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Background
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.
OUTLINE
EPIDEMIOLOGY CHARACTERIZATION PREVALENCE 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% 13-30% of transitional cell neoplasms 50-60% of transitional cell neoplasms <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% AGE RANGE-MEDIAN
- 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.50-70 years
Median and mean 64 and 68 yearsMean 62 years for nonurachal tumors
Mean 51 years for urachal tumors60-70 years 50-70 years 2.7:1 3:1 for nonurachal tumors
1:1 for urachal tumors<2:1 2:1 Whites>Blacks
PATHOGENESIS CHARACTERIZATION CHROMOSOMAL ABNORMALITIES
- 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.
ONCOGENES 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.
PROTEIN KINASE C 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.
LABORATORY/
RADIOLOGIC/OTHER TESTSCHARACTERIZATION Cystoscopy 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.
FISH-UROVYSION
- Yoder BJ,
- Skacel M,
- Hedgepeth R,
- Babineau D,
- Ulchaker JC,
- Liou LS,
- Brainard JA,
- Biscotti CV,
- Jones JS,
- Tubbs RR.
Department of Anatomic and Clinical Pathology, Cleveland Clinic Foundation, leveland, OH 44195, USA.
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.FISH
- 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 timeMultiprobe 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.
FLOW CYTOMETRY Transitional cell carcinoma (TCC) 20% with DNA aneuploidy >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 Sensitivity 60%
Specificity 77%Sensitivity 67%
Specificity 72%Sensitivity 77%
Specificity 85%Sensitivity 89%
Specificity 100%HUMAN CARCINOMA-ASSOCIATED ANTIGEN 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.
HISTOLOGICAL TYPES CHARACTERIZATION GENERAL
*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.
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.
Department of *Pathology daggerUrology and Oncology, The Johns Hopkins Medical Institutions, Baltimore, MD.
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.
Department of Pathology, Reina Sofia University Hospital and Cordoba University Medical School, E-14004 Cordoba, Spain.
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.
PRECURSOR OR BENIGN TRANSITIONAL CELL LESIONS 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.
INVERTED PAPILLOMA 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 anaplasiaTUMORS 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.
TRANSITIONAL CELL CARCINOMA Papillary with uniform cells
At least 7 urothelial layers in thickness
Rare mitotic figuresInfiltrating neoplasms with papillary and flat configurations
Numerous mitotic figuresAlmost 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 variantAm 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).
Conclusion:
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, MDHum 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.
MICROINVASION
Hemamali Samaratunga, etal.
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 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 ProblemsEsther 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 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
- 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.NEUROENDOCRINE CARCINOMA (SMALL CELL CARCINOMA) 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
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 VARIANT
*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.
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.RHABDOID FEATURES
- 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
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