Morphologic typing of papillary renal cell carcinoma: comparison of growth kinetics and patient survival in 66 cases.

Whereas papillary renal cell carcinoma is now established as a subtype of renal cell neoplasia, division of these tumors into 2 distinctive morphotypes has been proposed. Type 1 tumors have cells with scanty pale cytoplasm arranged in a single layer on the basement membrane of papillary cores. In these tumors, psammoma bodies and foamy macrophages are frequently seen, and the tumors frequently express cytokeratin 7. Type 2 tumor cells have pseudostratified nuclei and usually have voluminous eosinophilic cytoplasm. Recent studies have supported this subclassification of papillary renal cell carcinoma by demonstrating differing genotypes for type 1 and 2 tumors. To further study the subclassification of papillary renal carcinoma, we compared clinical features, nuclear grade, stage, tumor growth kinetics, and survival in a series of 50 type 1 and 16 type 2 papillary renal cell carcinomas. Comparison of patient age at presentation, sex, and primary tumor size shows no significant difference between the 2 tumor types. Type 1 tumors were of significantly lower Fuhrman grade (P =.0001) and higher Robson stage (P =.009) than type 2 tumors. There was no significant difference when tumors were staged according to the TNM classification. Assessment of tumor growth kinetics showed significantly different mean silver-staining nucleolar organizer region (AgNOR) scores and Ki-67 indices (AgNOR type 1, 3.83, type 2, 7.24, P =.0001; Ki-67 type 1, 3.17%, type 2, 6.01%, P =.0002). Multivariate analysis showed tumor type (P =.03), presence of metastases (P =.04), AgNOR score (P =.001), and Ki-67 index (P =.03) to be independently associated with survival. These results provide evidence of the clinical utility of dividing papillary renal cell carcinomas into 2 types according to histologic characteristics.

Effect of tumour associated tissue eosinophilia on survival of women with stage IB carcinoma of the uterine cervix.

AIMS: To examine the survival of a group of women with stage IB invasive carcinoma of the uterine cervix, divided according to the expression of tumour associated tissue eosinophilia (TATE). METHODS: Histological material from 81 women with stage IB squamous and adenosquamous cervical carcinomas before radiotherapy was assessed for the extent of tissue stromal eosinophilia, quantified using antibodies to human major basic protein. RESULTS: Twenty eight (38%) of the cases demonstrated TATE of over 30 eosinophils/mm2, with 12 (16%) having greater than 100 eosinophils/mm2. Eleven women in the series developed distant spread or recurrent pelvic disease, this group having a stromal eosinophil density significantly less (13.8/mm2) than the remainder (69.9/mm2) (p = 0.03). The actuarial five year survival rate for women with a tumour eosinophil density over 30/mm2 was 92% compared with 70% with a density under 30 mm2, with a significant difference in the survival curves for these two groups (p = 0.03). CONCLUSIONS: As a univariate parameter, a tumour associated tissue eosinophilia of at least modest proportions is associated with statistically improved survival in women with stage IB cervical carcinomas.

Luminal epithelial antigen (LEA.135) expression correlates with tumor progression for transitional carcinoma of the bladder.

Luminal epithelial antigen (LEA.135) expression has been shown to have prognostic significance in breast carcinoma, however its relationship to tumor progression in other forms of malignancy is unknown. This study evaluates LEA.135 expression in bladder transitional cell carcinoma (TCC) and compares the findings with tumor stage and grade, and polyclonal Ki-67 derived cell cycle activity. LEA.135 expression was evaluated by immunohistochemical staining using the streptavidin-biotin method. Staining distribution was graded 0 to 4 and the results were compared with World Health Organisation tumor grade, UICC TNM stage and fraction of actively cycling cells showing positive pKi-67 immunohistochemical staining. In normal bladder epithelium, LEA.135 staining was confined to the luminal surface of superficial epithelium. In lower grade, superficial TCC LEA.135 overexpression was noted and there was a progressive loss of expression in tumors of higher grade (p = 0.0001) and advanced stage (p = 0.0001). No LEA.135 staining was seen in carcinoma-in-situ. Loss of LEA.135 expression correlates with tumor progression for bladder TCC.

Comparison of silver-staining nucleolar organizer region (AgNOR) counts and proliferating cell nuclear antigen (PCNA) expression in reactive mesothelial hyperplasia and malignant mesothelioma.

Previous workers have used counts of colloidal silver-stained nucleolar organizer regions (AgNORs) to help distinguish reactive from malignant mesothelial processes. We sought to compare the demanding technique of AgNOR counting with the identification of proliferating cell nuclear antigen (PCNA) in 10 pleural malignant mesotheliomas and 11 reactive mesothelial proliferations. The mean AgNOR count was significantly higher in malignant compared to reactive lesions (5.10 [95% confidence interval, CI 4.35-5.84] vs 3.68 [95% CI 3.17-4.19], p = 0.004), as was the PCNA index (26.9 [95% CI 17.37-36.49] vs 9.67 [95% CI 4.94-14.39], p = 0.004). Less overlap was seen with PCNA indices and no reactive mesothelial proliferations had a PCNA index greater than 20%, suggesting that scores over this level may be a specific indicator of malignancy in this setting. There was only a weak correlation between the 2 proliferation indices suggesting that PCNA and AgNORs are present at somewhat different times of the cell cycle and/or persist in the post-S phase cell for variable lengths of time.

Computerized nuclear morphometry and survival in renal cell carcinoma: comparison with other prognostic indicators.

Morphometric nuclear parameters were compared with patient survival for a series of 174 renal cell carcinomas (RCC) collected over a 30 yr period. Stepdown regression showed long diameter, average feret diameter, form factor and the ratio of average feret diameter to equivalent diameter to be significantly associated with survival. Nuclear area, nuclear perimeter, equivalent diameter, ratio of long diameter to average feret diameter and coefficients of variation of nuclear area and nuclear perimeter were not significantly correlated with survival. All parameters were correlated with a 3 division nuclear grading classification using analysis of variance. Multivariate analysis showed nuclear form factor, tumor stage, silver staining nucleolar organizer region numbers and proliferating cell nuclear antigen expression to be independently associated with survival. The results of this study indicate that form factor is the most discriminate morphometric parameter for RCC, providing survival data additional to that derived from tumor staging and from markers of tumor proliferation.

Bizarre parosteal osteochondromatous proliferation of the hand in a young man.

We report a case of a solitary osteochondromatous tumor on the hand of a 38 yr old man. This had radiological and histological features distinct from an osteochondroma and demonstrated the features first described as bizarre parosteal osteochondromatous proliferation. These lesions have a tendency for local recurrence but no metastatic behaviour has yet been reported. We highlight 2 histological features which have not been previously described.

Polyclonal Ki-67 expression in transitional cell carcinoma of the bladder.

The proliferation kinetics of 101 cases of transitional cell carcinoma (TCC) and seven cases of transitional cell carcinoma-in-situ of the bladder were assessed following staining with polyclonal Ki-67 antibody (pKi-67). Labeling indices ranged from 49% to 60.2% with a mean value of 22.2% for all cases. A significant association between pKi-67 indices, tumor grade and tumor stage was observed, with significant differences between pKi-67 indices of Grade 1 and 3 tumors and Grade 2 and 3 tumors. Significant differences in labeling indices were also found between superficial (Ta) tumors and both musculoinvasive (T2/T3a) tumors and those infiltrating the perivesical fat (T3b). pKi-67 indices for carcinoma-in-situ were similar to those noted for Grade 1 TCC. No difference in pKi-67 index was found when tumors were classified according to the morphology of the tumor invasion front. It is concluded that pKi-67 index is a useful marker for tumor progression for vesical TCC and that this immunohistochemical stain may assist clinical assessment of the potential behaviour of tumors in individual cases.

Infiltration by immunocompetent cells in early stage invasive carcinoma of the uterine cervix: a prognostic study.

In various tumor types dentritic cell, infiltration and the presence of tumor-infiltrating lymphocytes have been associated with an improved clinical outcome. In the uterine cervix these immunocompetent cells have been associated with improved prognosis in high stage disease. The current study examines the significance of stromal and tumor T-lymphocyte infiltration together with S-100 positive dendritic cell infiltration in a series of 73 women with low stage (FIGO 1b) invasive squamous and adenosquamous cervical carcinoma. Thirty four percent of cases contained S-100 positive dendritic cells. These were under-represented in cases showing pelvic recurrence or distant disease (1 of 11 compared to 24 of 62 free of recurrence, P = 0.05) and over-represented in cases showing lymphatic/capillary space involvement (12 of 23 compared to 13 of 46 without vascular space invasion, P = 0.05). The women were followed up for an average of 5.2 years and the five-year survival for women whose tumors contained S-100 positive dendritic cells was 92% compared to 73% for negative cases (P = 0.04). There was a significant association between a low density of tumor infiltrating T-cells and risk of pelvic lymph node spread and subsequent local or distant disease control failure (P = 0.008). A five year survival advantage was seen with five or more CD 3 positive tumor infiltrating T-lymphocytes per high power field (90%) compared to a lower count (68%) (P = 0.04). A similar advantage could not be demonstrated for a high stromal infiltrate of T-cells. As yet neither the specific mechanisms that induce these cells to infiltrate some cervical carcinomas nor the nature of the immunological injury that the cells co-ordinate in tumor tissue are well understood.

An educational experience evaluated: the Christchurch Clinical School of Medicine.

This study explored the response of recent graduates to their clinical training at the University of Otago, Christchurch Clinical School of Medicine. Graduates rated their competence at dealing with a number of clinical problems and the adequacy of teaching received in relation to their anticipated requirements as medical practitioners. They also recorded information concerning their personal response to training--role identity, stress and anxiety felt during the course, and their commitment to ongoing education and research following training. Overall the course was regarded positively. In the light of anticipated requirements as medical practitioners some curricular gaps were perceived and criticisms of the course identified. Graduates were critical of their teachers' abilities in demonstrating interviewing and interpersonal skills. Over 70% of graduates felt that they had little or no role during much of their undergraduate clinical training. Many graduates felt that they had little opportunity to carry out research during training, nor the motivation to undertake research subsequently, but they were committed to continuing education.

Mutation at chromosome 11q23 in human non-familial breast cancer: a microdissection microsatellite analysis.

Allelotypic evaluation of loss of heterozygosity (LOH) has been instrumental in the identification of tumour suppressor genes. Here we report a high incidence of LOH at chromosome 11q23 in non-familial breast cancers with in situ, invasive, and metastatic tumour cells microdissected from archival haematoxylin and eosin (H & E) sections for polymerase chain reaction (PCR)-LOH analysis at polymorphic microsatellite loci. Ninety-four cases of non-familial breast cancer were examined at the D11S29 microsatellite locus on chromosome 11q23. Eighty-three cases (88 per cent) were informative and 35 cases overall (42 per cent) had LOH at this locus, comprising 23 per cent of in situ, 36 per cent of invasive, and 28 per cent of metastatic cancers. The DNA from those cancer cells with LOH was amplified at microsatellite loci D11S554 (11p12-p11.2) and D11S534 (11q13). In 19 of 67 cases overall (28 per cent), LOH occurred solely at 11q23. There was an association between LOH at 11q23 and tumour size > or = 2 cm (P < 0.01) in the overall results and the invasive cancers. The data revealed heterogeneity for LOH at D11S29 in in situ, invasive, and metastatic cells from the same case. In general, however, there was concordance between LOH (or its absence) in in situ and invasive disease. We conclude that the distal part of the long arm of chromosome 11 contains a region involved in breast carcinogenesis and that there is molecular heterogeneity at this chromosomal region in individual breast cancer cells.

Occupational risk for renal cell carcinoma. A case-control study based on the New Zealand Cancer Registry.

OBJECTIVE: To evaluate occupational risk factors for renal cell carcinoma. SUBJECTS AND METHODS: A case control design was employed using data reported to the New Zealand Cancer Registry from 1978 to 1986 inclusive. The occupational risk for renal cell carcinoma was derived by comparison with the occupation of cases of non-urinary tract malignancy reported to the Registry over the same period. RESULTS: An active occupational code was derived for 86.2% of all cases and 98.9% (710) of male cases. In a series of case-control studies for selected occupational groups, adjusting for patient age and smoking history, a significantly increased relative risk for the development of renal cell carcinoma among firefighters (RR 4.89, 95% CI 2.47-8.93) and painters (RR 1.79, 95% CI 1.31-3.44) was demonstrated. CONCLUSION: The data suggest that both firefighters and painters may be at an increased risk of developing renal cell carcinoma, which is likely to be of significance as both occupational groups are frequently exposed to known carcinogens.

Prognostic significance of microscopic vascularity for clear cell renal cell carcinoma.

OBJECTIVE: To investigate the association between tumour vascularity and patient survival in a series of clear-cell renal cell carcinoma (RCC), which often metastasizes via the vascular route and frequently has a prominent vascular network. MATERIALS AND METHODS: Vessels were labelled in sections from 150 cases of clear cell RCC by factor VIII immunohistochemistry. The mean microvessel density (MMD), expressed as the number of vessels per 10 high-power fields (HPFs, x400, aggregate field area 1.452 mm2) and tumour microvessel area (TMA), expressed as the percentage of the total tumour area within 10 HPFs, were measured for each case. The relationship between MMD and TMA, tumour stage and grade, and patient survival over a 5-year follow-up was determined. RESULTS: Tumour MMD ranged from 1 to 238 vessels per HPF, while the TMA was 1.2-60.8%. There was a weak but significant difference for MMD between tumour grades (P < 0.01) and stages (P < 0.05). There was no significant association between TMA and either tumour stage or grade. Division of cases according to MMD < or = 40 and > 40 per HPF showed a significant difference in survival curves between both groups, with a higher MMD being associated with longer patient survival. The significant association between MMD and survival was retained for stage 3 tumours only when cases were stratified according to Robson's stage at presentation. TMA did not correlate with survival. CONCLUSIONS: The assessment of tumour vascularity is of prognostic significance for clear cell RCC. The significant inverse relationship between MMD and patient survival suggests that for tumours with a poor prognosis, decreased MMD is associated with tumour fibrosis and the development of large diameter vascular channels.

Cancer risks in painters: study based on the New Zealand Cancer Registry.

Painters are exposed to a range of complex chemical mixtures which include organic solvents and dye products with known carcinogenic and mutagenic potential. Trade painters or those manufacturing paints and coatings have increased rates of non-malignant diseases and cancers; including lung cancer, acute leukaemia, bladder cancer, and cancers of the oesophagus, larynx, biliary system, liver, skin, and large bowel. A series of case-control studies of painters, based on the New Zealand Cancer Registry, are presented. These concerned 19,904 male patients registered for the period 1980-4 who were aged 20 or older at the time of registration. For each cancer site studied, the registrants for all other cancer sites formed the control group. Three cancer sites were associated with work as a painter--namely, bladder tumours (odds ratio (OR) 1.52, 95% confidence interval (95% CI) 1.00-2.31), kidney and other urothelial tumours (OR 1.45, 95% CI 0.85-2.50), and multiple myeloma (OR 1.95, 95%, CI 1.05-3.65). Risks for multiple myeloma were greater among car or spray painters and signwriters (OR 2.81) compared with construction and general painters (OR 1.80). No increased risk was found for leukaemia or for respiratory, biliary, skin, or gastrointestinal cancers.

Proliferating cell nuclear antigen (PCNA) expression as a prognostic indicator for renal cell carcinoma: comparison with tumour grade, mitotic index, and silver-staining nucleolar organizer region numbers.

Proliferating cell nuclear antigen (PCNA) expression in renal cell carcinoma (RCC) was determined by immunohistochemical staining using the PC10 clone. PCNA indices ranged from 2.4 to 53.1 per cent with mean indices of 12.6, 19.0, and 31.6 per cent for grades 1 to 3 RCC and 31.9 per cent for sarcomatoid RCC. There was a significant difference between the indices of grades 1 and 3 and grades 2 and 3 tumours and between grades 1 and 2 RCC and sarcomatoid RCC. AgNOR scores and mitotic indices were determined for each tumour and comparison of PCNA indices with mean AgNOR scores and mitotic indices showed only a weak correlation (PCNA/AgNOR r = 0.406, PCNA/mitotic index r = 0.315). Tumours were divided according to PCNA index (< or = 18 per cent and > 18 per cent) and there was a significant difference in survival between the two groups, for all cases, and for each of the Robson stages. Multivariate analysis using Cox's proportional hazard model showed PCNA index, tumour stage, and mean AgNOR score to be independent predictors of survival, while tumour grade and mitotic index were found to be dependent variables.

Nucleolar organizer regions and prognosis in renal cell carcinoma.

The prognostic significance of nucleolar organizer regions (NORs) in renal cell carcinoma (RCC) was evaluated. NORs were quantified in a series of 182 cases of RCC using the silver-colloid method. The cases were staged according to Robson's method (48 stage I, 26 stage II, 33 stage III, 75 stage IV) and mean NOR numbers for each tumour were correlated with survival over a 5-year period. Localized tumours (stages I and II) with low NOR numbers had an almost 100 per cent 5-year survival. Those patients with clinical evidence of metastases at presentation showed a high mortality, although those with low numbers of NORs had a significantly increased disease-free interval. Statistical analysis using the log rank test indicated NORs to be a significant predictor of survival over the whole series (P = 0.0001) and within each of Robson's stages (P = 0.0008 stage I, P = 0.0154 stage II, P = 0.0009 stage III, P = 0.0001 stage IV). Analysis of data using Cox's proportional hazard model showed mean NOR numbers to be independent of stage as a predictor of survival.

Lymphoid follicular hyperplasia--a distinctive feature of diversion colitis.

Diversion colitis refers to the inflammatory changes that occur in the defunctioned segment of the large intestine following diversion of the faecal stream. We report the histological features in the defunctioned rectums from seven patients: one each with severe constipation and Behçet's disease, two with Crohn's disease with rectal sparing and three with ulcerative colitis. The appearances of diversion colitis in a previously normal rectum are compared with diversion colitis with superimposed inflammatory bowel disease. Lymphoid follicular hyperplasia was found in all cases. This was marked in patients with inflammatory bowel disease, with or without initial rectal involvement. Other changes comprised surface epithelial degeneration and ulceration, mucosal inflammation including crypt abscesses, and crypt branching. Inflammatory and crypt changes were mild, except in ulcerative colitis where changes were marked and resembled those of the proximal colon. Lymphoid hyperplasia is a distinctive feature in diversion colitis. The term follicular proctitis, previously used to indicate chronic ulcerative colitis exclusively, should be re-examined.

Proliferation of renal cell carcinoma assessed by fixation-resistant polyclonal Ki-67 antibody labeling. Correlation with clinical outcome.

BACKGROUND: Although tumor staging is an important prognostic parameter for renal cell carcinoma (RCC), postnephrectomy survival interval is often difficult to predict for individual patients. This is the result of varied growth characteristics, which in tumors of similar stage govern both time to recurrence and rate of tumor dissemination. Polyclonal Ki-67 antibody labels a proliferation-specific antigen expressed in actively proliferating cells and is applicable to formalin fixed paraffin embedded archival tissue. This study was designed to test the prognostic utility of Ki-67 antigen labeling in a series of RCC and to compare the data with those derived from other markers of cell proliferation. METHODS: Polyclonal Ki-67 antibody staining of 206 cases of RCC was undertaken using the streptavidin-biotin method. Cases were grouped according to Ki-67 indices and Kaplan-Meier survival curves were constructed. Groups were compared in terms of survival for all cases and for each of Robson's stages using the log rank test. Further sections were stained for proliferating cell nuclear antigen (PCNA) and silver-staining nucleolar organizer regions (AgNORs). The prognostic significance of Ki-67 antigen, PCNA and AgNOR staining, histologic grade, and tumor stage were compared using Cox's proportional hazard model. RESULTS: Ki-67 immunostaining was achieved for 173 cases with indices ranging from 0.1% to 30.4%. Division of tumors with indices 6% or less and greater than 6% showed a significant difference in survival between groups for all cases and for each Robson stage. Ki-67 and PCNA indices, AgNOR scores, and tumor dissemination (Robson Stage 3 and 4) retained a significant association with survival on multivariate analysis. CONCLUSIONS: Polyclonal Ki-67 antibody immunostaining provides significant survival information that complements that derived by other markers of cell proliferation and tumor staging.

Loss of heterozygosity occurs at the D11S29 locus on chromosome 11q23 in invasive cervical carcinoma.

Allelotypic detection of loss of heterozygosity (LOH) has been used to identify putative tumour-suppressor genes. Loci on human chromosome 11q23 are frequently altered in malignant disease, and LOH has been reported at an anonymous D11S29 locus at 11q23 in a proportion of breast and ovarian cancers and malignant melanomas. Previous studies have reported a high frequency of LOH in cervical carcinoma mapping to 11q23. Using polymerase chain reaction techniques employing probes for a recently described polymorphic dinucleotide microsatellite within this locus, we have searched for LOH in 69 cases of invasive cervical carcinoma. Genomic material was microdissected from sections cut from archival paraffin-embedded material, using the patients' constitutional genotype as a control Sixty-two (90%) of the cases were informative, and LOH occurred in 25/62 (40%) of tumours. Loss of an arm or single chromosome 11 is a well-recognised event in cervical carcinoma, and by employing other microsatellite polymorphisms mapping to 11q13 and 11p11-p12 we excluded those cases with widespread allelic loss. By doing so, LOH at D11S29 was found in 16/53 (30%) of tumours. The findings suggest a putative tumour-suppressor gene on 11q involved in cervical carcinogenesis.

Assessment of proliferative activity in Wilms' tumour.

The proliferative activity in 26 cases of Wilms' tumour was studied by enumeration of silver-staining nucleolar organizer regions (AgNORs) and proliferating cell nuclear antigen (PCNA) staining of the blastemal, epithelial and stromal components of the tumours. The PCNA and AgNOR scores derived from the blastemal (PCNA range 18.9-81.4%, AgNOR range 2.11-4.95) and epithelial (PCNA range 24.1-74.2%, AgNOR range 2.47-4.41) components of the tumours were significantly higher than those of the stromal component (PCNA range 3.4-64.7%, AgNOR range 2.20-4.26). Ten of the patients had died with recurrent or metastatic tumour (mean survival 29 months) while the remaining 16 were disease free (mean follow-up 95 months) at the time of the study. The prognostic significance of PCNA and AgNOR for Wilms' tumour was evaluated by dividing the tumours into groups exhibiting low (PCNA < or = 40 or AgNOR < or = 4) or high (PCNA > 40 or AgNOR > 4) proliferative activity. There was a significant difference in the survival of the two groups for tumours treated with preoperative chemotherapy (PCNA, P = 0.049; AgNOR, P = 0.02), while no significant difference was observed from tumours resected prior to the administration of chemotherapy. The results of this study suggest that assessment of proliferation activity in postchemotherapy Wilm's tumours may be a useful indicator of prognosis.