 2008

BJUI Mini Reviews - In this review, the most common pathological variants of urothelial carcinoma are summarized, with an emphasis on clinical implications.

Pathological variants of invasive bladder cancer according to their suggested clinical significance Antonio Lopez-Beltran, Maria J. Requena*, Liang Cheng†‡ and Rodolfo Montironi¶ Departments of Pathology and *Urology, Reina Sofia University Hospital and Cordoba University Medical School, Cordoba, Spain, †Pathology and ‡Urology, Indiana University School of Medicine, Indianapolis, USA, and ¶Institute of Pathological Anatomy and Histopathology, Polytechnic University of the Marche Region, Ancona, Italy Accepted for publication 27 July 2007 pathologists and urologists to be aware of the diverse morphological patterns in invasive bladder cancer, as they might be relevant in patient management and prognosis, mainly because they can mimic benign lesions, secondary tumours or might require a specific therapeutic approach KEYWORDS bladder, neoplasms, pathological variant, urothelial carcinoma Several pathological variants of bladder cancer, reflecting tumour heterogeneity in urothelial carcinoma, have been recently recognized. In this review we summarize the most common pathological variants of urothelial carcinoma, with an emphasis on clinical implications. It is important for both INTRODUCTION Urothelial carcinoma (UC) is a heterogeneous tumour with a great propensity for divergent differentiation, resulting in a urothelial carcinoma admixed with other morphologically recognisable components [1]. The most common mixed differentiation is squamous, in ≈ 20% of urothelial bladder carcinomas, followed by glandular, that can reach up to 6% of cases in some series [1–5]. As seen in Table 1, virtually the whole spectrum of bladder carcinoma variants can be seen in variable proportions from an otherwise typical UC, but most importantly, these variants can be relevant in clinical practice, as they might simulate benign lesions, secondary tumours, or necessitate a more complex therapeutic approach beyond surgery [1,6]. Recent studies suggest an increasing likelihood of lymph node metastases associated with the finding of pathological variants in the primary tumour [7]. Recognising these variants is therefore clinically relevant in patient management. UC WITH DECEPTIVELY BENIGN APPEARANCE NESTED VARIANT The nested variant of UC is an aggressive neoplasm with fewer than 50 reported cases [1,8–10]. There is a male predominance, and 70% of patients died 4–40 months after diagnosis, despite therapy [9,11]. This rare pattern of UC was first described as a tumour with a ‘deceptively benign’ appearance that closely resembles Brunn’s nests infiltrating the lamina propria [8,12–14]. Nuclei generally show little or no atypia, but the invariable presence of an infiltrative growth should facilitate an accurate diagnosis. In terms of biology, there is high p53 accumulation and tumour cell proliferation, findings that are useful in difficult cases [1]. Despite the deceptively benign appearance of the tumour, recently it was proposed to grade this as high-grade, to assist the urologist in selecting the appropriated therapy [1]. UC WITH ENDOPHYTIC GROWTH (INVERTED PAPILLOMA-LIKE CARCINOMA) The recent interest in UC with endophytic growth arose because they can be misdiagnosed as a benign inverted papilloma [1,15–18]. This is because inverted papillomalike carcinoma can show variable-to-minimal cytological and architectural abnormalities, but invariably has a higher mitotic count and cell proliferation, as seen by Ki67, high p53 accumulation, aberrant cytokeratin 20 expression, and frequent polysomies at chromosome 3, 9 and 17 [19]. This profile has been very useful in the differential diagnosis with inverted papilloma [18,19]. In some instances, both inverted papilloma and inverted papilloma-like carcinoma are intimately mixed [18]. The other important feature in papillary tumours with endophytic growth is that they invade the lamina propria with a ‘pushing’ border [20]. Unless this pattern is accompanied by true destructive stromal invasion, the likelihood of metastasis is minimal because the basement membrane is not truly breached [15]. UC WITH FEATURES SUGGESTING SECONDARY INVOLVEMENT TO THE BLADDER MICROPAPILLARY UC This variant of UC was initially described because it resembles papillary serous carcinoma of the ovary [1,21]. This morphology has been further recognized in other organs such as lung, colon, breast, renal pelvis or salivary glands [1,22]. A recent report based on 100 consecutive cases treated by cystectomy showed a mean patient age of 64.7 years, with a male: female ratio of 10 : 1 [22]. The stage at the time of presentation was Ta in five patients, carcinoma in situ in four, T1 in 35, T2 in 26, T3 in seven, T4 in six; N + in nine and M + in eight. The 5- and 10-year overall survival rates were 51% and 24%, respectively. Intravesical BCG therapy was attempted in 27 of 44 patients with nonmuscle- invasive disease; 18 (67%) developed disease progression ( ≥ cT2), including 22% who developed metastatic disease [22]. Of 55 L O P E Z - B E L T R A N E T A L . © 2 0 07 T H E A U T H O R S 2 7 6 J O U R N A L C O M P I L A T I O N © 2 0 07 B J U I N T E R N A T I O N A L patients undergoing radical cystectomy for surgically resectable disease ( ≤ cT4a), 23 received neoadjuvant chemotherapy and 32 were treated with initial cystectomy, with no significant difference in stage distribution between the groups. For the 23 patients treated with neoadjuvant chemotherapy, the median overall survival was 43.2 months, with 32% of patients still alive at 5 years [22]. For the 32 patients treated with initial cystectomy, the median survival had not been reached at the time of the last follow-up, with 71% still alive at 5 years. It was concluded that micropapillary bladder cancer is associated with a poor prognosis, that intravesical therapy appears to be ineffective in this disease, and patients with surgically resectable disease should be offered early radical cystectomy [22]. Also, increased lymph node positivity was associated with the presence of micropapillary carcinoma in a recent study [7,23]. At histology, the micropapillary component is found in association with noninvasive papillary or invasive UC in 80% of reported cases [1]; 25% show glandular differentiation, and some authors consider it as a variant of adenocarcinoma. Vascular and lymphatic invasion is common, and most cases show invasion into muscularis propria or deeper, often with metastases at the time of diagnosis [24]. Immunohistochemical studies show immunoreactivity for epithelial markers, similar to conventional UC in all, and CA125 staining in 43% of cases [25]. The presence of a surface micropapillary component in bladder biopsy specimens is a useful clue for further investigation, and an indication for deeper biopsies to determine the level of invasion. In addition to stage, the prognosis seems to be related to the proportion and location of the micropapillary component [10,25]. Cases with a moderate or extensive micropapillary component are at high risk of having an advanced stage at presentation. Cases with < 10% micropapillary component have a high chance of detection at an early stage. PLASMACYTOID UC This is an unusual variant in which the tumour cells show eosinophilic cytoplasm and eccentric nuclei, producing a plasmacytoid appearance, thus suggesting multiple myeloma/lymphoma [1,6,10,26]. The epithelial nature of the malignancy is confirmed by positive immunohistochemistry of cytokeratin and negativity for lymphoma/ plasmacytoma markers. This tumour is an aggressive neoplasm with a stage-related outcome and frequent lymph node positivity at diagnosis [27]. In a series report of six cases, the male-to female ratio was 2 : 1, and the mean age at presentation was 58 years. Five of six patients died from disease (mean survival 23 months) [27]. Some of these cases were recorded in older reports as lymphomalike carcinoma [28,29]. CLEAR CELL (GLYCOGEN-RICH) UC Up to two-thirds of cases of UC have foci of clear-cell change resulting from abundant TABLE 1 Proposed classification of pathological variants of UC of the bladder according to their suggested clinical significance Pathological variants of invasive bladder cancer and their potential pitfalls Main lesions and tumours in differential diagnosis Deceptively benign features UC, nested variant Von Brunn’s hyperplasia UC, inverted papilloma-like variant Inverted papilloma Differential diagnosis with metastases to the bladder UC, micropapillary variant Serous carcinoma of the ovary; micropapillary carcinomas from other sites UC, plasmacytoid variant Plasmacytoma UC, clear cell (glycogen-rich) variant Clear cell carcinomas from kidney, prostate and others Large-cell undifferentiated carcinoma Large-cell undifferentiated carcinoma of lung Misdiagnosis as benign proliferative lesions UC, microcystic variant Cystitis cystica et glandularis, rarely adenocarcinoma Complex therapeutic approach UC, lymphoepithelioma-like variant Chemotherapy, metastases from other sites SCC Chemotherapy, metastases from lung Misdiagnosis as choriocarcinoma either 1ry/ 2ry UC with syncitiotrophoblastic giant cells Choriocarcinoma either primary or secondary Misdiagnosis as myofibroblastic proliferation Sarcomatoid UC (carcinosarcoma) Inflammatory myofibroblastic tumour (inflammatory pseudotumour) Misdiagnosis as squamous-cell carcinoma or adenocarcinoma, either 1ry or 2ry UC with squamous and/or glandular differentiation Squamous cell carcinoma, adenocarcinoma Misdiagnosis as other tumour types UC, lipoid-cell variant Carcinosarcoma/sarcomatoid carcinoma of heterologous type UC with peudosarcomatous stroma Sarcomatoid carcinoma UC with stromal osseous or cartilaginous metaplasia Carcinosarcoma/sarcomatoid carcinoma heterologous type UC with osteoclast-type giant cells Reactive granulomatous lesion UC with prominent lymphoid infiltrate Lymphoma Rare UCs with discohesive, prostate-like or endometrioid-like morphologies Lobular carcinoma of breast, endometrial carcinoma or Gleason 3 + 3 prostate cancer P A T H O L O G I C A L V A R I A N T S O F U R O T H E L I A L C A R C I N O M A © 2 0 07 T H E A U T H O R S J O U R N A L C O M P I L A T I O N © 2 0 07 B J U I N T E R N A T I O N A L 2 7 7 glycogen, but the glycogen-rich clear-cell ‘variant’ of UC, recently described [30], appears to represent the extreme end of the morphological spectrum, consisting predominantly or exclusively of cells with abundant clear cytoplasm that stains for cytokeratin 7, thus confirming a urothelial origin [30,31]. Recognising this pattern avoids confusion with clear-cell adenocarcinoma of the bladder and metastatic clear-cell carcinoma of the kidney and other sites. Recent data relates this morphology with lymph node metastases [7]. LARGE CELL UNDIFFERENTIATED CARCINOMA This is a poorly defined category that contains large-cell type carcinoma that cannot be otherwise classified [1,6]. They are extremely rare in the urinary tract, aggressive, and of high stage at presentation, including frequent lymph node metastases [7]. One reported case showed increased α -fetoprotein production in the patient’s serum, and by immunohistochemistry in the tumour cells [32]. Some might contain abundant epithelial tumour giant cells resembling giant cell carcinoma of the lung (so called pleomorphic giant cell carcinoma of the bladder) [1,6,33]; this is a very infrequent and aggressive variant with poor prognosis, similar to that associated with giant cell carcinoma in the lung or prostate. The giant cells have cytokeratin immunoreactivity. We think that this should be considered in the spectrum of the large-cell undifferentiated carcinoma of the bladder instead of a different pathological variant, until more experience is available [1]. The spectrum of neuroendocrine carcinomas of the urinary bladder might include rare examples of large-cell neuroendocrine carcinomas, similar to the more common counterpart in the lung. The experience with these cases suggests that they are at advanced stage at presentation [34,35]. UC WITH FEATURES SUGGESTING BENIGN PROLIFERATIVE LESIONS MICROCYSTIC UC This pathological variant is characterized by the formation of cysts ranging from microscopic to up to 1–2 cm in diameter [13,36,37]. The cysts or small tubules might be empty or contain necrotic debris or mucin. This variant of cancer can be confused with benign proliferations such as florid polypoid cystitis cystica and glandularis, nephrogenic adenoma, and rarely with adenocarcinoma [13,36]. UC WITH A COMPLEX THERAPEUTIC APPROACH LYMPHO-EPITHELIOMA-LIKE UC This tumour resembles lympho-epithelioma of the nasopharynx [38,39]; the male-tofemale ratio is 3 : 1, and occurs in late adulthood (mean 69 years, range 52–81). Most patients present with haematuria [39–41]. The tumour is solitary and usually involves the dome, posterior wall, or trigone, often with a sessile growth pattern. At histology, it can be pure, or mixed with typical UC [42]. The epithelial tumour cells show poorly defined cytoplasmic borders imparting a characteristic syncytial appearance. The background consists of a prominent lymphoid stroma that includes T- and B-lymphocytes, plasma cells, histiocytes, and occasional neutrophils or eosinophils [39]. Epstein-Barr virus infection has not been identified in lympho-epithelioma-like carcinoma of the bladder [43]. This tumour has been found to be responsive to chemotherapy when it is encountered in its pure form. SMALL-CELL CARCINOMA (SCC) A recent molecular study indicated that SCC and UC are derived from the same clonal population, and we consider SCC of the urinary bladder as a variant of UC, with a dismal prognosis [44,45]. In a recent series of 64 such cases the mean age at diagnosis was 66 years and the male : female ratio was 3.3 : 1; 88% presented with haematuria [44,46,47]. All the patients except one had muscle-invasive disease at presentation. Thirty-eight patients (59%) had a 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. Fortyfour cases (68%) cases consisted of SCC with other histological types (UC, 35; adenocarcinoma four; sarcomatoid UC two; and three with both adenocarcinoma and UC) [44,47]. No clinicopathological variables studied correlated with survival. There was no significant survival difference between patients who had a cystectomy and those who did not. Patients with organ-confined cancers had marginally better survival than those with extravesical cancer ( P = 0.06) [44]. Overall, the 1-year, 18-month, 3-year and 5-year cancer-specific survivals were 56%, 41%, 23%, and 16%, respectively. The prognosis of SCC of the urinary bladder remains poor, irrespective of therapy. Hypercalcaemia or hypophosphataemia, and ectopic secretion of adrenocorticotropic hormone, have also been reported as part of the paraneoplastic syndrome associated with primary SCC of the bladder [46]. On histological examination, they mimic its pulmonary counterpart. The immunohistochemical profile reveals neuroendocrine markers at variable frequency, but SCC can be diagnosed on morphological grounds alone, even if neuroendocrine differentiation cannot be detected. The recent finding of c-kit and epidermal growth factor receptor expression by immunohistochemistry opens new possibilities for targeted therapy in SCC of the bladder [46,48,49]. UC MISDIAGNOSED AS CHORIOCARCINOMA, EITHER PRIMARY OR SECONDARY UC WITH SYNCITIOTROPHOBLASTIC GIANT CELLS Up to 12% of cases of UC show syncitiotrophoblastic giant cells producing substantial amounts of β -hCG [50–53]. Secretion of hCG into the serum can be associated with a poor response to radiation therapy [53]. The most important differential diagnostic consideration is choriocarcinoma; most, but not all, cases previously reported as primary choriocarcinoma of the bladder represent UC with syncytiotrophoblasts rather than pure choriocarcinoma, a lesion that is very unusual in the bladder [1]. One reported primary choriocarcinoma of the bladder that occurred in a 19-year-old man showed a high copy number of the isochromosome 12p, supporting germ cell differentiation [54]. UC MISDIAGNOSED AS MYOFIBROBLASTIC PROLIFERATION OR SARCOMA SARCOMATOID UC (CARCINOSARCOMA, SPINDLE-CELL CARCINOMA) The term ‘sarcomatoid variant of UC’ should be used for all biphasic malignant neoplasms L O P E Z - B E L T R A N E T A L . © 2 0 07 T H E A U T H O R S 2 7 8 J O U R N A L C O M P I L A T I O N © 2 0 07 B J U I N T E R N A T I O N A L with morphological and/or immunohistochemical evidence of epithelial and mesenchymal differentiation (with the presence or absence of heterologous elements acknowledged in the pathology report) [55]. Some patients had a previous history of radiation or cyclophosphamide therapy [56]. The most frequent presenting signs and symptoms are haematuria, dysuria, nocturia, acute urinary retention and lower abdominal pain [56]. The mean (range) age is 66 (50–77) years. The pathological stage is the best predictor of survival in sarcomatoid carcinoma [56]. The tumours are often polypoid with large intraluminal masses. Microscopically, sarcomatoid carcinoma is composed of a urothelial, glandular or smallcell component showing variable degrees of differentiation; carcinoma in situ is present in 30% of cases and occasionally is the only apparent epithelial component [56]. A small subset of sarcomatoid carcinoma of the bladder and the renal pelvis might have a prominent myxoid stroma, a finding that misguides the pathologist to inflammatory pseudotumour (inflammatory myofibroblastic tumour), but this is characteristically positive for anaplastic lymphoma kinase stains, unlike sarcomatoid carcinoma, which is negative [56–61]. The most common heterologous element in a large series is osteosarcoma, followed by chondrosarcoma, rhabdomyosarcoma, leiomyosarcoma, liposarcoma, or angiosarcoma, but multiple types might be present [56]. By immunohistochemistry, epithelial elements react with cytokeratins, whereas stromal elements react with specific markers corresponding to the type of mesenchymal differentiation. Recent molecular evidence strongly argues for a monoclonal origin of both components in sarcomatoid carcinoma [62]. MISDIAGNOSIS AS SQUAMOUS CELL CARCINOMA OR ADENOCARCINOMA, EITHER PRIMARY OR SECONDARY UC WITH SQUAMOUS AND/OR GLANDULAR DIFFERENTIATION Squamous differentiation, defined by the presence of intercellular bridges or keratinization, occurs in 21% of UCs of the bladder [1,3,6,56]. Its frequency increases with grade and stage [3]. The proportion of the squamous component varies considerably, with some cases having UC in situ as the only urothelial component. These cases can have a less favourable response to therapy (surgical, radiation or systemic chemotherapy) than pure UC. Of 91 patients with metastatic carcinoma, 83% with mixed adenocarcinoma and 46% with mixed squamous cell carcinoma had disease progression despite intense chemotherapy, whereas progression occurred in < 30% of patients with pure UC [4,5]. Low-grade UC with focal squamous differentiation also has a higher recurrence rate. Tumours with any identifiable urothelial element are classified as UC with squamous differentiation [3]. Rare cases of squamous differentiation in the bladder with basaloid or clear cell features have been recognized [3]. Glandular differentiation is less common than squamous differentiation and can be present in ≈ 6% of UCs of the bladder [2]. Glandular differentiation is defined as the presence of true glandular spaces within the tumour. These can be tubular or enteric glands with mucin secretion. A colloid-mucinous pattern characterized by nests of cells ‘floating’ in extracellular mucin, occasionally with signetring cells, can be present. Cytoplasmic mucincontaining cells are present in 14–63% of typical UC and are not considered to represent glandular differentiation [1,6]. In rare cases, the glandular component has the morphology of hepatoid or clear cell adenocarcinoma [63]. A tumour with mixed glandular and urothelial differentiation is best classified as UC with glandular differentiation. MISDIAGNOSIS AS OTHER TUMOUR TYPES LIPOID-CELL UC The lipoid-cell variant is a rare neoplasm defined by the WHO (1999, 2004) as a UC which shows transition to a cell type resembling signet-ring lipoblasts [1,6]. It is currently considered to be an ill-defined tumour variant. The clinicopathological features in seven reported cases showed gross haematuria as the initial symptom [64]. All patients were elderly men (mean age 74 years, range 63–94). On microscopic examination the extent of the lipid cell pattern was 10–30% of the tumour specimen, with associated micropapillary (one), plasmacytoid (two), and grade 3/3 conventional UCs (four). The immunohistochemical results showed an epithelial phenotype of the lipoid cell component. The reported cases were pathological stage T2 in two, T3a in one, T3b in three and T4 in one [64]. Patient follow-up showed one dead and two alive with disease at 58, 14 and 55 months, respectively; two showed no evidence of disease at 11 and 29 months. Two additional patients died from other causes at 10 and 15 months [64]. Primary or secondary carcinosarcoma with a liposarcoma component is the main differential consideration. UC WITH STROMAL REACTIONS (PEUDOSARCOMATOUS STROMA; STROMAL OSSEOUS OR CARTILAGINOUS METAPLASIA; OSTEOCLAST-TYPE GIANT CELLS; PROMINENT LYMPHOID INFILTRATE) Infiltrating UC can be associated with a variety of stromal reactions, which are occasionally pronounced. The finding of a peudosarcomatous stroma raises serious concern about sarcomatoid carcinoma or true sarcoma of the bladder [65]. Tumourassociated stromal osseous and/or chondroid metaplasia is present in some cases of UC and its metastases, and this should be differentiated from osteosarcoma, chondrosarcoma or heterologous type of sarcomatoid carcinoma [66]. The presence of osteoclast-like giant cells in cases of invasive high-grade UC seems not to be related to tumour prognosis [67]. An inflammatory cell response in the stroma adjacent to the invasive tumours is relatively common [68]. This response usually takes the form of a lymphocytic infiltrate with a variable admixture of plasma cells. Generally, this cellular reaction is mild to moderate, but occasionally it can be dense [69]. Intense inflammation in bladder carcinoma was found to be associated with tumour angiogenesis and indicative of a good prognosis in one study [68]. UC WITH RARE DISCOHESIVE, PROSTATE-LIKE OR ENDOMETRIOID-LIKE MORPHOLOGY Baldwin et al. [70] described a series of 10 cases of UC with a striking discohesive growth pattern which showed morphological features that mimicked infiltrating lobular carcinoma of the breast and diffuse carcinoma of the stomach. The mean age of the patients was 67 years at presentation. All cases had an advanced stage at the time of diagnosis. It is important to recognize this pattern to avoid misdiagnosis of metastatic lobular carcinoma of the breast or diffuse P A T H O L O G I C A L V A R I A N T S O F U R O T H E L I A L C A R C I N O M A © 2 0 07 T H E A U T H O R S J O U R N A L C O M P I L A T I O N © 2 0 07 B J U I N T E R N A T I O N A L 2 7 9 carcinoma of the stomach, especially in small biopsies [70]. Gleason 3 prostate cancer with a tubular pattern of growth, which might be seen, is the main differential consideration for bladder cancer with small tubule formation [71]. 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Hum Pathol 2004; 35: 769–73 Correspondence: Antonio Lopez-Beltran, Unit of Anatomical Pathology, Faculty of Medicine, E-14004 Cordoba, Spain. e-mail: <script language='JavaScript' type='text/javascript'> <!-- var prefix = 'ma' + 'il' + 'to'; var path = 'hr' + 'ef' + '='; var addy54587 = 'em1lobea' + '@'; addy54587 = addy54587 + 'uco' + '.' + 'es'; document.write( '<a ' + path + '\'' + prefix + ':' + addy54587 + '\'>' ); document.write( addy54587 ); document.write( '<\/a>' ); //-->\n </script><script language='JavaScript' type='text/javascript'> <!-- document.write( '<span style=\'display: none;\'>' ); //--> </script>This email address is being protected from spam bots, you need Javascript enabled to view it <script language='JavaScript' type='text/javascript'> <!-- document.write( '</' ); document.write( 'span>' ); //--> </script> Abbreviations: UC, urothelial carcinoma; SCC, small-cell carcinoma.

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