Before interpreting the results of this study, it is important to acknowledge its limitations. First, the histologic categorizations used were based on diagnoses made by multiple pathologists in multiple institutions, and diagnostic criteria may vary somewhat by both individual pathologists and institutions, resulting in a certain degree of misclassification error. Studies evaluating the concordance between histologic classifications of breast tumours ascertained by SEER registries and those made through a centralized pathology review are needed to quantify the magnitude of this misclassification, as none have been reported in the literature. However, the misclassification of histologic type present in the SEER data is likely to be nondifferential, and as a result it may obscure differences but not lead to the identification of spurious differences. Also encouraging is that the proportions of cases in each histopathologic category were relatively similar across the 11 registries included in this study. One exception was that 10.9% of cases diagnosed in Los Angeles were ductal–lobular, while only 2.9% diagnosed in Hawaii were ductal–lobular. However, across the remaining nine registries, the proportions of cases that were ductal–lobular were relatively similar. Another concern is that we lacked information regarding certain potential confounders, including hormonal, reproductive, anthropometric, and lifestyle factors, that may be associated with both different histologic types of breast cancer and with the different clinical and pathologic tumour characteristics we evaluated. However, the strengths of this study are that it is large and population-based. Thus, it provides information on the tumour characteristics of different histologic types of breast cancer, some of which are quite rare, that are being observed in the general population.
Differences between various histologic types of breast cancer have been noted in prior studies. Two studies have explored the age distribution of different histologic types of breast cancer and have observed some striking differences. The first study by Stalsberg and Thomas (1993)
reported that, while the relative frequency of ductal carcinoma is essentially constant by age, the frequencies of papillary and mucinous carcinomas tend to increase with age, the frequencies of medullary and inflammatory carcinomas tend to decrease with age, and the frequencies of lobular and tubular carcinomas increase until age 50, after which they remain fairly constant. A recent update of age-specific rates by histologic type observed three different age-rate patterns (Anderson et al, 2004
). Specifically, rates of ductal, lobular, and tubular carcinomas were shown to rise sharply until age 50 and then rise more slowly, rates of papillary and mucinous carcinomas to rise steadily with age, and rates of medullary and inflammatory carcinoma to increase until age 50, after which they did not continue to rise. While this study also evaluated age-specific incidence rates by histologic type for ER+ and ER− tumours separately, it did not directly compare the distributions of ER status, or other clinical or tumour characteristics by histologic type.
In addition, risk of mortality has been observed to vary by histologic type as women with inflammatory breast cancers have an increased risk of mortality compared to women with other histologic types of breast cancer (Stierer et al, 1993
; Anderson et al, 2003
), while women with lobular, mucinous, comedo, tubular, medullary, and papillary carcinomas have lower risks of mortality compared to women with ductal carcinomas (Li et al, 2003c
). However, few previous studies have evaluated differences in clinical and pathologic tumour characteristics by histologic type. With respect to ER/PR status, lobular, ductal/lobular, and mucinous carcinomas have been shown to be more likely to be ER+/PR+ compared to ductal carcinomas, similar to what we observed here (Desai et al, 2000
; Arpino et al, 2004
; Korhonen et al, 2004
; Mathieu et al, 2004
). However, studies have not evaluated ER/PR status in rarer histologic types of breast cancer, or evaluated differences in stage, tumour size, lymph node status, or grade by histologic type.
Here we observed several differences in these characteristics by histologic type, which only varied somewhat by age at diagnosis. The primary differences seen between our groups of largely postmenopausal women vs
largely premenopausal women were differences in magnitudes rather than directions of risk. For example, among comedo carcinoma cases, the observed elevated risks of ER−/PR− tumours compared to ductal cases were more pronounced among the older women (OR=2.8) than among the younger women (OR=1.5). Exceptions to this were that lobular carcinomas diagnosed among younger women were less likely to be PR− compared to ductal cases, though this difference was not seen among the older women. In addition, older, but not younger, women with comedo carcinoma had an elevated risk of ER− tumours. Finally, the higher risk of tumours
cm and the lower risk of node-positive tumours seen among older women with papillary carcinomas were not observed among younger women with papillary tumours. However, our ability to detect differences among papillary cases 30–49 years of age was limited by a relatively small sample size (n
Despite these differences, among both age groups of women, mucinous, tubular, and papillary carcinomas generally had less aggressive phenotypes compared to ductal carcinoma cases, as they were each less likely to present at an advanced stage, to be node positive, to be hormone receptor negative, and to have a high grade. These features may explain why women with these tumours have relatively low risks of mortality (Stierer et al, 1993
; Li et al, 2003c
). In contrast, inflammatory carcinomas appear to have the most aggressive phenotype of any of the histologic types evaluated as these tumours were more likely to be node positive, to be hormone receptor negative, and to have a high grade. These findings are consistent with the poorer survival rates that women with these tumours experience, particularly for those with ER− inflammatory carcinoma (Anderson et al, 2003
; Li et al, 2003c
). Lobular, ductal/lobular, and comedo and medullary carcinomas had mixed phenotypes. Lobular and ductal/lobular tumours tended to be diagnosed at a more advanced stage and to be both >5.0
cm and node positive, but they were also much more likely to be hormone receptor positive. In contrast, comedo and medullary carcinomas were less likely to have an advanced stage at diagnosis and to be node positive, but more likely to be hormone receptor negative and to have a high grade. Interestingly, these characteristics appear to translate into all of these tumours having lower risks of mortality compared to ductal carcinoma cases, as we have reported previously (Li et al, 2003c
Beyond differences in their histopathologic appearances, the results of this study suggest that different histologic types of breast cancer also differ substantially in their clinical and tumour characteristics. Interestingly, while inflammatory carcinomas are more likely to be characterized by poor clinical and pathologic tumour characteristics that do translate into poorer survival rates; lobular, ductal/lobular, comedo, and medullary carcinomas are characterized by a mix of tumour characteristics that are associated with both better and poorer prognoses, though previous data indicate that women with these tumours have lower risks of mortality than do women with ductal carcinomas (Li et al, 2003c
). Thus, the prognostic importance and utility of the clinical and tumour characteristics evaluated here varies by histologic type. The differences in hormone receptor status and grade that we observed by histologic type may reflect the different aetiologies of these tumours. Further, the differences in stage, tumour size, and lymph node status observed here may reflect differences in the utility of screening approaches to detect different histologic types of cancer. For example, it is well known that lobular tumours are more difficult to detect with mammography compared to ductal tumours, and this is thought to be primarily due to the fact that lobular tumours tend to grow as linear strands or sheets of cancer cells rather than as more discrete masses, explaining why they are more likely to be diagnosed at a more advanced stage (Davis et al, 1979
; Dixon et al, 1982
; Silverstein et al, 1994
; Yeatman et al, 1995
). Thus, currently, available breast cancer screening tools appear to be relatively less or relatively more effective in detecting different histopathologic types of breast cancer.