Micropapillary variant of urothelial carcinoma of the urinary bladder; a clinicopathological and immunohistochemical study

AIMS: To investigate whether prognosis in micropapillary urothelial carcinoma is related to the proportion of the micropapillary component (MPC), and to identify the immunohistochemical features of MPC. METHODS AND RESULTS: This study presents a clinicopathological analysis of 20 patients with micropapillary urothelial carcinoma of the bladder with cystectomy specimens for evaluation. Tumours were stratified on the extent of MPC: focal, <10%; moderate, 10-50%; extensive, >50%; and this was correlated with tumour stage and prognosis. Sixteen males and four females were aged 56-81 years (mean 69 years). All cases had high-grade morphology in the micropapillary carcinoma and typical urothelial carcinoma. All cases with extensive MPC (n = 4) were of a high pathological stage (pT3 or pT4) and died of disease (DOD) or other causes. Eighty percent with moderate MPC (eight of 10 cases) were pT3 or pT4 and 50% DOD or are alive with disease. Eighty-four percent with focal MPC (five of six cases) were pT1 or pTa. In high-stage cases, the most invasive component was MPC. High-stage cases had an 85% risk of being advanced at presentation with micropapillary carcinoma. All pT2 or lower stage cases had micropapillary carcinoma on prior transurethral resections of bladder tumour (TURB). High-stage carcinomas had 30% and 54%, respectively, of surface MPC and urothelial carcinoma in situ, in comparison with 85% and 28% in lower stage carcinomas. Immunohistochemical staining was similarly positive in MPC and typical urothelial carcinoma with cytokeratin (CK)7, CK20, epithelial membrane antigen, carcinoembryonic antigen and cytokeratin 34betaE12. CA125 staining was seen only in MPC in 43% of cases. CONCLUSIONS: Micropapillary urothelial carcinoma is a high-grade carcinoma in which the prognosis is related to the proportion and location of the MPC. Cases with moderate or extensive MPC are at high risk of being advanced at presentation. Cases with <10% MPC and surface MPC have a high chance of detection at an early stage. The morphology and immunohistochemical profile of the MPC suggest that it is a form of glandular differentiation in urothelial carcinoma.     

Mixed micropapillary and trophoblastic carcinoma of bladder: report of a first case with new immunohistochemical evidence of urothelial origin

The micropapillary variant of urothelial carcinoma has a reported incidence of 0.7%. Trophoblastic urinary carcinoma is very rare, with roughly 30 cases reported during the last century. This is the first report of mixed micropapillary and trophoblastic bladder carcinoma. A 45-year-old man presented with gross hematuria. His tumor contained choriocarcinomatoid areas with syncytiotrophoblasts, classic micropapillary carcinoma, conventional high-grade urothelial carcinoma, and flat carcinoma in situ. He underwent radical surgery; tumor stage was T4N2M0. Despite postoperative combination chemotherapy, he developed pulmonary and retroperitoneal metastases and died 20 months after presentation. The tumor was immunopositive for human chorionic gonadotropin and human placental lactogen in trophoblast and for cytokeratin 20 and high-molecular-weight cytokeratin in all tumor components. Because high-molecular-weight cytokeratin is expressed by urothelium but is rarely found in placental trophoblast or germ-cell choriocarcinoma, its presence in trophoblastic bladder carcinoma is new evidence that the latter is a transformed neoplasm of urothelial origin.     

Plasmacytoid variant of urothelial carcinoma: A report of a rare case

Plasmacytoid variant of urothelial bladder carcinoma is rare. We report a case with a detailed discussion of features that help characterize this variant. A 50-year-old man originally presented with gross hematuria. Resections at that time revealed a grade I-II superficial urothelial carcinoma. He did not return for follow-up until recently, three years later, when he presented with recurrent gross hematuria. An extensive tumor was identified on cystoscopy. Resection revealed a high-grade non-invasive papillary urothelial carcinoma. CT scan revealed a large urinary bladder solid mass with bilateral hydronephrosis. Metastatic workup was negative. The patient underwent a radical cystectomy with creation of ileal conduit. Final pathology revealed plasmacytoid variant of urothelial carcinoma with extensive vascular invasion and extension to the perivesical adipose tissue. We present a rare variant of urothelial carcinoma with comprehensive analysis of the morphological and immunophenotypic clues that characterize this variant.     

Divergent differentiation in urothelial carcinoma and other bladder cancer subtypes with selected mimics

Conventional urothelial carcinoma accounts for most carcinomas of the urinary tract lining. However, neoplastic urothelium has the capacity to demonstrate enormous plasticity. A variety of unusual architectural patterns of urothelial carcinoma, such as the nested, microcystic and inverted variants, can be mistaken for reactive processes or benign tumours. Others such as the micropapillary, plasmacytoid and discohesive variants, can mimic metastatic tumour from other sites. The micropapillary variant in particular is more aggressive. In addition, urothelial carcinoma has a propensity to demonstrate divergent differentiation with glandular, squamous, small cell neuroendocrine, lymphoepithelioma-like, sarcomatoid or other elements. Pure squamous carcinoma or adenocarcinoma (the latter in particular) can be difficult to distinguish from contiguous or metastatic spread. Some variants have prognostic and potential therapeutic implications. Molecular genetic evidence has emerged recently supporting a close relationship between urothelial carcinoma and various divergent elements. Sarcomatoid carcinoma and its differential diagnosis with other spindle cell lesions of urinary tract will be covered in a separate review.     

Micropapillary variant of transitional cell carcinoma of the ureter

Micropapillary variant of transitional cell carcinoma (TCC) is a rare entity, having a distinct micropapillary component mimicking papillary serous carcinoma of the ovary and has been reported exclusively in the urinary bladder. We experienced a case of micropapillary variant of TCC in the ureter. The tumor showed a predominant proportion of micropapillary component and accompanied a TCC in situ lesion and a high-grade TCC. A metastatic lesion in the regional lymph node also showed an entirely micropapillary pattern. Initially, our case was confused with adenocarcinoma, especially metastatic, because the micropapillary architecture resembled an abortive glandular structure and tumor cell nests were predominantly located in empty spaces mimicking vascular invasion. The patient died with peritoneal metastases 20 months after the initial diagnosis. We report the first case of a micropapillary variant of TCC occurring in the ureter.     

Recently described and unusual variants of urothelial carcinoma of the urinary bladder

Urothelial carcinoma (UC) of the urinary bladder has a great propensity to undergo divergent differentiation. The resulting subtypes are morphologically unique and have significant prognostic and therapeutic differences. While squamous and glandular subtypes are the most common, a number of other well characterised morphological subtypes were described in the 2004 World Health Organization Classification. More recently additional variants of UC have been described, while others have been more fully characterised. In this review we report the details of recently described and selected unusual variants of UC. Specifically, the pathological and clinical details are discussed, relating to large nested and nested variant of UC, large cell undifferentiated carcinoma, lymphoepithelioma-like carcinoma, osteoclast rich undifferentiated carcinoma, pleomorphic giant cell carcinoma, UC with syncytiotrophoblastic giant cells, lipid cell variant of UC, micropapillary UC, UC with abundant myxoid stroma and plasmacytoid UC.     

Urine cytomorphology of micropapillary urothelial carcinoma

Micropapillary urothelial carcinoma (MPUC) is a rare subtype of urothelial carcinoma (UC) with an aggressive clinical course. The cytomorphologic features of MPUC in urine cytology have not been well described. In this study, 23 urine specimens (11 voided urines and 12 bladder washings) from 23 patients with MPUC on follow‐up surgical material and 28 specimens (14voided urines and 14 bladder washings) from 28 patients with high‐grade UCs (HGUC) were retrieved. Cytologic features (nuclear grade, cytoplasmic characteristics), architectural features (single cell pattern, true papillary structures, flat sheets/nests, three dimensional clusters, micropapillary (inside‐out, acinar‐like, or cauliflower with nuclei located peripherally)), and necrosis were evaluated. Clinical follow‐up was obtained by chart review. Two findings, micropapillae and cytoplasmic vacuoles, were seen more frequently in MPUC compared to HGUC, 81.0% vs. 14.3%, and 57.1% vs. 14.3%, respectively. The combination of these two findings had a sensitivity of 78%, a specificity of 86%, a positive predictive value of 82%, and a negative predictive value of 83% for the diagnosis of MPUC on subsequent biopsy. MPUC and HGUC can both exhibit a single cell pattern, papillary structures, flat sheets/nests, three dimensional clusters, high‐nuclear grade, and necrosis, thus these findings are not useful in distinguishing these entities. Chart review revealed that patients with MPUC had a higher rate of metastasis to lymph nodes and distant organs than HGUC, 57% vs. 4%. Therefore, the findings of cytoplasmic vacuoles and micropapillary structures in UC from a urine cytology specimen are associated with MPUC on subsequent biopsy. Diagn. Cytopathol. 2013. © 2012 Wiley Periodicals, Inc.     

Micropapillary carcinoma of the urinary bladder: report of a case and review of its cytologic features

Micropapillary carcinoma (MPC) is an aggressive variant of urothelial carcinoma. MPC has a propensity to invade lymphovascular spaces and detrusor muscle early in the disease that often leads to upstaging and/or lymph node metastasis in many cases at cystectomy. Its association with the usual high-grade urothelial carcinoma provides an easy recognition of malignancy in cytology specimens without attempt at separating or identifying the MPC component. This may be related to our limited familiarity of its cytologic features with only 4 cases described in the literature. We report another case of MPC and highlight its features in cytologic preparations including the presence of singly scattered tumor cells with high nuclear to cytoplasmic ratio and pleomorphic nuclei, clustered cells devoid of fibrovascular core (micropapillae), 3-dimensional cell aggregates, cytoplasmic vacuoles, and micropapillae exhibiting some features of low-grade urothelial neoplasm. Appreciation of these features may help facilitate its early diagnosis and hopefully a better outcome for these aggressive tumors.     

Immunohistochemical, molecular, and clinicopathological analyses of urothelial carcinoma, micropapillary variant

The prognosis of urothelial carcinoma, micropapillary variant (MPV), of the bladder has been shown to be worse than that of the conventional urothelial carcinoma (UC). However, it remains to be clarified why the MPV is more aggressive. We therefore here focused on the correlation between clinical features and histological, immunohistochemical and molecular findings for eight MPV and 35 UC, evaluating expression of MUC1, Ki-67, p53, CD147, CD34, D2-40, and extracellular matrix proteins. The Ki-67 labeling index was significantly higher in UC than in MPV but densities of venous and lymphatic tumor emboli were significantly higher in the MPV cases and lymph node metastasis was more frequent, with a poorer prognosis. Tenascin-C and fibronectin also showed significantly greater expression in MPV than in UC at the epithelial-mesenchymal interfaces. Direct sequencing showed point mutations of KRAS exon 1 in three MPV with significantly more frequency compared to UC. Occupation rate of the MPV area in the tumor showed significant inverse correlation with overall survival. Thus our histopathological findings provide clues to explaining why prognosis is poorer in the MPV than UC.     

Primary multiple clear cell variant urothelial carcinomas of urinary bladder: a rare case report

Clear cell variant urothelial carcinoma of urinary bladder was very rare. There were only 6 report articles included by Pubmed and total 8 cases had been described till now. All of the past reports described single tumor of urinary bladder, but multiple carcinomas had not been reported. Here we reported a 65-years-old Chinese man who complained of intermittent gross hematuria and odynuria for more than 2 months in January 2013. Only one cauliflower-like tumor was detected approximately in the left wall of the urinary bladder with cystoscopy and the biopsy specimen was diagnosed as “urothelial carcinoma, high grade”. However, three tumors were found in anterior wall (×2) near neck of urinary bladder and posterior wall (×1) of the urinary bladder during transurethral resection of the bladder tumor. Typical urothelial carcinoma with partial clear cell appearance made it difficult to make a precise pathological diagnosis and immunohistochemical stain helped to diagnose the case as clear cell variant urothelial carcinoma, but not metastasis of the renal cell carcinoma. Finally, computerized tomographic scanning confirmed that there was no primary tumor in the kidney. The clinical and pathological characteristic had not been identified for the limited reports. More work should be done to know this kind of tumor well for guiding clinical therapy.     

Micropapillary urothelial carcinoma: Clinico-pathologic review

Micropapillary carcinoma is a rare distinct variant of high grade urothelial carcinoma, which has specific morphological characteristics and is almost always associated with muscularis propria and vascular invasion. No currently defined imaging techniques can reliably diagnose some types of deeply invasive urothelial carcinoma of urinary bladder, in particular its micropapillary variant. Therefore, the pathological findings are crucial in making the diagnosis. Micropapillary carcinoma (MPC) is a tumor with an aggressive clinical course, an advanced stage of disease at the time of presentation, and usually a poor outcome. Metastatic micropapillary carcinoma to bladder should always be included in the differential diagnosis. Correct histological diagnosis of this aggressive neoplasm would allow timely, albeit intense, radical treatment of the disease. The current most generally favored treatment option for all patients who present with MPC is immediate radical cystectomy.     

Rhabdoid variant of urothelial carcinoma of the urinary bladder: a case report with emphasis on immunohistochemical analysis regarding the formation of rhabdoid morphology

Various histological variants of urothelial carcinoma (UC) have been described. They are associated with different clinical outcomes and/or therapeutic approaches; in addition, recognition of these histological variants is also important in preventing diagnostic misinterpretations. Histological variants based on cytoplasmic features, such as plasmacytoid, rhabdoid, clear-cell, and lipoid-rich variants, have been described in invasive UC. Herein, we report an exceedingly rare case of a rhabdoid variant of UC arising in the urinary bladder of a 61-year-old man. Including UC, the presence of rhabdoid cells has been described in various types of malignant tumors. These tumors are regarded as more aggressive neoplasms than those without rhabdoid cells. It has been previously found that non-degraded aggregation of intermediate filaments and membrane proteins conjugated with ubiquitin and p62 is a noticeable finding in the formation of rhabdoid morphology. We have validated the existence of this mechanism in a rhabdoid variant of UC by extensive immunohistochemical analysis.     

A case report of urothelial carcinoma with combined micropapillary and plasmacytoid morphology in the urinary bladder

A case of combined micropapillary and plasmacytoid urothelial carcinoma (UC) of the urinary bladder is presented for a 74‐year‐old male who was admitted to the hospital with gross hematuria and multifocal papillary bladder tumors. Abdominal computed tomography showed a large enhancing mass on the left lateral and anterior wall of the urinary bladder, which was highly suspicious for extravesicular extension and focal extension of the anterior lesion to the pubic bone. In voided urine, cancer cells were scattered as micropapillae or nests as well as single cells on the low power view. On a higher power view, micropapillae or nests were composed of pleomorphic, high grade tumor cells with an inverted nuclear arrangement and with acinar structures occasionally identified. Single cells were discohesive and large with a thick cytoplasm and eccentrically located nuclei. Histologically, the tumor from the resected bladder showed diffusely infiltrating micropapillae or nests with a surrounding halo and dense singly‐scattered plasmacytoid cells. Immunohistochemically, the cancer cells were positive for cytokeratin‐7 and cytokeratin‐20 but negative for S‐100, leukocyte common antigen, and vimentin. At the time of radical cystectomy, severe adhesions and peritoneal metastases were found and the surgery was discontinued. The patient received systemic chemotherapy, but died of bladder cancer 14 months after surgery. Diagn. Cytopathol. 2016;44:124–127. © 2015 Wiley Periodicals, Inc.     

Urinary bladder urothelial carcinoma with concurrent plasmacytoid and micropapillary differentiations: A report of two cases with an emphasis on serum carbohydrate antigen 19‐9

We report two cases of urinary bladder urothelial carcinoma (UC). In both, histological examination of a transurethral resection specimen of the bladder tumor revealed UC with plasmacytoid and micropapillary differentiations. In Case 1, residual plasmacytoid UC deeply invaded the extravesical fat tissue of the radical cystectomy specimen, and metastatic carcinoma was found in almost all the dissected lymph nodes. Despite adjuvant chemotherapy and radiotherapy, the patient died 25 months postdiagnosis. Elevated serum carbohydrate antigen 19‐9 (CA19‐9) returned to near normal levels after radical cystectomy, but they increased shortly before death. In Case 2, no residual carcinoma was found in the radical cystectomy specimen or lymph nodes. Postoperative serum CA19‐9 was maintained at normal levels, and the patient remains alive without recurrence or metastasis. Although plasmacytoid and micropapillary UC are known aggressive variants of UC, plasmacytoid UC may be more aggressive. Serum CA19‐9 could serve as a useful biomarker to monitor progression of plasmacytoid UC.     

A case of urothelial carcinoma,lipid cell variant

The lipid cell variant of urothelial carcinoma is a rare variant of urinary bladder cancer, comprised of lipoblast‐like cells. In this report, we describe a case of the lipid cell variant of aggressive urothelial carcinoma. A 78‐year‐old man was admitted to the hospital because of gross hematuria. On cystoscopy, an ulcerative lesion, non‐papillary architecture, was observed in the lateral wall of the bladder. Transurethral resection was performed. Histopathological findings of the bladder tumor indicated neoplastic cells forming irregular solid nests and sheets. Lipoblast‐like neoplastic cells that had eccentric nuclei and cytoplasmic vacuoles were observed, not only in the resected specimen, but also in urine samples. On mucin histochemistry, the tumor cell cytoplasm contained no neutral or acidic mucus. The lipoblast‐like cells were positive for cytokeratins (AE1/AE3, CK7) and adipophilin, known as a protein associated with neutral lipid synthesis. In general, it is difficult to prove the existence of intracytoplasmic lipid in formalin‐fixed paraffin‐embedded materials. This is the first report in which the presence of lipid in vacuoles of the lipid cell variant has been verified by immunohistochemistry.     

Microcystic urothelial carcinoma: a case report

Microcystic urothelial carcinoma (MUC) is a rare variant of urothelial carcinoma that is highly aggressive with poor prognosis. Due to the scarcity of cases, its histologic morphology and immunohistochemical characteristics are still not clear. This paper reports a 71-year old female patient with gross hematuria and abdominal pain. Imaging examination showed that the bladder wall was thickened, and rough. A soft tissue mass was seen in the bladder and the left lower ureter, and the boundary between the bladder and the uterus and bilateral adnexa was not clear. Multiple enlarged lymph nodes were seen around the abdominal aorta and left iliac artery. Cystoscopy showed diffuse thickening and edema of the left wall of the bladder, local rough bleeding, and histopathologic results showed that the lesions were consistent with high-grade invasive urothelial carcinoma. Radical cystectomy and bilateral ovariectomy were performed. By microscopic observation the tumor showed infiltrative growth with cystic structures of different sizes. Mitotic figures were frequent and a large amount of mucus was in the stroma. The same type of cancer was found in the left ovary. Immunohistochemistry showed CK5/6 +, p63 +, Pax-8, MUC5AC, CK7, and Ki67 was 50%. Postoperative pathology confirmed that MUC involved the left ureter with ovarian metastasis. Two months after the operation, the patient died of vascular invasion. Because tumor cells were bland in morphology and had no specific immunohistochemical markers, they were easily missed and misdiagnosed by pathologists. Here, we describe this case and analyze it with relevant literature to deepen understanding of MUC.     

浸润性微乳头型尿路上皮癌2例临床病理观察和文献复习

目的 探讨浸润性微乳头型尿路上皮癌的临床病理和免疫组化特征.方法 对2例具有特殊临床病理特征的输尿管和膀胱微乳头型癌作光镜和免疫组化染色观察,结合临床资料进行分析.结果 浸润性微乳头型尿路上皮癌的特殊组织学表现为肿瘤细胞排列成巢状和条索状,位于透明间质空隙内,间质空隙无内皮衬覆.大部分细胞团极向反转,核偏向外侧缘,成"内外倒置"状,极似乳头状结构.免疫组化:该肿瘤表达CK7、CK20、CEA、EMA及E-cadherin.结论 浸润性微乳头型尿路上皮癌为高级别癌,易发生血管和淋巴道转移,预后差.其特殊的形态学变异和免疫组化特点,为其鉴别诊断提供了依据.     

High-grade urothelial carcinoma of the urinary bladder showing acquisition of microcystic histology in the penile metastasis: Histogenetic considerations

Microcystic urothelial carcinoma is a rare variant of transitional cell carcinoma with an indefinite prognostic significance. Herein, we report for the first time the acquisition of microcystic histology in the penile metastasis of a high-grade urothelial carcinoma of the urinary bladder. The patient died of disseminated disease six months later. The immunohistochemical evaluation of mucin expression in the primitive and metastatic tumor suggests that the microcystic histotype may descend from the primitive urothelial carcinoma through a process of dedifferentiation and subsequent redifferentiation. In conclusion, the acquisition of microcystic histology seems to be associated with an aggressive clinical course of the urothelial carcinoma, as already suggested by other authors. Future studies investigating mucin expression in microcystic urothelial carcinoma may help to define the histogenesis of this tumor.     

Malignant glandular lesions and glandular differentiation in invasive/noninvasive urothelial carcinoma of the urinary bladder

Although the lumen of the urinary bladder is covered with only urothelial epithelium, malign glandular lesions (eg, nonurachal adenocarcinoma) and benign lesions (eg, cystitis cystica and cystitis glandularis) can also rarely occur in this site due to its characteristic embryologic development. Glandular differentiation is uncommon in urothelial carcinomas and is even less common in noninvasive urothelial cancers. In addition, in situ urothelial carcinomas are more likely to progress in the presence of glandular differentiation toward high-grade urothelial carcinomas and/or aggressive urothelial carcinomas. Pure nonurachal adenocarcinomas and mixed carcinomas (urothelial carcinoma and adenocarcinoma) are very rare, and their pathogenesis is not clear. Most of the nonurachal adenocarcinomas are thought to arise on the grounds of cystitis glandularus with intestinal metaplasia. Here, I present 2 cases with noninvasive urothelial carcinoma with substantial glandular differentiation showing progression to signet ring cell carcinoma and invasive urothelial carcinoma, one case with mixed carcinoma (urothelial carcinoma and adenocarcinoma) and another case with pure adenocarcinoma developing from cystitis glandularis with intestinal metaplasia, and discuss malign glandular lesions in the bladder and invasive/noninvasive urothelial carcinomas with glandular differentiation.