What is the lifetime risk of developing cancer?: the effect of adjusting for multiple primaries.

BACKGROUND: The 'lifetime risk' of cancer is generally estimated by combining current incidence rates with current all-cause mortality ('current probability' method) rather than by describing the experience of a birth cohort. As individuals may get more than one type of cancer, what is generally estimated is the average (mean) number of cancers over a lifetime. This is not the same as the probability of getting cancer. METHODS: We describe a method for estimating lifetime risk that corrects for the inclusion of multiple primary cancers in the incidence rates routinely published by cancer registries. The new method applies cancer incidence rates to the estimated probability of being alive without a previous cancer. The new method is illustrated using data from the Scottish Cancer Registry and is compared with 'gold-standard' estimates that use (unpublished) data on first primaries. RESULTS: The effect of this correction is to make the estimated 'lifetime risk' smaller. The new estimates are extremely similar to those obtained using incidence based on first primaries. The usual 'current probability' method considerably overestimates the lifetime risk of all cancers combined, although the correction for any single cancer site is minimal. CONCLUSION: Estimation of the lifetime risk of cancer should either be based on first primaries or should use the new method.

Breast and cervical cancer survival: making sense of "league tables".

During 1998, the Department of Health proposed to use survival rates of cervical and breast cancer in the 1989/90 incidence cohort as indicators of care. Valid interpretation was of concern within Trent and the Trent Cancer Registry responded by performing additional analyses. Trent Cancer Registry registrations for 1989/90 were re-analysed and the stability of districts' ranks for that cohort was investigated using random simulation techniques. Stability of ranks across more recent cohorts was investigated and attempts made to use all available information. The Department of Health's analyses were confirmed by our re-analysis of the 1989/90 cohort: Rotherham residents appeared to have the "worst" survival for cervical cancer, and Sheffield residents for breast cancer, although not statistically significantly so. Random simulations indicated that ranks based on a single cohort are not stable: for example Sheffield (ranked tenth for 1-y breast cancer survival) was ranked third or better in 6% of randomisations. Ranks were also unstable across cohorts: for example Rotherham 1-y cervical cancer survival was ranked tenth for 1989/90, fifth for 1991/92 and tenth for 1993/94. Analysis of 3-y running averages provided better information than the league table approach. Most districts improved over time, to different degrees, and similar sized gaps remained between the "best" and the "worst" districts. This analysis illustrates the need to be circumspect when interpreting "league tables" based on a single year or cohort analysis. League tables are based on ranks: clearly a large difference in rank may reflect only trivial (ie medically unimportant) differences in actual outcome. Lack of a statistically significant difference in survival between two districts does not mean their survival is equivalent. Even for a common cancer, like breast cancer, rankings were unstable from cohort to cohort. At the Registry we propose to perform these trend analyses routinely in future, adjusting, when possible, for the effects of deprivation and stage at diagnosis.

Life expectancy as a summary of mortality in a population: statistical considerations and suitability for use by health authorities.

OBJECTIVE: To investigate the sampling distribution and usefulness of expectation of life in comparisons of mortality at health district level or below. DESIGN: Derivation of a formula for the variance of the expectation of life, confirmation of the result and generation of the sampling distribution by Monte Carlo simulation; comparison of expectation of life with standardised mortality ratio (SMR) and other summary indices of mortality. SETTING: A health district in Trent Region, England. SUBJECTS: Routinely available mortality statistics at electoral ward level and above. MAIN RESULTS: Given reasonable and simple assumptions the sampling distribution of the expectation of life is approximately normal. Expectation of life shows a high negative correlation with SMR even if the oldest age band for the SMR is open ended. CONCLUSIONS: Where sampling error is an issue, inference concerning differences in mortality rates between populations can be based on expectation of life, which is better for illustrative purposes than SMR. The formula for the variance of the expectation of life is more complex however. If the final age band is open ended, its lower bound should be as high as possible to avoid misleading results caused by hidden differences in age structure.

Prognostic implications of qualitative assessment of left ventricular function compared to simple routine quantitative echocardiography.

OBJECTIVE: To compare the prognostic value of qualitative estimates of left ventricular function with that of routine simple quantitative indices used in echocardiography. DESIGN: Retrospective follow up study. SETTING: University hospital. PATIENTS: The records of 2,964 patients who had undergone echocardiography and who could be traced on the family health services register were examined; 919 cases were included in the study, and a further 458 were used to validate the statistical models for prognostic assessment. There were 928 exclusions on the basis of referral for or diagnosis of alternative conditions, and 659 because of incomplete collection of the qualitative and quantitative data used in the study. MAIN OUTCOME MEASURE: Survival over the study period. RESULTS: A qualitative "eyeball" estimate of left ventricular function was of prognostic significance (relative risk of poor v good, 2.248; P << 0.001; 95% confidence interval 1.620 to 3.119). None of the quantitative echocardiographic indices was of independent prognostic significance when all variables were tested simultaneously in the regression model. CONCLUSIONS: A qualitative echocardiographic estimate of left ventricular dysfunction is of prognostic value, supporting the view of many cardiologists who use their overall impression of left ventricular function at echocardiography as the basis for treatment decisions.

A case-control study of diet and prostate cancer.

We interviewed 328 men diagnosed with prostate cancer before the age of 75 years and 328 age-matched population controls. The principal hypotheses were that risk would increase with a high intake of total or saturated fat and would decrease with a high intake of carotene (beta-carotene equivalents) or lycopene. We also examined the associations of other nutrients and foods with risk. There was no evidence for an association between fat intake and risk, although the average fat intake was high and the range of fat intakes was narrow (medians of lower and upper thirds of percentage of energy from fat among controls were 34.3% and 42.9% respectively). Risk was lower in subjects with higher carotene intake: odds ratios 0.65 (95% CI 0.45-0.94) and 0.76 (0.53-1.10) in the middle and upper thirds of carotene intake respectively (P for trend = 0.150). Lycopene was not associated with risk. Among 13 other nutrients examined, the odds ratios in the top third of intake were below 0.8 for: potassium, 0.74 (0.51-1.09; P for trend = 0.054); zinc, 0.73 (0.49-1.08; P for trend = 0.126); iodine, 0.75 (0.51-1.11; P for trend = 0.077); vitamin B6 food only, 0.77 (0.53-1.12; P for trend = 0.077); and vitamin B6 including supplements, 0.70 (0.48-1.03; P for trend = 0.029). Among 18 foods examined, statistically significant associations were observed for: garlic as food, > or = 2/week vs never, 0.56 (0.33-0.93); garlic including supplements, > or = 2/week vs never, 0.60 (0.37-0.96); baked beans, > or = 2/week vs < 1/month, 0.57 (0.34-0.95); and garden peas, > or = 5/week vs < or = 3/month, 0.35 (0.13-0.91). This study does not support the hypothesis that fat increases risk and is equivocal in relation to carotene. The possible relationships of vitamin B6, garlic, beans and peas with risk for prostate cancer should be further investigated.

Effects of hormone replacement therapy on fine needle aspiration cytology of the breast.

To investigate the possibility that hormone replacement therapy (HRT) might induce morphologic changes in breast cytology simulating malignancy, we determined the subjective interpretation and objective morphometric features of 39 fine needle aspiration cytology samples from women who were using a variety of HRT preparations. Cases were matched for age and final diagnosis (assessed by a triple approach) with women who had never used HRT. Cytocentrifuge preparations stained with Papanicolaou stain were assessed by two observers for cellularity and diagnosis. Although diagnostic accuracy was slightly higher in HRT than non-HRT samples, there was no significant difference in the assessments of cellularity and diagnosis between the two observers or between HRT and non-HRT samples. Nuclear areas in HRT samples were larger than in non-HRT samples, measured using computerized image morphometry; this difference did not induce the observer to diagnose malignancy more frequently. HRT had no adverse effect upon the accuracy of interpreting breast fine needle aspiration cytology samples.

Proliferating cell nuclear antigen immunostaining in keratoacanthoma and squamous cell carcinoma of the skin.

Proliferating cell nuclear antigen expression was used to seek differences between keratoacanthoma and squamous cell carcinoma of the skin. These lesions of the skin continue to provoke interest due to their different biological behaviour in spite of histologically similar appearances. The primary antibody, PC10 was used in a three stage avidin biotin peroxidase complex technique on section from 27 cases of KA, 15 of well, 16 of moderately- and 15 of poorly differentiated SCC. The distribution of positive cells was determined and then one thousand randomly chosen lesional epithelial nuclei were categorised for PCNA immunoreactivity and the results expressed as percentage of epithelial nuclei stained. Statistical analysis revealed a highly significant trend in increasing %PCNA with histological grade of skin lesion (P < 0.0001). Poorly differentiated, although not other grades of squamous cell carcinoma have a significantly higher proportion of PCNA labelled nuclei than keratoacanthoma. In addition, the distribution of PCNA positive nuclei in keratoacanthoma are usually peripheral contrasting with the more diffuse pattern seen in most cases of SCC. %PCNA alone was a more powerful predictor of histological subtype than distribution alone. PCNA immunohistochemistry not only provides additional information facilitating the differential diagnosis between keratoacanthoma and moderate or poorly differentiated squamous cell carcinoma but also underlines the perplexing similarity between keratoacanthoma and well differentiated squamous cell carcinoma.

Prognostic value of c-erbB-2 and epidermal growth factor receptor in stage A1 (T1a) prostatic adenocarcinoma.

OBJECTIVE: To determine whether the presence or absence of the oncoproteins epidermal growth factor receptor (EGFR) and c-erbB-2 could predict tumour behaviour. PATIENTS AND METHODS: Tissue from 45 stage A1 (T1a) prostatic adenocarcinomas from patients with a mean age of 65 years were immunostained for EGFR (12E) and c-erbB-2 (NCL-CB11). Their expression in the tumour and surrounding benign hyperplastic epithelium was correlated with each other and with survival. RESULTS: Forty percent (18 of 45) and 36% (16 of 45) of patients respectively were EGFR and c-erbB-2 positive in the tumour. Expression of these tyrosine kinase oncogenes was not confined to the tumour and the surrounding hyperplastic prostate was also positive for EGFR in 76% (34/45) of patients and for c-erbB-2 in 16% (11 of 45). EGFR and c-erbB-2 expression was weakly associated in both benign and malignant epithelium. Statistical analysis of survival showed that tumour c-erbB-2 expression was associated with a significantly worse prognosis (exact two tailed P = 0.0316), whereas no significant association was observed between EGFR expression and survival (P = 0.737). CONCLUSION: As c-erbB-2 expression increases the rate of dying by 4.2 times, recording its expression by these tumours may be useful in selecting patients who would benefit from treatment in stage A1 (T1a) disease.

Nm23 protein expression in thyroid neoplasms.

The nm23 gene production has been heralded as a suppressor of metastasis in many human tumours but it is not clear at which stage in the metastatic process nm23 protein exerts its effect. The aim of this study was to test whether nm23 protein is associated with occurrence or category of angioinvasion. We have made use of the well documented fact that follicular carcinoma of the thyroid may show vascular invasion whereas papillary carcinomas may metastasis via the lymphatics. 65 thyroid tumours (20 follicular adenomas, 22 papillary carcinomas, 23 follicular carcinomas) were stained for nm23 protein using an immunopurified polyclonal antibody. Nm23 protein status showed no correlation with category of thyroid tumour. This is indirect evidence that nm23 does not suppress metastasis by influencing vascular invasion in this tumour type.

Diagnostic associations of p53 immunostaining in fine needle aspiration cytology of the breast.

Duplicate cytospin preparations were made from 46 symptomatic breast fine needle aspirates. One of each pair was assigned to benign or malignant categories by one experienced observer as part of the "triple approach" patient assessment. The other was immunostained with DO7, a monoclonal antibody to recombinant p53 protein, and rated by another observer as positive or negative for nuclear staining, unaware of the cytodiagnosis. Positive controls included carcinomas known to have mutant p53, while negative controls were of the reagent substitution type. Of the 26 aspirates with a benign cytodiagnosis (verified by the triple approach), 23 were p53 protein-negative and three positive. Of the 20 with a malignant cytodiagnosis (histologically confirmed), six were p53 protein-negative and 14 positive (exact P < 0.0001). As a diagnostic test this would give 70% sensitivity and 88% specificity.

Fractal geometric analysis of colorectal polyps.

Colorectal polyps have a subjectively self-similar structure which suggests that these structures may have fractal elements and that the fractal dimension may be a useful morphometric discriminant. The fractal dimensions of images from haematoxylin and eosin-stained sections of 359 colorectal polyps (214 tubulovillous adenomas, 41 'pure' tubular adenomas, 29 'pure' villous adenomas, 68 metaplastic polyps, and 7 inflammatory polyps) were measured using a box-counting method implemented on a microcomputer-based image analysis system. Results were assessed using polychotomous logistic regression, confusion matrices, and kappa statistics. All examined polyps were shown to have a fractal structure in the range of scales examined. The fractal dimension was significantly different between different diagnostic categories (P < 0.0001) and was a useful discriminant between these categories (kappa statistic 0.60 for the confusion matrix with size as the other variable). The fractal dimension did not shown any significant correlation with the grade of epithelial dysplasia (P > 0.05). This study shows that colorectal polyps have a fractal structure over a defined range of magnification and Euclidean morphometric measurements will be invalid outside precisely defined conditions of resolution and magnification. The fractal dimension is a better way of quantitating the polyp shape and is a useful morphometric discriminant between diagnostic categories.

Nm23 'anti-metastatic' gene product expression in colorectal carcinoma.

Nm23 is a putative metastasis suppressor gene and alterations in this gene have been reported in colorectal carcinomas suggestive of a role for nm23 in the dissemination of these tumours. In this study we used an affinity purified polyclonal antibody, ab-11, on formalin-fixed, paraffin-embedded sections of colorectal carcinomas from 46 patients in a three-stage avidin-biotin complex immunoperoxidase technique. Follow-up of these patients was until time of death or for 5 years, with a mean time of 31.2 months. Two observers scored the staining results from 1 to 3 according to the proportion of tumour cells positive. The association of nm23 staining with survival, sex, age, vascular invasion, and Dukes' stage was determined using Cox's regression model. The association of death from colorectal cancer and nm23 status reached marginal significance in this study (P = 0.0417). Moreover, there is some suggestion of a protective effect from nm23 as the relative risk of dying from colorectal cancer for each increment of nm23 positivity is 0.573 (95 per cent confidence limits 0.34-0.98).

Matrix metalloproteinase 9 expression in primary human prostatic adenocarcinoma and benign prostatic hyperplasia.

Matrix metalloproteinase (MMP) expression was investigated in patients with prostatic adenocarcinoma and benign prostatic hyperplasia (BPH). Forty-one men were studied: 26 had histologically proven prostate cancer, with 14 (54%) showing metastatic disease; 15 patients had BPH. Prostatic tissue was obtained from transurethral resection and needle core biopsies; gelatinolytic activity was determined by zymography. Seven gelatinolytic bands were detected, with molecular weights ranging from > 100 kilodalton (kDa) to 29 kDa. Nine of 14 patients (64%) with skeletal metastases had 92 kDa activity, present in only two of 12 patients (17%) with a negative bone scan, and absent in BPH. The 92 kDa gelatinolytic activity was expressed in 73% of aneuploid tumours compared with 20% of diploid tumours. A 97 kDa gelatinase was expressed in 80% of BPH samples and 23% of carcinoma patients. Enzyme bands of 72, 66 and 45 kDa were equally expressed in malignant tissue, irrespective of metastatic status, but were expressed in fewer BPH patients. The 97, 92, 66 and 45 kDa enzymes were identified as being pro-MMP-9 sequences by Western blotting, using a specific antibody directed against the pro sequence of the mature protein. MMP activity appeared to be increased in malignant prostatic tissue compared with BPH. Pro-MMP-9, in its 92 kDa form, was shown to be exclusively expressed by malignant prostatic tissue, and in particular by tumours that exhibited the aggressive and metastatic phenotype.

Attitudes of senior pathologists towards the autopsy.

The attitudes of 205 consultant British pathologists in four regions were assessed by a postal questionnaire in which they were asked to indicate their level of agreement with 15 statements relating to autopsies. A total of 144 pathologists completed the questionnaire (response rate 70 per cent). Senior pathologists strongly agreed with statements relating to the importance of autopsies within pathology workloads, medical audit, and accreditation for training posts. There was strong support for the attendance of clinicians at autopsy demonstrations and for the suggestion that material from medico-legal autopsies should be made available for teaching and research. There was strong disagreement with the suggestions that advances in diagnostic techniques have diminished the role of autopsies, that performing autopsies does not further pathologists' education, that the cost of autopsies may not be justifiable within a limited budget, and that the autopsy should no longer be part of the MRCPath examination. These results are discussed in the context of the current status of the autopsy in general.

Quantitation of the renal arterial tree by fractal analysis.

To determine whether the renal arterial system has a fractal structure, the fractal dimension of renal angiograms from 52 necropsy cases was measured using an implementation of the box-counting method on an image analysis system. The method was validated using objects with known fractal dimensions. The method was accurate with errors of less than 1.5 per cent and reproducible with initial values within 1.2 per cent of the mean of ten sets of measurements (reliability coefficient 0.968, 95 per cent confidence limits 0.911-0.984). In the 36 satisfactory angiograms the mean fractal dimension was 1.61 (SD 0.06), which was significantly greater than the topological dimension of 1 (P < 0.0001), indicating that the renal arterial tree has a fractal structure. There was no significant relationship between age (P = 0.494), sex (P = 0.136), or systolic (P = 0.069) or diastolic (P = 0.990) blood pressure, but two congenitally abnormal kidneys (hypoplastic dysplasia and renal artery stenosis) had fractal dimensions at the lower end of the normal range (third percentile). Since the renal arterial tree has a fractal structure, Euclidean geometric measurements, such as area and boundary length, are invalid outside precisely defined conditions of magnification and resolution.

p53 and c-myc expression in stage A1 prostatic adenocarcinoma: useful prognostic determinants?

Forty-five stage A1 prostatic adenocarcinomas from patients with a mean age of 65 years were examined for p53 and c-myc expression to determine whether the presence or absence of these proteins could predict tumor behavior. Thirteen (6 of 45) and seventy-three percent (33 of 45) of cases were respectively p53 and c-myc positive. p53 expression was confirmed to the tumor cells, whereas c-myc immunoreactivity was present in both malignant and surrounding hyperplastic prostate. Statistical analysis showed that although p53 and c-myc expression were positively correlated, expression of neither nuclear protein was associated with a significantly worse survival (p53: p = 0.0791 exact two-tailed; c-myc: p = 0.738 exact two-tailed). These results suggest that while both p53 and c-myc may play a role in prostatic carcinogenesis, neither appears to identify patients who may benefit from treatment in stage A disease.

Trabecular bone does not have a fractal structure on light microscopic examination.

The fractal dimension of the boundary of trabecular bone in 62 biopsies was measured on histological sections using a box-counting method implemented on a microcomputer image analysis system. The calculated fractal dimension had a mean value of 0.99 with a normal distribution. Since this value is not greater than the topological dimension, trabecular bone, when examined by light microscopy, does not have a fractal structure. Conventional Euclidean dimensions will continue to be the most useful measurements in bone histomorphometry.