On the occurrence of focal, occult in situ and invasive carcinoma in 250 mastectomy specimens

In 1982, a total of 250 breasts were removed for cancer in the surgical departments of the Oslo City Health Department, comprising 81% of all new breast cancers reported in Oslo in 1982. Invasive ductal carcinoma (68%) and invasive lobular carcinoma (12.4%) were the predominant types. Special attention was given to the presence of occult in situ or invasive carcinomas more than 1 cm from the periphery of the main carcinoma. In 24.8% of the specimens, carcinoma in situ was found in such locations, and an additional 6.9% showed a second, occult invasive carcinoma. Carcinoma in situ was equally common in invasive ductal and invasive lobular carcinoma. Occult invasive carcinoma was predominantly found in specimens with invasive lobular carcinoma. There was a significantly increased number of lymph node metastases in patients with carcinoma in situ or second, occult primary carcinoma more than 1 cm from the periphery of the main carcinoma.     

Staging and treatment of clinically occult breast cancer

Five hundred fifty-seven biopsies were performed for clinically occult mammary lesions, detected by mammography as clustered calcifications or nonpalpable masses within the breast. One hundred seventy-five cancers were demonstrated within this group, including 106 invasive carcinomas, 10 microinvasive carcinomas, 45 in situ ductal carcinomas, and 14 lobular carcinomas in situ (lobular neoplasia). No patient with in situ or microinvasive carcinoma had evidence of axillary node metastases in 33 specimens studied. However, a disturbingly high proportion of those patients with invasive carcinomas, approximately 35%, had histologically confirmed axillary node metastases, despite the small size of the primary tumors. These observations suggest that the use of the term "minimal" cancer is misleading when applied to invasive carcinoma. Staging systems for breast cancer have been imprecise when referring to nonpalpable lesions. Cancers detected as clustered calcifications only or as areas of parenchymal distortion without an accompanying mass are properly considered as T-0 cancers, with a suggested T-0(m) to indicate that the lesion was detected by mammography. However, when the mammogram indicates the presence of a mass that proves to be malignant, although the clinical examination may have been negative, the cancer should be staged according to the size of the mass on the mammogram, with the notation that it was detected by mammography, e.g., T-1(m), T-2(m), etc. The incidence of axillary node metastases even in these so-called occult cancers is significant, so that recommendations for treatment for any invasive cancer, regardless of its size, must take these observations into account. Similarly, the incidence of multifocal sites of cancer within the breast, even in the noninvasive cancers encountered, must be remembered when treatment is suggested.     

Evaluation of breast cancer with a computer-aided detection system by mammographic appearance and histopathology

BACKGROUND: The objective of this study was to evaluate the performance of a computer-aided detection (CAD) system for the detection of breast cancer, based on mammographic appearance and histopathology. METHODS: From 1000 consecutive screening mammograms from women with biopsy-proven breast carcinoma, 273 mammograms were selected randomly for retrospective evaluation by CAD. The sensitivity of the CAD system for breast cancer was assessed from the proportion of masses and microcalcifications detected. The corresponding tumor histopathologies also were evaluated. Normal mammograms (n = 155 patients) were used to determine the false-positive rate of the system. RESULTS: Of the 273 breast carcinomas, 149 appeared mammographically as masses, and 88 appeared as microcalcifications, including 36 carcinomas that presented as mixed lesions. The CAD system marked 125 of 149 masses correctly (84%), marked 86 of 88 microcalcifications correctly (98%), and marked 32 of 36 of mixed lesions correctly (89%.). The system showed a high sensitivity for the detection of ductal carcinoma in situ (95%; 73 of 77 lesions), invasive lobular carcinoma (95%; 18 of 19 lesions), invasive ductal carcinoma (85%; 125 of 147 lesions), and invasive mammary carcinoma (90%; 27 of 30 lesions). The highest CAD system sensitivity was for all invasive carcinomas that presented as microcalcifications (100%). On normal mammograms, there was an average of 1.3 false-positive CAD marks per image. CONCLUSIONS: The CAD system correctly marked a large majority of biopsy-proven breast cancers, with a greater sensitivity for lesions with microcalcifications and without significant impact of performance based on tumor histopathology. CAD was highly effective in detecting invasive lobular carcinoma (sensitivity, 95%) and ductal carcinoma in situ (sensitivity, 95%). CAD represents a useful tool for the detection of breast cancer.     

Changes in Incidence of in situ and Invasive Breast Cancer by Histology Type following Mammography Screening

Objective: To investigate secular trends and correlates of incidence of breast cancer by histology type following ‍the introduction of population-based mammography screening. Methods: Analysis of age-standardised incidence ‍rates for 1,423 in situ and 16,157 invasive carcinomas recorded on the South Australian population-based cancer ‍registry for the 1985-2004 diagnostic period. Multiple logistic regression was undertaken to compare sociodemographic ‍characteristics by histology. Progression from in situ disease was investigated using the Kaplan-Meier ‍method. Results: The incidence of in situ lesions increased approximately seven-fold over the 20-year period, compared ‍with an increase of about 40% for invasive cancers. The increase for in situ lesions was due to increases for ductal ‍carcinomas, with little change for lobular lesions. By comparison, the percentage increase in incidence for invasive ‍cancer was greater for lobular than ductal cancers. Both for in situ and invasive cancers, percentage increases were ‍greatest for the screening target age range of 50-69 years. One in 14 in situ cases was found to progress to invasive ‍cancer within seven years of diagnosis, but insufficient detail was available to determine whether the invasive cancers ‍were a progression of the in situ lesions or whether they originated separately. These invasive cancers were smaller ‍than generally applying for other invasive cancers of the female breast. Conclusions: The larger secular increases in ‍incidence for in situ than invasive cancers would reflect the dominant role of mammography in the detection of ‍ductal carcinoma in situ. The lack of an increase for lobular in situ lesions may have resulted from their poorer ‍radiological visibility. The greater percentage increase for lobular than ductal invasive lesions may have been due to ‍an increase in imaging sensitivity for these lesions, plus real increases in incidence. The smaller sizes of invasive ‍cancers found in women with a prior in situ diagnosis may have resulted from more intensive medical surveillance, ‍although the possibility of biological differences cannot be discounted.     

Immunohistochemical demonstration of metallothionein in normal human breast tissue and benign and malignant breast lesions

Metallothioneins (MTs) are a set of low molecular weight proteins with a high binding affinity to metal ions. MT over-expression has been recently demonstrated in invasive ductal carcinoma of the breast with poor clinical prognosis. In the present study, MTs have been immunohistochemically investigated in normal human breast tissue and a variety of benign, pre-invasive, and malignant breast lesions. In normal breast tissue, MTs were present in myoepithelial cells whereas the vast majority of luminal cells were MT negative. In lesions without increased cancer risk (adenosis and scleradenosis), MT was only immunolocalized in myoepithelial cells. In papillomas, MT was also found exclusively in myoepithelial cells. In most cases of epitheliosis, both the luminal and myoepithelial cells expressed MT. Atypicallobular hyperplasia, lobular carcinomain situ, and 13/15 invasive lobular carcinomas showed no MT over-expression. The two invasive lobular carcinomas with MT over-expression were classified as pleomorphic lobular carcinomas with apocrine differentiation. In contrast to lobular cancerization, 12/24 ductalin situ carcinomas and 9/20 invasive ductal carcinomas showed MT over-expression.In situ components found within invasive ductal carcinomas usually reflected the MT status of their invasive counterpart. It is concluded from our immunohistochemical results that breast carcinoma cases with MT overexpression arise from lesions which also show MT overexpression. Thus MT expression in carcinomas may be regarded as a genuine feature of the tumour cells and seems not to be related to endogenous or exogenous factors known to induce MT synthesis.     

Contralateral prophylactic mastectomy. Predictors of significant histologic findings

BACKGROUND: Women with unilateral breast carcinoma are at increased risk for developing contralateral breast carcinoma (CBC). The authors sought to identify predictors of malignant or moderate to high-risk histologic findings in contralateral prophylactic mastectomy (CPM) specimens, and to determine the efficacy of CPM. METHODS: The authors performed a retrospective review of 239 patients with unilateral early-stage breast carcinoma who underwent CPM. The number of CBCs expected if the contralateral breast had been left intact was calculated based on CBC rates observed in the Surveillance, Epidemiology, and End Results (SEER) database and on life-table analysis by family history. RESULTS: In the current study, 11 patients (4.6%) had occult contralateral malignancies (4 invasive carcinomas and 7 ductal carcinomas in situ) and 44 (18.4%) patients had moderate to high-risk pathology (8 lobular carcinoma in situ, 11 atypical lobular hyperplasia, 25 atypical ductal hyperplasia). At 1846 patient-years of follow-up, only 1 patient (0.4%) developed a new CBC compared with 11 expected cancers based on SEER data. One CBC was observed among 140 patients with a family history of breast carcinoma, compared with 16 expected cancers based on life-table analysis adjusted for adjuvant therapy. The determinants of significant findings at CPM were invasive lobular histology, estrogen and progesterone receptor positivity, additional ipsilateral moderate to high-risk pathology, and age > 40 years at cancer diagnosis. CONCLUSIONS: CPM was associated with a low risk of subsequent development of breast carcinoma. Evaluation of histologic findings in the ipsilateral breast may help to predict the likelihood of significant disease in the contralateral breast and assist in risk stratification.     

The occurrence of interval cancers in the Nijmegen screening programme

Since January 1975 a population-based screening programme for the early detection of breast cancer has been carried out in the city of Nijmegen. During five interscreening periods of 2 years each a total of 158 so-called interval cancers were diagnosed. Careful revision of all screening and diagnostic mammograms was executed. Of all interval cancers 26% were 'missed' at the previous screening examination (due to technical or observer error), 16% were radiographically occult at the time of diagnosis and 58% were 'true' interval cancers. Interval cancers were regarded as 'true' when an obvious lesion was observed on the diagnostic mammogram while no suspect signs were seen on the previous screening mammogram. The prevalence of 'missed' cancers did not decline in the course of the screening programme. Radiographically occult tumours were localised, mostly in Wolfe's P2/DY breast parenchyma (83%), 33% were lobular invasive and 25% ductal non-invasive. 'True' interval cancer cases (58%) showed the same overall survival as control breast cancer patients, diagnosed in a non-screening situation. Shortening the screening interval would reduce interval cancer rates and probably further decrease breast cancer mortality in a screened population. However, from the present series of interval cancers 63% would not have been prevented by an annual screening examination. As regards women under age 50 annual screening would still leave 66% of all interval cancers in this age group undetected. Probably more benefit will be gained by searching for new imaging techniques to reduce numbers of 'missed' cancers and to detect lobular invasive and ductal non-invasive cancers in dense breast parenchyma.     

Identification of cyclin D1- and estrogen-regulated genes contributing to breast carcinogenesis and progression

Tumors can become lethal when they progress from preinvasive lesions to invasive carcinomas. Here, we identify candidate tumor progression genes using gene array analysis of preinvasive and invasive tumors from mice, which were then evaluated in human cancers. Immediate early response protein IEX-1, small stress protein 1 (HSPB8), and tumor necrosis factor-associated factor-interacting protein mRNAs displayed higher expression levels in invasive lesions than in preinvasive lesions using samples obtained by laser capture microdissection (LCM) from transgenic erbB2, ras, and cyclin D1 mice. LCM-isolated tissues from patient-matched normal, ductal carcinoma in situ, and invasive ductal carcinoma revealed similar increased expression in invasive human cancers compared with preinvasive and normal samples. These genes induced anchorage independence, increased cell proliferation, and protected against apoptosis, singly or in collaboration with erbB2. Surprisingly, they were all up-regulated by 17beta-estradiol and cyclin D1, and cyclin D1 overexpression increased p300/CBP binding to their promoters, supporting the model that cyclin D1-estrogen receptor (ER) coactivator interactions may be important to its role in ER-positive breast cancer. Additionally, an irreversible dual kinase inhibitor of ErbB signaling inhibited expression of the same genes. The up-regulation of genes contributing to increased invasiveness of ER-positive cancers offers a novel explanation for the contribution of cyclin D1 to a worse prognosis in ER-positive cancers. As targets of estrogen, cyclin D1, and erbB2 signaling, these candidates offer insights into the nature of the second events involved in breast cancer progression, regulatory events contributing to invasion, and potential targets of combined inhibition of hormone and growth factor signaling pathways.     

Nerve fibers infiltrate the tumor microenvironment and are associated with nerve growth factor production and lymph node invasion in breast cancer

Infiltration of the tumor microenvironment by nerve fibers is an understudied aspect of breast carcinogenesis. In this study, the presence of nerve fibers was investigated in a cohort of 369 primary breast cancers (ductal carcinomas in situ, invasive ductal and lobular carcinomas) by immunohistochemistry for the neuronal marker PGP9.5. Isolated nerve fibers (axons) were detected in 28% of invasive ductal carcinomas as compared to only 12% of invasive lobular carcinomas and 8% of ductal carcinomas in situ (p = 0.0003). In invasive breast cancers, the presence of nerve fibers was observed in 15% of lymph node negative tumors and 28% of lymph node positive tumors (p = 0.0031), indicating a relationship with the metastatic potential. In addition, there was an association between the presence of nerve fibers and the expression of nerve growth factor (NGF) in cancer cells (p = 0.0001). In vitro, breast cancer cells were able to induce neurite outgrowth in PC12 cells, and this neurotrophic activity was partially inhibited by anti‐NGF blocking antibodies. In conclusion, infiltration by nerve fibers is a feature of the tumor microenvironment that is associated with aggressiveness and involves NGF production by cancer cells. The potential participation of nerve fibers in breast cancer progression needs to be further considered.     

Changing incidence rate of invasive lobular breast carcinoma among older women

BACKGROUND: In 1998, an unusually large number of invasive lobular breast carcinoma cases were seen at the University of Washington. The purpose of this study was to assess whether the incidence rate of invasive lobular carcinoma has been increasing disproportionately compared with the incidence rate of invasive ductal carcinoma. METHODS: Age specific and age-adjusted breast carcinoma incidence rates from 1977-1995 were obtained from the nine population-based cancer registries that participate in the Surveillance, Epidemiology, and End Results (SEER) program. Three histologic groupings were used: lobular, ductal, and all invasive breast carcinomas. Overall incidence rates for each grouping, as well as for each stage (local, regional, and distant), were obtained. RESULTS: The rate of incidence of lobular carcinoma increased steadily from 1977-1995 in women age >/= 50 years whereas it remained stable in women age < 50 years. Alternatively, the rate of incidence of ductal carcinoma increased steadily from 1977-1987, but from 1987-1995 it remained relatively constant across all age groups. CONCLUSIONS: The incidence rates of invasive lobular breast carcinomas increased steadily since 1977 whereas the incidence rates of invasive ductal carcinoma have plateaued since 1987. This rise occurred specifically among women age >/= 50 years and may be related to postmenopausal status. Further epidemiologic, clinical, and laboratory research is required to assess what factors are contributing to this trend.     

High rates of breast conservation for large ductal and lobular invasive carcinomas combining multimodality strategies

The literature reports low rates of breast conservation after neoadjuvant chemotherapy for operable breast cancers not amenable to initial breast-conserving surgery. This study aims to compare the outcome of lobular vs ductal carcinomas after neoadjuvant chemotherapy. Between 1989 and 1999, 750 patients with clinical stage II/IIIA ductal (672) or lobular (78) invasive breast carcinomas were treated at the Institut Curie with primary anthracycline-based polychemotherapy followed by either breast conservation (surgery and/or radiotherapy) or mastectomy. Median follow-up was 10 years. Clinical response to primary chemotherapy was significantly worse for lobular than for ductal carcinomas (47 vs 60%; P=0.04), but only histological grade remained predictive in multivariate analysis. Breast conservation was high for both ductal and lobular carcinomas (65 and 54%; P=0.07), due, in part, to the use of radiotherapy, either exclusive or preoperative, for respectively 26 and 40% of patients. The lobular type had no adverse effect, neither on locoregional control nor on overall survival, even in the group of patients treated with breast conservation.     

Expression and amplification of cyclin D1 in primary breast carcinomas: relationship with histopathological types and clinico-pathological parameters

Overexpression and amplification of cyclin D1 were investigated by immunohistochemistry and differential polymerase chain reaction (dPCR) in 440 formalin-fixed primary breast carcinoma tissues. Overexpression of cyclin D1 was detected in 60% (263/440) and amplification of cyclin D1 was noted in 27% (119/440) of the primary breast carcinomas. Molecular analysis demonstrated that cyclin D1 was amplified in 30% (7/23) of the comedo DCIS, 22% (9/41) of the comedo DCIS and 32% (13/41) of the adjacent invasive ductal carcinomas, 30% (82/270) of the invasive ductal carcinomas, 27% (9/33) of the invasive lobular carcinomas, 19% (4/21) of the colloid carcinomas and 13% (2/15) of the medullary carcinomas. Cyclin D1 was amplified in 11% (2/19) of the invasive ductal carcinomas but not in the adjacent non-comedo DCIS lesions. Our observation showed that cyclin D1 was strongly positive in 61% (14/23) of the comedo subtype, 61% (11/18) of the non-comedo subtype, 59% (24/41) of the comedo DCIS and 63% (26/41) of the adjacent invasive ductal carcinomas, 53% (10/19) of the non-comedo DCIS and 58% (11/19) of the adjacent invasive lesions, 58% (157/270) of the invasive ductal carcinomas, 73% (24/33) of the invasive lobular carcinomas, 52% (11/21) of the colloid carcinomas and 27% (4/15) of the medullary carcinomas. A significant association was observed between in situ components and adjacent invasive lesions for cyclin D1 expression (p<0.05) and amplification (p<0.05). A significant relationship was noted between amplification of cyclin D1 and lymph node metastases (p<0.05) but not with histological grade (p>0.05), estrogen receptor status (p>0.05) and proliferation index (Ki-67 and PCNA) (p>0.05). However, overexpression of cyclin D1 was statistically associated with well differentiated tumors (p<0.05) and estrogen receptor positivity (p<0.05). No relationship was seen with nodal status (p>0.05) and proliferation index (Ki-67 and PCNA) (p>0.05). These observations suggest that tumors positive for cyclin D1 protein may have features of good prognosis but amplification of cyclin D1 gene could be an indicator of tumors with poor prognostic features. Although majority of the Malaysian patients belong to younger age group (<50 years old), amplification and expression of cyclin D1 was not statistically associated with patient age (p>0.05). These observations indicate that amplification and up-regulation of cyclin D1 may be independent of patient age. Moreover, overexpression and amplification of cyclin D1 in preinvasive, preinvasive and adjacent invasive lesions, and invasive carcinomas suggest that the gene may play an important role in early and late stages of breast carcinogenesis.     

Recent data on lobular neoplasia of the breast: the pathologist's opinion

Lobular neoplasia is the new WHO terminology that encompasses the so-called lobular carcinoma in situ and atypical lobular hyperplasia. Besides the classical forms, particular variants have been described, which are mammographically detectable with distinct histologic patterns and behaviour. These variants are characterized by pleomorphic cells, necrosis with calcifications and may be associated to an invasive lobular carcinoma. Their clinical issue looks more like a preinvasive lesion than a marker of increased risk. Thus, their identification on biopsy requires a surgical reexcision. Hybrid forms, sharing a mixed lobular and ductal morphology and phenotype, have also been mentionned. Despite a lack of prognostic evaluation, it seems logical to recommend a subsequent surgical investigation when they are observed. Classical forms are usually managed by simple follow-up, although this attitude does not make a consensus among pathologists. Lobular neoplasia are not all indolent lesions and belong to an heterogeneous group that percutaneous guided biopsies have emphasized. They should be managed in a pluridisciplinar way and correctly diagnosed on percutaneous biopsies as well as surgical specimens.     

Immunohistochemical distribution of c-erbB-2 in infiltrating and in situ breast cancer

An immunohistochemical study of c-erbB-2 expression was performed on invasive and in situ breast cancer. Strong membrane staining was seen in 16% of the infiltrating ductal carcinomas and 44% of the in situ lesions. c-erbB-2 was overexpressed in ductal rather than lobular tumours. Our results indicate that a small sub-group of breast carcinomas are associated with over-expression of this oncogene which may define an important subgroup of in situ and infiltrating ductal carcinomas.     

Perspectives on margins in DCIS: pathology

All breast carcinomas must originate within the ductal/lobular system as carcinoma in situ, but only a subset of these lesions progress to invasive carcinoma. Although pathologic evaluation of the extent of ductal carcinoma in situ (DCIS), the distance to margins, and the degree of margin involvement provides an estimation of the likelihood of residual disease, the amount of disease in the remaining breast cannot be predicted with certainty. Factors other than residual disease may be more important in determining whether patients with DCIS survive or succumb to breast cancer, including biologically new ipsilateral cancers, contralateral cancers, and the degree of resistance of the normal stroma to invasion.     

Does intraductal breast cancer spread in a segmental distribution? An analysis of residual tumour burden following segmental mastectomy using tumour bed biopsies.

INTRODUCTION: Breast-conserving surgery for early breast cancer is now routinely used as an alternative to mastectomy. Despite post-operative radiotherapy, early local recurrence of tumour remains a concern. It has been reported that invasive and in-situ ductal carcinoma spread locally through the ductal tree in a segmental distribution, however, there is no consensus as to the best surgical method to maximize tumour clearance whilst leaving a good cosmetic result. AIM: We aimed to measure the effectiveness of segmental mastectomy (excision of tumour plus associated segmental ductal tissue) in the clearance of different tumour types. Bed biopsy of the excision cavity was employed to assess the rate of incomplete excision or the multifocality of certain breast cancers. METHODS: One hundred and one patients with breast cancers underwent segmental mastectomy and cavity bed biopsies. Specimens were assessed for tumour type and completeness of excision. An excision of the cancer was considered incomplete if the margins were involved or if any of the bed biopsies showed residual or multifocal tumour. RESULTS: A total of 24 patients had incomplete tumour excision. Invasive ductal carcinoma was more likely to be completely excised by segmental mastectomy than invasive lobular carcinoma (P<0.05). Incomplete excision was associated with multifocality and the presence of extensive DCIS. The report of clear pathological margins was significantly more likely to be accurate, as measured by negative bed biopsies, in invasive ductal carcinoma when compared to invasive lobular carcinoma (P<0.05). CONCLUSION: These results support the concept that ductal carcinomas spread locally in a segmental fashion. Patients with invasive ductal carcinomas are more likely to benefit from breast conserving surgery that is tailored to include the associated ductal tissue, in a segmental fashioned excision. Copyright Harcourt Publishers Limited.     

Conservation of breast cancer molecular subtypes and transcriptional patterns of tumor progression across distinct ethnic populations.

PURPOSE: Breast cancers can display distinct clinical characteristics in different ethnic populations. Previous studies involving European and United States patients have shown that breast tumors can be divided by their gene expression profiles into distinct "molecular subtypes." In this report, we surveyed a series of invasive and preinvasive breast tumors from Asian-Chinese patients to investigate whether similar subtypes could also be observed in this ethnic group. Experimental Design and RESULTS: An analysis of expression profiles generated from 11 nonmalignant breast tissues, 17 ductal carcinomas in situ (DCIS) and 98 invasive carcinomas identified three broad molecular subtypes of breast [estrogen receptor (ER)+, ERBB2+ and ER-] in the Asian-Chinese population. These subtypes were highly similar to the "Luminal," "ERBB2+," and "Basal" molecular subtypes defined in previous studies, and the subtype-specific expression signatures were also observed in preinvasive DCIS tumors. By comparing the expression profiles of nonmalignant DCIS and invasive breast cancers for two subtypes (ER+ and ERBB2+), we identified several genes that were regulated in both a common and subtype-specific manner during the normal/DCIS and DCIS/invasive carcinoma transitions. Several of these genes were validated by comparison with another recently published similar, but not identical, study. CONCLUSIONS: Our results suggest that molecularly similar subtypes of breast cancer are indeed broadly conserved between Asian and Caucasian patients, and that these subtypes are already present at the preinvasive stage of carcinogenesis. To our knowledge, this study is among the first to directly compare the expression profiles of breast tumors across two different ethnic populations.     

Nuclear morphometry of benign and malignant breast lesions

The mean nuclear area (MNA) of mammary gland epithelium was measured in 403 breast specimens, comprising 239 invasive carcinomas, 49 carcinomas in situ, 45 cases of fibrocystic disease (f.c.d.) with intraductal epithelial hyperplasia, and 60 cases of f.c.d. without intraductal hyperplasia. Normal breast tissue adjacent to other benign or malignant lesions was measured in 170 specimens. Statistical analysis revealed no difference between the MNA of invasive ductal carcinoma and ductal carcinoma in situ. The MNA of lobular and ductal carcinomas were significantly different. Significant differences were also found between ductal carcinoma and the two classes of f.c.d. The MNA of f.c.d. with and without intraductal hyperplasia were also significantly different, the former having the highest MNA. All breast lesions showed MNA significantly higher than that of normal breast epithelium. These findings show that there is a gradual increase in MNA from the baseline value of normal breast epithelium, via fibrocystic disease without and with intraductal proliferation to invasive carcinomas. Measurement of MNA may aid in pinpointing cases of intraductal epithelial hyperplasia with malignant potential.     

Relationship between menopausal hormone therapy and risk of ductal, lobular, and ductal-lobular breast carcinomas.

Combined estrogen and progestin hormone therapy (CHT) increases breast cancer risk, but this risk varies by breast cancer type. Several studies indicate that CHT is more strongly related to lobular carcinoma risk than to ductal carcinoma risk, but these studies have been limited in their assessments of recency and duration of use, and none included a centralized pathology review. We conducted a population-based case-control study consisting of 324 lobular, 196 ductal-lobular, and 524 ductal cases diagnosed from 2000 to 2004 and 469 controls ages 55 to 74 years old. Tissue specimens were centrally reviewed for 83% of cases. Associations between hormone use and breast cancer risk were evaluated using polytomous logistic regression. Current CHT users had 2.7-fold [95% confidence interval (95% CI), 1.7-4.2] and 3.3-fold (95% CI, 2.0-5.7) elevated risks of lobular and ductal-lobular carcinomas, respectively, regardless of tumor stage, size, or nodal status. Elevations in risk were observed only among users of CHT for > or =3 years. Among ductal-lobular cases, CHT increased risk of tumors that were > or =50% lobular (odds ratio, 4.8; 95% CI, 2.1-11.1) but not tumors that were <50% lobular (odds ratio, 1.9; 95% CI, 0.9-4.1). Current CHT users for > or =3 years have a substantially increased risk of lobular carcinomas. Although lobular carcinomas are less common than ductal carcinomas ( approximately 16% versus 70% of all invasive breast cancers in the United States), this duration is shorter than the 5 years of use widely cited to be needed to confer an increased risk of breast cancer overall. Further studies focusing on the etiology of lobular carcinomas are needed.