Results

In total, 769 subjects fulfilled at least two case criteria for PBC within the study area and period. Table 1 outlines some characteristics of this cohort of patients. Thirty nine per cent of them had been diagnosed with PBC between 1969 and 1986 and were still alive at the start of the study period, and 61% were diagnosed within the case finding period (9% after the end of 1993, so they could only contribute to the cancer mortality comparisons). The patients were predominantly female, with a median age at diagnosis of 63 years (range 17–91). In 97 individuals a cancer event occurred (death, registration, or information in hospital notes) during 1987–96, but in 15 of them the cancer event preceded diagnosis of PBC; these events were therefore excluded from later analysis. In 14 subjects the cancer registrations occurred before the diagnosis of PBC: the cancers had been registered between 17 days and 17 years before PBC was diagnosed. There were two stomach cancers, one respiratory, two breast, four reproductive, one urinary, and two haematological cancers. A table is available from the authors listing the cancer events which occurred after PBC diagnosis during the follow up period. This illustrates the distribution of cancer over the different sites, and over time, and the timing of PBC diagnosis, cancer registration, death from cancer, and first mention of cancer in hospital notes.

The total number of person years at risk of follow up in the incidence calculation was 2641 when using all incident cancers, and 2279 when omitting the first year of follow up after PBC diagnosis. Table 2 gives the standardised incidence ratios (SIR). These results show that for PBC patients there was a significantly raised risk of all cancers (SIR = 1.7), and considerably higher liver cancer risk (SIR = 74.3). However, the increased risk of cancer at all sites was no longer significant when the first year of follow up was excluded. There was no significantly increased risk of breast cancer with the SIR being 1.1 for total follow up period, and 1.0 excluding the first year after PBC diagnosis.

The total number of person years of follow up in the mortality calculation was 4190 years when including all deaths, and 3743 years when excluding cancer deaths within a year of diagnosis of PBC. The length of follow up for a subject varied between one day and 10 years with a median of 5.4 years. Table 3 gives the standardised mortality ratios (SMR). These results show that for PBC patients there were significantly raised risks of dying from all cancers (SMR = 1.8), respiratory cancer (SMR = 2.4), and haematological cancers (SMR = 3.9); the risk of liver cancer was considerably raised (SMR = 38.6). The results were similar when the first year of follow up was excluded. The SMR for breast cancer was 0.4 and 0.3 for these two analyses, and there was no evidence of a significantly increased risk of breast cancer mortality in either.

Discussion

These results come from a large cohort of PBC patients identified by comprehensive and strict case finding methods. The incidence and prevalence of PBC is high in this part of the UK. A recent study reported an average annual incidence of definite and probable PBC of 43 per million, and an average mid year prevalence of definite and probable PBC of 311 per million in 1987–94 in one of the districts in the study area6: figures of 28.6 and 202.5 per million respectively were found for the whole study area. The subjects were predominantly female, and were diagnosed in their sixth and seventh decades. This is at the upper end of the age range reported elsewhere and may have been affected by the case finding methods used. Many previous studies were based on cases from regional referral centres which would be more likely to include both younger and symptomatic patients, and those with more complex medical histories.

Cancer events were not always reported consistently across sources. However, very few cancer registrations were available after 1993, so a cancer death or hospital diagnosis post-1993 may not have had a matching registration, simply because these data had not yet been released. Nevertheless, the results show that many cancer events were only notified to the cancer registries at the death of the patient. This could be because diagnosis was only made after death, or because cancer registration did not happen after diagnosis as it should. This was investigated by looking at hospital notes, where they were available, to see if their information on cancer diagnosis was similar to registry records. There were some discrepancies between cancer registration and hospital records, but not in a particular direction. There were eight cancer events after PBC diagnosis which were only recorded in hospital notes. However, only five were pre-1993, when registration information was available. Hospital notes will not always contain details of any cancer diagnosis, if care is being entirely dealt with by a general practitioner. These results do not suggest that there was a large problem of non-registration of cancers. There seems little reason to suggest that these problems should be any worse for PBC patients than any other member of the population, so the standardised rates should not be biased.

Cancer events in which cancer registration occurred before the diagnosis of PBC were excluded from the analysis, as the person years of experience were only counted after the diagnosis of PBC. However, even if the diagnosis of PBC could have occurred before the cancer was recognised for some of them (making them eligible to be included in the main analysis), the small numbers at any one site would not have made a material difference to the results.

Early work by the group in west of Scotland noted an excess of extrahepatic cancer in patients with PBC3: the standardised incidence ratio in females was 3.5. Recent studies in Sweden and Denmark found a small but significant excess incidence of all cancers (SIR = 1.6 and 1.4 respectively), when they excluded cancers diagnosed in the year after PBC diagnosis.7 ,9However, a Dutch group found no excess deaths from cancers at all sites (SMR = 0.7) using death certificates as the source of subjects.10 In our study there was a small, but statistically significant excess of cancer incidence at all sites in PBC patients, if followed from the time of PBC diagnosis (SIR = 1.7; 95% confidence interval (CI) 1.3 to 2.2): after excluding the first year of follow up after PBC diagnosis, this SIR was reduced to a non-significant excess. Small but significant excesses were found for cancer mortality at all sites. While the precise size of any excess of all cause cancer mortality or incidence is unclear, the width of the confidence interval suggests that the data from this and other studies are consistent with a small excess cancer risk for PBC patients. Longer term follow up of this cohort may go some way to answer this question.

Some previous studies of hepatocellular cancer (HCC) in PBC using crude incidence rates concluded that the risk of HCC was not particularly high in PBC patients (although high in other forms of cirrhosis),11 ,12 while others concluded that the rate of HCC in PBC patients was high and similar to that seen in other females with cirrhosis from other causes.13-15 A local study recently noted 16 HCCs arising in 667 PBC patients with a total follow up of 2010 person years.16 However, this and the current study are not fully comparable, because although the case definition of PBC is the same, the series of 667 patients was taken from the whole tertiary referral practice of the one liver clinic over 20 years, and the cancer events were found by searching hospital notes as opposed to formal registration.

A few studies have attempted to compare HCC risks via adjusted rates. The Dutch study, based on death registrations, reported a significant excess of HCC mortality SMR = (25.5).10 The large Swedish study found no excess of HCC in terms of incidence (SIR = 2.9) when looking at cancers at least one year after diagnosis of PBC.7 However, the Danish study gave significantly increased rates of HCC (SIR = 47).9 We found an SIR of 74.3 (95% CI 32 to 146) and an SIR of 72.7 (95% CI 29 to 150) when excluding the first year of follow up after PBC diagnosis. The 95% confidence intervals were based on few events, so we were unable to estimate the excess risk precisely, but it seems likely that there is a large excess risk of liver cancers in PBC patients. Similar results were obtained in this study when looking at cancer mortality rather than incidence rates. The studies which had used adjusted rates found large excesses, except for the Swedish study. It has been suggested that increased risks of HCC are linked to fully developed cirrhosis.7 ,16 The nine subjects in this study who developed HCC had stage 4 disease: the lack of apparent increase in HCC in the Swedish study may be due to the fact that this study contained many early stage PBC patients.

An American study first reported an excess of breast cancer incidence in PBC patients (SIR = 4.4)5; the Scottish group who first reported an excess in all cancers also found excess breast cancer in a larger group of PBC patients (SIR = 3.8).4 A link between breast cancer and PBC by the potential role of hormonal factors and immunohistochemical similarities has been suggested, but little evidence has been gathered.17-19 However, these early findings were not supported by the results of studies in Italy,13 Holland (SMR = 0.1),10 Sweden (SIR = 0.9),7 or Denmark (SIR = 0.9).9 Our study also found little evidence for an excess incidence or mortality from breast cancer, whether or not the first year of follow up after PBC diagnosis was excluded (SIR = 1.1; 95% CI 0.4 to 2.4 for the former).

We found some small excess cancer mortality at sites not previously noted in PBC patients: there was some evidence of additional deaths from respiratory cancer, and lymphomas and leukaemias. Some studies have previously found evidence linking lymphomas to other autoimmune conditions,20 ,21 but not to PBC. However, as our results are based on few cancer events, the evidence is not conclusive, and may, indeed, be the result of the multiple comparisons within the analysis. It would nevertheless be interesting to see whether these results are replicated in future studies.

We have considered the risks of cancer at particular sites in four ways: incidence and mortality, and with or without the first year of follow up. The estimates of extra risk were similar whichever method was used. Those based on more years of follow up had more precise estimates, as would be expected. There was a tendency for the estimates based on incidence to be slightly higher than those for mortality, possibly because some of those diagnosed with cancer did not die of it, but the difference was not large.

In conclusion, when considering those cancers whose links with PBC have been studied on a number of occasions, the larger and more rigorous studies concur that it is unlikely that there is a clinically important excess incidence or mortality from any cancer associated with PBC (and specifically breast cancer), with the exception of liver cancer.