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Bladder cancer is a worldwide problem. It is linked to chemical agents as well as cigarette smoking. In third world countries, it is linked to chronic infection with Schistosomiasis. Because of these links, bladder cancer has served as an excellent model for the study of cancer. Who can forget the association of bladder cancer in rats and exposure to saccharin, forever changing the way we view these diet aids. One of the first signs is blood in the urine, or hematuria. This is why urinalysis and urine cytology plays an invaluable role in early detection of these tumors. Large tumors may present with a sensation of fullness in the pelvis.


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Bladder carcinomas account for 95% of all bladder tumors-of these tumors, the following histologic types comprise the majority of these tumors

Overall, it is 4-10% of all cancers in the USA

About 10,000 deaths/year in USA

Transitional cell carcinoma 75-90%
Low grade
13-30% of transitional cell neoplasms
High grade
50-60% of transitional cell neoplasms
Carcinoma in situ
<1% of patients with urinary symptoms but present in nearly 100% of bladders removed for invasive carcinoma
Adenocarcinoma <2%
Squamous cell carcinoma 2-15%
Small cell carcinoma <0.5%
Urothelial neoplasms in patients 20 years or younger: a clinicopathological analysis using the world health organization 2004 bladder consensus classification.

Fine SW, Humphrey PA, Dehner LP, Amin MB, Epstein JI.

Department of Pathology, Johns Hopkins Hospital, Baltimore, Maryland, USA.

J Urol. 2005 Nov;174(5):1976-80 Abstract quote.  

PURPOSE: Urothelial neoplasms in patients younger than 20 years are rare, with conflicting data regarding clinical outcomes.

MATERIALS AND METHODS: We identified 23 patients 4 to 20 years old with urothelial neoplasms, reclassified the microscopic diagnoses using the 2004 WHO/International Society of Urologic Pathology grading classification and collected data on presentation, risk factors and outcomes.

RESULTS: Pathological grading revealed 2 urothelial papillomas, 10 papillary urothelial neoplasms of low malignant potential (PUNLMPs), and 8 low grade and 3 high grade papillary urothelial cancers, all without invasion. Mean patient age was 13.2 years (range 4 to 20), 19 patients were male and 19 presented with gross hematuria. All lesions were solitary and measured 0.1 to 6 cm. One patient had a history of smoking and 1 had parents who smoked. Three patients (13%) had recurrences classified as either urothelial papilloma (1) or PUNLMP (2). All patients were alive with no evidence of disease after a mean followup of 4.5 years (range 6 months to 13 years).

CONCLUSIONS: Urothelial neoplasms in individuals younger than 20 years more commonly occur in males and are predominantly low grade with a favorable clinical outcome. Before the current classification system the 10 patients with a diagnosis of PUNLMP would have been classified as having papillary carcinoma. Thus, the diagnostic category of PUNLMP allowed 43.5% of patients in this series to avoid being labeled with "cancer" at a young age.
Transitional cell carcinoma
50-70 years
Median and mean 64 and 68 years
Mean 62 years for nonurachal tumors
Mean 51 years for urachal tumors
Squamous cell carcinoma
60-70 years
Small cell carcinoma
50-70 years
Transitional cell carcinoma
3:1 for nonurachal tumors
1:1 for urachal tumors
Squamous cell carcinoma
Small cell carcinoma


Transitional cell carcinoma Arylamine chemicals
Cigarette smoking
Adenocarcinoma Bladder exostrophy
Persistent urachal remnants
Squamous cell carcinoma 80% associated with Schistosoma hematobium infection secondary to the deposits of calcifed ova
Small cell carcinoma  


Improved clonality analysis of multifocal bladder tumors by combination of histopathologic organ mapping, loss of heterozygosity, fluorescence in situ hybridization, and p53 analyses.

Denzinger S, Mohren K, Knuechel R, Wild PJ, Burger M, Wieland WF, Hartmann A, Stoehr R.

Department of Urology, University of Regensburg, 93042 Regensburg, Germany.

Hum Pathol. 2006 Feb;37(2):143-51. Epub 2005 Dec 15. Abstract quote  

The clonality status of multifocal bladder tumors is still controversially discussed with experimental evidence for both monoclonality and field cancerization. Methodologically, loss of heterozygosity (LOH) and genomic sequencing analyses are widely used in clonality analysis of malignant tumors.

In the present study, we used LOH analysis and genomic sequencing in combination with fluorescence in situ hybridization (FISH) and extensive histopathologic whole-organ mapping to determine the clonal relationship of multifocal bladder cancer disease. Tissue sections (1 cm(2)) covering the entire urothelial lining were systematically dissected from 2 cystectomy specimens (cystectomy 1, no urothelial lesions, bladder infiltration by a leiomyosarcoma of the vaginal wall; cystectomy 2, multifocal pT3G3 tumors). The location of each sample was documented (bladder mapping). Urothelial cells were microdissected for LOH (chromosomes 9, 17p) and FISH analysis (CDKI2 (9p21), FACC (9q22), p53 (17p13.1), and centromeric probes for corresponding chromosome). Exons 5 to 9 of the p53 gene were sequenced in all tumor samples. No chromosomal alterations were detected in the cystectomy specimen without urothelial malignancies. The tumor-bearing bladder showed an increasing frequency of deletions with increasing malignancy of the investigated lesions. LOH analysis detected deletions only on chromosomes 9p and 17p. In contrast, FISH analysis revealed deletions of all investigated genes at chromosomes 9p, 9q, and 17p in all samples analyzed (preneoplastic and neoplastic tissue). An identical p53 mutation in codon 281 was found in all 7 analyzable tumor samples. Combination of molecular data with histopathologic bladder mapping suggested a monoclonal development of the multifocal lesions mostly via intraurothelial migration.

Our data strengthen the results from recently published studies that patients with advanced urothelial carcinoma seem to have a monoclonal panurothelial disease in most cases. FISH showed a much higher sensitivity for detection of chromosomal losses than classical LOH analysis, especially in preneoplastic and small lesions. Combining 3 molecular approaches together with histopathologic organ mapping presents a valuable tool to determine the clonality status of multifocal bladder tumors.

Allelic loss of the active X chromosome during bladder carcinogenesis.

Cheng L, MacLennan GT, Pan CX, Jones TD, Moore CR, Zhang S, Gu J, Patel NB, Kao C, Gardner TA.

Department of Pathology, Indiana University School of Medicine, Indianapolis, USA.
Arch Pathol Lab Med. 2004 Feb;128(2):187-90. Abstract quote  

CONTEXT: Previous studies have shown that loss of the X chromosome is involved in the carcinogenesis of certain human malignancies.

OBJECTIVE: To determine whether X-linked allelic losses occur during bladder tumorigenesis and whether such losses involve the active or the inactive X chromosome.

DESIGN: We analyzed the deletion status of the X-linked human androgen receptor gene locus in 6 female patients who underwent radical cystectomies for muscle-invasive urothelial carcinoma of the urinary bladder. Four patients had coexisting urothelial carcinoma in situ. Analysis for inactivation of the X chromosome was carried out in parallel.

RESULTS: Three cases were informative. Invasive tumor samples showed loss of heterozygosity involving the active allele at the androgen receptor locus in all 3 positive cases, whereas carcinoma in situ showed nonrandom X chromosome inactivation but not allelic deletion.

CONCLUSIONS: Our data suggest that allelic loss of the activated X chromosome is involved in bladder carcinogenesis and cancer progression.

Genetic instability in superficial bladder cancer and adjacent mucosa: An interphase cytogenetic study.

Cianciulli AM, Leonardo C, Guadagni F, Marzano R, Iori F, De Nunzio C, Franco G, Merola R, Laurenti C.

Department of Clinical Pathology, Regina Elena Cancer Institute, Rome, Italy and the Department of Urology, La Sapienza University, Rome, Italy

Hum Pathol 2003 Mar;34(3):214-21 Abstract quote

A systematic analysis of both tumors and the surrounding urothelium to help identify what lies behind the mechanism of multifocal tumor development has not yet been performed.

In this study we investigated chromosome 1, 7, 9, and 17 aneusomy in 25 superficial papillary carcinomas and in 51 tissue samples taken from sites of macroscopically uninvolved urothelium surrounding the tumors, using the fluorescence in situ hybridization method.

Our data demonstrated a close genetic relationship between all examined tumors and normal-appearing mucosa. Numeric aberrations of chromosomes 1, 7, 9, and 17 were found to exhibit similar patterns in all analyzed specimens, although with different frequencies.


Biologic Differences Between Noninvasive Papillary Urothelial Neoplasms of Low Malignant Potential and Low-Grade (Grade 1) Papillary Carcinomas of the Bladder

Achille Pich, M.D. ; Luigi Chiusa, M.D. ; Andrea Formiconi, M.D. ; Diego Galliano, M.D. ; Paola Bortolin, M.D. ; Roberto Navone, M.D.

From the Department of Biomedical Sciences and Human Oncology, Section of Pathology, University of Turin (A.P., L.C., D.G., P.B., R.N.) and the Division of Urology, S. Giovanni Hospital (A.F.), Turin, Italy.

Am J Surg Pathol 2001;25:1528-1533 Abstract quote

We investigated the expression of oncogenes p53 , c-erbB-2 , and bcl-2 and cell proliferative activity in 62 newly diagnosed superficial pTa papillary bladder tumors.

Based on the 1998 World Health Organization/International Society of Urological Pathology (WHO/ISUP) and 1999 WHO classifications, 19 were urothelial neoplasias of low malignant potential (LMP) and 43 low-grade (grade 1) papillary carcinomas. All the patients underwent transurethral resection and were followed up to 97 months; 42 had recurrences. Initial biopsies were tested for p53 , c-erbB-2 , and bcl-2 proteins using DO7, CB11, and bcl-2 124 monoclonal antibodies. Cell proliferation was assessed by MIB-1 mAb and mitotic count. LMP had significantly lower MIB-1 (p = 0.002) and p53 immunopositivity (p = 0.03), mitotic count (p = 0.006), and recurrence rates (p = 0.04) than did grade 1 cases, whereas no difference was observed for c-erbB-2 and bcl-2 expression. The median disease-free survival for LMP was 76 months but only 15 months for grade 1 cases (p = 0.002).

Although the cohort is small, the results indicate that the distinction between LMP and low-grade (grade 1) papillary urothelial neoplasias, as proposed by the 1998 WHO/ISUP and 1999 WHO classifications, reflects different biologic activity and clinical behavior; however, a long-term follow-up is advisable also for patients with LMP.


Patterns of Protein Kinase C Isoenzyme Expression in Transitional Cell Carcinoma of Bladder Relation to Degree of Malignancy

Leah Langzam, MS
Rumelia Koren, MD
Rivka Gal, MD
Valentina Kugel, MD
Adrian Paz, MD
Amicur Farkas, MD
Sanford R. Sampson, PhD


Am J Clin Pathol 2001; 116:377-385 Abstract quote

We determined the pattern of protein kinase C (PKC) isoform expression in human cell lines by Western blotting and immunofluorescent staining techniques. In addition, we examined PKC isoform expression in tissue samples of transitional cell carcinoma (TCC) of the bladder. PKC delta, PKC beta II, and PKC eta were found primarily in the RT4 cell line (low-grade tumor), and PKC zeta was expressed most strongly in the SUP cell line (invasive tumor). In tissue samples of urinary bladder cancer, PKC isoenzymes were expressed differentially as a function of tumor stage and grade; expression of PKC beta II and PKC delta was high in normal tissue and in low-grade tumors and decreased with increasing stage and grade of TCC. The opposite pattern was seen with PKC zeta.

The differences in expression of specific isoenzymes as related to levels of malignancy of the cell lines and tissue samples suggest that the PKC family has an important role in normal and neoplastic urothelium.



Correlation of cystoscopic impression with histologic diagnosis of biopsy specimens of the bladder

Stephen J. Cina, MD, Jonathan I. Epstein, MD, Joseph M. Endrizzi, MD, William J. Harmon, MD, Thomas M. Seay, MD, and Mark P. Schoenberg, MD

Hum Pathol 2001;32:630-637.Abstract quote

There is a paucity of information in the contemporary literature that would permit assessment of the urologist's ability to endoscopically discriminate between benign and malignant lesions of the bladder or to predict the grade and stage of papillary neoplasms.

This prospective study evaluates the correlation between cystoscopic impression of urothelial lesions and final histologic diagnoses. Sixty-four patients with 68 urothelial abnormalities requiring formal biopsy or endoscopic resection were evaluated prospectively. At the time of endoscopy, treating urologists completed questionnaires documenting the surgeon's endoscopic impression of disease type and extent and performed standard biopsy or resection of all suspicious lesions. Specimens were submitted for routine histopathologic analysis, and the results were correlated with the questionnaire data. Endoscopic evaluation correctly discriminated between dysplastic/malignant and benign/reactive lesions in this study with a sensitivity of 100%, specificity of 100%, and positive and negative predictive values of 100%. Urologists could not readily distinguish between low- and high-grade papillary urothelial lesions and were frequently unable to determine if a tumor was invasive, particularly if the degree of invasion was microscopic.

Endoscopic impression at the time of bladder biopsy or resection is accurate and discriminates between the presence and absence of cancer. Endoscopic impression alone is a relatively poor staging tool with respect to extent of invasive disease and must be coupled with careful histopathologic analysis of biopsy material, bimanual examination when appropriate, and axial imaging for complete assessment of a given tumor.

Reflex UroVysion testing of bladder cancer surveillance patients with equivocal or negative urine cytology: a prospective study with focus on the natural history of anticipatory positive findings.

Department of Anatomic and Clinical Pathology, Cleveland Clinic Foundation, leveland, OH 44195, USA.


Am J Clin Pathol. 2007 Feb;127(2):295-301. Abstract quote

A proportion of patients under surveillance for recurrent bladder carcinoma with no immediate evidence of bladder tumor recurrence have positive multitarget fluorescence in situ hybridization (FISH; UroVysion, Vysis, Downers Grove, IL) results. The course of these "anticipatory positive" cases and the time to bladder tumor recurrence remains unknown.

We followed up 250 patients with urine cytologic results, concurrent multitarget FISH, and cystoscopic examination for recurrent urothelial carcinoma. Of 81 cases (32.4%) with FISH-positive results, tumor recurrence developed in 60 (74.0%). Of 169 (67.6%) FISH-negative cases, recurrent urothelial carcinoma developed in 22 (13.0%). Of 211 patients (84.4%) with negative cystoscopic examination results, 56 (26.5%) had positive FISH results, and in 35 (62.5%) of these patients, recurrent urothelial carcinoma developed.

Approximately 27% of patients under bladder carcinoma surveillance without immediate evidence of tumor recurrence will have a positive FISH result, defining the anticipatory positive subset. In about 65% of this anticipatory positive group, recurrent bladder urothelial carcinoma developed within 29 months.

ImmunoCyt/uCyt+trade mark improves the sensitivity of urine cytology in patients followed for urothelial carcinoma.

Tetu B, Tiguert R, Harel F, Fradet Y.

1Department of Pathology, Centre Hospitalier Universitaire de Quebec, L'Hotel-Dieu de Quebec, Laval University, Quebec, Canada.
Mod Pathol. 2005 Jan;18(1):83-9 Abstract quote.

ImmunoCyt/uCyttrade mark is a fluorescent test combining three monoclonal antibodies. In this study, it has been tested as a complement to cytology in the detection of urothelial carcinoma in urine. It has been performed simultaneously with standard cytology and cystoscopy on 870 urine analyses from one hospital.

In 136 cases, one or more bladder tumors were found. Overall sensitivity of cytology, ImmunoCyt/uCyttrade mark and combined analyses reached 29, 74 and 84%, respectively, and overall specificity was 98, 62 and 61%. The negative predictive value of cytology, ImmunoCyt/uCyttrade mark and both analyses was 88, 93 and 95%, respectively, and the positive predictive value was 70, 26 and 29%. The sensitivity of cytology for low malignant potential neoplasms, low- and high-grade papillary carcinomas was 6, 18 and 53%, while it reached 71, 79 and 93% when combined with ImmunoCyt/uCyttrade mark. The sensitivity of cytology for stages Ta, T1, T2 and over and Tis tumors was12, 67, 47 and 50%, while it reached 78, 83, 79 and 100% when combined with ImmunoCyt/uCyttrade mark. In the absence of tumor on cystoscopy but with positive ImmunoCyt/uCyttrade mark, 18% of patients developed a tumor, 2-6 months later. Of the 109 cases diagnosed as suspicious for malignancy by cytology, a tumor was present in 30 cases and ImmunoCyt/uCyttrade mark was positive in 22 (73%) of them.

In conclusion, ImmunoCyt/uCyttrade mark may be used to postpone cystoscopies in patients followed for bladder cancer and may help to save cytologist and pathologist screening time

Multiprobe FISH for Enhanced Detection of Bladder Cancer in Voided Urine Specimens and Bladder Washings

Lukas Bubendorf, MD, Bruno Grilli, Guido Sauter, MD, Michael J. Mihatsch, MD, Thomas C. Gasser, MD, and Peter Dalquen, MD

Am J Clin Pathol 2001;116:79-86 Abstract quote

The aim of this study was to evaluate the UroVysion (Vysis, Downers Grove, IL) fluorescence in situ hybridization (FISH) test for improved detection of bladder cancer in urinary specimens.

Three groups of specimens were examined, including voided urine specimens (1) collected before resection of bladder cancer, (2) from cystoscopically negative bladders of patients with previous bladder cancer, and (3) from patients with benign prostatic hyperplasia (controls). FISH positivity was defined as more than 2 urothelial cells with an abnormal signal copy number of at least 1 of the 4 probes. FISH was positive in 1 of 27 control specimens and in 33 (73%) of 45 pTa, 12 (100%) of 12 pT1, and 13 (100%) of 13 pT2-4 tumors. The results were similar in a series of 68 bladder washings. In addition, FISH of voided urine specimens was positive in 5 of 10 patients with negative follow-up cystoscopy results. Subsequent recurrence was found in 4 of these patients but in none of 5 patients with FISH-negative results.

Multiprobe FISH markedly improves the sensitivity and specificity of cytology for the detection of bladder cancer in urine specimens.

Transitional cell carcinoma (TCC)  
Low grade
20% with DNA aneuploidy
High grade
>90% aneuploid
HCG Detected in serum of 10-30% of high grade TCC
Blood group-related antigens

Normal expression of ABH and Lewis a and b antigens and lost in neoplasia

Lewis X and T antigens in neoplastic epithelium

Tests for the detection of recurrent cancer Adv Anat Pathol 2001;8:37-45
Bard BTA test
Sensitivity 60%
Specificity 77%
Sensitivity 67%
Specificity 72%
Telomerase assay
Sensitivity 77%
Specificity 85%
Microsatellite assay
Sensitivity 89%
Specificity 100%
Overexpression of human carcinoma-associated antigen in urothelial carcinoma of the bladder.

Yao JL, Bourne PA, Yang Q, Lei J, di Sant'Agnese PA, Huang J.

Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, NY 14642, USA.
Arch Pathol Lab Med. 2004 Jul;128(7):785-7. Abstract quote  

CONTEXT: Human carcinoma-associated antigen (HCA) is a mucin protein whose level is increased in the sera of patients with a variety of carcinomas. We have previously shown that prostatic carcinoma overexpresses HCA in comparison to benign prostatic tissue. To our knowledge, expression of HCA in other tumors has not been reported previously.

OBJECTIVE: The current study was designed to determine if HCA is overexpressed in urothelial carcinoma (UCa) of the bladder.

DESIGN: Forty cystectomy specimens with UCa were selected, of which 27 cases had invasive UCa, 21 cases had a noninvasive component, and 36 cases had benign urothelium. Seven cystectomy specimens with benign conditions were chosen as controls. Anti-HCA monoclonal antibody HAE3 was used for immunohistochemical staining. Results were recorded as positive (> or =5% of cells staining and staining intensity 2+ or 3+) or negative (<5% of cells staining or staining intensity <2+) and analyzed using the Fisher exact test. RESULTS: HAE3 staining was positive in 67% of invasive UCa, 29% of noninvasive UCa, but only 5% of benign urothelium specimens. The difference in HCA expression between benign urothelium and UCa and that between invasive and noninvasive UCa was statistically significant (P =.008). No statistically significant difference was found between low-grade and high-grade noninvasive papillary UCa (P =.06).

CONCLUSIONS: Human carcinoma-associated antigen is selectively overexpressed in a significant number of cases of UCa of the bladder, suggesting the potential utility of monitoring the serum and/or urine levels of HCA in monitoring patients with HCA-positive UCa for recurrence or progression.


Urothelial Papilloma of the Bladder: A Review of 34 De Novo Cases.

Magi-Galluzzi C, Epstein JI.

From the *Department of Pathology, Cleveland Clinic Foundation, Cleveland, OH; and daggerDepartment of Pathology, Johns Hopkins Hospital, Baltimore, MD.
Am J Surg Pathol. 2004 Dec;28(12):1615-1620. Abstract quote  

BACKGROUND:: Urothelial papilloma of the bladder is an uncommon entity when using restrictive diagnostic criteria.

DESIGN:: We retrospectively studied 34 patients who were diagnosed with urothelial papilloma of the bladder using the criteria of the 1998 WHO/ISUP classification system. Six cases were in-house and the remaining 28 were referred from other institutions as consults to one of the authors. In all cases, the diagnosis of papilloma was the first manifestation of urothelial neoplasia.

RESULTS:: The mean age of the patients at diagnosis was 57.8 years (range, 23-87 years). The male-to-female ratio was 2.4:1 (24 males and 10 females). The tumor size averaged 3.3 mm (range, 1-20 mm; median, 2 mm). Simple papillary fronds were seen in all cases; in 5 cases the additional finding of secondary budding off of small fronds from larger ones was also seen. In all cases, the fronds had a round morphology; yet in 4 cases elongated fronds were also noted. In 5 cases, dilated lymphatics within the fibrovascular fronds were apparent. One case had foamy histiocytes within the fibrovascular stalks. In all cases, the lining consisted of normal-appearing urothelium without hyperplasia, dysplasia, and/or mitotic figures. Some of the distinctive histologic features seen were changes in the umbrella cells: vacuolization (n = 4), prominence with cytologic atypia (n = 2), eosinophilic syncytial morphology (n = 1), apocrine-like morphology (n = 1), and mucinous metaplasia (n = 1). Follow-up was available in 26 cases with a mean follow-up for those without evidence of progression of 28.9 months (range, 3-127 months). Three patients (8.8%) developed recurrent papilloma 4, 15, and 18 months after the initial diagnosis of papilloma; 1 of these patients also showed progression to noninvasive low-grade urothelial carcinoma at the time of recurrence (15 months). Three patients (8.8%) progressed to higher-grade disease: 2 to noninvasive low grade urothelial carcinoma (11 and 15 months after the original diagnosis) and 1 to a papillary urothelial neoplasm of low malignant potential at 104 months and a noninvasive low-grade urothelial carcinoma at 141 months from the initial diagnosis of papilloma. None of the patients demonstrated progression to either lamina propria (T1) or muscularis propria (T2) invasion. Two patients died of unrelated causes. None of the patients died of bladder cancer.

CONCLUSION:: Patients with urothelial papillomas have a low incidence of recurrence and rarely progress to develop urothelial carcinoma. It seems reasonable to avoid labeling these patients as having cancer. It remains to be studied whether and when patients with papillomas who have no evidence of recurrence or progression no longer need to be followed.
Inverted papilloma Solitary raised pedunculated or polypoid tumors
Usually <3cm
Exophytic papilloma These have been classified by some as low grade papillary transitional cell carcinomas
Transitional cell carcinoma  
Low grade
Predominantly papillary
High grade
Papillary or flat
Carcinoma in situ
Usually multifocal
Adenocarcinoma Usually single nodular tumors
58-67% arise at the bladder base and the remainder arise in the urachal remnants
Squamous cell carcinoma Usually fungating mass
Small cell carcinoma Usually large deeply invasive tumors


Further Characterization of the Muscle Layers and Lamina Propria of the Urinary Bladder by Systematic Histologic Mapping: Implications for Pathologic Staging of Invasive Urothelial Carcinoma.

*Department of Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, CA †Department of Pathology, Methodist Hospital, Houston, TX ‡Department of Pathology and Laboratory Medicine, Loyola University Medical Center, Maywood, IL §Department of Pathology, Emory University Hospital, Atlanta, GA.


Am J Surg Pathol. 2007 Sep;31(9):1420-1429. Abstract quote

The muscularis mucosae (MM) and muscularis propria (MP) are important landmarks for pathologic tumor (pT) staging of urinary bladder cancer, which is the quintessential prognostic factor. In our routine practice, we have occasionally noted patterns of MM, which do not always conform to the originally described configuration of thin slender bundles arranged in a single layer of interrupted, dispersed, or continuous muscle.

We evaluated the lamina propria (LP), MM, and MP characteristics in 35 urinary bladder resection specimens with systematic sampling from the dome, trigone, anterior, posterior, right, and left lateral walls. Among the subsites, the trigone had a relatively flatter surface and attenuated LP depth (0.46 to 1.58 mm), about half of the thickest region which was the dome (0.98 to 3.07 mm).

The MM was typically in individual or small groups of slender and wavy fascicles or wispy fibers. MM also had focal to rarely extensive hyperplastic appearance (53%, most common in dome) with 2 recognizable patterns: (a) aggregates of hyperplastic MM with haphazard outlines (33%) distinct from that of MP, and (b) hyperplastic compact MM with parallel muscle fibers and regular outline arranged singly or in small groups (45%) that occasionally strongly resembled MP muscle but distinguishable from it on the basis of the location in the LP. By distribution, these muscle bundles were more typically dispersed or formed a discernable layer (41%) as discontinuous or infrequently near-continuous layer. The LP vascular plexus was present in every section most often in association with the MM muscle; however, variations in the distribution were observed. The MP most commonly had a relatively regular interface with the LP. A distinctive pattern was noted in the trigone where occasionally there was gradual diminution of size of the MP muscle bundles as they extended to almost a suburothelial location. In 22%, isolated or small groups of compact regular hyperplastic MM muscle bundles were noted in deep LP situated between the more typical slender MM layer and the MP.

In conclusion, there are additional patterns of MM other than previously described. Awareness of the occasionally hyperplastic appearance of MM muscle is important to prevent overstaging of invasive urothelial carcinoma. In transurethral resection specimens, lack of orientation may preclude distinction of the hyperplastic MM from true MP in these rare situations. The number and orientation of muscle bundles, relationship to urothelium and vascular plexus, and comparison with more characteristic MP, if present, would be helpful; isolated bundles immediately adjacent to the urothelium with loose haphazard fiber orientation and irregular outlines favor MM over MP muscle. The hyperplastic MM mimicking MP may be more challenging; isolated muscle bundles immediately adjacent to the urothelium would favor hyperplastic pattern of MM over MP muscle. Topographical variations exist among the subsites, the more superficial location of the MP and the rarity of MM in the trigone, relative abundance of hyperplastic MM in dome, and presence of the more superficial ureteral MP at its insertion in the bladder complicate the traditional pT stage evaluation of invasion in these regions.

The inconsistency of a distinct MM layer and variations in the LP vascular plexus indicate that substaging of pT1 would be problematic and thus provides further support to the World Health Organization/International Society of Urological Pathology 1998 and World Health Organization 2004 recommendation against its implementation at the current time.
Significance of Denuded Urothelium in Papillary Urothelial Lesions.

Department of *Pathology daggerUrology and Oncology, The Johns Hopkins Medical Institutions, Baltimore, MD.


Am J Surg Pathol. 2007 Feb;31(2):298-303. Abstract quote

Flat urothelial carcinoma in situ (CIS) is often characterized by prominent dyscohesion with some cases having only a few clinging CIS cells remaining on biopsy. The finding of extensive denudation on urothelial biopsies is associated with a risk of CIS on either prior or subsequent biopsies. The significance of denudation in papillary urothelial lesions has not been formally studied.

We identified from our surgical pathology files 31 specimens (from 28 patients) of papillary urothelial lesions with extensive denudation. In cases in which denudation was associated with low-grade urothelial neoplasms, follow-up of subsequent cytologic and histologic specimens was obtained. Of the 28 patients, 25 (89%) were men and 3 (11%) were women with an age range of 40 to 88 years old (mean age 62). Of 31 biopsies, 15 were from anatomically confined areas (ie, renal pelvis, ureter, and urethra). In 22/28 (79%) patients, prominent denudation was associated with high-grade papillary carcinomas, 4/28 (14%) low-grade papillary carcinomas, and 2/28 (7%) papillary urothelial neoplasms of low-grade malignant potential. The average extent of urothelial denudation was 82% with 61% of cases having >/=90% denudation. Prominent cautery artifact was present in 17/31 (55%) cases. In 13/28 patients with high-grade lesions, there was a concurrent biopsy of a second urothelial lesion that was either high-grade papillary urothelial carcinoma or invasive urothelial carcinoma. Five of the 6 patients in which the prominent denudation was associated with a low-grade papillary urothelial lesion have not progressed to a high-grade lesion. One patient with a denuded papillary urothelial neoplasm of low malignant neoplasm was subsequently diagnosed with a noninvasive low-grade papillary urothelial carcinoma in the bladder and a high-grade infiltrating urothelial carcinoma of the ureter.

We conclude that (1) the majority of papillary urothelial lesions associated with prominent urothelial denudation are high grade; (2) a significant percentage of papillary urothelial lesions with denudation occur with either prominent cautery artifact or in anatomically confined areas, suggesting both iatrogenic and mechanical contributing factors, respectively; (3) a minority of cases with prominent urothelial denudation occur in association with low-grade papillary urothelial lesions and are not associated with progression to higher grade lesions on follow-up studies; and (4) prominent urothelial denudation in papillary lesions should prompt careful examination of these specimens for rare clinging high-grade carcinoma cells, although in a minority of cases the underlying lesion will be low grade.
Histologic variants of urothelial carcinoma: differential diagnosis and clinical implications.

Department of Pathology, Reina Sofia University Hospital and Cordoba University Medical School, E-14004 Cordoba, Spain.

Hum Pathol. 2006 Nov;37(11):1371-88. Epub 2006 Jul 31. Abstract quote

An increasing number of histologic variants of urothelial carcinoma have been recognized in recent years. It is important for surgical pathologists to be aware of these morphological variants that, on occasion, may lead to misinterpretation as benign. Some also require a specific therapeutic approach.

In this article, we review the most common histologic variants of urothelial carcinoma of the bladder. Emphasis is placed on clinical significance and differential diagnosis.

Impact of second opinion pathology in the definitive management of patients with bladder carcinoma.

Coblentz TR, Mills SE, Theodorescu D.

Department of Urology, University of Virginia Health Sciences Center, Charlottesville, Virginia.

Cancer 2001 Apr 1;91(7):1284-90 Abstract quote

BACKGROUND: The accurate diagnosis, staging, and grading of bladder neoplasms depend heavily on the interpretation of biopsies and transurethral resection (TUR) specimens. Although many centers require review of outside pathologic material before definitive treatment such as radical cystectomy, the authors are unaware of data supporting the utility of this approach in urothelial (transitional cell) carcinoma. The authors therefore examined the clinical and cost impact of pathologic review on patients referred to an academic urology department for treatment of bladder neoplasia.

METHODS: The pathologic material from 97 patients referred to an academic center for evaluation of urothelial carcinoma of the bladder from July 1996 to July 1999 was reviewed. This material was received from 30 community hospitals and 4 academic centers. The 97 patients had undergone 131 (mean, 1.35; range, 1-10) biopsies or TUR procedures before referral. Surgical pathologists at the authors' institution reviewed all outside patient material, and discordant cases were rereviewed by one of the authors (S.E.M), an experienced genitourinary pathologist. Follow-up chart review was performed in discordant cases to determine clinical and pathologic outcomes.

RESULTS: Upon review at the authors' institution, 24 of 131 (18%) specimens with a referring diagnosis of urothelial carcinoma exhibited significant discrepancies with regard to the diagnosis, stage, grade, or tumor histologic type made at the outside institution. Four tumors (3%) were found to be nonurothelial neoplasms. Five specimens (4%) were judged inadequate for staging because they contained no muscularis propria. Three patients were upstaged, including two patients shown to have muscle invasive disease. Eight patients were downstaged, including two patients referred with purported muscle invasive disease who were determined to have only superficial disease on pathology review. Two patients initially thought to have carcinoma in situ (tumor in situ [Tis]) showed no evidence of Tis on pathology review. One patient with purported muscle invasive disease was shown to have only metaplasia, and one patient had a highly significant change in tumor grade. As a result of the pathology review, five radical cystectomies were avoided, whereas five repeat TUR procedures were recommended for inadequate staging. One patient shown to have muscle invasion on pathology review proceeded directly to cystectomy, avoiding a planned repeat TUR. A cystectomy also was recommended to a second patient who was shown to have invasive disease by the pathology review. Pathology review of 131 specimens resulted in net savings of $86,176 or $658 per TUR reviewed.

CONCLUSIONS: The review of bladder pathologic materials before definitive therapy can impact clinical decisions significantly and can reduce overall expenditures for the management of this cohort of bladder carcinoma patients.

DYSPLASIA Variable thickness with crowded nuclei and overlap
Nucleoli absent or small
Mitoses rare

Immunohistochemical Expression of CK20, p53, and Ki-67 as Objective Markers of Urothelial Dysplasia.

Mallofre C, Castillo M, Morente V, Sole M.

Department of Pathology, Hospital Clinic, IDIBAPS, University of Barcelona, Barcelona, Spain.


Mod Pathol 2003 Mar;16(3):187-91 Abstract quote

Urothelial dysplasia and carcinoma in situ (CIS) are related to recurrence and progression of urothelial carcinoma. Distinguishing CIS and dysplasia from reactive atypia is often difficult on the basis of histological features alone. Cytokeratin 20 (CK20), p53, and Ki-67 are related either to neoplastic change or prognosis in urothelial proliferations.

The objective of the present study was to establish the immunohistochemical pattern of these three antibodies in urothelial dysplasia and CIS. Three groups of patients were evaluated: 40 nonneoplastic urothelial samples, 50 cases with histologically incontrovertible CIS, and 30 samples with nonconclusive atypical changes (atypia of unknown significance). Monoclonal antibodies (MoAb) against CK20, p53, and Ki-67 (MIB-1) were used on paraffin-embedded samples. Nonneoplastic urothelium showed no reactivity to CK20 except for umbrella cells; p53 and Ki-67 were negative or weakly positive in <10% of basal cells. In the CIS group, 42% showed positivity for all three MoAb; 44%, for two; and 14%, only for one. CK20 was positive through the full thickness of the urothelium in 72% of cases, p53 was positive in 80% of cases, and Ki-67, in 94% of cases. In the third group, the suspected dysplastic cells showed strong positivity in scattered cells through the epithelium in 75% of cases. Aberrant CK20 expression in urothelial cells plus overexpression of p53 and Ki-67 are indicators of dysplastic change in urothelial mucosa.

Thus, immunohistochemistry is a useful tool to confirm the diagnosis of CIS and could be helpful to distinguish dysplastic changes from reactive atypia.


Cords of transitional cells with papillary infoldings invaginating into the lamina propria
Central portions contain maturing transitional cells
Cellular atypia is common but anaplasia is rare

Atypia in inverted urothelial papillomas: Pathology and prognostic significance.

Broussard JN, Tan PH, Epstein JI.
Hum Pathol. 2004 Dec;35(12):1499-504. Abstract quote  

Inverted papillomas of the bladder are considered benign urothelial neoplasms, based on their histology and clinical course. There are scant data on inverted papillomas with atypical features. Whether to designate them as inverted papillomas with atypia or low-grade transitional cell carcinomas with inverted features is controversial.

In the present study, 11 cases of inverted papillomas with atypia and 10 controls of classic inverted papillomas without atypia were collected from 2 institutions. The inverted papillomas with atypia had the typical architectural features of inverted papillomas consisting of thin anastomosing trabeculae of urothelium growing downward into the stroma without an exophytic papillary component. The atypical areas in the current series were focal, with other areas exhibiting the benign cytology of classic inverted papillomas. Cases with atypia were subdivided into the following groups: (1) 5 cases notable for areas containing prominent nucleoli, (2) 2 cases with foci with atypical squamous features, (3) 2 cases with areas of dysplasia, approaching the level of carcinoma in situ, (4) 1 case with degenerative-appearing multinucleated giant cells, and (5) 1 case notable for nests of atypical squamous cells associated with large, atypical squamoid cells with a pagetoid appearance in addition to degenerative-appearing multinucleated giant cells. Ki67 was slightly increased in 1 case, with focal dysplasia approaching carcinoma in situ and in 1 case with prominent nucleoli (increased Ki67 in both the atypical and non-atypical areas) and in the case with atypical squamous, pagetoid, and giant cells (no increased Ki67 in the atypical components). Two of the atypical inverted papilloma cases with prominent nucleoli demonstrated an increase in p53 staining throughout the lesions. Cytokeratin (CK) 20 staining was negative in all cases of inverted papillomas. No significant increase in Ki67 staining was found in any of the 10 control cases; increased p53 staining was seen in 1 control case. CK20 staining was negative in the 10 control cases. In the 11 cases with atypia, clinical follow-up revealed no history of prior or subsequent bladder neoplasms. In the cases reviewed, most inverted papillomas with atypia did not demonstrate significantly increased cellular proliferation in comparison with inverted papillomas without atypical features.

To date, there has been no association with urothelial carcinoma in the individuals diagnosed with atypical inverted papillomas. These findings suggest that these lesions are currently best classified as inverted papillomas with atypia, not as low-grade transitional carcinomas, and that they merit continued evaluation as a distinct group.
EXOPHYTIC PAPILLOMA Papillary tumors with low grade nuclei
No invasion
Delicate fibrovascular stalks lacking anaplasia

A Clinicopathologic Analysis of Urothelial Carcinomas Diagnosed on Prostate Needle Biopsy

Bahram R. Oliai, M.D.; Hillel Kahane, M.D.; Jonathan I. Epstein, M.D.

Am J Surg Pathol 2001;25:794-801 Abstract quote

No data exist on urothelial carcinoma diagnosed on prostatic needle biopsy. We reviewed 21 cases (19 consultations) of urothelial carcinoma diagnosed on prostate needle biopsy from 1991 to 1998.

In 13 of 21 (62%) cases, urothelial carcinoma showed in situ urothelial carcinoma involving prostatic ducts and acini (DCIS) only; 6 of 21 (29%) cases showed both DCIS and invasive carcinoma and 2 of 21 (9%) cases showed widespread stromal invasion without DCIS. In contrast to prostatic adenocarcinoma, cases exhibited greater nuclear pleomorphism, variably prominent nucleoli, increased mitoses, and necrosis.

Immunostains for PSA and PSAP were negative in all 18 cases studied. CK7 was positive in 14 of 16 cases, CK20 was positive in 13 of 16 cases, and 34E12 was positive in 11 of 17 cases. A total of 7 of 17 (41%) men had no prior or subsequent history of urothelial carcinoma outside the prostate, 6 of 17 (35%) had concurrent urothelial cell carcinomas of the bladder (1 with extensive carcinoma in situ [CIS] at cystoprostatectomy), 2 of 17 (12%) had a prior urothelial cell carcinoma, and 2 of 17 (12%) developed urothelial cell carcinomas outside the prostate subsequent to the needle biopsy diagnosis. A total of 14 of 18 (78%) men had an elevated prostate specific antigen (PSA), abnormal digital rectal examination, or abnormal ultrasound suggestive of prostatic adenocarcinoma.

Follow-up information was available in 17 cases. Six of nine (67%) patients with DCIS eventually died of disease (DOD) (2 with prior urothelial cell carcinoma, 1 with no prior or subsequent history, 3 without information), and 3 of 9 (33%) patients with DCIS were alive with residual disease (AWD). Of the patients with invasive carcinomas, 4 of 8 (50%) were DOD, 2 of 8 (25%) were AWD, and 2 of 8 (25%) were alive without evidence of disease. All men who are alive were treated aggressively with surgery and often adjuvant chemotherapy–radiation. Overall, 10 of 17 (59%) men were DOD with a mean survival after diagnosis of 23.2 months (2–72 months).

The diagnosis of urothelial carcinoma on prostate needle biopsy is difficult because it is rare and clinically can mimic prostatic adenocarcinoma; often there is no history of urothelial carcinoma elsewhere. Although the prognosis is poor even with only apparent DCIS, histologic recognition is essential because the only opportunity for improved outcome is early and aggressive treatment.

Low grade
Papillary with uniform cells
At least 7 urothelial layers in thickness
Rare mitotic figures
High grade
Infiltrating neoplasms with papillary and flat configurations
Numerous mitotic figures
Carcinoma in situ

Almost always observed with high grade TCC but rare with papillomas

Cells have high nuclear:cytoplasmic ration with indistinct borders with sharp demarcation from adjacent mucosa

Lack intercellular cohesion with extensive denudation of the surface mucosa

Small cell variant
Pagetoid variant

Morphologic Expressions of Urothelial Carcinoma In Situ A Detailed Evaluation of Its Histologic Patterns With Emphasis on Carcinoma In Situ With Microinvasion

Am J Surg Pathol 2001;25:356-362 Abstract quote

In this study, cases were examined with respect to histologic patterns and microinvasion (invasion into the lamina propria to a depth of less than 2 mm).

Five major patterns of CIS, often occurring in the same specimen (160 patterns in 77 cases), were noted. Common to each pattern was the presence of high-grade cytologic atypia, the definitional feature.

The patterns found include 1) large cell CIS with pleomorphism (57%), in which the cells had abundant cytoplasm and nuclear pleomorphism; 2) large cell CIS without nuclear pleomorphism (48%); 3) small cell CIS (14%), in which the cytoplasm was relatively scant and pleomorphism was usually minimal; 4) clinging CIS (40%), in which the urothelium was denuded with a patchy, usually single layer of atypical cells; and 5) cancerization of urothelium (16%) with either pagetoid spread (clusters or isolated single cells) or undermining or overriding of the normal urothelium.

Carcinoma in situ with microinvasion into the lamina propria (13 cases: 3 of 77 CIS cases studied above and 10 additional cases) was evident as invasive cells with retraction artifact mimicking vascular invasion (77%, 10 cases); nests, irregular cords, and strands, or isolated single cells with desmoplasia (8%, 1 case); or absent stromal response (15%, 2 cases).

Although the diagnostic terminology for all of these patterns, for the purposes of the surgical pathology report, should be simply urothelial CIS with no specific mention of the morphologic pattern, awareness of the histologic diversity of CIS will facilitate the diagnosis of this therapeutically and biologically critical flat lesion of the urothelium. These lesions may be associated with microinvasion, which may be clinically unsuspected and histologically subtle.

An objective morphologic parameter to aid in the diagnosis of flat urothelial carcinoma in situ

Rolando A. Milord, MD
Kristen Lecksell, BS
Jonathan I. Epstein, MD

Hum Pathol 2001;32:997-1002 Abstract quote

The diagnosis of carcinoma in situ (CIS) lacks objective criteria and is subject to misdiagnosis.

We identified 20 bladder biopsy cases each of CIS, urothelial dysplasia, and normal urothelium according to the 1998 World Health Organization/International Society of Urological Pathology consensus classification of urothelial neoplasms. Lymphocytes from 10 bladder biopsy specimens were chosen as reference cells.

Using an image analysis system, we measured the following nuclear features: area, diameter, roundness, ellipticity, and optical density (maximum, minimum, mean, median, standard deviation, and quartiles). We measured a mean of 75 urothelial nuclei/case and a total of 500 lymphocytes. Roundness and ellipticity were not useful in distinguishing among the 3 groups. The best discriminators were mean nuclear area and mean nuclear area of the 25% largest nuclei (upper quartile) of urothelial cells compared with lymphocytes. The mean nuclear area relative to lymphocytes was 1.8 times (1.2 to 2.5 times) in normal urothelium, 2.4 times (1.6 to 3.0 times) in urothelial dysplasia, and 3.6 times (2.8 to 5.7 times) in CIS. The mean upper quartile nuclear area relative to lymphocytes was 2.2 times (1.4 to 2.8 times) in normal urothelium (P < .0001), 2.9 times (1.8 to 3.6 times) in urothelial dysplasia (P < .0001), and 4.9 times (4.0 to 7.6 times) in CIS (P < .0001). The difference in optical density was statistically significant between CIS and the other 2 histologic categories (P < .0001). Nuclear area is an easy and objective morphologic parameter for the evaluation of bladder biopsy specimens. Pathologists can assess the size of urothelial nuclei without using an image analysis system and compare them with the size of nuclei of lymphocytes, which are almost always present in a bladder biopsy specimen. Dysplasia, which is a somewhat ambiguous lesion, overlaps in its measurements with those of benign urothelium.

The most useful morphologic parameter is the mean nuclear area of the 25% largest nuclei; CIS nuclei are approximately 5 times the size of lymphocytes, whereas normal urothelial nuclei are only 2 times the size of lymphocytes.

Significance of Stromal Reaction Patterns in Invasive Urothelial Carcinoma

Hemamali Samaratunga, etal.
Am J Clin Pathol 2005;123:851-857 Abstract quote

We evaluated the types, frequency, and significance of stromal reaction patterns in urothelial carcinoma (UC) of the bladder in 60 transurethrally resected pT1 specimens (low-grade UC, 12; high-grade UC, 48). We observed 5 reaction patterns with 1 pattern in 37 cases (62%) and 2 or more patterns in the remainder. Dominant and secondary patterns, respectively, were as follows: stromal retraction, 30 (50%) and 4 (7%); edema, 18 (30%) and 1 (2%); inflammation, 8 (13%) and 14 (23%); fibroblastic proliferation, 3 (5%) and 5 (8%); fibrosis, 1 (2%) and 4 (7%). Progression occurred in 21 cases, including 9 (30%) of 30 with stromal retraction, 8 (45%) of 18 with edema, 2 (25%) of 8 with inflammation, 1 (33%) of 3 with fibroblastic proliferation, and 1 (100%) of 1 with fibrosis. Differences in progression rates and mean progression-free survival times were not statistically significant.

We found that the most common stromal reaction in UC of the bladder is stromal retraction. Stromal reaction patterns seem to have some prognostic usefulness. Cases with stromal edema might benefit from closer follow-up. Awareness of the different types of stromal reactions also is useful for diagnosing invasion.

In Situ Adenocarcinoma of the Bladder

Theresa Y. Chan, M.D.; Jonathan I. Epstein, M.D.

From the Department of Pathology, The Johns Hopkins Medical Institutions, Baltimore, Maryland, U.S.A.

Am J Surg Pathol 2001;25:892-899 Abstract quote

In situ adenocarcinoma of the bladder has not been well studied. Only one other case not associated with infiltrating adenocarcinoma has been reported in the literature.

We identified 19 biopsies of in situ adenocarcinoma of the bladder without concurrent infiltrating adenocarcinoma or villous adenoma from the surgical pathology files of the Johns Hopkins Hospital between May 1984 and July 2000. The majority of patients (89%) were seen in consultation.

The mean age at diagnosis was 70.4 years (range 48–88 years) and 79% were male. None of the patients developed a pure infiltrating adenocarcinoma; however, two patients had invasive urothelial carcinoma with focal glandular differentiation on prior or subsequent specimens. Two cases were pure in situ adenocarcinoma and 10 were seen with carcinoma in situ and/or papillary transitional cell cancer without invasion. Most patients (74%) had invasive carcinoma on either concurrent or subsequent specimens (five small cell and nine transitional cell [four micropapillary]). The majority (84%) of in situ adenocarcinomas were papillary, often seen in combination with either cribriform or flat architecture. In most cases the in situ adenocarcinoma was the predominant component when it was present with another in situ urothelial carcinoma. Seventy-nine percent of in situ adenocarcinomas showed >5 mitoses/10 HPF and 42% showed >10 mitoses/10 HPF. Moderate to severe nuclear pleomorphism was seen in 84% of cases. All cases showed apoptosis, and only one case showed focal necrosis. Seven patients were treated with cystectomy within 2–12 months. Of the other 12 patients, 10 were followed for a mean of 19.3 months (range 1–62 months). Ten (52%) patients were treated with bacille Calmette-Guérin, of whom four had no residual tumor on subsequent biopsy or cystectomy specimens. Three patients developed metastatic disease. In situ adenocarcinoma is a rare lesion that has a high incidence of association with small cell and micropapillary transitional cell carcinomas.

When identified, in situ adenocarcinoma may indicate subsequent development of specific types of prognostically poor invasive carcinomas.

Villous adenoma of the urinary tract: A lesion frequently associated with malignancy.

Seibel JL, Prasad S, Weiss RE, Bancila E, Epstein JI.

Departments of Urology and Pathology, The Johns Hopkins Hospital, Baltimore, MD; and the Division of Urology, The Robert Wood Johnson Medical School, New Brunswick, NJ.


Hum Pathol 2002 Feb;33(2):236-41 Abstract quote

Villous adenomas arising in the urinary tract are rare.

We identified 18 cases of villous adenomas of the bladder, urachus, and prostatic urethra. Patients ranged in age from 53 to 93 years with an average age of 69.6 years and a male preponderance of 67%. In six cases (33%), the lesion was pure villous adenoma. In three cases (17%), there was villous adenoma with in situ adenocarcinoma. In six cases (33%) there was villous adenoma with in situ and infiltrating adenocarcinoma. One case (6%) had villous adenomas with in situ (noninvasive) papillary urothelial carcinoma. One case (6%) had villous adenomas with in situ adenocarcinoma and in situ papillary (noninvasive) and infiltrating urothelial carcinoma. The remaining case (6%) had villous adenoma with in situ and infiltrating adenocarcinoma and in situ (noninvasive) papillary and infiltrating urothelial carcinoma.

Clinical outcome was available in eight of the cases, with a mean follow-up of 4.6 years. No evidence of recurrence was found in two patients with pure villous adenoma or in two patients with villous adenoma and only in situ adenocarcinoma, all of whom were treated by nonradical excision. However, two of three cases with infiltrating cancer developed distant metastases despite radical surgery; the remaining patient was disease-free 11 years after transurethral resection. The case with villous adenoma and in situ urothelial carcinoma progressed to sarcomatoid urothelial carcinoma following partial cystectomy. Eight of 10 villous adenomas cases studied expressed the epitope for mAbDas1, found on colonic epithelium and primary adenocarcinomas of the bladder and urachus but not on normal or neoplastic urothelium. This study expands the spectrum of histologic features accompanying villous adenomas of the urinary tract. Coexisting infiltrating adenocarcinoma is often present, necessitating thorough sampling of any lesion diagnosed by biopsy as villous adenoma.

Pure villous adenoma and those well-sampled lesions also containing in situ adenocarcinoma portend a favorable prognosis, even without radical treatment. Coexisting in situ or infiltrating carcinoma suggests a more aggressive course. Histologically, immunohistochemically, and prognostically, these lesions appear analogous to their counterparts in the intestine.

Clear Cell Carcinoma of the Urinary Bladder
A Report and Comparison of Four Tumors of Mullerian Origin and Nine of Probable Urothelial Origin With Discussion of Histogenesis and Diagnostic Problems

Esther Oliva, M.D. ; Mahul B. Amin, M.D. ; Rafael Jimenez, M.D. ; Robert H. Young, M.D.

From the James Homer Wright Pathology Laboratories of the Massachusetts General Hospital and the Department of Pathology (E.O., R.H.Y.), Harvard Medical School, Boston, Massachusetts; and the Department of Pathology (M.B.A., R.J.), Emory University Hospital, Atlanta, Georgia, U.S.A.

Am J Surg Pathol 2002;26:190-197 Abstract quote

Carcinomas of the bladder that resemble clear cell carcinoma of mullerian type are rare. Whether such neoplasms 1) arise from mullerian elements in the bladder and are histogenetically identical to the female genital tract cancer, 2) are a peculiar variant of vesical adenocarcinoma of nonmullerian derivation, or 3) represent a peculiar morphologic expression of transitional cell (urothelial) carcinoma with gland differentiation is often uncertain.

We reviewed the clinical, conventional pathologic, and immunohistochemical features of 13 neoplasms with exclusive, or predominant, morphologic features of clear cell carcinoma. The 11 female and two male patients were 22–83 (mean 57) years of age. The clinical and gross features had no unique aspects.

On microscopic examination the most common pattern, present in all cases, was tubulocystic, with a papillary pattern, present in six tumors and a predominant solid growth in one. Cells with abundant clear cytoplasm were conspicuous in nine tumors and hobnail cells were seen in eight. Four tumors showed focally recognizable patterns of transitional cell (urothelial) carcinoma in the available material. In five other tumors pseudostratified epithelium reminiscent of transitional epithelium was present focally. Endometriosis was present in two cases. In two other cases benign cysts focally lined by ciliated epithelium and surrounded by elastosis were interpreted as most likely mullerian.

Immunohistochemistry was performed in 10 cases. All tumors stained for CA 125 (usually strong, ranging from focal to diffuse) and nine tumors stained for CK7 (usually strong and diffuse). CK20 was focally and weakly positive in four tumors and extensively positive in another. The same immunohistochemical panel was performed on 10 typical transitional cell carcinomas, 4 transitional cell carcinomas with gland differentiation, not otherwise specified, and 5 pure adenocarcinomas of the bladder (one of urachal origin). Minimal CA 125 positivity was seen in two transitional cell carcinomas. CA 125 staining was seen in the areas of gland differentiation in three of four transitional cell carcinomas and three of five pure adenocarcinomas but was focal in most cases.

All transitional cell carcinomas and transitional cell carcinomas with gland differentiation showed extensive CK7 positivity. In contrast, only one of four positive pure adenocarcinomas showed >5% CK7-positive cells. Although all groups showed CK20 positivity, the percentage of CK20 positive cells was higher in pure adenocarcinomas. Prostate specific antigen was negative in all tumors.

The cytokeratin immunoprofile of clear cell carcinomas of the bladder is closer to transitional cell carcinomas and transitional cell carcinomas with gland differentiation than pure adenocarcinomas arguing against an unusual form of adenocarcinoma.

Our finding of CA 125 expression in bladder tumors of apparent urothelial origin contrasts with some studies that have regarded CA 125 expression as evidence for a mullerian origin. The frequency of gland differentiation in transitional cell carcinomas and the rarity of vesical endometriosis could be taken to suggest that these tumors are mostly of urothelial derivation, but the strong female preponderance in our series argues for a mullerian origin in at least some cases, and this is almost certain in the four cases with benign mullerian components.

In the absence of endometriosis or conventional foci of transitional cell carcinoma, it may be impossible to determine whether a tumor with the morphology of clear cell carcinoma is of mullerian or transitional (urothelial) cell lineage, and at this time immunochemistry does not solve this problem.


Collecting-Duct Carcinoma of the Kidney with Prominent Signet Ring Cell Features

Maomi Li, M.D., Ph.D., Magalis A. Vuolo, M.D., Karen M. Weidenheim, M.D. and Lloyd S. Minsky, M.D.

Department of Pathology, The Jack Weiler Hospital of Albert Einstein College of Medicine,

Mod Pathol 2001;14:623-628 Abstract quote

We report a case in a 74-year-old woman of collecting-duct carcinoma of the kidney with prominent signet ring cell features.

Grossly, the tumor measured 5.5 cm in greatest dimension, occupied the entire upper pole of the kidney, and was well circumscribed.

Microscopically, it displayed a predominant tubulopapillary pattern of growth with a hyalinizing stroma. The tumor tubules were lined by a single layer of cells with large, pleomorphic nuclei, some of which had a hobnail appearance. Large intracytoplasmic vacuoles with compression of nuclei (signet ring cells) were present throughout the tumor. Alcian blue, mucicarmine, and periodic acid–Schiff stains failed to identify intracellular mucin or glycogen in the signet ring cells. Enlarged cells with intracytoplasmic vacuoles were also noted in the adjacent collecting ducts. The tumor cells were immunohistochemically positive for cytokeratin including cytokeratin 7, CAM 5.2, AE1/3, and 34ßE12, vimentin, peanut lectin agglutinin, and Ulex europaeus agglutinin. Electron microscopy revealed that the intracytoplasmic vacuoles were due to intracellular edema.

To the best of our knowledge, this is the first reported case of renal collecting-duct carcinoma with prominent signet ring cell features.

Micropapillary carcinoma of the urothelial tract. A clinicopathologic study of 38 cases.

Alvarado-Cabrero I, Sierra-Santiesteban FI, Mantilla-Morales A, Hernandez-Hernandez DM.

Department of Pathology, Mexican Oncology Hospital, National Medical Center, Mexico City 06700, Mexico.
Ann Diagn Pathol. 2005 Feb;9(1):1-5. Abstract quote  

Micropapillary carcinoma (MPC) of the bladder is a rare and aggressive variant of bladder carcinoma. The goals of this study are to investigate whether this variant of bladder carcinoma represents a more aggressive disease than conventional urothelial carcinoma (CUC) and to determine the incidence of MPC in our country.

A total of 630 urothelial carcinomas diagnosed from 1997 to 2003 at the Department of Pathology, Oncology Hospital, in Mexico City were analyzed to identify MPC. Thirty-eight patients were found to have this diagnosis and along with a group of 76 patients diagnosed with CUC serve as the basis for this study. In 37 patients with MPC, the lesions were located in the bladder, and in 1 patient in the ureter. The mean patients' age at diagnosis was 68 years, and the male-female ratio was 37:1. The initial stage at presentation was high in most of the patients: Three patients had stage T1, 8 had stage T2, 18 had stage T3, and 9 had stage T4. The disease-specific survival rate for patients with MPC at 3.1 years was 39.5% (95% confidence interval [CI], 2.7%-3.4%) whereas for patient with CUC was 55.3% (95% CI, 3.9%-4.4%). Patients with a micropapillary component of more than 50% had a relative mortality risk of 2.4 (1.3-4.2), whereas patients with less than 50% of MPC did not have a significantly increased mortality risk (RR, 1.8; 0.5-6.0).

In summary, in this study, MPC was far more aggressive clinically than CUC. In Mexico, the incidence of 6% of MPC in relation to CUC and the male-female ratio of 37.1 for MPC are much higher than reported in the literature.

Classic neuroendocrine carcinoma appearance resembling small cell carcinoma of the lung and other organs

Neurosecretory dense core granules present on ultrastructural examination

Thyroid transcription factor 1 expression in small cell carcinoma of the urinary bladder: an immunohistochemical profile of 44 cases.

Jones TD, Kernek KM, Yang XJ, Lopez-Beltran A, Maclennan GT, Eble JN, Lin H, Pan CX, Tretiakova M, Baldridge LA, Cheng L.

Department of Pathology and Laboratory Medicine, Indiana University, Indianapolis, IN 46202, USA.
Hum Pathol. 2005 Jul;36(7):718-23. Abstract quote  

Small cell carcinoma of the urinary bladder is a rare and aggressive tumor resembling small cell carcinoma of the lung. Thyroid transcription factor 1 (TTF-1) expression is common in small cell carcinomas arising in the lung. However, studies of its expression in extrapulmonary small cell carcinomas have yielded varying results.

Because information concerning the immunohistochemical profile of small cell carcinoma of the urinary bladder is limited, we investigated the immunoreactivity of this tumor to a battery of antibodies in a series of 44 cases. Using 5-mum sections cut from paraffin-embedded tissue blocks, immunohistochemistry was performed to detect TTF-1, cytokeratin (CK) 7, CK20, and uroplakin antigenicity in 44 cases of small cell carcinoma of the urinary bladder. None of the patients had primary lung tumors. The TTF-1 immunohistochemical stain showed nuclear positivity in 17 cases (39%). Positive immunostaining for CK7 was observed in 26 cases (59%). There was no positive staining with either CK20 or uroplakin. There was no correlation between TTF-1 expression and survival (P = .27). In addition, TTF-1 expression did not correlate with clinicopathological characteristics, including age (P = .74), sex (P = .53), smoking history (P = .96), clinical stage (P = .10), pathological T stage (P = .50), lymph node metastasis (P = .40), and distant metastasis (P = .58). In summary, TTF-1 expression in small cell carcinoma of the urinary bladder was found in 39% of the tumors, demonstrating that this marker is expressed in small cell carcinomas other than those of pulmonary origin. Small cell carcinoma of the urinary bladder is positive for CK7 immunostaining in 59% of cases consistent with its origin from urothelium.

Unlike urothelial carcinoma, expression of CK20 and uroplakin in small cell carcinoma of the urinary bladder is consistently negative, and thus, these stains do not appear to be useful in the diagnosis of this neoplasm. TTF-1 positivity is not a significant prognostic factor in small cell carcinoma of the urinary bladder.

Primary large cell neuroendocrine carcinoma of the urinary bladder.

Evans AJ, Al-Maghrabi J, Tsihlias J, Lajoie G, Sweet JM, Chapman WB.

Departments of Pathology and Laboratory Medicine (Drs Evans, Al-Maghrabi, Lajoie, Sweet, and Chapman) and Surgical Oncology (Dr Tsihlias), University Health Network, University of Toronto, Toronto, Ontario.

Arch Pathol Lab Med 2002 Oct;126(10):1229-32 Abstract quote

Reports of primary large cell neuroendocrine carcinomas of the urinary bladder are few; we identified only 2 cases in the literature. Both of these cases involved male patients with rapid progression of disease culminating in death with widespread metastases.

We report a case of primary large cell neuroendocrine carcinoma of the bladder, with an admixed minor element of adenocarcinoma, in an 82-year-old man. This solitary lesion arose in a bladder diverticulum lateral to the left ureteric orifice. Two attempts at transurethral resection were unsuccessful at achieving local control. The patient underwent a partial cystectomy with left-sided pelvic lymphadenectomy following preoperative staging investigations that found no metastatic disease.

Pathologically, the tumor invaded into the deep aspect of the muscularis propria, without extension into perivesical fat. The lateral resection margin was microscopically positive for tumor, but no malignancy was found in the pelvic lymph nodes. The adenocarcinoma comprised less than 5% of total tumor volume, and areas of transition between the neuroendocrine and adenocarcinoma components were apparent. The patient developed a local recurrence 8 months postoperatively, which was managed by a combination of transurethral resection and radiation therapy.

Currently, the patient has no evidence of local or metastatic disease 2 years after initial diagnosis.


Nested variant of urothelial carcinoma: a clinicopathologic and immunohistochemical study of 12 cases.

Lin O, Cardillo M, Dalbagni G, Linkov I, Hutchinson B, Reuter VE.

Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA.
Mod Pathol. 2003 Dec;16(12):1289-98 Abstract quote.  

Nested variant of urothelial carcinoma is characterized by confluent small nests and abortive tubules of mildly atypical neoplastic cells infiltrating the lamina propria and/or muscularis propria of the bladder. Despite its deceptively bland histomorphologic appearance, the lesion is reported to have an aggressive behavior.

The collective immunohistochemical expression of suppressor genes, growth factor, and proliferation activity marker has not been previously studied in this disease. Formalin-fixed, paraffin-embedded archival tissues from 12 cases of nested variant of urothelial carcinoma were stained with monoclonal antibodies to p21, p27, p53, EGF-R, and bcl-2, as well as the proliferation marker MIB-1. The area of predominant immunoreactivity was also evaluated.

The pattern of immunostaining was compared with the clinical parameters. p21 was positive in 10 of 12 cases and located at the deepest portion of the tumor in 5 of 10 positive cases. Immunoreactivity for p27 was seen in 11 of 12 cases and limited to the superficial portion of the tumor in 9 of 11 positive cases. Only 3 and 2 of 12 cases were positive for p53 and bcl-2, respectively. MIB-1 immunoreactivity ranged from 2 to 35% of the neoplastic cells, with most tumors showing a proliferation index of >15%. Follow-up ranged from 3 to 30 months (mean, 17.6 mo). All patients except one were alive, although three patients developed metastases. Nested variant of urothelial carcinoma is a deceptively benign-appearing neoplasm with potential of deep invasion and metastases.

Immunohistochemically, nested variant of urothelial carcinoma shares some features with high-risk conventional urothelial carcinomas, such as loss of p27 expression and high proliferation index. Nevertheless, p53, bcl-2, or EGF-r immunoreactivity is not frequently seen.
Plasmacytoid Transitional Cell Carcinoma of Urinary Bladder: A Clinicopathologic Study of 9 Cases.

*Department of Pathology, The Methodist Hospital and Weill Medical College of Cornell University, Houston, TX †Asan Medical Center §Yonsei University College of Medicine ¶Catholic University, St Maryʼs Hospital, Seoul ∥Paik Hospital, University of Inje, Pusan, Korea ‡National Cancer Center, Goyang, Geongido.

Am J Surg Pathol. 2008 May;32(5):752-757 Abstract quot

In this report, we summarized the clinicopathologic features of 9 cases of plasmacytoid transitional cell carcinoma (TCC) of the urinary bladder, a rare variant of TCC. All 9 patients were men with a mean of age 64.3 years (range, 46 to 81 y). All but 1 patient presented with gross hematuria; the remaining patient had urgency and microscopic hematuria.

Cystoscopic findings revealed a dominant solid mass with surrounding multiple papillary lesions in 6 cases and multiple masslike lesions in 3 other cases. The initial diagnosis of plasmacytoid TCC was made on transurethral resection in 8 cases and cystoscopic biopsy in 1. One patient had TNM stage I disease, 2 had stage II disease, 3 had stage III disease, and 3 had stage IV disease. Four patients were treated by radical cystectomy with chemotherapy, 2 by radical cystectomy alone, 1 each by chemotherapy or intravesical bacillus Calmette-Guerin infusion alone, and 1 did not receive any further therapy. Microscopically, all tumors contained plasmacytoid cells, which composed 30% to 100% of the entire tumor. Eight of 9 cases were associated with high-grade TCC, and transitional cell carcinoma in situ was present in 4 cases. The plasmacytoid tumor cells were characterized by eccentrically located nuclei and abundant eosinophilic cytoplasm. Interestingly, plasmacytoid transitional cell carcinoma in situ was noted in 1 case.

Immunohistochemical staining demonstrated that both plasmacytoid and conventional TCC components were positive for cytokeratins 7 and 20. The mean Ki-67 labeling index was 30% (range, 10% to 50%), and p53 expression in the majority of cases was low (5% to 10%), except for in 2 cases (70% and 80%). The mean follow-up in 8 patients was 24.5 months (range, 5 to 47 mo); the other patient was lost to follow-up. Five patients died of disease from 5 to 36 months, 2 patients were alive with disease at 30 and 47 months, and 1 patient was alive and well at 36 months with no evidence of disease.

In summary, plasmacytoid TCC tends to present at an advanced stage and to have a poor prognosis. Morphologic recognition and distinction from other plasmacytoid malignant neoplasms is critical for its clinical management and immunohistochemical studies may be required for differential diagnosis.
Urothelial carcinoma with rhabdoid features: report of 6 cases.

Parwani AV, Herawi M, Volmar K, Tsay SH, Epstein JI.

Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, PA, USA.


Hum Pathol. 2006 Feb;37(2):168-72. Abstract quote  

Extrarenal rhabdoid tumors have been described in a variety of primary sites with only rare case reports of urothelial carcinomas with rhabdoid features in the literature.

In this report, we describe the clinicopathologic characteristics, including clinical follow-up on 6 cases of urothelial carcinoma with prominent rhabdoid features. Four cases were retrieved from the consultation files of one of the authors and 2 were retrieved from the surgical pathology files at our institution. The patients were all men, with ages ranging from 53 to 86 years (mean, 66.5 years). Patients initially presented with hematuria or obstructive symptoms. The sites included bladder (n = 4) and renal pelvis (n = 2). All cases had a prominent rhabdoid component (mean, 60%), ranging from 40% to 80%. In addition to the rhabdoid component, multiple coexistent histological components were seen, including in situ urothelial carcinoma (carcinoma in situ) and high-grade papillary urothelial carcinoma (n = 2), poorly differentiated carcinoma with small-cell features (n = 1), sarcomatoid (n = 2), and a myxoid component (n = 2).

All cases in this series had focal or diffuse positive staining with one or more cytokeratin markers (epithelial membrane antigen, CAM 5.2, AE1/AE3). Of the 6 patients, 4 were treated initially with surgery (radical cystoprostatectomy, n = 2; radical nephrectomy, n = 2). Of 6 patients, 2 died within 1 month, whereas a third patient died within 4 months. The remaining 3 patients were alive at 3, 3, and 9 months after diagnosis.

The histological and immunohistochemical findings in this study serve to broaden the morphological spectrum of urothelial carcinomas with prominent rhabdoid features and add further evidence as to their poor prognosis.

Sarcomatoid carcinoma of the urinary bladder. A clinicopathologic analysis of 12 cases and review of the literature.

Young RH, Wick MR, Mills SE.

Department of Pathology, Harvard Medical School, Boston, Massachusetts.

Am J Clin Pathol 1988 Dec;90(6):653-61 Abstract quote

Twelve carcinomas of the urinary bladder with a prominent component of spindle-shaped cells (sarcomatoid carcinomas) that arose in patients from 60 to 83 (average, 71.5 years) years of age are reported.

The seven male and five female patients typically complained of hematuria. Seven tumors were sessile and five were polypoid. On microscopic examination, the malignant spindle cells merged with in situ transitional cell carcinoma or various forms of invasive carcinoma, including transitional cell carcinoma (11 cases), adenocarcinoma (2 cases), squamous cell carcinoma (2 cases), and small cell undifferentiated carcinoma (2 cases). Immunocytochemical stains were performed in 11 cases; the spindle cells stained for cytokeratin, epithelial membrane antigen, and vimentin.

Limited follow-up in this series does not allow for conclusions concerning differences in behavior between sarcomatoid carcinoma and conventional transitional cell carcinoma of similar grade and stage. However, the typically deep invasion of the former tumors and their histologic features indicate that they are highly aggressive neoplasms.

Sarcomatoid carcinoma of the urinary bladder. Clinicopathologic analysis of 18 cases with immunohistochemical and electron microscopic findings.

Torenbeek R, Blomjous CE, de Bruin PC, Newling DW, Meijer CJ.

Department of Pathology, Free University Hospital, Amsterdam, The Netherlands.

Am J Surg Pathol 1994 Mar;18(3):241-9 Abstract quote

Sarcomatoid carcinoma is a rare tumor in the urinary bladder and accounts for approximately 0.3% of all bladder malignancies.

In this study, the clinicopathologic findings of 18 cases are described. Distribution of sex and age and clinical symptoms are not distinctive from transitional cell carcinoma. The tumor behaves as a high-grade malignancy with advanced initial stage and unfavorable outcome. Surgery is the therapy of choice.

Histological differentiation from true sarcoma may be difficult. Recognition rests on the co-existence of an overt carcinomatous component or demonstration of the epithelial nature by immunohistochemistry or electron microscopy.

Sarcomatoid carcinoma of the urinary bladder: a clinicopathologic and immunohistochemical analysis of 14 patients.

Ikegami H, Iwasaki H, Ohjimi Y, Takeuchi T, Ariyoshi A, Kikuchi M.

Department of Pathology and Urology, School of Medicine, Fukuoka University, Japan.

Hum Pathol 2000 Mar;31(3):332-40 Abstract quote

Sarcomatoid carcinoma of the urinary bladder is a rare entity, in which both the histogenesis and biological behavior remain controversial.

We herein describe the clinicopathologic and immunohistochemical profiles of sarcomatoid carcinomas and discuss the significance of cell adhesion molecules in the development of this peculiar neoplasm. The authors examined formalin-fixed and paraffin-embedded tissue samples from 14 patients with sarcomatoid carcinoma of the urinary bladder. An immunohistochemical analysis was performed by using antibodies against epithelial and mesenchymal antigens as well as adhesion molecules. Most patients suffered from an advanced stage of the tumor, extending to the muscular layer (7 cases) or to the perivesical tissues (5 cases).

Microscopically, all 14 tumors were composed predominantly of a carcomatoid component and an obviously carcinomatous component. The sarcomatoid component was composed of a mixture of spindle cells, round cells, and pleomorphic giant cells. The carcinomatous components consisted of papillary or nonpapillary high-grade transitional cell carcinoma (TCC). The zones of gradual transition between the carcinomatous and the sarcomatous elements were focally apparent in each tumor.

The findings of an immunohistochemical examination indicated that both carcinomatous and sarcomatoid components expressed epithelial antigens (pankeratin or EMA), even though the staining pattern varied from case to case. As for cell adhesion molecules, the carcinomatous components were positive for E-cadherin (8 of 12), CD44s (8 of 12), and CD44v6 (6 of 12). Although the sarcomatoid components were also positive for E-cadherin (5 of 12), CD44s (4 of 12), and CD44v6 (3 of 12), these rates were lower than those in the carcinomatous components. Six patients died of their disease between 5 and 36 months after the diagnosis was made.

The recognition of sarcomatoid carcinomas has important therapeutic and prognostic implications. It seems appropriate to treat these neoplasms in the same manner as conventional high-grade TCCs with similar degrees of invasion.

We consider that sarcomatoid carcinomas should be regarded as a high-grade carcinoma that shows a prominent pseudosarcomatous dedifferentiation. The sarcomatoid component of sarcomatoid carcinomas may result from either anaplastic changes or dedifferentiation related to the process of losing cell adhesion molecules.

Sarcomatoid carcinoma of urinary bladder: immunohistochemical study of an uncommon case.

Cappello F, Aragona F, Serretta V, Randazzo G, Melloni D.

Institute of Pathological Anatomy, University of Palermo, Italy.

Urol Int 2002;69(2):141-4 Abstract quote

A case of sarcomatoid carcinoma of the bladder is reported herein. Immunohistochemical staining with human pancytokeratin antibody was negative, while vimentin staining was strongly positive, suggesting a diagnosis of sarcoma of the bladder. Further immunohistochemical analysis revealed positivity for AE1/AE3 cytokeratins, permitting a correct diagnosis of sarcomatoid carcinoma of the bladder.

It can be difficult to distinguish between sarcomatoid carcinoma, undifferentiated carcinoma and sarcoma, particularly if the biopsy specimens are of small size.

In rare cases, sarcomatoid tumors may express epithelial markers different from those revealed by human pancytokeratin staining.

Variant of adenocarcinoma with predominately signet rings
Usually diffusely infiltrating and high stage
SQUAMOUS CELL CARCINOMA Infiltrative nests and islands of pleomorphic squamous epithelial cells-graded well, moderately, and poorly differentiated
Squamous Cell Carcinoma of the Bladder: A Clinicopathologic Analysis of 45 Cases.

Departments of *Anatomic Pathology †Urology ‡Oncology, The Cleveland Clinic, Cleveland, OH.


Am J Surg Pathol. 2007 Dec;31(12):1777-1787. Abstract quote

Squamous cell carcinoma of the bladder comprises less than 5% of all bladder cancers in the United States and its long-term prognosis has remained controversial.

We examined a large series of patients who underwent radical and partial cystectomies for squamous cell carcinoma to identify associated histopathologic findings and clinical outcomes associated with these tumors. Patient age ranged from 46 to 83 years (average 68.5 y) with a male:female ratio of 3:2. Forty-three patients were white and 2 patients were African-American. No patient had a history of schistosomal infection and only 1 patient had a history of condyloma acuminatum. The majority of patients with reported signs and symptoms presented with hematuria (n=29/34), with the remainder presenting with lower urinary tract symptoms.

Tumor size ranged from 0.8 to 6.4 cm (average 3.8 cm). Invasion was identified into the lamina propria (pT1, n=1/45), muscularis propria (pT2, n=14/45), perivesical fat (pT3, n=27/45), and adjacent structures (pT4, n=3/45). Concurrent metastases were identified in 11 of 45 patients (24%) to pelvic lymph nodes (n=9), perivesical lymph nodes (n=3), obturator lymph nodes (n=1), and bowel wall (n=1).

Most tumors were moderately (n=29/45) or poorly (n=13/45) differentiated, whereas only 3 tumors were well differentiated (n=3/45). Keratinization was present in all cases within the invasive component and ranged from 5% to 95% of tumor bulk. Necrosis ranged from 0% to 60% and inversely correlated with tumor differentiation. Eighteen cases demonstrated a prominent giant cell reaction to keratin, and 30 tumors were associated with a desmoplastic reaction. Extensive perineural (n=11/45) and angiolymphatic invasion (n=7/45) were identified in a subset of tumors.

The majority of cases demonstrated associated superficial lesions including keratinizing squamous metaplasia (n=28/45), nonkeratinizing squamous metaplasia (n=20/45), squamous cell carcinoma in situ (n=16/45), squamous metaplasia with dysplasia (n=4/45), verrucous squamous hyperplasia (n=3/45), and extensive condyloma acuminatum (n=1/45).

Seven cases additionally demonstrated separate small foci of focal flat urothelial carcinoma in situ. Three cases demonstrated a markedly atypical squamous lining of the prostatic ducts at the prostatic urethra.

Clinical follow-up was available on 35 patients (78%) and ranged from 1 to 175 months (average 33 mo, median 15 mo). Two patients developed recurrent local disease (n=2/35, 6%) and 13 patients developed subsequent metastatic disease (n=13/35, 37%). Ten patients were dead of disease (29%), with a time to death for most patients of less than 2 years (range 2 to 21 mo, average 10.5 mo). Thirty-seven percent of patients (n=13/35) were alive without disease.

In conclusion, squamous cell carcinoma often presents at an advanced stage; however, radical cystectomy with lymph node dissection appears to offer a significant benefit in survival in a subset of patients.
Noninvasive Squamous Lesions in the Urinary Bladder: A Clinicopathologic Analysis of 29 Cases.

Guo CC, Fine SW, Epstein JI.

Departments of *Pathology daggerUrology double daggerOncology, The Johns Hopkins University School of Medicine, Baltimore, MD.

Am J Surg Pathol. 2006 Jul;30(7):883-891. Abstract quote  

Noninvasive squamous lesions are distinctively uncommon in biopsies of the urinary bladder with the exception of nonkeratinizing squamous metaplasia. The clinical significance of these squamous lesions in the bladder remains to be explored.

A total of 29 cases of transurethral biopsies and resections of the bladder containing noninvasive squamous lesions (excluding nonkeratinizing metaplasia) were studied from the consult files of one of the authors. These cases included keratinizing squamous metaplasia (5), verrucous squamous hyperplasia (5), squamous papilloma (5), condyloma acuminatum (3), and squamous cell carcinoma in situ (CIS) (11). Immunohistochemistry for epithelial growth factor receptor (EGFR) and in situ hybridization for wide-range human papillomavirus was performed on 23 cases. The follow-up period ranged from 2 months to 3 years with an average of 1.5 years. After the initial diagnoses in biopsies of the bladder, 10 patients received cystectomies, and 7 patients received repeat tissue sampling of the bladder.

Of the 5 patients with keratinizing squamous metaplasia, 2 patients had invasive urothelial carcinoma with squamous features in their cystectomy specimens at intervals of 3 and 14 months, respectively, 1 had persistent keratinizing squamous metaplasia on rebiopsy. Of the 5 patients with verrucous squamous hyperplasia, 1 patient had invasive squamous cell carcinoma at cystectomy at an interval of 14 months, 1 had squamous cell CIS on rebiopsy, 1 had persistent verrucous squamous hyperplasia on rebiopsy, and 2 had no evidence of disease at 6 and 24 months. Of the 5 patients with squamous papilloma, 1 patient had low-grade urothelial carcinoma at cystectomy at an interval of 21 months (h/o low-grade urothelial carcinoma preceding papilloma diagnosis), 2 were free of lesions at rebiopsy. Of the 3 patients with condyloma acuminatum, 1 had squamous CIS at cystectomy at an interval of 3 months, 1 had invasive squamous cell carcinoma at 20 months.

Of the 11 patients with squamous cell carcinoma in situ (CIS), 3 patients had invasive squamous cell carcinoma at intervals of 2, 3, and 4 months, respectively, 1 had invasive urothelial carcinoma with squamous features in cystectomies at an interval of 12 months, 1 had squamous cell CIS at 10 months, 1 had high-grade urothelial carcinoma (not otherwise specified) at rebiopsy at an interval of 6 months, and 1 had no evidence of disease at 8 months. Among the 9 patients with invasive carcinoma, 4 patients died in the period of 0.5 to 3 years after the diagnoses.

Immunohistochemical study with EGFR demonstrated strong signals in 20 cases and no signals in 2 cases. Wide-range human papillomavirus DNA signal was detected in 1 case of condyloma acuminatum and 1 case of squamous cell CIS. Keratinizing squamous metaplasia, verrucous squamous hyperplasia, and condyloma acuminatum in the urinary bladder can be associated with subsequent or concurrent in situ, or invasive squamous carcinoma and should be closely followed.

Squamous cell CIS in the urinary bladder is often associated with subsequent or concurrent invasive carcinoma with squamous differentiation. Enhanced expression of EGFR in these bladder squamous lesions suggests that EGFR may represent a logic therapeutic target in those squamous lesions that are difficult to manage clinically.

Muscle invasive schistosomal squamous cell carcinoma of the urinary bladder: frequency and prognostic significance of p53, BCL-2, HER2/neu, and proliferation (MIB-1).

Badr KM, Nolen JD, Derose PB, Cohen C.

Urology Department, Minia Faculty of Medicine, Minia University, Abb Assia, Cairo, Egypt.
Hum Pathol. 2004 Feb;35(2):184-9 Abstract quote.

Muscle invasion is the usual presentation of schistosomal squamous cell carcinoma of the urinary bladder. It is unclear whether this invasive behavior is secondary to the aggressive nature of the disease or to delay in diagnosis.

Fixed paraffin-embedded hematoxylin and eosin-stained sections of 15 cystectomy specimens from 15 patients (14 males, 1 female) (age range, 40 to 67 years), histologically confirmed as schistosomal squamous cell carcinoma, were assessed for grade (G1, n = 3; G2, n = 7; G3, n = 5) and pathological stage (PT category: PT2, n = 4; PT3a, n = 9; PT3b, n = 2). Immunostaining was performed for mutant p53, bcl-2, HER2/neu, and MIB-1 (proliferation), using steam antigen retrieval and an avidin-biotin complex method. Frequency of strong immunoreactivity was high for mutant p53 (73%) and MIB-1 (87% intermediate or high) but low for bcl-2 (20%) and HER2/neu (27%). There was no significant correlation of any of the four markers with either grade or stage.

Hence, schistosomal bladder squamous cell carcinoma is felt to be an aggressive carcinoma de novo. The high frequency of mutant p53 expression (73%) and an intermediate to high proliferation index (87%) suggests this. The lack of correlation between histological grade and all four markers studied suggests that grading is not of prognostic value.
Osteoclast-rich undifferentiated carcinomas of the urinary tract.

Baydar D, Amin MB, Epstein JI.

1Department of Pathology, The Johns Hopkins University School of Medicine, The James Brady Urological Institute, The Johns Hospital, Baltimore, MD, USA.

Mod Pathol. 2006 Feb;19(2):161-71. Abstract quote  

Osteoclast-like giant-cell neoplasms of the urinary tract are rare. They are composed of ovoid or spindle-shaped mononuclear cells with evenly spaced osteoclast-like giant cells. Terminology, histogenesis, and biologic behavior of these tumors remain controversial.

Six cases of osteoclast-like giant-cell neoplasms of the urinary tract were identified from the consultation files of two of the authors. Patients were all male and elderly (range 65-82), with the exception of one 39-year-old male. In all, 3/6 tumors developed in the bladder and 3/6 in the renal pelvis. Size ranged from 5 to 11 cm. One bladder and three renal pelvis tumors were high stage (pT3) at time of presentation. Adjacent to the osteoclast-like giant-cell neoplasm in the same specimen, all patients had urothelial carcinoma in situ and/or high-grade papillary urothelial carcinoma.

Multinucleated cells had identical morphological and immunohistochemical properties of osteoclasts; positive for CD-68, LCA, CD51 and CD54, and negative for cytokeratins and EMA. Varying percentages of mononuclear cells expressed alpha-smooth muscle actin (4/6), desmin (1/6), S-100 (4/6), LCA (2/6) and CD68 (6/6). However, mononuclear cells were also positive for epithelial markers in 4/6 tumors (cytokeratins AE-1/AE-3, Cam 5.2, CK7 and/or EMA). p53 stained mononuclear tumor cells in three cases, paralleling the staining on the accompanying urothelial carcinoma. Ki-67 stained mononuclear tumor cells, but not osteoclast-like giant cells. Follow-up data were available in five cases. One patient developed recurrence of noninvasive urothelial carcinoma and is still alive. Four patients were dead due to disease within 15 months, three with distant metastases.

The intimate association of these tumors with urothelial carcinoma along with their immunohistochemical profile supports an epithelial origin for the mononuclear cells and non-neoplastic reactive histiocytic lineage for the osteoclast-like giant cells.
Variant of squamous cell carcinoma with acanthotic rounded pushing margins
Indistinguishable from villous adenomas of the colon
Most associated with urachal remnants
Invasive tumors have been identified


Special stains  

Potential Utility of Uroplakin III, Thrombomodulin, High Molecular Weight Cytokeratin, and Cytokeratin 20 in Noninvasive, Invasive, and Metastatic Urothelial (Transitional Cell) Carcinomas.

Parker DC, Folpe AL, Bell J, Oliva E, Young RH, Cohen C, Amin MB.

Am J Surg Pathol 2003 Jan;27(1):1-10 Abstract quote

The morphology of urothelial carcinomas, particularly when poorly differentiated or in metastatic sites, is not distinctive and overlaps significantly with other poorly differentiated nonurothelial carcinomas. Currently, there is no widely used single marker or panel of markers to confirm urothelial origin.

We evaluated a panel consisting of antibodies to uroplakin III (UROIII), thrombomodulin (THR), high molecular weight cytokeratin (HMWCK), and cytokeratin 20 (CK20) in a wide range of urothelial tumors.

Immunohistochemistry was performed on 112 paraffin-embedded urothelial neoplasms: 14 low malignant potential, 16 low-grade noninvasive, 16 high-grade noninvasive, 36 invasive, and 25 metastatic and 5 small cell carcinomas of the urinary bladder. Tissue microarray analysis was used to examine 498 tissue cores of nonurothelial tumors and normal tissue using antibodies to UROIII, THR, and HMWCK. Overall positive staining results in all urothelial tumors are as follows: UROIII, 64 of 112 (57.1%); THR, 77 of 112 (68.8%); HMWCK, 88 of 110 (80%); and CK20, 53 of 110 (48.2%). The expression of the four markers varied with tumor grade and stage.

All small cell carcinomas were negative for all markers. Variant morphologic subtypes showed similar staining as conventional urothelial carcinomas. Tissue microarray analysis showed no UROIII immunoreactivity in tissue cores of nonurothelial tumors. THR was expressed by a limited number of nonurothelial cores (10 of 37 [27%] non-small cell lung carcinomas, 2 of 36 [5.6%] lymphomas). HMWCK was expressed by 43.8% of non-small cell lung carcinomas and essentially absent in other nonurothelial tumor cores. Based on the results of the study, the expression of UROIII in a tumor is essentially diagnostic of urothelial origin; however, it is expressed in only slightly more than half of urothelial tumors.

The coexpression of THR, HMWCK, and CK20 strongly suggests urothelial origin. The coexpression of two of three non-UROIII markers (THR, HMWCK, CK20) suggests urothelial origin but requires clinicopathologic correlation.

The results of the study indicate a role for an antibody panel that includes UROIII, THR, HMWCK, and CK20 in the diagnosis of urothelial tumors.

CD117 (c-kit)  
c-kit Expression in small cell carcinoma of the urinary bladder: prognostic and therapeutic implications.

Pan CX, Yang XJ, Lopez-Beltran A, Maclennan GT, Eble JN, Koch MO, Jones TD, Lin H, Nigro K, Papavero V, Tretiakova M, Cheng L.

1Department of Medicine, Indiana University, Indianapolis, IN, USA.

Mod Pathol. 2005 Mar;18(3):320-3. Abstract quote  

The prognosis for small cell carcinoma of the urinary bladder is poor, and strategies for improved therapy are needed. Targeted therapy against the c-kit proto-oncogene has been successful in the management of gastrointestinal stromal tumor.

We investigated the expression of c-kit in 52 cases of small cell carcinoma of the urinary bladder. Specimens with more than 10% of cells demonstrating strong membrane staining were considered to have positive immunostaining for c-kit. c-kit expression was detected in 21 of 52 specimens from these patients. Among the 21 specimens, seven had less than 10% staining, and were considered to be negative. Nine had 11-50% staining, and five had more than 50% staining. Overall, 14 of 52 (27%) small cell carcinomas of the urinary bladder were positive for c-kit expression. During a median follow-up of 11 months, 60% of the patients died of bladder cancer. No association was found between c-kit expression and survival or other clinicopathologic parameters.

Five-year cancer-specific survivals for c-kit-positive and c-kit-negative tumors were 9 and 15%, respectively (P=0.36). A significant proportion (27%) of small cell carcinomas of the urinary bladder expressed c-kit, suggesting that it may prove useful as a therapeutic target in small cell carcinoma of the urinary bladder.

Expression of c-erbB-2 and cytokeratins 7 and 20 in urothelial carcinoma with gland-like lumina.

Fernandez-Flores A, Manzarbeitia F, Alonso JG.
Ann Diagn Pathol. 2003 Oct;7(5):281-4 Abstract quote.  

Urothelial carcinoma with gland-like lumina is an uncommon type of tumor, reported only occasionally in literature. Its diagnosis usually does not offer any difficulties, and its prognosis is determined by the accompanying classic transitional or squamous component.

It is important though, not to misdiagnose it as a mixed transitional cell adenocarcinoma. In that respect, features such as the type of epithelium lining, the gland-like structures, as well as the type of luminal mucin have been used to make the diagnosis. Recently, an immunohistochemical panel of antibodies has proven helpful in differentiating primary and metastatic adenocarcinomas of urothelial tract from urothelial carcinoma with gland differentiation. In their series of 16 cases, Tamboli et al included only one case of transitional cell carcinoma with gland differentiation.

We present two additional cases of urothelial carcinoma with gland-like lumina in two men, 60 and 79 years old, respectively. Both tumors were grade 2 of Ash-Bergkvist, and the stage was pT(1) in both cases. Immunohistochemical study with cytokeratins 7 and 20, and with c-erbB-2, was performed. Both tumors expressed cytokeratins 7 and 20; c-erbB-2 was only expressed in one, in spite of the same staging.

Although some relation has been found in animals between gland-like lumina phenotype and expression of epidermal growth factor (the receptor of which is homologous to c-erbB-2), it seems that this relationship might not be constant in humans.

Cytokeratin 7 and Cytokeratin 20 in Primary Urinary Bladder Carcinoma and Matched Lymph Node Metastasis

Jiazhong Jiang, MD, PhD, Thomas M. Ulbright, MD, Cheryl Younger, MD, Katya Sanchez, MD, David G. Bostwick, MD, Michael O. Koch, MD, John N. Eble, MD, and Liang Cheng, MD

From the Departments of Pathology (Drs Jiang, Ulbright, Younger, Sanchez, Eble, and Cheng) and Urology (Drs Koch and Cheng), Indiana University School of Medicine, Indianapolis, Ind; and the Bostwick Laboratories, Richmond, Va (Dr Bostwick).

Arch Pathol Lab Med 2001;125, No. 7:921–923. Abstract quote

Background.—Cytokeratin 7 (CK7) and cytokeratin 20 (CK20) are 2 types of intermediate filament protein. Expression of CK7 is seen in the majority of primary urinary bladder carcinomas. CK20 is restricted to superficial and occasional intermediate cells of the normal urothelium of the bladder. Aberrant CK20 expression has been documented in urothelial carcinoma and has proved useful as an ancillary diagnostic aid for urinary bladder tumor. Our hypothesis is that the pattern of CK7 and CK20 expression in metastatic urothelial carcinoma duplicates the expression of the same markers in the primary tumors. Therefore, immunohistochemical staining of metastatic tumors for these 2 markers may be helpful for differential diagnosis in ambiguous metastatic tumor deposits.

Objective.—To determine the concordance of CK7 and CK20 expression in primary bladder urothelial carcinoma and the matched lymph node metastasis.

Design.—We studied 26 patients with lymph node metastases who underwent radical cystectomy and bilateral lymphadenectomy for bladder carcinoma. Immunohistochemical staining for CK7 and CK20 was performed on formalin-fixed paraffin-embedded tissues containing primary cancers and lymph node metastases.

Results.—In all cases, there was a concordant expression of CK20 in the primary cancer and its matched lymph node metastasis. Twelve cases (46%) showed positive CK20 immunoreactivity in the primary tumor and its matched lymph node metastases, whereas 14 cases (54%) were negative for CK20 in both the primary tumor and lymph node metastasis. All cases showed positive CK7 immunoreactivity in the primary cancers and matched lymph node metastases.

Conclusions.—CK20 immunoreactivity is reliably observed in metastases from bladder cancer when the primary tumor expresses CK20.


E-cadherin expression in urothelial carcinoma in situ, superficial papillary transitional cell carcinoma, and invasive transitional cell carcinoma.

Sun W, Herrera GA.

Department of Pathology, Louisiana State University Health Sciences Center, Shreveport, LA.

Hum Pathol 2002 Oct;33(10):996-1000 Abstract quote

Flat urothelial carcinoma in situ (CIS) is a precursor of invasive transitional cell carcinoma (TCC). High-grade TCCs frequently are accompanied by CIS in surrounding urothelium.

In contrast, superficial, noninvasive papillary TCCs are often low grade and generally are unaccompanied by CIS. E-cadherin (E-CD) is a member of a family of transmembrane glycoproteins involved in intercellular adhesion. Loss or decreased expression of E-CD has been linked to the invasive phenotype of a wide variety of human neoplasms, including bladder tumors.

The objective of this study was to compare the expression of E-CD in high-grade urothelial dysplasia (HD)/CIS, superficial papillary TCC, benign urothelium, and invasive TCC. Staining for E-CD was performed in formalin-fixed, paraffin-embedded sections using a Ventana NexES immunostainer (Tuscon, AZ). Percentage and intensity of cell membrane staining for E-CD was calculated for the 4 groups using the quantitative Automatic Cellular Imaging System (ChromaVision, San Juan Capistrano, CA).

The results were as follows: The CIS group (n = 23) had percentage and intensity (92.8%, 120.0 U) of E-CD expression similar to the superficial noninvasive papillary TCC group (n = 16, 97.8%, 123.0 U) and the benign urothelium group (n = 17, 87.9%, 104.6 U), but it had statistically significant higher percentage and intensity than the invasive TCC group (n = 15, 45.4%, and 39.2 U, P <.05).

Our data indicate that CIS and superficial, noninvasive papillary TCCs strongly express E-CD. In contrast, loss of E-CD expression is associated with the invasive TCC phenotype. Only when TCCs become invasive does E-CD expression decrease in directly proportion to the depth of invasion.

Invasive Potential of "Noninvasive" Human Bladder Carcinoma
An Electron Microscopy Study

Peter J. Effert, MD and Peter Seifert, PhD

Am J Clin Pathol 2003;120:188-193 Abstract quote

In classification systems for bladder tumors, a clear distinction between superficial noninvasive and urothelial carcinoma invasive to the lamina propria is of prognostic and therapeutic significance. However, a subset of tumors classified as noninvasive is characterized by increased recurrence and progression rates.

This study was done to look for ultrastructural characteristics in histopathologically noninvasive urothelial bladder carcinomas that might predict an unfavorable prognosis. In 10 (83%) of 12 bladder tumors studied extensively, electron microscopy revealed the presence of different degrees of lamina propria penetration by individual tumor cells (microlesions and microinvasions). In 10 (77%) of 13 "normal" control tissues, no such lesions or microinvasions were detected. These findings indicate that ultrastructural analysis may contribute to more precise staging of superficial bladder carcinoma.

Undetected microinvasions may explain more aggressive biologic behavior in a subset of bladder tumors classified as noninvasive by conventional histopathologic assessment.



Immunohistochemical Distinction Between Primary Adenocarcinoma of the Bladder and Secondary Colorectal Adenocarcinoma

Hanlin L. Wang, M.D. , Ph.D. ; Danielle W. Lu, M.D. ; Lisa M. Yerian, M.D. ; Nejd Alsikafi, M.D. ; Gary Steinberg, M.D. ; John Hart, M.D. ; Ximing J. Yang, M.D. , Ph.D.

From the Departments of Pathology (H.L.W., L.M.Y., J.H., X.J.Y.) and Surgery/Urology (N.A., G.S., X.J.Y.), University of Chicago Hospitals, Chicago, Illinois; and the Department of Pathology (H.L.W., D.W.L.), Washington University School of Medicine, St. Louis, Missouri, U.S.A.

Am J Surg Pathol 2001;25:1380-1387 Abstract quote

Primary adenocarcinoma of the urinary bladder sometimes causes a diagnostic dilemma because it can be indistinguishable morphologically from adenocarcinoma of colorectal origin secondarily involving the bladder by metastasis or direct extension. It is much less well studied than conventional urothelial carcinoma and colorectal adenocarcinoma because of its rarity. The current study was specifically designed to investigate whether an important mechanism involved in the pathogenesis of colorectal adenocarcinoma, -catenin dysregulation, was also important for the development of primary bladder adenocarcinoma and whether these two morphologically similar tumors could be distinguished immunohistochemically.

Formalin-fixed, paraffin-embedded tissues from 17 primary adenocarcinomas of the urinary bladder, 16 colorectal adenocarcinomas involving the bladder, and 10 conventional urothelial (transitional) carcinomas were included in this study. Thirteen of the primary bladder adenocarcinomas were moderately to well differentiated (enteric type) and morphologically indistinguishable from colorectal cancers. The remaining four primary tumors were poorly differentiated (two cases) or of clear cell type (two cases). Immunohistochemical studies using a panel of monoclonal antibodies demonstrated positive nuclear staining for -catenin expression in 13 of the 16 (81%) colorectal adenocarcinomas secondarily involving the bladder but in none of the primary adenocarcinomas or the urothelial carcinomas. Instead, positive membranous (and some cytoplasmic) staining was present in all primary bladder tumors with the exception of two poorly differentiated adenocarcinomas where no -catenin staining was detected. All secondary colorectal adenocarcinomas stained negatively for CK7 and thrombomodulin (TM), whereas positivity for CK20 was observed in 15 (94%) cases. All urothelial carcinomas stained positively for CK7 and TM, and four of them also for CK20. Primary adenocarcinomas of the bladder showed mixed staining patterns for CK7, CK20, and TM with a positive rate of 65%, 53%, and 59%, respectively.

These data indicate that dysregulation of -catenin, an important aberration seen in colorectal carcinogenesis, does not appear to play a role in the pathogenesis of the bladder adenocarcinoma. In addition, our data demonstrate that a panel of immunostains, including CK7, CK20, TM, and -catenin, is of diagnostic value in differentiating primary bladder adenocarcinoma from secondary adenocarcinoma of colorectal origin.

Colonic adenocarcinoma metastatic to the urinary tract versus primary tumors of the urinary tract with glandular differentiation: a report of 7 cases and investigation using a limited immunohistochemical panel.

Tamboli P, Mohsin SK, Hailemariam S, Amin MB.

Department of Pathology, The University of Texas M. D. Anderson Cancer Center, Houston 77030, USA.

Arch Pathol Lab Med 2002 Sep;126(9):1057-63 Abstract quote

OBJECTIVE: To determine whether a limited immunohistochemical panel can help differentiate metastatic colonic adenocarcinoma from primary enteric-type adenocarcinoma of the urinary tract and urothelial (transitional cell) carcinoma with glandular differentiation, which appear morphologically similar but most often necessitate different treatment protocols.

DESIGN: We examined lower urinary tract tumors (5 urinary bladder, 2 urethral) from 7 patients with a history of colonic adenocarcinoma. The differential diagnoses in these cases included metastatic colonic adenocarcinoma, primary enteric-type adenocarcinoma of the urinary tract, and urothelial carcinoma with glandular differentiation. An immunohistochemical panel consisting of cytokeratin 7 (CK-7), cytokeratin 20 (CK-20), and villin was evaluated in all cases. Four primary enteric-type adenocarcinomas of the urinary tract and 5 conventional urothelial carcinomas were also studied to compare morphologic features and immunohistochemical staining patterns.

RESULTS: Of the 7 cases, 6 were determined to be metastatic colonic adenocarcinoma and 1 was diagnosed as a primary urothelial carcinoma with glandular differentiation. All 6 metastatic colonic adenocarcinomas, 6 of the 7 primary colonic adenocarcinomas, and all 4 primary enteric-type adenocarcinomas of the urinary tract were CK-20 positive (1 was CK-20 negative), villin positive, and CK-7 negative. The single urothelial carcinoma with glandular differentiation and all 5 control cases of urothelial carcinoma were CK-7 and CK-20 positive, and villin negative.

CONCLUSIONS: We conclude that (1) villin is expressed in primary enteric-type adenocarcinoma of the urinary tract; (2) in difficult cases, urothelial carcinoma with glandular differentiation can be distinguished from colonic adenocarcinoma because the former is CK-7 positive, CK-20 positive, and villin negative, whereas the latter is CK-20 positive, villin positive, and CK-7 negative; (3) clinical information is essential when evaluating lower urinary tract tumors that are clinically and morphologically similar to enteric-type adenocarcinoma of the urinary tract; and (4) the similar immunohistochemical profiles of metastatic colonic adenocarcinoma and primary enteric-type adenocarcinoma of the urinary tract may be in keeping with the hypothesis that the latter arise from intestinal metaplasia.


Prognostic significance of atypical papillary urothelial hyperplasia.

Swierczynski SL, Epstein JI.

Department of Pathology, The Johns Hopkins Hospital, Baltimore, MD 21231, USA.


Hum Pathol 2002 May;33(5):512-7 Abstract quote

Typical papillary hyperplasia, a recently recognized precursor lesion to low-grade papillary urothelial neoplasms, consists of undulating folds of cytologically benign urothelium. Well-developed, branching fibrovascular cores of a papillary neoplasm are not evident. We have noted lesions with the architectural pattern of papillary hyperplasia; however, the overlying urothelium demonstrated varying degrees of cytologic atypia.

We identified 15 cases of atypical papillary hyperplasia (13 males, 2 females, age 55 to 92) with overlying urothelium showing cytologic atypia. Of these cases, 8 (53%) were received in consultation. Of the 15 cases, 8 exhibited overlying flat carcinoma in situ (CIS), 4 had overlying dysplasia, and 3 were transitional between papillary hyperplasia with atypia and the earliest lesions of papillary neoplasia. Of these cases, 5 patients had multiple specimens with atypical papillary hyperplasia (range, 2 to 8) over time. Concurrent to the diagnosis of atypical papillary hyperplasia, there were 25 different urothelial lesions: CIS (n = 11), papilloma (n = 1), papillary neoplasm of low malignant potential with CIS (n = 1), high-grade papillary urothelial carcinoma (n = 10; 3 with CIS), small-cell carcinoma (n = 1), and infiltrating urothelial carcinoma (n = 1). Of 11 patients with known prior history, 2 had 12 prior urothelial neoplasms (9 low-grade papillary neoplasms, 2 papillary urothelial neoplasms of low malignant potential, and 1 high-grade papillary cancer). Of 10 patients with atypical papillary hyperplasia and a minimum of 1 year of follow-up, 9 had 19 recurrences: CIS (n = 4), papilloma (n = 1), papillary neoplasm of low malignant potential (n = 1), infiltrating urothelial carcinoma (n = 3; 1 with CIS), and high-grade papillary urothelial carcinoma (n = 10; 5 with invasion and 2 with CIS). Whether the papillary hyperplasia had overlying CIS or dysplasia did not affect the correlation with urothelial neoplasms. Immunohistochemical analysis of p53 and Ki-67 expression in 8 cases demonstrated overexpression of p53 (n = 2; 1 with overlying dysplasia and 1 with overlying CIS), and Ki-67 (n = 5; 2 with overlying dysplasia and 3 with overlying CIS).

Taken together, these results suggest that atypical papillary hyperplasia is most frequently associated with CIS and high-grade papillary cancer. In some cases, CIS or dysplasia may evolve into atypical papillary hyperplasia, with further progression to high-grade papillary cancer. This process may be analogous to papillary hyperplasia without cytologic atypia progressing to low-grade papillary urothelial neoplasms.


Invasive micropapillary carcinoma of the breast metastatic to the urinary bladder and endometrium: Diagnostic pitfalls and review of the literature of tumors with micropapillary features.

Ramalingam P, Middleton LP, Tamboli P, Troncoso P, Silva EG, Ayala AG.

Department of Pathology, The University of Texas M. D. Anderson Cancer Center, Houston, TX.


Ann Diagn Pathol 2003 Apr;7(2):112-9 Abstract quote

Carcinomas with micropapillary features have been described in the breast, urinary bladder, lung, and ovary. They are characterized by the presence of micropapillary tufts in clear spaces. Unequivocal vascular invasion is usually present at the periphery of the tumor. Consequently, these tumors have a high propensity for lymph node metastases and high-stage disease. The metastatic carcinoma can consist exclusively of the micropapillary component, which may elicit an erroneous diagnosis if located in the bladder or lung, as in the patient presented herein.

We present a case of a 59-year-old woman with a history of bilateral breast carcinoma status post-bilateral mastectomy, chemotherapy, and tamoxifen therapy. She presented with urinary frequency, and a pelvic mass was noted. A biopsy of the endometrium revealed a poorly differentiated carcinoma. Urinary bladder biopsies showed a carcinoma with micropapillary features diagnosed as micropapillary transitional cell carcinoma. She presented to M.D. Anderson Cancer Center (Houston, TX) for further treatment recommendations.

The urinary bladder and endometrial biopsies both contained carcinomas with micropapillary features. The mastectomy specimen showed an invasive ductal carcinoma with a significant micropapillary component. The tumor cells from the breast, endometrium, and urinary bladder were positive for cytokeratin (CK) 7 and estrogen receptor and negative for CK20. In view of the morphologic and immunohistochemical profile, the carcinoma in the endometrium and urinary bladder were interpreted as metastatic lesions from the breast primary.

Carcinomas with a micropapillary component are morphologically identical in the breast, urinary bladder, and lung. However, micropapillary serous carcinoma has a different appearance more akin to borderline tumors of the ovary. Immunohistochemical stains are useful in distinguishing these lesions in that thyroid transcription factor-1 positivity suggests a lung primary, CK7 and estrogen receptor suggest a breast primary, and both CK7 and CK20 positivity suggest a urinary bladder primary. It is important to exclude metastatic carcinomas with micropapillary features before making a definite diagnosis of a primary tumor.

Carcinomas with micropapillary features have a propensity for lymph node metastases and advanced stage disease. This article discusses the differential diagnosis of carcinomas with micropapillary features in different organs.

Polypoid/Papillary Cystitis: A Series of 41 Cases Misdiagnosed as Papillary Urothelial Neoplasia.

Departments of *Pathology †Urology ‡Oncology, The Johns Hopkins Hospital, Baltimore, MD.


Am J Surg Pathol. 2008 May;32(5):758-764. Abstract quote

Polypoid cystitis and its more chronic phase papillary cystitis, which results as a reaction to injury to the bladder mucosa, is a benign lesion mimicking various papillary urothelial neoplasms. Analogous lesions occur throughout the urothelial tract and are referred to as polypoid urethritis, polypoid ureteritis, and polypoid pyelititis when present in the urethra, ureter, and renal pelvis, respectively. For simplicity, these lesions in different sites and papillary cystitis will typically be referred to as polypoid cystitis in this manuscript.

A search of the consultation files from our institution from January 2000 to July 2007 was performed. Of 155 cases diagnosed as polypoid cystitis, we identified 41 cases that were diagnosed as papillary urothelial neoplasms by contributing pathologists and only sent to us, typically at the request of the urologist after the case had be signed out. For cases where information was available, clinical symptoms included bladder obstruction (n=7), gross hematuria (n=6), colovesicular fistula (n=4), follow-up status posttreatment of bladder and ureter carcinoma (n=4), bladder/urethral stones (n=2), benign prostate hyperplasia (n=2), follow-up after radiation for prostate cancer (n=2), long-standing urinary stents (n=2), and voiding dysfunction (n=1).

Original diagnoses included noninvasive low grade papillary urothelial carcinoma (n=23), noninvasive high grade papillary urothelial carcinoma (n=6), papillary urothelial neoplasm of low malignant potential (n=5), papilloma (n=3), urothelial neoplasia (n=2), carcinoma in situ (n=1), and squamous carcinoma (n=1). The mean age at diagnosis was 63 years (range, 19 to 93 y; median 63 y). Male to female ratio was 3.1 to 1. Clinical symptoms varied with the most common manifestations, including gross hematuria, bladder/urethral stones, history of prostate cancer treated with radiation, follow-up after bladder/ureter carcinoma treatment, long-term urinary stents, and colovesicular fistulas. At cystoscopy, lesions were variably described as polypoid, trabeculations, bullous polyps, and diffuse erythema and edema. The locations of polypoid cystitis were bladder (n=34), ureteral orifice (n=2), urethra (n=2), renal pelvis (n=2), and undesignated (n=1). Architecturally, 31 cases had isolated papillary fronds with in 1 case branching papillary structures. The base of the papillary stalks were characterized as both broad and narrow (n=24), only broad (n=9), and only narrow (n=3). The overlying urothelium of polypoid cystitis was diffusely and focally thickened in 8 cases and 5 cases, respectively. Umbrella cells were identified in 32 cases. Acute and chronic inflammation was present in 28 cases, moderate in 15, and mild in 13 cases. Eleven cases showed chronic inflammation, mild in 10, and moderate in 1 case. Reactive urothelial atypia was noted in 26 cases with mitotic figures present in 22 cases, frequent in 3 and rare in 19 cases. Stroma edema was seen in 32 cases with fibrosis within the polypoid stalks seen in 16 cases. The key to correctly diagnosing polypoid/papillary cystitis is to recognize at low magnification the reactive nature of the process with an inflamed background that is edematous or densely fibrous with predominantly simple, non-branching, broad-based fronds of relatively normal thickness urothelium, and not focus at higher power on the exceptional frond that may more closely resemble a urothelial neoplasm either architecturally or cytologically.

In cases where the diagnosis of papillary neoplasia is not straightforward and there is a question of polypoid cystitis, pathologists should seek clinical history that might suggest a reactive process. Because the urologist can more often better recognize the inflammatory nature of the lesion than the pathologist, the pathologist should hesitate diagnosing urothelial neoplasia when the cystoscopic impression is that of an inflammatory lesion.
Radiation or chemotherapy cystitis with "pseudocarcinomatous" features.

Chan TY, Epstein JI.

Department of Pathology, Johns Hopkins Hospital, Baltimore, MD.
Am J Surg Pathol. 2004 Jul;28(7):909-13. Abstract quote  

BACKGROUND:: The features of radiation or chemotherapy cystitis mimicking invasive urothelial cancer are not widely known.

DESIGN:: A search of the consultation files from our institution between January 1996 and September 2003 identified 20 patients with bladder biopsies showing cystitis mimicking invasive urothelial cancer.

RESULTS:: The mean age at diagnosis was 69 years (range, 40-85 years); 80% were males. Complete history was not available in 1 patient. Seventeen patients had a history of pelvic irradiation (15 prostate cancer and 2 endometrial cancer). Two patients had systemic chemotherapy (1 metastatic colon cancer and 1 mixed connective tissue disease). All patients presented with hematuria. The mean time from radiation and/or chemotherapy to presentation was 27 months (range, 0-84 months). All cases showed epithelial proliferation that mimicked invasive cancer within the lamina propria, with marked proliferation seen in 45% of cases. Mild to moderate nuclear pleomorphism was seen in all cases. A characteristic feature was the presence of pseudoinvasive urothelial nests wrapping around the vessels associated with fibrin deposition. Most cases did not show any mitoses (75%). Ulceration was seen in 39% of cases. All cases showed some degree of hemorrhage, fibrin deposition and fibrin thrombi, fibrosis, and acute and chronic inflammation, with hemosiderin identified in 60% of cases. Edema and vascular congestion were common features (95% and 80%, respectively). Thickened vessels and vascular changes associated with radiation injury were identified in 75% of cases. Seventeen patients were followed for a mean of 9 months (range, 0.25-37 months), and none developed bladder cancer.

CONCLUSIONS:: Radiation or chemotherapy cystitis can show epithelial proliferations that may be confused with invasive urothelial carcinomas. Other findings characteristic of radiation or chemotherapy cystitis, such as hemorrhage, fibrin, and vascular changes, are often seen in association with the epithelial proliferations and are helpful in distinguishing it from invasive cancer. Pathologists must be aware that these changes may be seen with a remote radiation or chemotherapy history, where this information may not be provided or known at the time of the biopsy evaluation.

Radiation-induced pseudocarcinomatous proliferations of the urinary bladder: a report of 4 cases.

Baker PM, Young RH.

James Homer Wright Pathology Laboratories of the Massachusetts General Hospital, Harvard Medical School, Boston 02115, USA.

Hum Pathol 2000 Jun;31(6):678-83 Abstract quote

Four cases of radiation cystitis that caused diagnostic difficulty because of an epithelial proliferation with architectural complexity and reactive cytologic atypia are described.

The patients, 2 male, 2 female, were from 43 to 77 years of age. Two presented with hematuria. Cystoscopy disclosed abnormalities in 3 patients. Microscopic examination showed irregularly shaped and arranged aggregates of epithelial cells in the upper and mid zones of the lamina propria. The cells, which typically showed at least mild, and sometimes severe, pleomorphism, were usually transitional, but squamous differentiation was seen focally in 3 cases. Ulceration of the overlying epithelium was present in all cases and was prominent and associated with conspicuous fibrin and hemorrhage in one of them. Edema of the lamina propria was present in 3 cases, whereas lamina propria fibrosis and chronic inflammation were present in all cases. The presence in all 4 cases of vascular ectasia and other changes characteristic of radiation injury, such as atypical fibroblasts, prompted investigation of the clinical history in 2 cases in which the pathologist was unaware that the patient had received radiation.

Pseudocarcinomatous proliferations in the bladder caused by radiation injury have received limited attention in the literature. Our cases illustrate the potential diagnostic errors with which these lesions may be associated.

Fibroepithelial Polyp of the Lower Urinary Tract in Adults.

Tsuzuki T, Epstein JI.

From the Departments of *Pathology and daggerUrology, Johns Hopkins Hospital, Baltimore, MD; and the double daggerDepartment of Pathology, Nagoya Daini Red Cross Hospital, Nagoya, Japan.

Am J Surg Pathol. 2005 Apr;29(4):460-466. Abstract quote  

OBJECTIVE:: Fibroepithelial polyps of the urinary tract are rare with most cases reported in children.

DESIGN:: We report the clinicopathologic features of 12 fibroepithelial polyps of the lower urinary tract in adults.

PATIENTS:: There were 9 males, 2 females, and 1 patient where the gender was unknown (median age, 44 years; range, 17-70 years).

RESULTS:: Chief clinical symptoms were hematuria, urinary urgency, and hesitancy. Five patients were asymptomatic, where the lesions were discovered incidentally. Most lesions were located near the verumontanum or the bladder neck. Ten patients were treated by transurethral resection. Of the 10 patients with follow-up information, none showed recurrence (mean, 20 months; median, 17 months). Histologically, all of the fibroepithelial polyps were lined by normal-appearing urothelium, with in one lesion the additional finding of a columnar epithelial lining. There were three overall architectural patterns seen within fibroepithelial polyps. The most common pattern (Pattern 1) seen in 5 cases consisted of a polypoid mass with club-like projections resembling a cloverleaf with florid cystitis cystica et glandularis of the nonintestinal type in the stalk. The second pattern (Pattern 2) seen in 4 cases consisted of a papillary tumor composed of numerous small, rounded fibrovascular cores containing dense fibrous tissue. The last morphologic pattern (Pattern 3) consisted of a polypoid lesion with secondary tall finger-like projections, which was seen in 3 cases. All lesions lacked prominent edema and inflammation seen in polypoid cystitis. Fibroepithelial polyps contained broader stalks with dense fibrous tissue, in contrast to the thin delicate loose fibroconnective tissue seen in the stalk of papillomas. One lesion contained atypical degenerative-appearing stromal cells.

CONCLUSIONS:: Although fibroepithelial polyps have been considered to be congenital, we think that some of these polyps could develop after birth because all of our patients first showed clinical symptoms in adulthood. Because fibroepithelial polyps in adults are rare, some of these cases can be misdiagnosed as urothelial neoplasms or reactive conditions. Recognition of the precise histologic features of fibroepithelial polyp can facilitate its correct diagnosis.

Symptomatic nephrogenic metaplasia of ureter: a morphologic and immunohistochemical study of four cases.

Gokaslan ST, Krueger JE, Albores-Saavedra J.

Division of Anatomic Pathology, The University of Texas Southwestern Medical Center, Dallas, Texas.

Mod Pathol 2002 Jul;15(7):765-70 Abstract quote

Nephrogenic metaplasia of the bladder and urethra has been the subject of extensive studies in recent years. However, information about ureteral involvement is still limited because of the rarity of the lesion.

We described four cases of nephrogenic metaplasia of the ureter. They occurred in two men and two women whose ages ranged from 46 to 69 years. Three patients had stones, and one had multiple episodes of cystitis and chronic pyelonephritis. The lesions led to ureteral obstruction that in two patients was radiographically suspicious for carcinoma. Microscopically, three lesions were composed of tiny mucin-containing microcysts and medium-sized tubular structures lined by cuboidal cells that showed cytologic atypia characterized by enlarged vesicular nuclei and prominent nucleoli. However, there were no mitotic figures. Two lesions invaded the full thickness of the wall of the ureter and exhibited an infiltrative growth pattern highlighted by cytokeratin stains. The remaining two lesions were confined to the lamina propria. The cells of nephrogenic metaplasia were immunoreactive to cytokeratin 7 and AE1-AE3. They lacked reactivity for monoclonal and polyclonal CEA and p53. The MIB-1-labeling index was <5%.

The cytologic atypia and infiltrative growth pattern of ureteral nephrogenic metaplasia should not be misinterpreted as evidence of malignancy. All four patients are alive and symptom free 8 months to 7 years after diagnosis.


Paraganglioma of the urinary bladder: a lesion that may be misdiagnosed as urothelial carcinoma in transurethral resection specimens.

Zhou M, Epstein JI, Young RH.

Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, Maryland, and dagger James Homer Wright Pathology Laboratories, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.

Am J Surg Pathol. 2004 Jan; 28(1): 94-100. Abstract quote  

SUMMARY: Paraganglioma of the urinary bladder is a rare tumor with characteristic histologic and immunohistochemical features. However, in our experience, it may be misdiagnosed as urothelial cancer because of 1) its frequent involvement of the muscularis propria; 2) morphology that may suggest urothelial cancer in transurethral resection specimens, particularly if there are artifactual changes induced by that procedure; 3) failure of pathologists to include it in their differential diagnosis when evaluating a bladder tumor; and 4) only a minority of the cases are associated with symptoms that might prompt consideration of the diagnosis.

Distinction between paraganglioma and urothelial cancer is important because of likely different therapeutic options. In this report, we describe our experience with the histopathology of paragangliomas of the urinary bladder with emphasis on the histologic features that have led to their being misdiagnosed as conventional urothelial cancer and, most importantly, those that will help pathologists recognize this rare tumor of the bladder. Fifteen cases of paraganglioma of the urinary bladder were studied, 11 of them consult cases. They affected patients (8 male, 7 female) with a mean age of 49.5 years; only two had symptoms suggestive of the diagnosis, including hypertension during cystoscopy and episodic headache. Three consult cases were submitted with a diagnosis of "transitional cell carcinoma" and 4 with a diagnosis only of "bladder tumor." Histologically, "zellballen" and diffuse patterns were present in 12 (80%) and 3 (20%) of the cases. A delicate fibrovascular stroma was obvious in 14 (93%) cases. Other patterns included irregular nests and pseudorosette formation. Tumor necrosis, significant cautery artifact, and muscularis propria invasion were present in 1 (7%), 3 (20%) cases, and 10 (67%) cases, respectively. All 15 tumors were composed of large polygonal cells with abundant granular cytoplasm. Focal clear cells were present in 3 (20%). The nuclei were mostly uniform, although occasional pleomorphic nuclei were seen in 6 (40%) cases, and 2 (13%) had frequent pleomorphic nuclei. Mitoses were rare overall, and no abnormal mitotic figures were found. The major histologic features that led to misdiagnosis included a diffuse growth pattern, focal clear cells, necrosis, and muscularis propria invasion, with significant cautery artifact compounding the diagnostic problems.

Immunohistochemically, 2 of 2 tumors were positive for neuron-specific enolase, 9 of 10 tumors for chromogranin, and 2 of 3 tumors for synaptophysin; 3 of 3 tumors were negative for cytokeratin and 1of 1 tumor negative for HMB-45.

Paraganglioma of the urinary bladder may be misdiagnosed as urothelial cancer, but a careful search for the characteristic histologic features and, if necessary, supportive immunohistochemical studies, should lead to a correct diagnosis.

PROSTATE CARCINOMA Use PSA immunoperoxidase

Immunohistochemical profile of high-grade urothelial bladder carcinoma and prostate adenocarcinoma.

Mhawech P, Uchida T, Pelte MF.

Office of Biostatistics, The University of Texas Medical Branch at Galveston, Galveston, TX; and the Department of Pathology, Geneva University Hospital, Geneva, Switzerland.


Hum Pathol 2002 Nov;33(11):1136-40 Abstract quote

The differential diagnosis between poorly differentiated prostate adenocarcinoma (PAC) involving the bladder and high-grade urothelial bladder cancer (UC) with prostate extension can be very challenging.

The aim of this study is to evaluate the use of a panel of antibodies to distinguish the poorly differentiated forms of these two tumors. We evaluated a series of 40 PAC cases (Gleason's grade >/= 8) and 45 (G3) UC cases obtained from transurethral endoscopic resection material. Immunohistochemical analysis was performed using the following antibodies: prostate acid phosphatase (PAP), prostate-specific antigen (PSA), uroplakin III (UP), thrombomodulin (TM), cytokeratin (CK) 7, and CK20. PAC expressed PSA and PAP in 34 and 38 cases, respectively. The sensitivity and specificity of expressing at least 1 marker (PSA+ or PAP+) is 95% and 100%, respectively. All UC cases were negative for both markers. UC expressed UP and TM in 27 and 22 cases, respectively. In addition, 36 of 45 cases stained positively for at least 1 marker (UP + or TM +) with specificity and sensitivity of 80% and 100%, respectively. All cases of PAC were negative for both markers. Twenty-eight UC cases were CK7+/CK20 +, and 4 PAC cases stained positively for both markers. On the other hand, 29 PAC cases and 4 UC cases were CK7-/CK20-.

We concluded that PSA, PAP, UP, and TM are very useful markers in differentiating poorly differentiated UC from PAC. Finally, when all 4 markers (PAP, PSA, UP, and TM) were negative, CK7 and CK20 appeared of no major use in making the differential diagnosis.

Detection of Residual Tumor Cells in Bladder Biopsy Specimens: Pitfalls in the Interpretation of Cytokeratin Stains.

Departments of *Pathology daggerUrology double daggerOncology, Johns Hopkins Hospital, Baltimore, MD.


Am J Surg Pathol. 2007 Mar;31(3):390-397. Abstract quote

Some patients who have had prior bladder biopsies or transurethral resections undergo a repeat resection within several months for various reasons. The detection of a few residual tumor cells in bladder specimens with prior biopsy site changes can be challenging based on histology alone. Immunohistochemistry for cytokeratins may be used as an adjunct in this situation.

We have noted several cases in which keratin stains were performed and positive cells were noted, raising the issue as to whether the cytokeratin positive cells were residual tumor cells or stromal cells. Immunohistochemistry for a panel of antibodies [AE1/AE3, CAM 5.2, high molecular weight cytokeratin, smooth muscle actin (SMA), desmin, and anaplastic lymphoma kinase (ALK)] was performed on 29 cases of bladder biopsies with prior biopsy site changes.

Of 29 patients, 25 had a prior history of bladder tumor: 17 had invasive high-grade urothelial carcinoma (T1, 5 cases; T2, 11 cases; T3,1 case); 7 had noninvasive high-grade papillary urothelial carcinoma; 1 had noninvasive low-grade papillary urothelial carcinoma). One of the patients with noninvasive high-grade papillary urothelial carcinoma and one of the patents with invasive high-grade urothelial carcinoma had associated carcinoma in-situ. Four patients had prior benign bladder diagnoses: cystitis cystica et glandularis; polypoid cystitis; follicular cystitis; and neurogenic bladder with benign prostate hyperplasia.

Of the 29 cases, 6 (21%) had cells with staining for at least 2 of the cytokeratin markers. Cytokeratin (CK) AE1/ AE3 was positive for cells in 8/29 cases (28%). In 6 of these cases, cells displayed a spindle cell and 2 cases a more epithelioid morphology. CAM 5.2 was positive in cells in 5/29 cases (17%); 3 of the cases had spindle cell and 2 cases epithelioid morphology. High molecular weight cytokeratin was expressed in cells in 2/29 cases (7%) with 1 case having spindle cell and 1 epithelioid morphology. SMA was positive in cells with a spindle cell morphology and negative in the more epitheloid cytokeratin positive cells. Desmin was positive in 3/6 keratin positive spindle cells and negative in keratin positive epithelioid cells. ALK was negative in all the cases. Three cases with spindle cell morphology and positivity for at least 1 of the keratins and SMA stains were interpreted as aberrant keratin expression in myofibroblastic cells based on the staining and the morphology of the spindle cells. Another 3 cases with concurrent staining for at least 1 of the keratins, SMA and desmin were consistent with smooth muscle cells on the basis of their cellular morphology. Another 2 cases had cells, which expressed at least 2 CK markers but did not express SMA, desmin, or ALK and a more epithelioid morphology. These cells were interpreted as residual tumors cells.

When interpreting CK stains for the detection of residual tumor cells, one should pay attention to the nature of the cells and not assume all CK staining cells are residual tumor cells.

Inflammatory Pseudotumor and Sarcoma of Urinary Bladder: Differential Diagnosis and Outcome in Thirty-Eight Spindle Cell Neoplasms

Kenneth A. Iczkowski, M.D., Jonathan H. Shanks, M.D., Virgil Gadaleanu, M.D., Liang Cheng, M.D., Edward C. Jones, M.D., Roxann Neumann, R.N., Antonio G. Nascimento, M.D. and David G. Bostwick, M.D.

Departments of Pathology and Laboratory Medicine of the University of Florida and Veterans Administration Medical Center (KAI)Gainesville, Florida, Christie Hospital (JHS), Manchester, United Kingdom, University of Malmö (VG), Malmö, Sweden, Indiana University (LC), Indianapolis, Indiana, Vancouver General Hospital (ECJ), Vancouver, B.C., Canada, Mayo Clinic (RN, AGN), Rochester, Minnesota, University of Virginia (DGB), Charlottesville, Virginia, and Bostwick Laboratories (DGB), Richmond, Virginia

Mod Pathol 2001;14:1043-1051 Abstract quote

We assessed diagnostic criteria among 38 spindle cell tumors of the urinary bladder and obtained follow-up in 36 patients.

Patients comprised 28 males and 10 females aged 2.5 months to 87 years. Hematuria was the commonest presenting symptom (27 patients). After review and immunohistochemical workup, 17 patients had inflammatory pseudotumor (myofibroblastic tumor), 4 postoperative spindle cell nodule, 1 leiomyoma, 13 sarcoma (7 low-grade; 6 high-grade), and 3 carcinoma. Mean age was 38 years for pseudotumor (range 15 to 74), 65 for postoperative spindle cell nodule, 51 for sarcoma, and 76 for carcinoma. Size of pseudotumor averaged 4.4 ± 0.7 cm (range 1.5 to 13.0), similar to sarcoma, 4.0 ± 0.6 cm (range 0.5 to 7.0). Similar proportions of benign tumors and sarcomas had muscularis propria invasion.

The criteria that best differentiated sarcoma from inflammatory pseudotumor were presence of necrosis at the tumor-detrusor muscle interface in muscle-invasive cases, and nuclear atypia. Sarcoma also had less prominent microvasculature, less variable cellularity, consistently 1 mitotic figure per 10 high-power fields, and predominant acute inflammation without plasma cells. p53 protein nuclear immunostaining was moderate, unlike the rare to absent staining in pseudotumors. Because all 12 sarcomas were desmin-negative, we did not call them leiomyosarcoma; they overlapped with benign tumor in epithelial, mesenchymal, and actin immunostaining. Among 12 sarcoma patients, 2 died of tumor (at 3 months). Two of four experienced tumor recurrence after partial cystectomy (2 and 26 months). No pseudotumors recurred after transurethral resection or partial cystectomy, although one patient, 5 months after transurethral resection, had histologically identical pseudotumor that the surgeon considered residual. Another patient with pseudotumor, not a candidate for tumor ablation after transurethral resection, had continued tumor growth and he died of urosepsis.

In conclusion, inflammatory pseudotumor, although overlapping with sarcoma in presentation, age range, and size, does not metastasize and remains histologically distinct from low-grade sarcoma.


Florid von Brunn nests mimicking urothelial carcinoma: a morphologic and immunohistochemical comparison to the nested variant of urothelial carcinoma.

Volmar KE, Chan TY, De Marzo AM, Epstein JI.

Department of Pathology, Johns Hopkins Hospital, Baltimore, MD 21231, USA.

Am J Surg Pathol. 2003 Sep;27(9):1243-52. Abstract quote  

We examined formalin-fixed, paraffin-embedded tissue from 21 cases of florid von Brunn nests and 11 cases of nested variant of urothelial carcinoma. Morphologic features were recorded in detail. Also, cases were stained with monoclonal antibodies against MIB-1, p53, p27, and cytokeratin 20. Percentage positivity was calculated by counting 300 to 500 cells from each case. Clinical follow-up information was also obtained. Florid von Brunn nests from the bladder were comprised of large nests with regular spacing, and all the nests extended to the same horizontal level at the base of the proliferation. Central lumen formation was often seen within florid von Brunn nests, at times with cystic dilatation, such that there was a spectrum from proliferating von Brunn nests to cystitis glandularis to cystitis cystica. Small, crowded nests with variable spacing and an infiltrative base characterized nested variant of urothelial carcinoma. Four cases showed detrusor muscle invasion on biopsy with an additional case showing detrusor muscle invasion at cystectomy. One additional patient with nested variant of urothelial carcinoma had distant metastases and another had prostatic invasion. Nine of 21 florid von Brunn nests cases were from either the ureter or renal pelvis, whereas all cases of nested variant of urothelial carcinoma arose in the bladder. The ureteral and pelvic florid von Brunn nest cases showed smaller, more variable nests with irregular spacing closely mimicking nested variant of urothelial carcinoma but had a noninfiltrative base and often areas with either a lobular or linear array.

Immunohistochemical studies showed nested variant of urothelial carcinoma to have higher MIB-1 expression (8.8% vs. 2.8%, P = 0.01). Nested variant of urothelial carcinoma had nonsignificantly higher p53 positivity (4.2% vs. 1.5%, P = 0.06) and lower p27 positivity (4.7% vs. 7.8%, P = 0.22). Cytokeratin 20 staining was not discriminatory. However, staining with each antibody was widely variable. Wide variation in staining for MIB-1, p53, p27, and cytokeratin 20 was seen in both florid von Brunn nests and nested variant of urothelial carcinoma, such that except for a few cases, a specific cutoff value could not be determined for diagnostic purposes.

The findings underscore the importance of morphologic assessment in the distinction of florid von Brunn nests and nested variant of urothelial carcinoma.


PROGNOSIS Stage is the most important prognostic factor
Inverted papilloma

No progression to cancer

Exophytic papilloma Benign
Transitional cell carcinoma  
Low grade
High grade
Carcinoma in situ
Indolent lesion which does not spontaneously regress but invades sporadically and late

Poor correlation with histologic grade and type although signet ring adenocarcinomas are uniformly aggressive tumors

Patients with urachal tumors have better short term survival than nonurachal tumors but overall survival at 5 and 10 years is not significantly different

Squamous cell carcinoma Invasion of the muscle wall usually present in about 80%
Small cell carcinoma

Aggressive tumor which usually presents with high clinical stage and metastases to regional lymph nodes, liver, and bone

Outcome depends more upon response to treatment rather than the size of the neoplasm or type of therapy

5 Year Survival  
Transitional cell carcinoma  
Low grade
8-12% mortality
High grade
40-60% mortality
Adenocarcinoma 20-40%
If tumor is confined to the urinary bladder, survival may range from 75-100% but low stage cancers are uncommon
Squamous cell carcinoma <25%
Small cell carcinoma 10-20%
Prognostic Factors in Survival of Patients With Stage Ta and T1 Bladder Urothelial Tumors
The Role of G1-S Modulators (p53, p21Waf1, p27Kip1, Cyclin D1, and Cyclin D3), Proliferation Index, and Clinicopathologic Parameters

Antonio Lopez-Beltran, MD, PhD, etal.
Am J Clin Pathol 2004;122:444-452 Abstract quote

We studied 159 cases of superficial (stage Ta or T1) bladder tumors to determine the significance on survival of a subset of regulators of transition from G1 to S phase of the cell cycle (p53, p21Waf1, p27Kip1, cyclin D1, cyclin D3) and tumor proliferation (Ki-67 [MIB-1]). Clinical findings (patient age, sex, tumor size, grade, stage [Ta or T1]) were included in the analysis.

Univariate analysis revealed association of tumor size (P = .0353), grade in stage Ta tumors (P = .0074), cyclin D1 expression (P = .0182), and Ki-67 index (P = .0033) with disease-free survival and of tumor size (P = .0005), stage (P = .0494), cyclin D3 expression (P = .0105), and Ki-67 index (P = .0272) with overall survival. Cox multivariate analysis revealed cyclin D1 expression and high proliferation index (disease-free) and tumor size, cyclin D3 expression, and high proliferation index (overall survival) as independent predictors.

Results suggest that alterations of the progression from the G1 to S phase of the cell cycle are common in papillary urothelial bladder tumors. High tumor proliferation, expression of cyclins D1 and D3, and tumor size at diagnosis might be relevant predictors of survival in patients with stage Ta and T1 bladder urothelial tumors.
Expression of Caveolin-1 and Caveolin-2 in Urothelial Carcinoma of the Urinary Bladder Correlates With Tumor Grade and Squamous Differentiation

Andrew Fong, MD, Ediberto Garcia, MS, Lucas Gwynn, MD, Michael P. Lisanti, MD, PhD, Melissa J. Fazzari, MS, and Maomi Li, MD, PhD

Am J Clin Pathol 2003;120:93-100 Abstract quote

We immunohistochemically evaluated 94 cases of urothelial carcinoma (UC) of the urinary bladder for the expression of caveolin (Cav)-1 and Cav-2.

Neither benign urothelium present in 22 cases nor flat carcinoma in situ present in 10 cases stained for Cav-1 or Cav-2. Thirty-five (37%) of 94 cases and 45 (51%) of 89 cases of UC stained positively for Cav-1 and Cav-2, respectively. The percentages of positive cases for Cav-1 in grades 1, 2, and 3 tumors were 0% (0/6), 0% (0/25), and 56% (35/63), respectively (P < .001), and for Cav-2, 0% (0/6), 13% (3/23), and 70% (42/60), respectively (P < .001). Multivariate analysis showed no significant correlation between tumor stage and Cav-1 or Cav-2 expression after correction for tumor grade. Eighty-two percent (14/17) of cases with squamous differentiation were positive for Cav-1 compared with 43% (20/46) of grade 3 tumors without squamous differentiation (P < .001).

These results indicate a positive correlation of the expression of Cav-1 and Cav-2 with tumor grade and squamous features of UC and suggest that Cav-1 and Cav-2 be studied further for a possible role in tumor progression and squamous differentiation.

A new system for substaging pT1 papillary bladder cancer: a prognostic evaluation.

van der Aa MN, van Leenders GJ, Steyerberg EW, van Rhijn BW, Jobsis AC, Zwarthoff EC, van der Kwast TH.

Department of Pathology, Erasmus MC, Rotterdam 300 DR, The Netherlands; Department of Urology, Erasmus MC, Rotterdam 300 DR, The Netherlands.

Hum Pathol. 2005 Sep;36(9):981-6 Abstract quote.  

Superficially invasive (pT1) papillary urothelial cell carcinomas (UCCs) may run a variable course. Several attempts have been made for the substaging of UCC to identify the clinically aggressive tumors.

We present a new substaging system, based on the extent of invasion. From a series of 53 primary pT1 UCC, 24 cases showed invasion of the subepithelial stroma by an invasive front extending more than a maximum length of 0.5 mm (pT1mic), and 29 showed extensively (>0.5 mm) infiltrating UCC (pT1ext).

We tested diagnostic reproducibility between 2 pathologists and found 81% agreement. Furthermore, all cases were analyzed for mutations in the fibroblast growth factor receptor 3 (FGFR3) gene, which represents the favorable pathway of urothelial cell carcinogenesis. Mutant FGFR3 was commonly observed in pT1mic UCC (15/24, 63%), but rarely (2/29, 7%) in pT1ext UCC (chi(2) test, P < .001). The presence of pT1ext at initial diagnosis proved to be the strongest predictor for progression, also when adjusted for FGFR3 mutation status in a Cox regression model.

If confirmed on a larger series of pT1 UCC, this relatively simple and new substaging system for pT1 UCC may prove to be of prognostic value and supportive to clinical decision-making.
Histologic Grading of Noninvasive Papillary Urothelial Tumors
Validation of the 1998 WHO/ISUP System by Immunophenotyping and Follow-up

Hui Yin, MD, and Anthony S.-Y. Leong, MBBS, MD
Am J Clin Pathol 2004;121:679-687 Abstract quote

Cytokeratin (CK) 20, Ki-67, and p53 were applied to 84 noninvasive papillary urothelial tumors graded by the 1973 World Health Organization (WHO) and 1998 WHO/International Society of Urological Pathology (ISUP) systems.

In the WHO/ISUP classification, all benign lesions showed normal CK20 staining and all carcinomas showed abnormal staining. The Ki-67 index was significantly different between benign and malignant lesions (P < .05) and between low- and high-grade carcinomas (P < .001). p53 was negative in all benign lesions, with a significant difference between low- and high-grade carcinomas (P < .001). Tumor recurrence was significantly different between low- and high-grade carcinomas (no recurrences among the papillary urothelial neoplasms of low malignant potential).

By the 1973 WHO classification, normal CK20 staining was present both in benign lesions and in carcinomas. Ki-67 staining did not distinguish between grade 2 and grade 3 carcinomas (P > .05), and there was no difference in p53 staining in grades 1 and 2 carcinomas (P > .05). Recurrences were not different between grades 1, 2, and 3 carcinomas.

All biologic markers studied and tumor recurrences were significantly different among papillary lesions classified by the WHO/ISUP system but not by the 1973 WHO system, validating the predictive value of the WHO/ISUP system and providing objective markers for the grading of papillary urothelial tumors.

Comparison of the WHO/ISUP Classification and Cytokeratin 20 Expression in Predicting the Behavior of Low-Grade Papillary Urothelial Tumors

A. Alsheikh, etal.

Mod Pathol 2001;14:267-272 Abstract

It has not been possible to identify those low-grade papillary transitional cell bladder tumors that will recur based on conventional histopathologic assessment. Both the new World Health Organization/International Society of Urologic Pathology (WHO/ISUP) classification of transitional cell papillary neoplasms and the pattern of tumor cytokeratin 20 (CK20) immunostaining have been suggested as means of improving prognostication in low-grade transitional cell tumors.

Forty-nine low-grade, noninvasive papillary transitional cell tumors were identified for the period between 1984 and 1993. The recently described WHO/ISUP classification was applied, and the tumors were classified histologically as papilloma, papillary neoplasm of low malignant potential (LMP) or low-grade papillary carcinoma. After CK20 immunostaining, the expression pattern in the tumor was classified as normal (superficial) or abnormal. Of 49 tumors, 20 were classified as papillary neoplasms of LMP and five of these patients (25%) experienced a recurrence. Of 29 tumors classified as low-grade papillary carcinoma, 14 (48.2%) recurred. In 46 of 49 cases, the CK20 immunostaining could be evaluated. Sixteen tumors showed normal (superficial) pattern of CK20 expression, and four (25%) of these patients experienced a recurrence. In contrast, of 30 patients with abnormal CK20 staining of their tumors, 15 (50%) patients had one or more recurrences. In this study, papillary neoplasms of LMP (as per the WHO/ISUP classification system) had a lower recurrence rate than low-grade papillary transitional cell carcinoma. Similarly low-grade urothelial tumors showing a normal CK20 expression pattern recurred less frequently than tumors with an abnormal pattern of CK20 staining.

Neither of these differences was statistically significant, and recurrences were observed in 20% of patients whose tumors were both classified as papillary neoplasms of LMP and showed normal CK20 immunostaining; thus they do not allow a change in our current management of patients with low-grade papillary urothelial tumors, with close follow-up for all patients.

Comparison of WHO/ISUP and WHO classification of noninvasive papillary urothelial neoplasms for risk of progression.

Samaratunga H, Makarov DV, Epstein JI.

Department of Pathology, Royal Brisbane Hospital, Brisbane, Australia.


Urology 2002 Aug;60(2):315-9 Abstract quote

OBJECTIVES: To investigate the relation of the World Health Organization/International Society of Urological Pathology (WHO/ISUP) system for bladder neoplasia to prognosis.

METHODS: A total of 134 patients with pTa bladder tumors were identified. We excluded cases with prior or concurrent carcinoma in situ or invasion (pT1 or pT2). Progression was defined as a tumor recurrence with either lamina propria (pT1) or muscularis propria (pT2) invasion or carcinoma in situ. Age at diagnosis, sex, tumor size, multifocality, and grade (WHO, WHO/ISUP) were entered into a Cox multivariate analysis to predict progression.

RESULTS: The distribution of WHO papilloma, WHO G1, WHO G2, and WHO G3 was 5.2%, 31.3%, 59%, and 4.5%, respectively. The distribution of WHO/ISUP papilloma, tumors of low malignant potential, low-grade carcinomas, and high-grade carcinomas was 2.2%, 21.6%, 13%, and 21.6%, respectively. The mean and median follow-up was 56.2 and 50 months, respectively. The 90-month actuarial risk of progression for WHO papilloma, G1, G2, and G3 was 0%, 11%, 24%, and 60%, respectively. The corresponding progression rate for WHO/ISUP papilloma, tumors of low malignant potential, low-grade carcinoma, and high-grade carcinoma was 0%, 8%, 13%, and 51%, respectively. In separate analyses, WHO grade (P = 0.003) and tumor size (P = 0.03), as well as WHO/ISUP (P = 0.002) and tumor size (P = 0.04), independently predicted progression.

CONCLUSIONS: WHO G3 has a more rapid progression rate and a slightly worse long-term progression rate compared with WHO/ISUP high-grade carcinoma. However, although only 4.5% of tumors were WHO G3, we were able to classify 21.6% as WHO/ISUP high-grade carcinoma with a poor prognosis. Use of the WHO/ISUP system allows urologists to more closely follow a larger group of patients at high risk of progression.

Invasion of the bladder by transitional cell carcinoma: its relation to histologic grade and expression of p53, MIB-1, c-erb B-2, epidermal growth factor receptor, and bcl-2.

Vollmer RT, Humphrey PA, Swanson PE, Wick MR, Hudson ML.

Laboratory Medicine, VA Medical Center, Durham, North Carolina, USA.

Cancer 1998 Feb 15;82(4):715-23 Abstract quote

BACKGROUND: Although pathologic level of invasion and histologic grade are helpful in predicting the clinical outcome of transitional cell carcinoma of the bladder, they also create uncertainty. Immunohistochemical staining for p53, MIB-1, epidermal growth factor receptor (EGFR), c-erb B-2, and bcl-2 have shown promise as prognostic factors when evaluated singly, although multivariate analyses that include histologic grade and the interactive effects of these markers have not been studied extensively. The authors have initiated a prospective study to determine whether these markers add prognostic information to that provided by level of invasion and histologic grade. This initial report details how these five markers relate to invasion of the bladder after controlling for the effects of histologic grade.

METHODS: The authors evaluated 229 transitional cell carcinomas in 229 patients using the World Health Organization grading schema and immunohistochemical staining with antigen retrieval for p53, MIB-1, EGFR, c-erb B-2, and bcl-2, and they related these markers to invasion after controlling for grade with a multivariate logistic regression model.

RESULTS: Although Grades 2 and 3 were the most important for predicting invasion, Grade 2 tumors that stained for either MIB-1 or p53 indicated a significantly greater probability of invasion than suggested by grade alone. bcl-2 and p53 had an opposing and interactive effect: when p53 was absent, the presence of bcl-2 implied less probability of invasion; but when both bcl-2 and p53 were present, the protective effect of bcl-2 was no longer observed. Although neither EGFR nor c-erb B-2 were as important as the other three markers in determining the risk of invasion, Grade 3 tumors that stained for one, and especially both, of these markers were less likely to be invasive.

CONCLUSIONS: These five markers sort into three interactive pairs: MIB-1 and p53, bcl-2 and p53, and EGFR and c-erb B-2. MIB-1 and p53 together imply a greater probability of invasion. bcl-2 appears to have a dual role, which depends on the presence of accumulated p53. Finally, EGFR and c-erb B-2 related closely to each other and in Grade 3 tumors imply a lesser probability of invasion. It is likely that combinations of markers, or correlations between markers and grades, will yield prognostic information that is more powerful than what histologic grade alone can provide.

Intravesical Adipose Tissue A Quantitative Study of Its Presence and Location With Implications for Therapy and Prognosis

Abraham T. Philip, M.D.; Mahul B. Amin, M.D.; Pheroze Tamboli, M.D.; T. J. Lee, M.D.; Charles E. Hill, M.D.; Jae Y. Ro, M.D., Ph.D. Flemming ID, Cooper JS, Henson DE, Walsh PC, Retik AB, Vaughn ED, Wein AJ, eds. Sternberg SS, ed. Sternberg SS, Antonioli DA, Carter D, Mills SE, Oberman HR, eds.

From the Department of Pathology, Emory University Hospital, Atlanta, Georgia, U.S.A. (A.T.P. M.B.A., C.E.H.); The University of Texas, M.D. Anderson Cancer Center, Houston, Texas, U.S.A. (P.T., J.Y.R.); and Asan Medical Center, Seoul, Korea (T.J.L.).

Am J Surg Pathol 2000;24:1286-1290 Abstract quote

Accurate pathologic staging of carcinomas of the urinary bladder involves assessment of invasion by the tumor into the bladder wall and beyond into perivesical soft tissue. The presence of tumor within perivesical soft tissue implies pathologic stage pT3 (AJCC/UICC system, 1997). In traditional textbooks of histology, anatomy, pathology, and in the literature, other than a single case report and a brief reference in another paper, there is no information on the presence of adipose tissue in the lamina propria or muscularis propria of the urinary bladder.

Nine hundred forty-three sections from 139 cystectomy specimens were evaluated for the presence, location, and quantity of adipose tissue within the lamina propria and muscularis propria.

The histology of the perivesical soft tissues and the nature of its delineation from muscularis propria were also analyzed. Adipose tissue was seen within the lamina propria in 53% (74 of 139) of cystectomies and in 17.6% (166 of 943) of the examined sections. It was located predominantly in the deep lamina propria (at or below the muscularis mucosae) in 81.1% (60 of 74) of the cystectomies and in 91% (151 of 166) of the sections. Within the lamina propria it was predominantly seen as small localized aggregates in 92% (153 of 166) of sections. All cases showed adipose tissue within the muscularis propria. Adipose tissue was identified within the superficial (inner) muscularis propria in 54% (512 of 943) of sections and was predominantly in small aggregates in 80.5% (412 of 512) of sections. It was in moderate to abundant quantities within the deep (outer) muscularis propria in 60.7% (572 of 943) of sections. The perivesical soft tissue was almost exclusively composed of adipose tissue with variable vascularity. Delineation of the perivesical adipose tissue from the deep (outer) muscularis propria was typically indistinct because muscle bundles of the latter haphazardly merged with the perivesical adipose tissue.

Based on these findings, we conclude that adipose tissue is frequently present in the lamina propria and muscularis propria of the urinary bladder wall, and is usually scant in the former location and frequently abundant in the latter. Awareness of the high frequency of adipose tissue within the urinary bladder wall has prognostic and therapeutic implications.

In transurethral resection of bladder tumor (TURBT) specimens, misinterpretation of tumor infiltrating adipose tissue within lamina propria (pT1) as perivesical soft tissue involvement (pT3) may potentially result in unwarranted aggressive management. Substaging of muscle invasive tumors should be performed in cystectomy specimens only, because the junction of muscularis propria and the perivesical adipose tissue is typically ill-defined.

Muscularis propria adipose tissue in TURBT specimens may be erroneously assumed to be perivesical adipose tissue, potentially leading to overstaging of the primary tumor.

Grading the Invasive Component of Urothelial Carcinoma of the Bladder and Its Relationship With Progression-Free Survival

Rafael E. Jimenez, M.D.; Edward Gheiler, M.D.; Peter Oskanian, M.D.; Rabbi Tiguert, M.D.; Wael Sakr, M.D.; David P. Wood Jr., M.D.; J. Edson Pontes, M.D.; David J. Grignon, M.D.

From the Departments of Pathology (R.E.J., W.S., D.J.G.) and Urology (E.G., P.O., R.T., D.W., J.E.P.), Harper Hospital, the Barbara Ann Karmanos Cancer Institute, and Wayne State University, Detroit, Michigan

Am J Surg Pathol 2000;24:980-987 Abstract quote

Although grading is valuable prognostically in pTa and pT1 papillary urothelial carcinoma, it is unclear whether it provides any prognostic information when applied to the invasive component in muscle-invasive carcinoma.

The authors analyzed 93 cases of muscle-invasive urothelial carcinoma of the bladder treated with radical cystectomy for which follow-up information was available.

Each case was graded using the Malmström grading system for urothelial carcinoma, applied to the invasive component. Pathologic stage, lymph node status, and histologic invasion pattern were also recorded and correlated with progression-free survival. Thirty-four cases (37%) were pT2, 40 (43%) were pT3, and 19 (20%) were pT4. Of the 77 patients who had a lymph node dissection at the time of cystectomy, 34 (44%) had metastatic carcinoma to one or more lymph nodes. The median survival for pT2, pT3, and pT4 stages was 85, 24, and 29 months, respectively (p = 0.0001). Lymph node-negative and lymph node-positive patients had a median survival of 63 and 23 months, respectively (p = 0.0001). Fifteen patients (16%) were graded as 2b and 78 patients (84%) were graded as 3. Median survival of patients graded as 2b was 34 months compared with 31 months for patients graded as 3 (p value not significant). Three invasive patterns were recognized: nodular (n = 13, 14%), trabecular (n = 39, 42%), and infiltrative (n = 41, 44%). The presence of any infiltrative pattern in the tumor was associated with a median survival of 29 months, compared with 85 months in tumors without an infiltrative pattern (p = 0.06). Pathologic T stage and lymph node status remain the most powerful predictors of progression in muscle-invasive urothelial carcinoma.

In this group of patients histologic grade, as defined by the Malmström system and as applied to the invasive component, provided no additional prognostic information. An infiltrative growth pattern may be associated with a more dismal prognosis.

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

Tong GX, Yee H, Chiriboga L, Hernandez O, Waisman J.

Department of Pathology, Columbia University College of Physicians and Surgeons, New York, NY 10032, USA.

Hum Pathol. 2005 Jul;36(7):741-6. Abstract quote  

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.

Expression of Telomerase Catalytic Subunit (hTERT) mRNA Does Not Predict Survival in Patients with Transitional Cell Carcinoma of the Upper Urinary Tract

Kuniaki Nakanishi, M.D., Sadayuki Hiroi, M.T., Toshiaki Kawai, M.D., Shinsuke Aida, M.D., Hiroyasu Kasamatsu, M.T., Takashi Aurues, M.D. and Tomosumi Ikeda, M.D.

Division of Environmental Medicine (KN, TA, TI), National Defense Medical College Research Institute; and Departments of Pathology (SH, TK) and Laboratory Medicine (SA) and Central Research Laboratory (HK), National Defense Medical College, Tokorozawa, Japan

Mod Pathol 2001;14:1073-1078 Abstract quote

Telomerase is a ribonucleoprotein enzyme that synthesizes telomeric repeats onto chromosomal ends using a segment of its RNA component as a template. Its activity has become an established indicator of the diagnosis, biological behavior, and prognosis of several tumors. However, few studies have investigated the diagnostic and prognostic importance of the expression of telomerase catalytic subunit (hTERT) mRNA in transitional cell carcinoma of the upper urinary tract (TCC-UUT).

We investigated the expression of hTERT mRNA using in situ hybridization in 125 cases of TCC-UUT, and also its relation with the expression of telomerase RNA component (hTERC), proliferating cell nuclear antigen (PCNA) immunoreactivity, clinicopathologic parameters, and clinical outcome. A positive expression of hTERT mRNA was recognized in 93.6% of the samples and was apparent within the cytoplasm of tumor cells. In the normal urothelium examined in a few cases, its expression was barely detected. hTERT mRNA scores showed a significant association with hTERC score. However, no relationship was found between the expression of hTERT mRNA and clinicopathologic findings, PCNA index, or prognosis.

These results suggest that the expression of hTERT mRNA does not predict prognosis in TCC-UUT.

Prognostic Implications of Extracapsular Extension of Pelvic Lymph Node Metastases in Urothelial Carcinoma of the Bladder.

Fleischmann A, Thalmann GN, Markwalder R, Studer UE.

From the Departments of *Pathology and daggerUrology, University of Bern, Bern, Switzerland.
Am J Surg Pathol. 2005 Jan;29(1):89-95. Abstract quote

To determine whether extracapsular extension of pelvic lymph node metastases from urothelial carcinoma of the bladder is of prognostic significance. From a consecutive series of 507 patients with urothelial carcinoma of the bladder preoperatively staged N0M0, 101 of 124 patients with lymph node metastases detected on histologic examination fulfilled the inclusion criteria for this study and were evaluated.

All underwent radical cystectomy between 1985 and 2000 with standardized extended bilateral pelvic lymphadenectomy in curative intent and were prospectively followed for recurrence-free (RFS) and overall (OS) survival. Staging was done according to UICC 2002. A total of 2375 lymph nodes were examined. The median number of nodes examined per patient was 22 (range, 10-43). The median number of positive nodes was 2 (range, 1-24). Median RFS and OS were 17 and 21 months (range for both, 1-191), respectively. The 5-year RFS and OS rates were 32% and 30%, respectively. There were 59 patients (58%) with extracapsular extension of lymph node metastases. They had a significantly decreased RFS (median, 12 vs. 60 months, P = 0.0003) and OS (median, 16 vs. 60 months, P < 0.0001) compared with those with intranodal metastases.

There were no significant differences in survival between pN1 and pN2 categories with extracapsular extension of the lymph node metastases (RFS, P = 0.70; OS, P = 0.65) or those without extension (RFS, P = 0.47; OS, P = 0.34). On a multivariate analysis, extracapsular extension of lymph node metastases was the strongest negative predictor for RFS. Meticulous lymph node resection and subsequent thorough histologic examination in patients undergoing radical cystectomy for bladder cancer reveals a high incidence of lymph node-positive disease (24%) despite negative preoperative staging.

Lymph node metastases with extracapsular extension in pN1 and pN2 stages carry a very poor prognosis. Therefore, this feature should be used to designate a separate pN category in the staging system. The discrimination of pN1/pN2 in the UICC 2002 classification seems to be arbitrary and of no significant prognostic relevance.
Prevalence and prognostic significance of microsatellite alterations in young patients with bladder cancer.

Migaldi M, Sartori G, Rossi G, Garagnani L, Faraglia B, Gaetani CD, Cittadini A, Trentini GP, Sgambato A.

1Dipartimento Misto di Anatomia Patologica e di Medicina Legale, Sezione di Anatomia Patologica, University of Modena and Reggio Emilia, Modena, Italy.
Mod Pathol. 2005 Sep;18(9):1176-86. Abstract quote  

Mutations in microsatellite sequences are a hallmark of neoplastic transformation and have been reported in the majority of human cancers. Conflicting results have been reported on the role of microsatellite alterations in bladder tumorigenesis and it has been suggested that they might be mainly involved in the development of bladder cancers in young patients.

In this study, DNA was extracted from laser-microdissected samples of 51 superficial papillary bladder urothelial carcinomas arising in young patients and was analyzed for the status of 19 microsatellite loci previously reported to be associated with bladder tumorigenesis. The occurrence and the pattern of microsatellite alterations, in form of loss or length variation, was evaluated and correlated with other clinicopathologic and molecular markers.

The prognostic significance of these alterations was also evaluated. Loss of heterozygosity at one or more loci was detected in all 51 tumors analyzed. Length variation in at least one locus was observed in 48 (94%) of the cases. The microsatellite that was more frequently altered was D11S488 (69%), followed by D9S162 (61%), D3S3050 (55%), D3S1300 (51%) and D4S243 (51%), all the remaining being altered in less than 50% of cases. The occurrence of microsatellite alterations was not associated with tumor grade nor with tumor stage, the expression of p53, cyclin D1 or the cyclin-dependent kinase-inhibitor p27(Kip1) while it was significantly more frequent in tumors with increased expression of the proliferation marker MIB-1 (P=0.003). The occurrence of alterations at the analyzed loci was associated with a reduced risk of tumor recurrence (P=0.04 by log-rank test) and disease progression (P=0.02) in a univariate analysis.

These findings demonstrate that microsatellite alterations are frequent and early events and might have a prognostic significance in bladder cancers arising at young age.
Kinetic Profiles by Topographic Compartments in Muscle-Invasive Transitional Cell Carcinomas of the Bladder
Role of TP53 and NF1 Genes

Alfredo Blanes, MD, PhD, etal.

Am J Clin Pathol 2002;118:93-100 Abstract quote

We evaluated 71 muscle-invasive transitional cell carcinomas (TCCs) of the bladder by tumor compartments. Kinetic parameters included mitotic figure counting, Ki-67 index, proliferation rate (DNA slide cytometry), and apoptotic index (in situ end labeling [ISEL] of fragmented DNA using digoxigenin-labeled deoxyuridine triphosphate and Escherichia coli DNA polymerase [Klenow fragment]).

At least 50 high-power fields per compartment were screened from the same tumor areas; results are expressed as percentage of positive neoplastic cells. Mean and SD were compared by tumor compartment. DNA was extracted from microdissected samples (superficial and deep) and used for microsatellite analysis of TP53 and NF1 by polymerase chain reaction–denaturing gradient gel electrophoresis. Significantly higher marker scores were revealed in the superficial compartment than in the deep compartment. An ISEL index of less than 1% was revealed in 63% (45/71) of superficial compartments and 86% (61/71) of deep compartments. Isolated NF1 alterations were observed mainly in superficial compartments, whereas isolated TP53 abnormalities were present in deep compartments.

Lower proliferation and down-regulation of apoptosis define kinetically the deep compartment of muscle-invasive TCC of the bladder and correlate with the topographic heterogeneity, NF1-defective in superficial compartments and TP53-defective in deep compartments.


Transitional cell carcinoma of the urinary bladder with regional lymph node involvement treated by cystectomy.

Frank I, Cheville JC, Blute ML, Lohse CM, Nehra A, Weaver AL, Karnes RJ, Zincke H.

Department of Urology, Mayo Clinic, Rochester, Minnesota.


Cancer 2003 May 15;97(10):2425-31 Abstract quote

BACKGROUND: Patients with transitional cell carcinoma (TCC) of the urinary bladder metastatic to regional lymph nodes (LN) typically have a poor prognosis. However, some patients are cured by radical cystectomy alone. The goal of this study was to identify predictors of survival in this cohort.

METHODS: The authors identified 154 patients with TCC metastatic to regional LNs treated by cystectomy between 1970 and 1998. Clinical characteristics collected included age, gender, and preoperative computed tomographic or magnetic resonance image scan findings, as well as neoadjuvant and adjuvant therapy. Pathologic features evaluated included multifocality, size, pathologic stage, grade, and margin status of the primary tumor, as well as the number, location, and bilaterality of the positive LNs. Capsular penetration, greatest linear extent, and surface area of the largest metastatic LN deposit were also recorded. The Kaplan-Meier method was used to evaluate survival rates. Cox proportional hazards models were used to identify predictors of outcome.

RESULTS: The mean follow-up was 4.5 years (range, 0.1-13.9 years). In a multivariate setting, only adjuvant chemotherapy and the number of positive LNs were associated significantly with death from TCC. Patients treated adjuvantly with chemotherapy were 2.1 times less likely to die of their disease (P = 0.005). Each increase in one positive LN increased the risk of death from TCC by 20% (P < 0.001). Recursive partitioning indicated that the optimal cutoff point to predict death from TCC was five or more positive LNs.

CONCLUSIONS: Adjuvant chemotherapy and the number of positive LNs were associated significantly with death from TCC.

Selective bladder preservation by combination treatment of invasive bladder cancer.

Kaufman DS, Shipley WU, Griffin PP, Heney NM, Althausen AF, Efird JT.

Department of Medical Oncology, Massachusetts General Hospital, Boston 02114. definitive results.

N Engl J Med 1993 Nov 4;329(19):1377-82 Abstract quote

BACKGROUND. For patients with invasive bladder cancer the usual recommended treatment is radical cystectomy, although transurethral resection of the tumor, systemic chemotherapy, and radiotherapy are each effective in some patients. We sought to determine whether these treatments in combination might be as effective as radical cystectomy and thus might allow the bladder to be preserved and the cancer cured.

METHODS. We enrolled 53 consecutive patients with muscle-invading bladder cancer (stages T2 through T4, NXM0) in a trial of transurethral surgery, combination chemotherapy, and irradiation (4000 cGy) with concurrent cisplatin administration. Urologic evaluation of the tumor response directed further therapy: radical cystectomy in the 8 patients who had incomplete responses, additional chemotherapy and radiotherapy (6480 cGy) in the 34 patients who had complete responses or who were unsuited for cystectomy, and alternative care in the 11 patients who could not tolerate either irradiation or chemotherapy.

RESULTS. After a median follow-up of 48 months, 24 of the 53 patients (45 percent) were alive and free of detectable tumor. In 31 patients (58 percent) the bladder was free of invasive tumor and functioning well, even though in 9 (17 percent) a superficial tumor recurred and required further transurethral surgery and intravesical drug therapy. Of the 28 patients who had complete responses after initial treatment, 89 percent had functioning tumor-free bladders.

CONCLUSIONS. Conservative combination treatment may be an acceptable alternative to immediate cystectomy in selected patients with bladder cancer, although a randomized clinical trial that included a group for simultaneous comparison would be required to produce definitive results.

Phase II study of a new combined primary chemotherapy regimen, intravenous methotrexate and vincristine and intraarterial adriamycin and cisplatin, for locally advanced urinary bladder cancer: preliminary results.

Kuroiwa T, Naito S, Hasuo K, Kishikawa T, Masuda K, Kumazawa J.

Department of Radiology, Kyushu University, Fukuoka, Japan.

Cancer Chemother Pharmacol 1995;35(5):357-63 Abstract quote

A phase II study of a new combination therapy was performed using intraarterial (i.a.) cisplatin and Adriamycin in combination with i.v. methotrexate and vincristine for 27 patients with invasive urinary bladder carcinoma of stages T2-3NOMO, and the therapeutic effects were assessed.

Methotrexate (20 mg/m2) was given i.v. on days 1,15, and 22, and vincristine (0.7 mg/m2) was injected i.v. on day 2 before i.a. infusion therapy and on days 15 and 22. The i.a. chemotherapy was performed after both superior gluteal arteries had been embolized using 3- or 5-mm stainless-steel coils. A mixture of cisplatin (50-70 mg/m2) and Adriamycin (20 mg/m2) was infused i.a. via both internal iliac arteries over a period of 20-30 min. Angiotensin II (mean dose, 21 micrograms) was simultaneously infused i.a. in 15 of 27 patients. In 24 of the 27 patients, at least 2 cycles of full-dose chemotherapy were completed. The dose was decreased in the remaining 3 patients because of their poor health status and advanced age. Among the 27 patients, 9 and 14 had complete (CR) and partial responses (PR), respectively; 3 manifested no change (NC), and 1 had progressive disease (PD). The objective response rate (CR+PR) was 85.2%. Among the 27 patients staged T2-3 NOMO, 6 (CR, 1; PR, 5) underwent total cystectomies and 18 (CR, 8; PR, 8; NC, 2) had transurethral resection of a bladder tumor (TUR-Bt) or partial resections following chemotherapy. The remaining 3 diminished-dose patients had no surgery. Of the 27 patients, 22 were alive after a median follow-up period of 21+ (range, 7-48+) months. No significant side effect was observed except for lower extremity paresthesias in 5 patients (18.5%).

These results point to the effectiveness of this therapy and to the possibility of urinary bladder preservation in patients with invasive, advanced urinary bladder cancers.

A randomized trial of radical cystectomy versus radical cystectomy plus cisplatin, vinblastine and methotrexate chemotherapy for muscle invasive bladder cancer.

Freiha F, Reese J, Torti FM.

Department of Urology, Stanford University School of Medicine, California, USA.

J Urol 1996 Feb;155(2):495-9 Abstract quote

PURPOSE: Standard treatment for muscle invasive transitional cell cancer of the bladder is radical cystectomy. Despite careful staging, the majority of cancers with regional lymph node involvement and/or invasion to adjacent organs eventually recur. We investigated the benefit of chemotherapy with cisplatin, methotrexate and vinblastine (CMV) after radical cystectomy.

MATERIALS AND METHODS: A prospective trial was done in which patients were randomized after cystectomy to receive either 4 cycles of CMV chemotherapy or observation. At relapse, patients were treated with standard CMV chemotherapy for metastatic disease at our institution.

RESULTS: Of 55 patients who entered this trial 1 was ineligible and in 4 it is too soon to be evaluated. Of the 50 evaluable patients 25 were randomized to receive adjuvant CMV chemotherapy and 25 were observed. In the CMV arm 12 (48%) and in the observation arm 5 (25%) never had recurrence. With a median followup of 62 months and no patient with less than 2 years of followup, the freedom from progression in the adjuvant chemotherapy group was superior to that in the observation group (median 37 versus 12 months, respectively, p = 0.01). Median survival in the adjuvant group was 63 months compared to 36 months for the observation group. Surprisingly, some cases with relapse could be salvaged with CMV chemotherapy, perhaps contributing to this lack of difference in overall survival (p = 0.32).

CONCLUSIONS: Treatment with CMV chemotherapy after radical cystectomy is an acceptable approach in patients with stages p3b and p4N0 or N1 transitional cell carcinoma of the bladder. Further studies must be performed to determine whether these results can be extrapolated to patients with more limited disease (stages p2 and p3a) who are currently treated with radical cystectomy or definitive irradiation.

A phase I/II trial of transurethral surgery combined with concurrent cisplatin, 5-fluorouracil and twice daily radiation followed by selective bladder preservation in operable patients with muscle invading bladder cancer.

Zietman AL, Shipley WU, Kaufman DS, Zehr EM, Heney NM, Althausen AF, McGovern FJ.

Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston 02114, USA.

J Urol 1998 Nov;160(5):1673-7 Abstract quote

PURPOSE: We describe a protocol designed to evaluate the use of twice daily radiation used together with cisplatin and 5 fluorouracil (5-FU) in the treatment of operable transitional cell carcinoma of the bladder with potential bladder preservation.

MATERIALS AND METHODS: A total of 18 consecutive patients with T2-T4a bladder tumors underwent as complete a transurethral resection as possible, which was visibly complete in 14 cases. They then received twice daily radiation and infusion cisplatin and 5-FU during an induction phase. No therapy was given for 3 weeks, following which patients were reevaluated cystoscopically. Cases of clinical complete response by biopsy and cytology were consolidated with further chemotherapy/radiation using the same chemotherapeutic agents and radiation schedule. Patients who had incomplete responses were advised to undergo an immediate radical cystectomy. Of the 18 patients 15 subsequently received 3 cycles of adjuvant chemotherapy, consisting of methotrexate, cisplatin and vinblastine. Median followup for the entire group is 32 months.

RESULTS: Of the 18 patients 14 had no detectable tumor after induction therapy. Of the 4 patients with persistent tumor 2 underwent radical cystectomy and 2 refused cystectomy, 1 of whom was treated with partial cystectomy and the other with consolidation chemotherapy/radiation. The actuarial overall survival at 3 years was 83%. The chance of a patient being alive at 3 years with a native bladder was 78%. No patient required cystectomy for hematuria or bladder shrinkage. Three patients in whom superficial tumors developed were treated successfully with bacillus Calmette-Guerin. Small bowel obstruction in 1 case was corrected surgically.

CONCLUSIONS: This pilot study demonstrates a high rate of response to this combined chemotherapy/radiation regimen in conjunction with a visibly complete transurethral resection. Reevaluation after a short induction phase allows for the early selection of patients with persistent disease for radical cystectomy.

Prognostic factors in invasive bladder carcinoma treated by combined modality protocol (organ-sparing approach).

Matos T, Cufer T, Cervek J, Bornstnar S, Kragelj B, Zumer-Pregelj M.

Institute of Oncology, University Medical Center, Ljubljana, Slovenia.

Int J Radiat Oncol Biol Phys 2000 Jan 15;46(2):403-9 Abstract quote

PURPOSE: The results of bladder sparing approach for the treatment of muscle-invasive bladder cancer, using a combination of transurethral resection (TUR), chemotherapy, and radiotherapy, are encouraging. The survival of patients treated by this method is similar to the survival of patients treated by radical cystectomy. The aim of our study was to find out which pretreatment characteristics influence the survival of patients treated by organ sparing approach that would enable us to identify the patients most suitable for this type of treatment.

METHODS AND MATERIALS: The prognostic value of different factors, such as age, gender, performance status, hemoglobin level, clinical stage, histologic grade, presence of obstructive uropathy, and completeness of TUR, has been studied in 105 patients with invasive bladder cancer, who received a bladder sparing treatment in the period from 1988 to 1995. They were treated with a combination of TUR, followed by 2-4 cycles of methotrexate, cisplatinum, and vinblastine polychemotherapy. In complete responders the treatment was completed by radiotherapy (50 Gy to the bladder and 40 Gy to the regional lymph nodes), whereas nonresponders underwent cystectomy whenever feasible.

RESULTS: Our study has confirmed an independent prognostic value of performance status, histologic grade, and obstructive uropathy, for the disease-specific survival (DSS) of bladder cancer patients treated by a conservative approach. We believe that performance status best reflects the extent of disease and exerts significant influence on the extent and course of treatment, while obstructive uropathy is a good indicator of local spread of the disease, better than clinical T-stage. Our finding that histologic grade is one of the strongest prognostic factors shows that tumor biology also is a very important prognostic factor in patients treated by conservative approach.

CONCLUSION: Patients with muscle-invasive bladder cancer who are most likely to benefit from conservative treatment approach include those with good performance status, absence of hydronephrosis, and histologic low grade transitional cell carcinoma.

Combination cisplatin, 5-fluorouracil and radiation therapy for locally advanced unresectable or medically unfit bladder cancer cases: a Southwest Oncology Group Study.

Hussain MH, Glass TR, Forman J, Sakr W, Smith DC, Al-Sarraf M, Jones J, Balcerzak SP, Crawford ED, Grossman HB.

Wayne State University, Barbara Ann Karmanos Cancer Institute, Detroit, MI, USA.

J Urol 2001 Jan;165(1):56-60 Abstract quote

PURPOSE: Patients with locally advanced bladder cancer or who are not medically fit for surgery are a therapeutic dilemma. Radiotherapy with or without single agent cisplatin has been the major therapeutic modality. A phase II Southwest Oncology Group trial investigated the efficacy and feasibility of 5-fluorouracil, cisplatin and radiation in this patient subset.

MATERIALS AND METHODS: Eligible patients had muscle invasive bladder cancer (clinical stages T2-T4) with nodal involvement at or below the level of bifurcation of the iliac vessels, were medically or surgically inoperable, or refused cystectomy. Patients underwent pretreatment cystoscopy and detailed tumor mapping, and were treated with 75 mg. /m.2 cisplatin on day 1 and 1 gm./m.2 daily, 5-fluorouracil on days 1 to 4 and definitive radiotherapy. Chemotherapy was repeated every 28 days, twice during and twice after radiation.

RESULTS: From October 1993 to April 1998, 60 patients were enrolled in study. Of the 56 eligible patients 34% had unresectable tumors, 21% were not medically fit for surgery and 45% refused cystectomy. Overall, 68% of the patients had clinical T3 tumors or greater and 22% had nodal metastasis. Treatment was completed as planned in 32 of 56 (57%) patients. The most frequent grade 3 or 4 toxicities were neutropenia, stomatitis or mucositis, diarrhea, neuropathy and nausea. There were 53 patients who were evaluable for response, although response was not determined for 18. The overall response rate was 51% (95% confidence interval [CI] 37 to 65) based on intent to treat with a complete response rate of 49% (95% CI 35 to 63). Estimated median survival of the 56 patients was 27 months (95% CI 21 to 40 months) with an overall 5-year survival of 32%. The 5-year survival of the 25 patients who refused surgery was 45%.

CONCLUSIONS: Concurrent 5-fluorouracil, cisplatin and radiation therapy is feasible. Despite a promising complete response rate, the overall 5-year survival suggests the need for more effective systemic therapy. The 5-year survival of patients who refused cystectomy suggests that this combined modality may provide another alternative to cystectomy for these patients.

Combination chemotherapy with gemcitabine and ifosfamide as second-line treatment in metastatic urothelial cancer. A phase II trial conducted by the Hellenic Cooperative Oncology Group.

Pectasides D, Aravantinos G, Kalofonos H, Kiamouris C, Bafaloukos D, Xiros N, Nicolaides C, Visvikis A, Dimopoulos MA.

First Department of Medical Oncology, Metaxas Memorial Cancer Hospital, Piraeus Greece.

Ann Oncol 2001 Oct;12(10):1417-22 Abstract quote

PURPOSE: The aim of the study was to evaluate the efficacy and safety of the combination of gemcitabine and ifosfamide as a second-line treatment for advanced urothelial cancer.

PATIENTS AND METHODS: Thirty-four patients with metastatic urothelial cancer previously treated with cisplatin (CDDP)/ carboplatin (CBDCA) and/or taxanes-based chemotherapy were studied. Gemcitabine was administered at a dose of 800 mg/m2 on days 1 and 8 and ifosfamide at a dose of 2 g/m2 on days 1 and 8 with adequate amount of Mesna. every three weeks. Hematopoietic growth factors were given between days 3 to 5 and 12 to 16 to maintain the treatment schedule.

RESULTS: On an intent to treat basis, there was one complete response (CR) (3%) (95% confidence interval (95% CI): 0% to 10%) and six partial responses (PR) (18%) (95% CI: 7% to 34%). inducing an objective response rate (RR) of 21% (95% CI: 9% to 38%); 12 (35%) patients achieved a stable disease (SD) and 15 (44%) a progressive disease (PD). The median time to tumor progression (TTP) was four months (range, 0.52 to 21.6 months) and the median survival nine months (range 0.52 to 28 months). This regimen also provided the opportunity for symptomatic improvement of pain, dysuria, haematuria and leg oedema. Grade 3-4 neutropenia was experienced by 9 (27%) patients, grade 3 4 anemia by 6 (18%) and grade 3-4 thrombocytopenia by 4 (12%). Six patients were hospitalized due to febrile neutropenia. Despite the prophylactic use of hematopoietic growth factors, 8 (23.5%) patients required dose reduction due to myelosuppression. Grade 3 alopecia occurred in 14 (41%) patients, grade 3-4 nausea in 1 (3%), grade 2 fever in 3 (9%), grade 2-3 diarrhea in 2 ( 6%) and grade 2 allergic reaction in 1 (3%).

CONCLUSION: We conclude that the combination of gemcitabine and ifosfamide is an active salvage regimen for the treatment of urothelial cancer and that the treatment also has a tolerable toxicity profile; it warrants further investigation in combination with CDDP in chemotherapy-naive patients.

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