Stromelysin-3 expression in invasive ovarian carcinomas and tumours of low malignant potential

Stromelysin (ST)-3 is considered to be a marker of invasion and preinvasive lesions to indicate the likelihood of subsequent invasion. The expression of ST-3 has not been systematically studied in ovarian neoplasms. We studied 47 ovarian carcinomas and 49 ovarian tumours of low malignant potential (LMP) to see whether the expression of ST-3 correlated with any histopathologic features and, in the LMP tumours, whether its expression might be a prognostic indicator. All of the primary tumours and available metastases or implants were studied using immunohistochemistry (IHC) for ST-3 and, in 52 selected lesions, in situ hybridisation (ISH) using a cDNA probe. Expression of ST-3 was seen in 42 of 47 (89%) of the carcinomas and in 16 of 49 (33%) of the LMP cases. A significantly higher percentage of carcinomas than LMP tumours (P<0.00001) expressed ST-3 in the stroma adjacent to the tumour, with a correlation to increasing FIGO (International Federation of Gynecology and Obstetrics) tumour stage. ST-3 was expressed in the surrounding stroma of 1 of 8 LMP implants and 46 of 55 (84%) of the carcinoma metastases. The single LMP patient who died of tumour recurrence had ST-3 expression, but a significant prognostic impact was not found. The infrequent expression of ST-3 in LMP compared with carcinoma metastases appears to be more consistent with a peritoneal "field effect" than spread from the ovarian LMP tumour.     

Nonepithelial neoplasms of the urinary bladder

Nonepithelial tumors are rare in the urinary bladder, but their exact classification is very important in the differential diagnosis between these tumors and epithelial lesions. In the new WHO classification and in the third series of the Armed Forces Institute of Pathology (AFIP) "Atlas of Tumor Pathology" on urinary bladder tumors, various mesenchymal tumors, mixed epithelial and mesenchymal tumors and myofibroblastic proliferations are summarized. In the following we will describe the histology, immunohistology, and cytogenetics of nonepithelial tumors and lesions.     

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

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

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

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

Cytohistological study of urinary bladder neoplasms

Eighty patients presenting with painless hematuria and 24 patients of transitional cell carcinoma bladder coming for follow up were included in this study to assess the role of exfoliative (voided urine) and lavage (saline lavage) cytology in initial diagnosis and follow up of the patient with carcinoma bladder. Freshly voided urine samples and saline lavage bladder washing samples were collected. A thorough cystoscopic examination was done and biopsy was taken from any apparent growth. Cytological smears were stained with hematoxylene and eosin and PAP's stain, histology sections were stained with hematoxylene and eosin. A statistically significant correlation (p < 0.001) was observed between the increasing grade of malignancy and cytopositivity. A good association was observed between histology and two methods of cytology (p < 0.01). The sensitivity, specificity and overall diagnostic accuracy of lavage cytology was more as compared to exfoliative cytology (71.05%, 56.0%, 78.85% Vs 47.37%, 41.18% and 61.54%). Cystopositivity was more with single large sessile tumour as compared to multiple small pedunculated tumours. Cytohistological discrepancy was observed in patients of transitional cell carcinoma with recurrence. It is concluded that cytology may act as a good adjuvant to histology in picking up early flat lesions and/or follow up of patients with transitional cell carcinoma.     

Recommendations for the reporting of urinary bladder specimens containing bladder neoplasms

The Association of Directors of Anatomic and Surgical Pathology have developed recommendations for the surgical pathology report for common malignant tumors. The recommendations for carcinomas of the urinary bladder are reported herein.This report was prepared by an ad hoc committee composed of William M. Murphy (Chair), John D. Crissman, Sonny L. Johansson, and Alberto G. Ayala.     

Contiguous but dissimilar epithelial neoplasms of the urinary bladder

An unusual tumour of the urinary bladder is described. It consists of two distinct nodules each with a quite different histological appearance, one being mucus-secreting adenocarcinoma, the other transitional cell carcinoma. Where the nodules are in contact there is little intermingling of the two histological patterns and it is suggested that the findings are probably due to the collision of two separate neoplasms. Metaplastic changes are present in the bladder mucosa adjacent to the tumour. The significance of these changes in the pathogenesis of adanocarcinoma is discussed.     

Stromelysin-3 protein expression in invasive breast cancer: relation to proliferation, cell survival and patients' outcome.

Matrix metalloproteinases constitute one of the major extracellular matrix degrading enzymic families implicated in cancer development. Stromelysin-3 in particular, a member of the matrix metalloproteinases belonging to the stromelysins' subgroup, seems to be closely related to invasiveness and tumor progression. In this study, we proceeded to the evaluation of stromelysin-3 protein's expression in paraffin sections of 133 cases of invasive breast carcinomas and statistically estimated its relations with known clinicopathological prognostic parameters and patients' survival, proliferation markers Ki-67 and TopoIIalpha and the antiapoptotic protein bcl-2. Presence of stromelysin-3 was immunodetected, in the 73% of our cases, in stromal cells (65%) and in epithelial tumor cells (26.26%). Stromelysin-3 epithelial positivity presented statistically significant correlations with TopoIIalpha and Ki-67 proliferation indices (P =.042 and P =.031, respectively) and worse disease outcome through multivariate statistics (P =.014). Stromelysin-3 fibroblastic expression was significantly associated with nuclear grade (P =.024), ductal histological type (P =.037), TopoIIalpha (P =.001) and Ki-67 (P =.019), inversely with bcl-2 protein (P =.027) and with adverse overall survival through univariate analysis (P =.017). The subgroup of patients with stromelysin-3 co-expression in stromal and malignant epithelial cells showed statistically significant associations with Ki-67 and TopoIIalpha (P =.019, P <.0001, respectively), an inverse one with bcl-2 protein (P =.027) and furthermore with impaired survival (P =.002) through multivariate analysis. In conclusion, stromelysin-3 protein expression correlated with proliferation indices TopoIIalpha and Ki-67 and the anti-apoptotic protein bcl-2, data confirming stromelysin-3's contribution to breast cancer progression. Moreover its expression was shown to have a direct negative effect on patients' survival, especially in the subgroup of patients with simultaneous epithelial and stromal expression.     

Current status of urinary cytology in the evaluation of bladder neoplasms

Pathologic examination of urinary specimens is increasingly recognized as an essential component of detection and monitoring for patients with bladder neoplasms. Among the available techniques, urinary cytology is the most useful. The current status of urinary cytology can be summarized as follows: 1. The demand for urinary cytology is steadily increasing as clinicians have realized the limitations of cystoscopy and even biopsy for monitoring bladder cancer patients, especially those having carcinoma in situ or receiving topical therapy. 2. Urinary cytology is currently an essential procedure for monitoring all patients with urothelial neoplasms and, if consistently used, can actually decrease the frequency with which patients need to be subjected to cystoscopy. 3. Even in moderately experienced hands, urinary cytology can detect almost all high-grade urothelial neoplasms. 4. The cytologic interpretation of low-grade transitional cell neoplasia requires expertise. These cells lack many of the features of malignancy, a source of confusion for the diagnostician but a positive factor for the patient since neoplasms composed of these cells are almost never aggressive. 5. The most useful type of urinary specimen for routine diagnostic interpretation is freshly voided, randomly collected urine. Catheterized specimens and bladder washings may yield more and better preserved cells, but no patient should be catheterized solely to obtain diagnostic material. 6. Preservation of urinary specimens in alcohols is not necessary unless prolonged storage is contemplated. Refrigeration to prevent bacterial growth and inhibit further cellular degeneration is required, however. 7. Cytologic details are best displayed with membrane filtration but other types of processing are adequate. The computer-programmed cytocentrifuge is currently most popular. 8. Optimal recognition of cytologic details requires some form of Papanicolaou staining; Romanovsky dyes are less desirable. 9. Urothelial cells with nuclear:cytoplasmic ratios of 1:2 or less should not be interpreted as malignant regardless of the degree of anaplasia of their nuclei. 10. Papillary aggregation is not a reliable feature of low-grade neoplasia in urinary samples. 11. Using appropriate criteria, the differential diagnosis of urothelial neoplasia versus the reactive/regenerative/reparative changes secondary to urinary stones can almost always be accomplished. 12. Alkylating agents such as Cytoxan, thio-TEPA, and mitomycin C produce characteristic but nonspecific changes in urothelial cells. These changes rarely mimic those of carcinoma. The diagnosis of urothelial neoplasia need not be confounded by previous treatment. 13. Flow cytometry and digitized image analysis are currently used for diagnostic interpretations of urinary specimens in selected centers. Their routine use must await further refinements in instrumentation and the formulation of more searching questions.     

The role of immunohistochemistry in the diagnosis of urinary bladder neoplasms

The spectrum of neoplasms involving the urinary bladder is diverse, and, at times, different entities with distinct prognostic and managerial implications may have significant morphologic overlap. The presence of a neoplasm with an unusual morphologic appearance, such as an undifferentiated spindled, or plasmacytoid pattern may necessitate immunohistochemistry to establish the diagnosis. In this review, we discuss a series of distinct diagnostic scenarios, including high-grade undifferentiated carcinoma versus prostatic adenocarcinoma, enteric-type adenocarcinoma versus secondary colorectal adenocarcinoma, spindle cell proliferations, neoplasms with plasmacytoid morphology, endophytic tumors with a nested growth pattern, and flat urothelial lesions with atypia. We also discuss markers supporting urothelial differentiation in the context of a metastatic carcinoma from an unknown primary. The importance of using a morphologically derived differential diagnosis to guide the selection and interpretation of immunohistochemical studies is emphasized, and the varying utility (specificity) of the individual immunohistochemical markers within each setting is addressed.     

Lectin binding and expression of blood group-related antigens in carcinoma-in-situ and invasive carcinoma of urinary bladder

To determine whether histochemical reactivities of carcinoma- in-situ of the urinary bladder differ from those of invasive transitional cell carcinoma, we tested a profile of eight different lectins and three antibodies directed against blood group-related antigens for 15 cases of carcinoma- in-situ and 26 cases of non-papillary (6 superficially and 20 deeply) invasive transitional cell carcinoma that had been diagnosed according to the histopathological criteria of the International Union against Cancer. For biotin-labelled lectins and monoclonal antibodies to mouse blood group-related antigens, the avidin–biotin peroxidase complex method was applied. Positive histochemical reactions of peanut agglutinin without neuraminidase treatment—PNA N(–)—in the 20 deeply invasive tumour cases were significantly higher than those in the 15 carcinoma- in-situ cases ( P <0.05). In contrast, the reactions of blood group-related antigens in the 20 deeply invasive tumour cases were significantly lower than those in the 15 carcinoma- in-situ cases or the 11 normal controls ( P <0.05). The results confirm previously reported studies of the staining of PNA N(–) and blood group-related antigens on carcinoma- in-situ and invasive tumours of urothelial organs. The application of lectins and blood group-related antigens to the histopathology of urinary bladder cancer may be helpful in the differential diagnosis of carcinoma- in-situ from invasive cancer, but neither PNA N(–) nor blood group-related antigens can be solely reliable in this.     

CD34<Superscript>+</Superscript> fibrocytes in chronic cystitis and noninvasive and invasive urothelial carcinomas of the urinary bladder

CD34⁺ fibrocytes are constitutive elements of the connective tissue where they play a role in matrix synthesis and tumor-associated stromal remodeling. Secreted protein, acidic, and rich in cysteine (SPARC) is a pivotal mediator of stromal remodeling precipitated by invasive carcinomas. The present study was undertaken to investigate CD34⁺ fibrocytes in the stroma of the tumor-free urinary bladder, chronic cystitis, and urothelial carcinomas together with stromal expression of α-smooth muscle actin (α-SMA), CD117, and SPARC. In tumor-free urinary bladder and chronic cystitis, CD34⁺ fibrocytes were found in the deep lamina propria and tunica muscularis, whereas the superficial lamina propria disclosed a CD34-negative and α-SMA-positive fibrocyte-like cell. Invasive urothelial carcinomas revealed a complete loss of CD34⁺ fibrocytes and concomitant appearance of α-SMA-reactive myofibroblasts which showed strong expression of SPARC. CD117 expression of tumor-free and tumor-associated stroma revealed no differences. We in this study for the first time describe CD34⁺ fibrocytes in the urinary bladder and an up-to-now unknown population of α-SMA-positive fibrocytes exclusively occurring in the superficial lamina propria. Stromal remodeling associated with invasive carcinomas in the urinary bladder is characterized by a loss of CD34⁺ fibrocytes paralleled by a gain of α-SMA-positive myofibroblasts and increased expression of SPARC.     

Decreased expression of Bax-interacting factor-1 (Bif-1) in invasive urinary bladder and gallbladder cancers

Aims: Mounting evidence indicates that deregulation of apoptosis is involved in the mechanisms of cancer development. Bax-interacting factor-1 (Bif-1) interacts with both Bax and Bak that are crucial for the intrinsic apoptosis signalling. Functionally, loss of Bif-1 expression has been proven to enhance tumorigenesis. The aim of this study was to explore whether loss of Bif-1 expression occurs in urinary bladder (UB) and gallbladder (GB) cancer tissues. Methods: We analysed Bif-1 protein expression in 41 transitional cell carcinomas of UB and 26 GB adenocarcinomas by immunohistochemistry. Results: In both UB and GB, normal mucosal epithelial cells strongly expressed Bif-1 protein. In the UB cancers, Bif-1 expression was strongly positive in 25 cases (61.0%), but the remaining 16 cases showed no (14.6%) or markedly decreased (24.4%) Bif-1 immunostaining compared with the normal mucosal epithelial cells. Similarly, in the GB cancers, Bif-1 immunostaining was strong in 17 cases (65.4%), while the remaining nine cases showed no (15.4%) or markedly decreased (19.2%) Bif-1 immunostaining compared with the normal mucosal epithelial cells. Conclusion: The decreased expression of Bif-1 in large fractions of both UB and GB cancers (39.0% and 34.6%, respectively) compared with their normal mucosal cells suggested that loss of Bif-1 expression might play a role in tumorigenesis in both UB and GB cancers, possibly by inhibiting apoptosis mediated by Bif-1.     

Soft tissue tumors of the urinary bladder Part II: malignant neoplasms

Most bladder tumors arise from the urothelium. However, there are several uncommon but significant malignant bladder lesions that must be differentiated from urothelial carcinomas and from benign lesions of the bladder. The second half of this two-part review will describe rare nonurothelial malignant tumors of the urinary bladder including leiomyosarcoma, rhabdomyosarcoma, angiosarcoma, malignant fibrous histiocytoma (undifferentiated sarcoma), primitive neuroectodermal tumor, malignant peripheral nerve sheath tumor, hemangiopericytoma, and alveolar soft-parts sarcoma. Common clinical presentations, morphologic characteristics, and immunohistochemical features are described to aid the practicing pathologist in the identification of these entities. Because the distinction between malignant and benign lesions has significant therapeutic and prognostic implications, key factors for differentiating them are presented.     

Prognostic markers in low-grade papillary urothelial neoplasms of the urinary bladder: an update

Papillary urothelial neoplasms of the urinary bladder comprise a heterogeneous spectrum of ‘continuous’ lesions in which the assessment of an accurate histological grade and tumour stage is mandatory for the clinical management of patients. The 1998 World Health Organization/International Society of Urologic Pathologists (WHO/ISUP) consensus classification and the 1999 WHO classification proposed new malignancy grading schemes, mainly based on morphometric studies for the replacement of the 1973 WHO grading system. In accordance with these novel grading systems, two major categories of papillary urothelial neoplasms were distinguished: low-grade and high-grade papillary urothelial neoplasms. Concerning the specific subgroup of low-grade tumours, two other entities were defined: papillary urothelial neoplasms of low malignant potential (PUNLMP) and low-grade papillary urothelial carcinomas (LGPUC). In long-term follow-up programmes, PUNLMP have demonstrated low recurrence rates and minimal risk for tumour progression in comparison with LGPUC. However, grade assessment is a subjective decision and, on occasion, the use of reproducible criteria by urological pathologists is difficult due to tumour heterogeneity and to the existence of a variable number of cases situated between consecutive groups. As a result, to determine a better correlation with clinicopathological patient outcome, other predictive markers are being investigated. Among these, the prognostic significance of classical clinicopathological, morphometric, cytometric, immunohistochemical and molecular markers have been widely reported. This review summarizes the prognostic importance of all these markers in the prediction of tumour recurrences and progression in low-grade papillary urothelial bladder neoplasms.     

Recommendations for the reporting of urinary bladder specimens containing bladder neoplasms Association of Directors of Anatomic and Surgical Pathology

The Assoclatlon of Directors of Anatomic and Surgical Pathology have developed recornmendatlons for the surgical pathology reporting of common malignant tumors. The recommendations for carcinomas of the urinary bladder are reported herein.     

Recommendations for the reporting of urinary bladder specimens containing bladder neoplasms Association of Directors of Anatomic and Surgical Pathology

The Association of Directors of Anatomic and Surgical Pathology have developed recommendatlons for the surgical pathology repotting of common malignant tumors. The recommendations for carcinomas of the urinary bladder are reported herein.     

Stromelysin-3 expression in early (pT1) carcinomas and pseudoinvasive lesions of the colorectum

Pseudoinvasion in colorectal adenomas is often difficult to distinguish from invasive carcinoma. Previous studies have indicated that expression of stromelysin-3 (ST 3), one of the metalloproteinase family of enzymes, may be useful for the identification of early invasive carcinoma. The goal of our study was to detect ST-3 expression in colorectal adenomatous polyps to see if it could be helpful for the differential diagnosis of pseudoinvasion vs. true invasion. We studied 25 polypectomy specimens which were divided histologically into 2 groups; the first consisted of 15 adenomas with invasive carcinoma, 8 of these carcinomas were more diffusely infiltrative (pT1), and 7 tended to be expansively invasive. The second group was composed of 10 adenomas with pseudoinvasion. A 35S labelled cDNA probe was used for in situ hybridization (ISH) and a monoclonal antibody (5ST4A9) for immunohistochemistry (IHC). The distribution of ST-3 expression as detected by IHC and ISH was identical. All diffusely infiltrative carcinoma cases showed ST-3 expression, but only focally in 2 cases with marked lymphocytic infiltration. None of the expansive carcinoma or pseudoinvasion cases showed ST-3 expression. ST-3 expression seems to be an indicator of invasion, but a negative reaction for ST-3 does not rule out an expansive invasive neoplasm or a diffusely infiltrative invasive tumour with a dense lymphocytic reaction.