Pathways to diagnosis of cervical cancer: screening history, delay in follow up, and smear reading.

BACKGROUND: The aim of this study was to determine the most important ways to reduce incidence of and mortality from cervical cancer by a nationally co-ordinated screening programme. DESIGN: Descriptive study. SETTING: The New Zealand National Cervical Screening Programme: a nationally organised and co-ordinated programme. SAMPLE: Women aged younger than 80 years with histologically proven primary invasive cervical cancer, including microinvasive disease, diagnosed between 1 January 2000 and 30 September 2002. Consent for access to medical records was gained for 371 of 445 eligible women (83%). A total of 359 (81%) of eligible women or their next of kin consented to interview. METHODS: Data on events prior to diagnosis were obtained from routine sources, interview, medical record review and slide reread. MAIN OUTCOME MEASURES: Frequency of screening in the 7 years prior to diagnosis, time from abnormal smear or symptoms to appropriate diagnostic confirmation, proportion of negative smears upgraded to high grade on reread. RESULTS: Half of the 371 participants (83% of 445 eligible women) had not had a screening smear in the 3 years prior to diagnosis, and 80% were defined as inadequately screened. A maximum of 17% of women overall or within any defined subgroup experienced delays in follow up of abnormal smears or bleeding. Only 11% of women overall had had a high-grade smear, which was originally read as negative. CONCLUSIONS: The most important factor in women's pathways to a diagnosis of cervical cancer was inadequate screening. While delays in diagnosis could be reduced and laboratory performance improved, priority must be given to improving uptake and frequency of screening.

Malignant mixed Müllerian tumour of the cervix treated with concurrent chemoradiation.

Malignant mixed Müllerian tumours of the cervix are very uncommon. Of the 26 cases reported in the literature only 8 consist of homologous sarcoma with squamous cell carcinoma. Historically, treatment has been with radiation or surgery or a combination of both. We describe a locally advanced case treated with concurrent chemoradiation.

Adult-onset acute leukemia and employment in the meat industry: a New Zealand case-control study.

OBJECTIVES: To assess the risks for adult-onset acute leukemia associated with employment in the New Zealand meat industry. METHODS: A total of 110 incident leukemia cases identified from referrals to one of six treatment centers between 1989 and 1991 were compared with 199 general population controls. Detailed occupational exposure histories were obtained by interview. RESULTS: There was an elevated risk associated with ever having worked in an abattoir (OR = 2.3, 95% CI 1.0-5.2), which appeared confined to those with over 2 years exposure (OR = 4.9, 95% CI 1.5-15.6). The excess risk was confined to abattoir workers having direct contact with animals or animal products (OR = 5.2 95% CI 1.2-22.2). Ever having worked as a butcher was associated with elevated risk (OR = 2.9, 95% CI 1.1-7.2), confined to those individuals who worked as a butcher in an abattoir (OR = 4.8) or who butchered livestock on farms (OR = 8.2). No increased risk was found for work as a retail/wholesale butcher or meatpacker (OR = 1.2). CONCLUSIONS: This study found increased leukemia risks associated with employment in the meat industry. These were confined to abattoir workers with over 2 years employment in the industry, and to persons whose jobs involved contact with animals or animal tissue, implying that biological exposures may be responsible.

Acute leukemia in electrical workers: a New Zealand case-control study.

OBJECTIVES: To assess the risks for adult-onset acute leukemia associated with electrical employment in New Zealand. METHODS: The occupational and environmental exposures histories of 110 incident leukemia cases and 199 general population controls were compared. The cases were recruited through referrals to treatment centers in New Zealand between 1989 and 1991. For subjects classified as having worked in one or more of the "electrical occupations," the degree of exposures to extremely low frequency electromagnetic fields (ELF-EMFs) was assessed in detail using a job-exposure matrix. RESULTS: An odds ratio of 1.9 (95% Cl 1.0-3.8) was found for subjects who had ever worked in an electrical occupation. Significantly increased risks for leukemia are seen amongst welders/flame cutters (OR = 2.8 (95% CI 1.2-6.8)) and telephone line workers (OR = 5.81 (95% CI 1.2-27.8)). The excess leukemia risk appeared to be confined to acute non-lymphocytic leukemia (OR=2.31 (95% CI 1.2-4.6)), in comparison to acute lymphoblastic leukemia (OR = 0.9 (95% CI 0.3-2.9)) but for the latter category the numbers were very small. A dose-response effect was also found, with acute leukemia risk rising with increasing occupational magnetic field exposure, based on both current and historical occupational field exposure estimates. CONCLUSIONS: The findings of the current study indicate a significantly elevated risk of acute leukemia for electrical workers overall, and for the specific occupational categories of welders/flame cutters and telephone line workers. A dose-response effect was also found, indicating that acute leukemia risk was related to historical and current magnetic field exposures in an occupational context.

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.

Immunohistochemical evidence for mesothelial origin of paratesticular adenomatoid tumour.

AIMS: To investigate the histogenesis of paratesticular adenomatoid tumour by use of immunohistochemical markers for a variety of carcinomas and mesothelioma. METHODS AND RESULTS: Immunohistochemical staining of sections from 12 cases of paratesticular adenomatoid tumour was undertaken using primary antibodies to antigens expressed by benign epithelial cells and carcinoma (cytokeratin AE1/AE3, cytokeratin 34ssE12, epithelial membrane antigen, MOC-31, Ber-EP4, CEA, B72.3, LEA.135, Leu M1), stromal and vascular markers (vimentin, CD34, factor VIII), and mesothelioma-associated antigens (thrombomodulin, HBME-1, OC 125) and p53 protein. There was absence of immunohistochemical expression of epithelial/carcinoma markers MOC-31, Ber-EP4, CEA, B72.3, LEA.135, Leu M1 and to factor VIII and CD34. All tumours expressed cytokeratin AE1/AE3, epithelial membrane antigen and vimentin, with weak expression of cytokeratin 34ssE12 in 25% of tumours. Each tumour showed expression of thrombomodulin, HBME-1 and OC 125 in a membranous distribution. p53 protein expression was not detected. CONCLUSIONS: The immunohistochemical profile of paratesticular adenomatoid tumour is strongly supportive of a mesothelial cell origin.

Reproducibility of new classification schemes for the pathology of ductal carcinoma in situ of the breast.

AIM: To compare the interobserver variation in the pathological classification of ductal carcinoma in situ of the breast using two recently proposed classification schemes. METHODS: 11 pathologists classified a set of 25 cases of ductal carcinoma in situ chosen to reflect a range of lesions, using the traditional architectural classification together with the modified cytonuclear grading scheme of Holland et al and the Van Nuys classification scheme. Participating pathologists received a standard tutorial, written information, and illustrative photomicrographs before their assessment of the cases. RESULTS: Interobserver agreement was poorest when using the architectural scheme (kappa = 0.44), largely owing to variations in classifying lesions with a mixed component of patterns (kappa = 0.13). Agreement was better using the modified cytonuclear grading scheme (kappa = 0.57), with most consistency achieved using the Van Nuys scheme (kappa = 0.66). Most discordant results using the later scheme were due to inconsistency in assessing the presence or absence of luminal necrosis. CONCLUSIONS: Both the new classification schemes assessed in this study were an improvement over the traditional architectural classification system for ductal carcinoma in situ, and resulted in more reproducible pathological assignment of cases. The Van Nuys classification scheme is easy to apply, even to small areas of carcinoma, resulting in acceptable interobserver agreement between reporting pathologists. Additional work will be required to arrive at a consensus definition of necrosis for cases in the non-high-grade group.

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.

Social class and male cancer mortality in New Zealand, 1984-7.

Social class differences in cancer mortality among New Zealand men aged 15-64 years are examined for the period 1984-7. Age-standardised rates are presented for all cancer deaths, and for 23 specific cancer sites. The strongest social class mortality gradients were found for cancers of the larynx, liver, buccal cavity/pharynx, oesophagus, lung and for soft tissue sarcoma. On the other hand, rectal cancer, malignant melanoma, colon cancer, brain/nervous system cancers, and multiple myeloma showed higher death rates for the more advantaged socioeconomic groups. Lung cancer accounted for 54.1% of the overall social class gradient, and the major smoking related cancers (these include buccal/pharynx, oesophagus, larynx, lung and bladder, although it should be stressed that not all cases of these cancers are caused by smoking) accounted for 77.6% of the overall gradient.

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.

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.

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.

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.

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.

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.