Sonny L. Johansson

The World Health Organization/International Society of Urological Pathology consensus classification of urothelial (transitional cell) neoplasms of the urinary bladder

In October 1997, Dr. F.K. Mostofi assembled a group of individuals interested in bladder neoplasia at a meeting in Washington DC. The participants included urologic pathologists, urologists, urologic oncologists, and basic scientists with an interest in bladder neoplasia. The purpose of this meeting was to discuss bladder terminology and make recommendations to the World Health Organization (WHO) Committee on urothelial tumors. Following this meeting, a group of the urologic pathologists who attended the Washington meeting decided to broaden the representation of the group and arranged a meeting primarily of the members of the International Society of Urologic Pathologists (ISUP) at the 1998 United States and Canadian Academy of Pathology Meeting held in Boston. Massachusetts. At this meeting. issues regarding terminology of bladder lesions, primarily neoplastic and putative preneoplastic lesions, were discussed, resulting in a consensus statement. The WHO/ ISUP consensus classification arises from this consensus conference committees recommendations to the WHO planning committee and their agreement with virtually all of the proposals presented herein. 29 The effort involved in reaching such a consensus was often considerable. Many of those involved in this process have compromised to arrive at a consensus. The aim was to develop a universally acceptable classification system for bladder neoplasia that could be used effectively by pathologists, urologists, and oncologists.

Clinical Evaluation of a Multi-target Fluorescent in Situ Hybridization Assay for Detection of Bladder Cancer

PURPOSE The UroVysion fluorescence in situ hybridization assay (UroVysion Bladder Cancer Recurrence Kit, Vysis, Inc., Downers Grove, Illinois) is a multi-target assay that detects aneuploidy of chromosomes 3, 7 and 17, and loss of the 9p21 band in exfoliated cells in urine from patients with transitional cell carcinoma. We performed 2 multicenter trials. In 1 trial we compared the sensitivity of the FISH assay to the BTA Stat test (Bion Scientific, Redmond, Washington) and voided cytology in the detection of transitional cell carcinoma. In a separate study of healthy volunteers and patients with other (nontransitional cell carcinoma) conditions we determined the specificity of the FISH assay. MATERIALS AND METHODS A total of 176 patients with transitional cell carcinoma in the previous 9 months provided voided urine before cystoscopy. Each specimen was split, preserved and shipped to a central laboratory where all 3 tests were performed. All sites were blinded to results. Sensitivity calculations were based on central pathology review of resected tissue. Specificity was determined by testing 275 volunteers who were healthy and with nontransitional cell carcinoma conditions. RESULTS The 21 sites enrolled 176 patients with a history of transitional cell carcinoma, with 62 recurrences while undergoing surveillance. Overall sensitivities (with 95% CI) were FISH 71% (95% CI 58 to 82), BTA Stat test 50% (37 to 63) and cytology 26% (16 to 39). FISH was negative in 260 of the 275 healthy volunteers or patients with no history of transitional cell carcinoma (specificity 94.5%). CONCLUSIONS Sensitivity of the FISH assay is superior to that of cytology and at least equivalent to the BTA Stat test in detecting recurrent transitional cell carcinoma. Its specificity approaches that of cytology. Further testing of its clinical use is warranted.

EPIDEMIOLOGY AND ETIOLOGY OF BLADDER CANCER

The incidence of bladder cancer continues to increase, with an estimated 53,000 new cases diagnosed in the United States in 1996-90% of which are transitional cell carcinomas. The male-to-female ratio is 3:1. A number of etiological factors are associated with the development of bladder cancer, but in industrialized countries, cigarette smoking is the most important. Specific chemicals have also been identified as causing bladder cancer, as have a number of occupational exposures to less well-defined specific agents. Treatment with cytostatic drugs, especially cyclophosphamide, is associated with increased risk of bladder cancer, as is treatment with radiotherapy for uterine cancer. In developing countries, especially in the Middle East and parts of Africa, infections with members of the genus Schistosoma are responsible for a high incidence of bladder cancer-75% of which are squamous cell carcinomas. Arsenic has been indicated as a bladder carcinogen in Argentina, Chile, and Taiwan. The reason for the high incidence of urinary tract cancer in individuals suffering from Balkan nephropathy has yet to be determined. A careful history of patients with bladder cancer is an important and useful process in helping to identify causal factor and, in more than one-half the cases, a known relationship is found. Bladder cancer is a potentially preventable disease, with a significant morbidity and mortality in many parts of the world.

Clinical Features and Spectrum of Light Microscopic Changes in Interstitial Cystitis

Transurethral resection material from a series of 64 patients with classical (ulcer) interstitial cystitis (60 women and 4 men, with a mean age of 64 years), 44 with nonulcer interstitial cystitis (40 women and 4 men, with a mean age of 39 years) and 20 control women (mean age 49 years) were studied by light microscopy. Patients with classical disease had mucosal ulceration and hemorrhage, granulation tissue, intense inflammatory infiltrate, elevated mast cell counts and perineural infiltrates. Patients with nonulcer disease, despite the same severe symptoms, had a relatively unaltered mucosa with a sparse inflammatory response, the main feature being multiple, small, mucosal ruptures and suburothelial hemorrhages that were noted in a high proportion of the patients. It is suggested that these features are characteristic, specific and prevalent enough to allow for morphological differentiation of the 2 clinical subtypes of interstitial cystitis.

STAGE PROGRESSION IN TA PAPILLARY UROTHELIAL TUMORS: RELATIONSHIP TO GRADE, IMMUNOHISTOCHEMICAL EXPRESSION OF TUMOR MARKERS, MITOTIC FREQUENCY AND DNA PLOIDY

PURPOSE We studied 363 patients with stage Ta bladder tumors during long-term followup who were classified according to the 1998 WHO and International Society of Urological Pathology consensus classifications. We determine whether various immunohistochemical and molecular markers could predict tumor progression. MATERIALS AND METHODS A total of 680 patients in western Sweden with a first diagnosis of bladder carcinoma in 1987 and 1988 were registered and followed for at least 5 years. There were 363 (53%) tumors that were papillary stage pTa. The tumors were classified as papillary urothelial neoplasm of low malignant potential in 95 patients, low grade papillary urothelial carcinoma in 160 and high grade carcinoma in 108. Of the patients in the latter group 95 were subdivided into WHO grade 2 and 13 into WHO grade 3. Tissue from the primary tumors that progressed in stage during followup was further analyzed with immunohistochemical methods (p21, p53, Ki67 and pRb), DNA ploidy and mitotic frequency. The results were compared with those in matched controls (nonprogressors). RESULTS Recurrence developed in 35% of patients with papillary urothelial neoplasm of low malignant potential compared to 71% with low grade urothelial carcinoma and 73% with high grade carcinoma (p <0.0001). No papillary urothelial neoplasm of low malignant potential progressed in stage. Disease progressed in 4% of patients with low grade compared to 23% with high grade carcinoma (p <0.0001). Of the patients with WHO grade 3 disease progressed in 45% compared to grade 2 in 20% (p <0.0011). At first diagnosis p53 score was significantly higher (p <0.0022) among patients with WHO grade 2 carcinoma which later progressed compared to that in matched controls but there was no significant difference regarding the other markers. In contrast to grade 2 most grade 3 carcinoma was aneuploid, had high mitosis frequency, high p53 and Ki67 scores as well as loss of retinoblastoma gene expression. CONCLUSIONS The 1988 WHO and International Society of Urological Pathology consensus classifications divide noninvasive papillary bladder tumors into 3 subgroups with different clinical behavior, which seems to be an advantage compared with the 1973 WHO classification. A disadvantage is that the high grade carcinoma group contains 2 subgroups with different progression rates and immunohistochemical marker profiles, corresponding to the 1999 WHO grades 2 and 3. Grade 2 tumors in patients that progressed in stage years later seem to have different immunohistochemical and molecular marker profiles compared to those in matched controls.

Chronic interstitial cystitis: a heterogeneous syndrome.

A series of 28 patients with interstitial cystitis and 14 healthy volunteers were studied. We found marked histopathological differences between classic (ulcerative) interstitial cystitis and early (nonulcerative) interstitial cystitis. The bladder mucosa of patients with classic disease exhibited focal ulceration, edema and perineural-perivascular infiltrates. There was a marked increase in 2 distinct mast cell populations. Mast cells increased in the detrusor muscle and mucosa. Mucosal mast cells, unlike those in the muscular coat, are susceptible to aldehyde fixation, and require special fixation and staining techniques for proper demonstration. These cells were numerous in the epithelium and were recovered in bladder washings, consistent with the finding that they have a migratory capacity. In nonulcerative interstitial cystitis all signs of mast cell activation were absent, and the histopathological changes were few and fairly uncharacteristic. We also observed some marked clinical differences between ulcerative and nonulcerative interstitial cystitis. These 2 conditions appear to represent separate entities and should be evaluated separately in clinical studies.

RECURRENCE AND PROGRESSION IN LOW GRADE PAPILLARY UROTHELIAL TUMORS

PURPOSE We report long-term followup data on patients with World Health Organization (WHO) grade I bladder tumors, and determine whether histopathological subgrouping as papillary neoplasm of low malignant potential and low grade papillary carcinoma is of clinical value. MATERIALS AND METHODS All 680 patients in western Sweden with first diagnosis of bladder carcinoma in 1987 to 1988 were registered and followed for at least 5 years. Of the tumors 255 (37.5%) were stage Ta, WHO grade I. Tumors were further classified as papillary neoplasm of low malignant potential in 95 patients and low grade papillary carcinoma in 160 according to WHO and the International Society of Urological Pathology consensus classification of urothelial (transitional cell) neoplasms of the bladder. RESULTS Mean age of patients at first diagnosis of low grade papillary carcinoma was 69.2 years, which was 4.6 years higher than those with papillary neoplasm of low malignant potential (p<0.005). During a mean observation time of 60 months our 255 patients underwent 577 operations for recurrences and had 1,858 negative cystoscopies. The risk of recurrence was significantly lower in patients with papillary neoplasm of low malignant potential compared to those with low grade papillary carcinoma (35 versus 71%, p<0.001). The risk of recurrence was higher in patients with multiple tumors at first diagnosis as well as those with recurrence at the first followup after 3 to 4 months. Stage progressed in 6 patients (2.4%), all with low grade papillary carcinoma at diagnosis. CONCLUSIONS More than 90% of patients with stage Ta, WHO grade I have a benign form of bladder neoplasm, and few have truly malignant tumors. Future research should focus on reducing the number of recurrences and followup cystoscopies, and finding methods to identify malignant tumors so that pertinent treatment can be instituted. Subgrouping of WHO grade I bladder tumors as papillary neoplasm of low malignant potential and low grade papillary carcinoma seems to add valuable prognostic information.

Chronic Pancreatic Inflammation Induced by Environmental Tobacco Smoke Inhalation in Rats

OBJECTIVE: Despite a strong epidemiological association between cigarette smoking and pancreatic diseases, such as pancreatic cancer and chronic pancreatitis, the effects of long-term cigarette smoke inhalation on the pancreas have not been clearly determined. In the present study, we investigated the effect of cigarette smoke inhalation on the pancreas.METHODS: Thirty-six female Sprague Dawley rats were exposed to two different doses of environmental tobacco smoke averaging 100 mg or 160 mg/m3 total suspended particulate matter (TSP) per m3 for 70 min twice a day for 12 wk. The animals were sacrificed and examined for the effects of tobacco smoke exposure on pancreatic morphology and function.RESULTS: In 58% (7/12) of the animals, exposure to 160 mg/m3 TSP cigarette smoke induced a chronic pancreatic inflammatory process with fibrosis and scarring of pancreatic acinar structures. Animals with fibrotic alterations showed an induction of pancreatic pro-collagen 1 gene expression, and the infiltration of immune cells was accompanied by the expression of the inflammatory mediators MIP-1α, IL-1β, and TGF-β in 33% (4/12) of the animals. Acinar cell stress was manifested by a significant up-regulation of pancreatitis-associated protein expression (PAP) in smoke-exposed animals (smoke-exposed 6,932 ± 1,236 vs control 3,608 ± 305, p < 0.05). Possibly contributing to the morphological damage to the exocrine pancreas, the inhalation of cigarette smoke induced trypsinogen and chymotrypsinogen gene expression and, furthermore, reduced pancreatic enzyme content.CONCLUSIONS: This study provides experimental evidence of morphological pancreatic damage induced by the inhalation of cigarette smoke, which is likely to be mediated by alterations of acinar cell function.

Translocation t(1;3)(p36.3;q25) is a nonrandom aberration in epithelioid hemangioendothelioma.

The cytogenetic findings for two epithelioid hemangioendotheliomas are reported. An identical chromosomal translocation involving chromosomes 1 and 3 [t(1;3)(p36.3;q25)] was detected in both cases of epithelioid hemangioendothelioma, possibly representing a characteristic rearrangement for this histopathologic entity. The presence of clonal karyotypic abnormalities supports a neoplastic origin for the epithelioid variant of hemangioendothelioma. Identification of the 1;3 translocation may be useful diagnostically. Should additional studies confirm these data, this could lead to the identification of the gene(s) central to this neoplastic process.

Uroepithelial tumors of the renal pelvis associated with abuse of phenacetin‐containing analgesics

This is a review of 62 patients with abuse of phenacetin‐containing drugs and uroepithelial tumors of the renal pelvis. Most of the patients had a pre‐existing nephropathy with papillary necrosis as a prominent feature. Fifty‐six per cent of the patients have died, most of them from the tumor disease, but many were uremic at the time of death. Thus, the co‐existing nephropathy contributed to the poor prognosis. The risk of overlooking an early tumor diagnosis is emphasized. Patients with a known nephropathy with papillary necrosis should be followed continuously, and even the finding of a discrete microscopic hematuria should prompt reinvestigation with radiologic examination of the kidneys. The diagnosis of a uroepithelial tumor of the renal pelvis should always lead to an analysis of the analgesic consumption, besides looking for occupational factors. On the basis of present knowledge of urinary tract carcinogens and phenacetin metabolites it is assumed that phenacetin is the crucial factor for the development of uroepithelial tumors in this study.