Papillary transitional-cell carcinoma of the upper urinary tract: a cytological review

Urinary cytology is a well-accepted diagnostic procedure for bladder carcinomas but it is utilized less frequently for diagnosis of upper urinary tract tumors. Accurate diagnosis depends on a suitable specimen as well as knowledge of diagnostic traps. This review article with several case studies emphasizes the various techniques used to obtain optimal samples, correct interpretative criteria, and diagnostic pitfalls. Technological advances for objective grading and predicting the biological behavior of tumors are also discussed.     

Cytology of small cell carcinoma of the urinary bladder

To characterize the cytologic spectrum of small cell carcinoma of the urinary bladder, a review of 42 urinary cytology specimens from 13 patients with histologically proven tumors was conducted. Patients' ages ranged from 45 to 81 yr (mean 68.9). In four tumors, small cell carcinoma was the sole malignant cellular component; all 11 urinary specimens in these patients harbored cells with features of an undifferentiated small cell carcinoma. In the remaining nine tumors, small cell carcinoma appeared with transitional, squamous cell or adenocarcinoma, but in four, small cell carcinoma was the sole invasive component. Almost one third of urinary specimens in this group lacked a small cell component. Neuroendocrine differentiation was confirmed by immunopathology in eleven cases (neuron specific enolase positive in 11 of 12, synaptophysin in 2/11, chromogranin in 2/13, Leu 7 in 2/7), and by ultrastructural analysis in two. Small cell carcinoma is a cytologically recognizable variant of bladder cancer, but admixture with other malignant components may mask its appearance in urinary specimens. Diagn Cytopathol 1996;14:292–297. © 1996 Wiley-Liss, Inc.     

Urine cytology of micropapillary carcinoma of the urinary bladder

A case of micropapillary carcinoma (MPC) of urinary bladder is presented, in which the urine smear was studied in detail in an attempt to better characterize the cytologic findings of MPC. When the voided urine was examined in low power, cancer cells were scattered in the specimens as compact papillary/spheroidal clusters composed of pleomorphic cancer cells. Solitary carcinoma cells were occasionally observed. High power view of the smear revealed that the papillae/spheroids consisted of high-grade urothelial carcinoma cells. The cancer cells had pleomorphic nuclei with coarsely granular chromatin and thickened, irregular nuclear membrane, and thick cytoplasm. Histologically, the tumor in the resected bladder appeared as small nests with surrounding hallo both in the luminal surface and in the site of wall involvement. These tightly bound papillary/spheroidal clusters comprised of highly atypical cancer cells were the most specific cytologic finding in the urine of MPC, which were considered as a key diagnostic clue of MPC. The background of the urine smear showed numerous granulocytes and bacilli compatible with cystitis, which is a previously known complication of MPC. Differential diagnoses of MPC from those with pertinent cytologic findings such as conventional UC (including glandular differentiation), and primary/secondary adenocarcinoma of urinary bladder are discussed with a brief review of literature.     

Plasmacytoid urothelial carcinoma of the urinary bladder: A case report and immunohistochemical study

We report a rare case of plasmacytoid urothelial carcinoma (PUC) of the urinary bladder. A 50-year-old man complained of pollakiuria and urinary incontinence. MRI detected a bladder tumor invading the rectum and bilateral hydroureteronephrosis. Radical cystectomy with partial resection of the rectum was performed, and ileus due to peritoneal dissemination occurred 2 years after surgery. He died of the disease 42 months after the initial presentation. Histologically, urothelial carcinoma in situ with a focal invasive urothelial carcinoma (IUC) component and widely spread PUC was observed. There was no lymph node metastasis. PUC cells had eccentrically placed nuclei and eosinophilic cytoplasm resembling plasmacytoma cells, and proliferated with a single-cell infiltrative pattern to the outside of the bladder. IUC cells with intracytoplasmic lumina were focally intermingled with PUC cells. Immunohistochemically, PUC cells were positive for cytokeratin 7, epithelial membrane antigen, and CA19-9, but negative for cytokeratin 20, E-cadherin, p63, and lymphoid markers. The Ki-67 labeling index of PUC cells was 9.3%. IUC containing intracytoplasmic lumina showed intermediate features of conventional IUC and PUC morphologically and immunohistochemically. PUC is a distinct entity of bladder cancer with a high propensity for invasion and poor prognosis.     

Cytologic features of sarcomatoid carcinoma of the urinary bladder: A case report

Sarcomatoid carcinoma of the urinary bladder is a rare entity, whose histogenesis and biological behavior remain controversial. The cytological literature on sarcomatoid carcinoma in voided urine is very scarce. Clinically, the diagnosis of this tumor can be made by computed tomography (CT), magnetic resonance imaging (MRI), cytology, and biopsy material. In this study, cytology, histopathology, and radiological imaging were employed in order to reach a diagnosis of sarcomatoid carcinoma. CT imaging showed increased thickness of the bladder wall associated to a polypoid mass. MRI showed a 4‐cm sized, broadly necked polypoid mass with calcification and ulceration at the right side of the bladder wall. T2W1 imaging showed low signal. Voided urinary cytology showed a scattered cellular presentation. The tumor cells had a high nucleo‐ cytoplasmic ratio, with elongated cytoplasm with faint with indistinct cytoplasm border. The nucleus was oval to round, with large and irregular nucleoli and irregular nuclear membrane. These tumor cells were positive for cytokeratin (CKAE1/AE3), vimentin, p53, carcinoembryonic antigen (CEA), α1‐smooth muscle actin (SMA) by the immunoperoxidase staining. Histopathology showed spindle‐shaped and clumped large tumor cells with abundant cytoplasm. Mitotic figures were frequently seen and varied from area to area (50% of the tumor cells were positive for MIB1). Diagn. Cytopathol. 2013. © 2011 Wiley Periodicals, Inc.     

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.     

Fine-needle sampling of salivary gland lesions V: Cytology of 22 cases of acinic cell carcinoma with histologic correlation

Fine-needle sampling (FNS) of 22 acinic cell carcinomas, including 17 primary tumors, 4 local recurrences, and 1 lymph node metastasis was performed preoperatively in 17 patients. Cytologic diagnoses were concordant with histology in 3 (13.7%) cases, whereas 15 (68.2%) cases were cytologically classified as malignant, 2 (9.1%) as suspicious, and 1 (4.5%) as benign (pleomorphic adenoma). The material was unsatisfactory for cytologic evaluation in 1 (4.5%) case. Preoperative FNS technique is, therefore, useful in acinic cell carcinoma with a concordant malignant/suspicious rate of 91%. Diagn. Cytopathol. 1997;17:347–352. © 1997 Wiley-Liss, Inc.     

The role of routine outpatient cytological screening for early detection of carcinoma of the cervix in India

Cytological evaluation of cervical smears has been carried out in 4,338 women attending the Gynecology and Obstetrics Department and Family Planning Clinic of Queen Mary's Hospital, Lucknow, India, since April 1971. The incidence of cervical dysplasia was found to be 4.6% (205 out of 4,338) in the series, while malignant smears were detected in 54 patients (1.2%). In five cases, malignant smears were encountered in women with apparently normal cervices, highlighting the advantage of exfoliative cytology in screening subjects without cervical pathology. The remaining 49 cases with malignant smears had lesions on the cervix that had been clinically diagnosed as carcinoma. The diagnosis of malignancy was confirmed by biopsy in all 54 cases showing malignant smears; however, in 10 cases clinically diagnosed as carcinoma of the cervix, and subsequently confirmed histologically, the diagnosis was missed by cytology, the smears being reported as inflammatory in seven and inadequate in three. Cytological evidence of herpes simplex infection was seen in the smears in 23 out of 54 cases of carcinoma, and trichomonal infection was present in 15, indicating some relationship of these infections with the development of neoplastic changes in the cervical epithelium. Eleven of the total 54 cases of carcinoma of the cervix were in the age group of 26-35 yr, and four were in subjects with only two children. This emphasizes the need for the routine cytologic screening of all child-bearing women with parities of two and above, regardless of their age, if any meaningful results are to be obtained in a cancer-screening program in India in view of the prevailing custom of early marriage.     

Cytologic features of clear cell carcinoma of the urethra and urinary bladder

Clear cell carcinoma (CCL) arising in the lower urinary tract is unusual and we report the cytohistologic findings of three cases retrieved from our files. All patients presented with bleeding, and the tumors were localized in either the urethra or bladder base. Filter and cytocentrifuge preparations of the urine were studied and all cases displayed numerous scattered aggregates or single tumor cells in an inflammatory background. The enlarged cells had abundant clear, wispy cytoplasm with discrete vacuolation. Hobnail and signet ring cells were apparent. The nuclei had granular to vesicular chromatin with prominent often multiple nucleoli. The tumors were histologically distinctive and typically had a tubulocystic configuration with varying proportions of papillary and diffuse patterns. One patient has died of metastatic cancer and two are presently free of tumor. The cytohistologic features of this cancer are characteristic and from our review we conclude that this lesion can be diagnosed by cytologic means. Diagn Cytopathol 1996;14:150–154. © 1996 Wiley-Liss, Inc.     

Pigmented composite paraganglioma-ganglioneuroma of the urinary bladder

We report a case of a pigmented composite paraganglioma-ganglioneuroma of the urinary bladder in a 70-year-old female. Grossly, the tumor measured 6.5 cm in diameter and had arisen from the base of the urinary bladder. Histologically, the tumor was composed of approximately equal components of paraganglioma and ganglioneuroma, which were partly separated and partly mixed, and intermingled with each other. There were foci of ample dark brown pigmentation in the cytoplasm of chromaffin paraganglioma cells. The pigment was Masson-Fontana-positive and had been bleached by hydrogen peroxide (H2O2). Electron microscopy showed large, abundant, pleomorphic electron-dense granules consistent with neuromelanin. In addition, there were numerous electron-dense neurosecretory-type granules. Neuromelanin, melanin or lipofuscin are occasionally observed in paragangliomas, although the occurrence of these pigments has never been described in a composite tumor originating from either adrenal medulla or extraadrenal paraganglia. To the best of our knowledge, our report represents the first case of pigmented composite paraganglioma-ganglioneuroma and expands the morphological spectrum of these unusual tumors.     

Urothelial carcinoma with oncocytic features: an extremely rare case presenting a diagnostic challenge in urine cytology

Recognizing histological variants in urothelial carcinoma (UC) is important because some may be associated with different clinical outcomes and/or therapeutic approaches; being aware of unusual histological variants may also be crucial in preventing diagnostic misinterpretations. Histological variants based on cytoplasmic features, such as clear-cell, plasmacytoid, rhabdoid, and lipoid-rich variants, are described in invasive UC; however, these cytoplasmic features are not formally defined and not usually encountered in non-invasive UC. Oncocytic cytoplasm has not been well described in either invasive or non-invasive UC. Herein, we report an exceedingly rare case of UC with oncocytic features arising in the right renal pelvis, which presented a diagnostic challenge in urine cytology due to the relatively low nuclear-to-cytoplasmic ratio; however, it could definitively be diagnosed using histological specimens. UC diagnosis is based on the presence of papillary architecture and widespread p53 nuclear accumulation, suggesting malignancy. An oncocytic tumor is generally considered to be not actively dividing, as shown by the low Ki-67 labeling index in this case. In spite of the low proliferative activity, the possibility of intravesicle recurrence (IVR) should be considered since positive preoperative cytology of upper tract UC is a risk factor for IVR after nephroureterectomy.     

Undifferentiated small-cell carcinoma of the urinary bladder: Report of two cases with a primary urinary cytodiagnosis

Two undifferentiated small-cell carcinomas of the urinary bladder are reported. The patients, 68- and 55-yr-old men, respectively, presented with painless hematuria. In the first case, numerous small, lymphocyte-like cells with coarse chromatin, sometimes with small nucleoli, and high nuclear/cytoplasmatic ratios were found in cytologic urine specimens. A cytodiagnosis of undifferentiated small-cell cancer was made. In the second case, urine samples showed rare aggregates of small, undifferentiated cells in association with malignant urothelial cells. The cytodiagnosis of mixed tumor composed of undifferentiated small cell and transitional carcinoma was confirmed by histologic examination. The presence of focal reactivity with anti-chromogranin antibody and neurosecretory granules via electron microscopy supports a neuroendocrine differentiation for the small neoplastic cells. The patients died 13 and 8 mo after diagnosis, respectively. © 1995 Wiley-Liss, Inc.     

Accuracy of grading of urothelial carcinoma on urine cytology: an analysis of interobserver and intraobserver agreement

Background: Urine samples of known urothelial carcinoma were independently graded by 3 pathologists with (MS, MR) and without (AO) fellowship training in cytopathology using a modified version of the 2004 2-tiered World Health Organization classification system. By measuring interobserver and intraobserver agreement among pathologists, compared with the gold standard of biopsy/resection, specimen accuracy and reproducibility of grading in urine was determined. Methods: 44 urine cytology samples were graded as low or high-grade by 3 pathologists with a 2-3 week interval between grading. Pathologists were blinded to their and others’ grades and histologic diagnoses. Coefficient kappa was used to measure interobserver and intraobserver agreement among pathologists. Accuracy was measured by percentage agreement with the biopsy/resection separately for each pathologist, and for all pathologists and occasions combined. Results: The overall accuracy was 77% (95% C.I., 72% - 82%). Pathologist AO was significantly more accurate than MR on occasion 1 (p = 0.006) and 2 (p = 0.039). No other significant differences were found among the observers. Interobserver agreement using coefficient kappa was unacceptably low, with all but one of the kappa value being less than 0.40, the cutoff for a “fair” degree of agreement. Intraobserver agreement, as measured by coefficient kappa, was adequate. Conclusions: Our study underscores the lack of precision and subjective nature of grading urothelial carcinoma on urine samples. There was poor inter- and intraobserver agreement among pathologists despite fellowship training in cytopathology. Clinicians and cytopathologists should be mindful of this pitfall and avoid grading urothelial carcinoma on urine samples, especially since grading may impact patient management.     

An update on the molecular pathology of urinary bladder tumors

Urothelial carcinoma is the fourth most common tumors after prostate cancer, lung, and colorectal carcinoma but the second most common urologic malignancy. Urothelial carcinoma composed more than 90% of bladder tumors while squamous cell carcinoma and adenocarcinomas composed 5% and 2% respectively. The intense research involving the different molecular aspects of bladder cancer has provided a great insight into identifying more about molecular profiling and pathways of bladder cancer.In this review, we will highlight the general concepts of the molecular features; profiling and classification as well as the molecular pathways for bladder carcinomas, especially urothelial carcinoma. Also, we will discuss the advances of molecular biomarkers for screening, early diagnosis, surveillance and potential prognosis of urothelial carcinoma of the bladder. Studies showed that accumulation of genetic alterations involving the clonal expansion of altered cells with growth advantages through sequential multi-step pathways results in progression of bladder tumors.The accumulated research data from literature has revealed that the genomic signatures of urothelial carcinoma are required to subclassify bladder cancer into genetically distinct subgroups. These findings could improve the understating of pathogenesis as well as will provide new therapeutic modules e.g. targeted therapy.     

Needle aspiration cytology of metastatic high-grade transitional-cell carcinomas of the urinary tract

We reviewed 4 cases of high-grade transitional-cell carcinoma (TCC) of the urinary tract with solitary pulmonary metastases that were studied by transthoracic needle aspiration biopsy cytology. There were two grade II and two grade III TCCs. The two grade II tumors yielded, in needle aspirates, syncytial tumor-cell clusters showing ill-defined, granular cytoplasm and slightly pleomorphic nuclei with inconspicuous nucleoli. In one case the tumor-cell clusters showed a focal acinar arrangement, mimicking cells of an adenocarcinoma. In both cases the electron microscopy (EM) study of aspirated tumor cells revealed epithelial cells with well-formed cell junctions, intracytoplasmic vesicles, apical short microvilli, and focal interdigitation of lateral cell membranes, suggesting a urothelial neoplasm. The two grade III TCCs yielded, in needle aspirates, pleomorphic malignant cells singly and in small clusters, showing well-defined, granular cytoplasm and pleomorphic nuclei containing prominent nucleoli, suggesting a poorly differentiated adenocarcinoma or an anaplastic large-cell carcinoma. By EM examination the aspirated tumor cells from one case revealed well-formed cell junctions, intracytoplasmic vesicles, poorly formed microvilli, and focal interdigitation of lateral cell membranes, suggesting a urothelial differentiation. In the other case the tumor cells were pleomorphic cells with occasional cell junctions and no ultrastructural features as seen in the other 3 cases of TCC. The tumor cells from the two grade II TCCs showed strong immunopositive reaction with keratin 7 antibody and weakly positive reaction with carcinoembryonic antigen antibody (CEAA), while those of the two grade III TCCs displayed only a weak and focal immunopositive staining with keratin 7 antibody and strong reaction with CEAA. Diagn. Cytopathol. 1998;18:409–415. © 1998 Wiley-Liss, Inc.     

Inverted variant of urothelial carcinoma of the urinary bladder: a report of three cases and a proposal for a new clinicopathologic entity

Inverted urothelial carcinoma (UC) without papillary areas is very rare; only 31 cases of three papers have been reported. The author herein reports three additional cases, and proposes the term “inverted variant” (IV) of UC. The materials were 3 cases of IV of UC, 5 cases of inverted papilloma (IP), and two cases of nested variant (NV) of UC. The three cases of IV of UC consisted of 56-year-old woman, 63-year-old man, and 78-year-old man. Presenting symptoms were hematuria in all cases. The cystoscopic findings were elevated tumors without papillary proliferations in all cases. The treatment was transurethral tumor resection (TUR-BT) in all cases. The sizes was 0.6 cm, 0.5 cm, and 3 cm. Microscopically, IV of UC showed inverted growth of atypical cells without papillary proliferations. Compared to IP, the inverted growth pattern was similar, but cytological atypia and thick trabeculae were noted in IV of UP while they were absent in IP. Compared to NV of UC, the growth pattern is different; NV of UC showed nested and vague tubular pattern. The cellular atypia is more pronounced in IV of UC than NV of UC. Immunohistochemically, p53 expression was seen in all the cases of IV of UC and in all the cases of NV of UC, while p53 expression was negative in all the cases of IP. Ki-67 labeling index was 25, 30 and 40% in IV of UC, 15 and 30% in NV of UC, and 3, 5, 6, 7, 9% in IP. Invasive features were seen in 1 case of IV of UC and 2 cases of NV of UC. In all cases of IV of UC, IP, and NV of UC, the TUR-BT, but one case of IV of UC, showed no recurrence after TUR-BT, while one case of IV of UC showed a recurrence. In conclusion, the IV and UC were structurally and cytologically very different from the NV of UC. The IV of UC was structurally similar to IP, but cellular atypia and thickened trabeculae were seen in IV and UC. p53 expression and Ki-67 labeling status were entirely different between in IV of UC and IP. The author proposes the term of IV of UC as a new clinicopathological entity.     

Cytologic features of recurrent lymphoma involving the urinary bladder

Recurrent lymphoma of the bladder only occasionally presents with genitourinary symptoms, and there are very few cases in the literature reporting the cytologic findings of involvement of the urinary bladder by lymphoma. We report the findings from a case of diffuse large B-cell lymphoma with immunoblastic morphology that was identified in a bladder barbotage specimen of a 77-year-old man who presented with recurrent urinary tract infection and hematuria. We describe the cytomorphological features of lymphoma cells in the urine and discuss the differential diagnoses. Correlation of cytologic findings with immunohistochemical results is crucial in the diagnosis of lymphoma involving the urinary bladder.     

Small cell undifferentiated carcinoma of the urinary bladder: A cytodiagnostic case report of its variant type

Presented is a case report of a urinary bladder carcinoma that had an unusual morphology and phenotype. A 65-year-old Japanese man complained of gross hematuria. Cytological examination of the urine before a partial cystectomy revealed small, round atypical cells with a high nuclear/cytoplasmic ratio, scant cytoplasm, and hyperchromatic nuciel with coarse and granular chromatin in a bloody background. Several tumor cells had relatively large and vesicular nuclel with prominent eosinophilic nucleoll and obscure perinucleolar halos. A small number of large atypical urothellal cells were also recognized. The tumor recurred locally 3 months after the operation. The urine cytology during recurrence showed the same features without the etypical urothellal cells. These cytological findings suggested a case of small cell undifferentiated carcinoma (SCUC) combined with transitional cell carcinoma (TCC). An histology of the resected specimen before the recurrence revealed that the SCUC was consistent with a variant type of SCUC proposed for the lung and showed transition with TCC In situ . M-VAC chemotherapy after a total cystectomy was less effective. The patient died 6 months after diagnosis. A variant subtype of SCUC of the urinary bladder associated with TCC In situ has not been previously reported. Although this histological type is very rare, its earlier cytological detection is needed for appropriate therapy.     

Fascin-1 expression in papillary and invasive urothelial carcinomas of the urinary bladder

Fascin-1 is an actin-bundling protein that plays an important role in cell motility and adhesion. The level of fascin-1 is low or undetectable in normal epithelial cells. However, overexpression is reported in transformed epithelial cells and in several common types of carcinomas [Bioessays. 2002;24:359-361]. Up-regulation of fascin-1 is associated with higher grades and with aggressive tumors with poorer prognoses. We found no report on the role or the protein expression of fascin-1 in urothelial carcinomas (UCs) of the urinary bladder. In this study, we examined by immunohistochemistry the expression of fascin-1 in the normal human transitional epithelium, benign vesical lesions, and different types of UCs. We found no detectable fascin-1 in the normal transitional epithelium. There was no increase of fascin-1 expression in cystitis cystica, cystitis glandularis, nephrogenic adenoma (n = 10), inverted papilloma (n = 5), and classic exophytic papilloma (n = 4) or in adjacent transitional epithelia associated with these conditions. Patchy or diffusely weak fascin-1 expression was observed in 42% (5/12) of superficial papillary UCs (Ta), and 95% (19/20) of invasive UCs (T2 or higher) demonstrated diffuse strong staining for fascin-1. The microinvasive foci in the lamina propria of UC (T1, n = 8) were also positive for fascin-1, although they were not as strongly stained as in the deeply invasive tumors. Interestingly, the neoplastic cells in the tips of microinvasive carcinomas were distinctly positive for fascin-1. There were significant numbers of fascin-1-positive cells (>50% of the neoplastic cells) in UCs in situ (n = 10). These findings suggest an association between increased fascin-1 expression and increased invasiveness of carcinomas in the urinary bladder.