Background

Breast cancer causes 20% of cancer deaths in women and is increasing in incidence. There appears to be a leveling off in the incidence of breast cancer but up to 1988, the incidence had been increasing. A typical pathology report should indicate the type of breast cancer, the histologic grade, the size, and a comment on the surgical margins. In addition, depending upon the case, ancillary studies examining for estrogen and progesterone receptors and Her2-neu may be ordered. The pathologist should also strive to correlate the histologic findings to the clinical and radiologic findings. For example, if the biopsy was originally performed for suspicious calcifications, the surgical pathology report should indicate whether microcalcifications were present and the location of these changes, that is, within benign breast tissue or tumor. Prognosis for breast cancer and treatment for breast cancer are discussed in other sections.

Breast cancer genes (BRCA1 and BRCA2)
CA15-3
Colloid Carcinoma (Mucinous Carcinoma)
Ductal carcinoma in situ (DCIS)
Herceptin
Lobular carcinoma in situ (LCIS)
Invasive ductal carcinoma with Paget's disease
Invasive lobular carcinoma
Medullary carcinoma
Paget's disease
Tubular carcinoma

Outline

Epidemiology	Synonyms Incidence Age Antibiotics Diet Estrogen Geography Genetics Lactation Reproductive Life Obesity Parity Race Radiation Sex
Disease Associations	Cowden's syndrome Endometrial carcinoma Granular cell tumor Hodgkin Disease Ovarian adenofibromas Prolactinoma Thyroid cancer
Pathogenesis	Animal Model Apoptosis Estrogen Receptor Loss of Heterozygosity Progression Oncogenes
Laboratory/ Radiologic/ Other Diagnostic Testing	Screening mammography Breast Ductal Lavage Imaged guided biopsies MRI CA15-3 Her2-neu
Gross Appearance and Clinical Variants	Bilateral Inflammatory breast cancer Non-palpable breast cancer
Histopathological Features and Variants	Adequacy of biopsy Adenoid cystic carcinoma Adenosquamous cell carcinoma Apocrine carcinoma Centrally necrotizing carcinoma Choriocarcinomatous Clear cell carcinoma Colloid carcinoma Estrogen receptor negative carcinoma Histiocytoid carcinoma Invasive micropapillary carcinoma Metaplastic carcinoma Myoepithelial tumors Papillary carcinoma Pigmented (melanin) Pleomorphic carcinoma Sarcomatoid carcinoma Secretory carcinoma Small cell carcinoma
Special Stains/ Immunohistochemistry/ Electron Microscopy	Tissue Microarrays Her2-neu Cadherins CD10 Epidermal growth factor receptor Estrogen Receptor GCDFP-15 GLUT-1 Melatonin receptors p63
Differential Diagnosis	Benign Mechanical Transport Carcinoid tumor, metastatic Cylindromas Ectopic breast tissue Homologous carcinomas Intramammary lymph nodes Lymphoma, anaplastic Megakaryocytes Ovarian Carcinoma, Metastatic Xanthomatous Pseudotumor
Prognosis
Treatment
Commonly Used Terms	Estrogen and progesterone receptors Pagetoid Scarff-Bloom-Richardson Grading
Internet Links	Gross and Microscopic pictures

EPIDEMIOLOGIC ASSOCIATIONS
SYNONYMS	Duct carcinoma with productive fibrosis Scirrhous carcinoma Carcinoma simplex Invasive duct carcinoma, not otherwise specified (NOS)
INCIDENCE/ PREVALENCE	One in nine women will develop breast cancer within her lifetime 27 per 100,000 in USA 44,000 women dying yearly 60-80% of all malignant breast tumors
Trends in incidence rates of invasive lobular and ductal breast carcinoma. Li CI, Anderson BO, Daling JR, Moe RE. Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, 1100 Fairview Ave N, MP 381, PO Box 19024, Seattle, WA 98109-1024.	JAMA 2003 Mar 19;289(11):1421-4 Abstract quote CONTEXT: Research has suggested that use of combined estrogen and progestin hormone replacement therapy (CHRT) increases breast cancer risk and that CHRT use is more strongly associated with the risk of invasive lobular breast carcinoma than that of invasive ductal carcinoma. Lobular carcinoma is less common than ductal carcinoma but can be more difficult to diagnose because of its subtle elusive infiltrative pattern. OBJECTIVE: To evaluate trends in invasive lobular and ductal carcinoma incidence rates from 1987 through 1999, during which time use of CHRT increased in the United States. DESIGN: Descriptive epidemiologic study. SETTING: Nine cancer registries that participate in the Surveillance, Epidemiology, and End Results (SEER) program of the National Cancer Institute and that cover Atlanta, Ga; Detroit, Mich; San Francisco-Oakland, Calif; Seattle, Wash; and Connecticut, Hawaii, Iowa, New Mexico, and Utah. POPULATION: Women 30 years of age and older residing in the areas covered by the 9 SEER registries. MAIN OUTCOME MEASURES: Proportional changes in incidence rates of invasive lobular and ductal carcinoma among women with no prior history of breast cancer. RESULTS: A total of 190 458 women were included in this analysis who were identified through the registries as having invasive breast cancer; 7682 of the 198 140 potentially eligible women (ie, those identified as not having in situ breast cancer) were excluded from this analysis because stage of cancer was unknown. Invasive breast cancer incidence rates adjusted for age and for SEER historic stage increased 1.04-fold (95% confidence interval [CI], 1.004-1.07) from 1987-1999 (206.7/100 000 to 214.1/100 000, age-adjusted). However, incidence rates of tumors classified as lobular increased 1.52-fold (95% CI, 1.42-1.63), and those classified as mixed ductal-lobular increased 1.96-fold (95% CI, 1.80-2.14); rates of these types combined increased 1.65-fold (95% CI, 1.55-1.78) (19.8/100 000 to 33.4/100 000, age-adjusted). In contrast, ductal carcinoma rates remained largely constant (153.8/100 000 to 155.3/100 000, age-adjusted; proportional change, 1.03 [95% CI, 0.99-1.06]). The proportion of breast cancers with a lobular component increased from 9.5% in 1987 to 15.6% in 1999. CONCLUSIONS: Ductal carcinoma incidence rates remained essentially constant from 1987-1999 while lobular carcinoma rates increased steadily. This increase presents a clinical challenge given that lobular carcinoma is more difficult to detect than ductal carcinoma by both physical examination and mammography.
AGE	Steady rise to menopause Average age of diagnosis is 64 yrs
ANTIBIOTICS
Antibiotic use in relation to the risk of breast cancer. Velicer CM, Heckbert SR, Lampe JW, Potter JD, Robertson CA, Taplin SH. Department of Epidemiology, University of Washington, Seattle, USA.	JAMA. 2004 Feb 18;291(7):827-35 Abstract quote.   CONTEXT: Use of antibiotics may be associated with risk of breast cancer through effects on immune function, inflammation, and metabolism of estrogen and phytochemicals; however, clinical data on the association between antibiotic use and risk of breast cancer are sparse. OBJECTIVE: To examine the association between use of antibiotics and risk of breast cancer. DESIGN, SETTING, AND PARTICIPANTS: Case-control study among 2266 women older than 19 years with primary, invasive breast cancer (cases) enrolled in a large, nonprofit health plan for at least 1 year between January 1, 1993, and June 30, 2001, and 7953 randomly selected female health plan members (controls), frequency-matched to cases on age and length of enrollment. Cases were ascertained from the Surveillance, Epidemiology, and End Results cancer registry. Antibiotic use was ascertained from computerized pharmacy records. MAIN OUTCOME MEASURE: Association between extent of antibiotic use and risk of breast cancer. RESULTS: Increasing cumulative days of antibiotic use were associated with increased risk of incident breast cancer, adjusted for age and length of enrollment. For categories of increasing use (0, 1-50, 51-100, 101-500, 501-1000, and > or =1001 days), odds ratios (95% confidence intervals) for breast cancer were 1.00 (reference), 1.45 (1.24-1.69), 1.53 (1.28-1.83), 1.68 (1.42-2.00), 2.14 (1.60-2.88), and 2.07 (1.48-2.89) (P<.001 for trend). Increased risk was observed in all antibiotic classes studied and in a subanalysis having breast cancer fatality as the outcome. Among women with the highest levels of tetracycline or macrolide use, risk of breast cancer was not elevated in those using these antibiotics exclusively for acne or rosacea (indications that could be risk factors for breast cancer due to altered hormone levels), compared with those using them exclusively for respiratory tract infections, adjusted for age and length of enrollment (odds ratio, 0.91; 95% confidence interval, 0.44-1.87). CONCLUSIONS: Use of antibiotics is associated with increased risk of incident and fatal breast cancer. It cannot be determined from this study whether antibiotic use is causally related to breast cancer, or whether indication for use, overall weakened immune function, or other factors are pertinent underlying exposures. Although further studies are needed, these findings reinforce the need for prudent long-term use of antibiotics.
DIET	Moderate or heavy alcohol consumption No association with coffee or cigarette smoking
EXOGENOUS ESTROGEN	Controversial but may have a slightly increased risk
ENDOGENOUS ESTROGEN EXCESS	Functioning ovarian tumors producing estrogen and postmenopausal women with high circulating levels of estrogen
GEOGRAPHY	4-7x more common in US than Asia
Predominance of high-grade pathway in breast cancer development of Middle East women. Al-Kuraya K, Schraml P, Sheikh S, Amr S, Torhorst J, Tapia C, Novotny H, Spichtin H, Maurer R, Mirlacher M, Simon R, Sauter G. [1] 1King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia [2] 2Institute of Pathology, University Hospital Eppendorf, Hamburg, Germany.	Mod Pathol. 2005 Jul;18(7):891-7 Abstract quote.   Recent data have suggested considerable molecular differences in cancers from various ethnical groups. As molecular features are increasingly used for predicting cancer prognosis and response to therapy, better knowledge of ethnic molecular features is important. To identify potential molecular differences between breast cancers in Europe and the Middle East, we analyzed consecutive breast cancer series from Switzerland (n=2197) and Saudi Arabia (n=204). Tissue microarrays were analyzed by fluorescence in situ hybridization for HER2, CCND1, MYC, and EGFR amplification. The data revealed marked differences between Saudi and Swiss patients. Saudi breast cancers had a markedly higher frequency of HER2 (31 vs 17%; P<0.0001) and MYC (16 vs 5%; P<0.0001) amplifications than Swiss breast cancers. Remarkably, this was partly due to a much higher incidence of grade 3 cancers in the Saudi than in the Swiss population (65 vs 32%; P<0.0001). However, differences in amplification frequency hold also true within grade 3 cancers (HER2: 40 vs 30%, P<0.05; MYC: 22 vs 11%, P=0.002). Interestingly, in combination with known age standardized incidence rates of breast cancer in Saudi Arabia (21.6/100 000) and Switzerland (70.1/100 000), these data suggest that the incidence of high-grade breast cancer is comparable for Saudi and Swiss women, while the incidence of low-grade breast cancers is about 14 times lower in Saudi than for Swiss women. These observations suggest that a difference in genetic susceptibility and/or lifestyle between Saudi and Swiss women has a substantial and much higher than expected impact on the risk of low-grade breast cancer.
Proliferation in african breast cancer: biology and prognostication in nigerian breast cancer material. Ikpatt OF, Kuopio T, Collan Y. Department of Pathology (OFI, University of Calabar Teaching Hospital, Nigeria.	Mod Pathol 2002 Aug;15(8):783-9 Abstract quote Three hundred cases of invasive breast carcinoma from the University of Calabar Teaching Hospital, Nigeria were subjected to evaluation of proliferative activity by mitotic counts. The prognostic significance and association with other prognostic factors were evaluated. The mitotic activity was expressed as mitotic activity index (MAI), and standardized mitotic index (SMI). Pearson's correlation and univariate and multivariate Cox's regression were used. The mean follow-up time was 25.9 months. The mean values of SMI and MAI were 42.6 mitotic figures per square millimeter and 30.5 mitotic figures per 10 high-power fields, respectively, and these were much higher than values reported for Europe or other Western countries. The SMI had a positive correlation with tumor size (r = 0.31, P <.0001), histologic grade (r = 0.68, P <.0001), nuclear area (r = 0.45, P <.0001), and negative correlation with fraction of fields with tubular differentiation (FTD; r = -0.56, P = <0.0001). There was no statistically significant difference in the mitotic activity between the postmenopausal and the premenopausal patients. Also, lymph node-positive patients had higher counts than did lymph node-negative patients. Earlier determined grading associated decision thresholds divided the patients into groups of favorable and unfavorable prognosis. However, the statistically optimal thresholds for Nigerian material were different (32 and 92 mitotic figures per square millimeter for SMI). Tumor size of 5 cm, SMI, and MAI were independent prognostic factors. Nigerian breast cancers are high-grade, high-stage, and high-proliferating cancers occurring in a younger population than those of the Western countries. Proliferation is also more active. Evaluation of SMI or MAI can improve the distinction between aggressive and less aggressive variants of breast cancer.
GENETICS	5-10% of women have inheritance of a mutation in the breast cancer gene (BRCA1 and BRCA2) 1.5-2x risk for women with first degree relatives with breast CA 4-6x risk with two affected relatives Familial syndromes (Li-Fraumeni syndrome, Cowden's syndrome, Ataxia-Telangiectasia)
HORMONE REPLACEMENT THERAPY
LACTATION
Lactation and breast carcinoma risk in a South African population. Coogan PF, Rosenberg L, Shapiro S, Hoffman M. Slone Epidemiology Unit, Boston University School of Medicine, Brookline, Massachusetts 02446, USA.	Cancer 1999 Sep 15;86(6):982-9 Abstract quote BACKGROUND: A number of epidemiologic studies have reported a reduced risk of breast carcinoma among women who have lactated but others have not. The current study presents data regarding lactation and breast carcinoma risk from a hospital-based case-control study of black and colored South African women. METHODS: Incident breast carcinoma cases treated between January 1994 and October 1997 (n = 446) at 2 major hospitals in Cape Town and hospital patients admitted for conditions unrelated to breast carcinoma (controls, n = 1471) were queried regarding the duration of breast-feeding each liveborn child and breast carcinoma risk factors. Multivariate logistic regression models were used to calculate odds ratios (ORs) for various categories of lactation compared with a reference category of never having breast-fed among women who had had at least one full term live birth. RESULTS: Approximately 83% of cases and 85% of controls had ever breast-fed (OR = 0.9; 95% confidence interval [95% CI], 0.7-1.3). Among all subjects, the ORs for those who lactated for <3 years were near or at unity. Beyond 3 years, ORs extending up to >/=7 years were less than unity, but the 95% CIs included 1.0 (OR for duration of >/=7 years = 0.7; 95% CI, 0.4-1.3). ORs did not vary by menopausal status. Breast carcinoma risk was not found to be related to the duration of breast-feeding the first child, the number of children breast-fed, or the patient's age at first lactation. CONCLUSIONS: The results of the current study suggest lactation has little or no protective effect on breast carcinoma risk.
LENGTH OF REPRODUCTIVE LIFE	Early menarche (start of menstruation) and late menopause increases risk
OBESITY	Increased risk due to excess estrogen synthesis from peripheral fat in postmenopausal women Decreased risk in obese women <40 yrs
ORAL CONTRACEPTIVES
Oral contraceptives and the risk of breast cancer. Marchbanks PA, McDonald JA, Wilson HG, Folger SG, Mandel MG, Daling JR, Bernstein L, Malone KE, Ursin G, Strom BL, Norman SA, Wingo PA, Burkman RT, Berlin JA, Simon MS, Spirtas R, Weiss LK. Division of Reproductive Health, Centers for Disease Control and Prevention, Atlanta, USA.	N Engl J Med 2002 Jun 27;346(26):2025-32 Abstract quote BACKGROUND: It is uncertain whether the use of an oral contraceptive increases the risk of breast cancer later in life, when the incidence of breast cancer is increased. We conducted a population-based, case-control study to determine the risk of breast cancer among former and current users of oral contraceptives. METHODS: We interviewed women who were 35 to 64 years old. A total of 4575 women with breast cancer and 4682 controls were interviewed. Conditional logistic regression was used to calculate odds ratios as estimates of the relative risk (incidence-density ratios) of breast cancer. RESULTS: The relative risk was 1.0 (95 percent confidence interval, 0.8 to 1.3) for women who were currently using oral contraceptives and 0.9 (95 percent confidence interval, 0.8 to 1.0) for those who had previously used them. The relative risk did not increase consistently with longer periods of use or with higher doses of estrogen. The results were similar among white and black women. Use of oral contraceptives by women with a family history of breast cancer was not associated with an increased risk of breast cancer, nor was the initiation of oral-contraceptive use at a young age. CONCLUSIONS: Among women from 35 to 64 years of age, current or former oral-contraceptive use was not associated with a significantly increased risk of breast cancer.
PARITY	Increased risk if first child born after 30 yrs of age Increased risk in nulliparous than multiparous women
RACE	Overall incidence is lower in black women but do present with more advanced stage with increased mortality as compared to white women
AFRICAN-AMERICAN
Impact of breast carcinoma on African-American women: the Detroit experience. Newman LA, Carolin K, Simon M, Kosir M, Hyrniuk W, Demers R, Grossbart Schwartz A, Visscher D, Peters W, Bouwman D. Department of Surgery, Barbara Ann Karmanos Cancer Institute and Wayne State University, Detroit, Michigan 48230, USA.	Cancer 2001 May 1;91(9):1834-43 Abstract quote BACKGROUND: National and regional population-based data have demonstrated substantially worse outcome in African-American patients with breast carcinoma when compared with white patients, as well as a younger age distribution among African-American patients with breast carcinoma. The extent to which various socioeconomic, environmental, lifestyle, and genetic factors interact to account for this ethnicity-related disparity in survival is poorly understood. Greater than one-half of the inner-city population of Detroit, Michigan is African American, and greater metropolitan Detroit has been one of the contributing registries for the Surveillance, Epidemiology, and End Results (SEER) program since its inception in 1973. The impact of breast carcinoma on African Americans in the Detroit area is therefore well documented and provides significant insight into the history, epidemiology, and biology of this major public health care problem. METHODS: A review of the medical literature published over the past 20 years regarding African-American patients with breast carcinoma was performed. The pertinent findings were summarized in the context of advances made in breast carcinoma screening, treatment, and risk reduction during that period. RESULTS: The large African-American population of Detroit is a major factor contributing to the excessive breast carcinoma mortality rate reported for this city, which is one of the highest in the United States. Improvements in early detection of breast carcinoma by using screening mammography have been apparent in the earlier stage distributions of breast carcinoma observed in both white and African-American patients; however, progress has lagged substantially for the latter group. Detroit SEER registry data also have shown a younger age distribution of African-American patients with breast carcinoma and higher rates of estrogen receptor negative tumors. Finally, preliminary data from health maintenance organizations have suggested improved breast carcinoma outcome for African Americans who possess greater socioeconomic benefits, but disparities in disease stage at presentation persist. CONCLUSIONS: The diverse Detroit community is ideally suited for breast carcinoma screening programs and clinical investigations that seek to address and overcome ethnicity-related survival disparities and barriers to health care. Findings from these studies can be correlated with results from similar projects in other geographic areas.
MEXICAN
Breast carcinoma presents a decade earlier in Mexican women than in women in the United States or European countries. Rodriguez-Cuevas S, Macias CG, Franceschi D, Labastida S. Department of Surgery, Hospital de Oncologia, CMN, IMSS, Mexico City, Rebsamen 1142, col. del Valle, Mexico D.F. 03100.	Cancer 2001 Feb 15;91(4):863-8 Abstract quote BACKGROUND: In Mexico, breast carcinoma is the second most frequent malignancy, representing 10.6% of all cases and 16.4% of all cancers in women, with an increase in breast carcinoma mortality rates from 3.6 per 100,000 women in 1985 to 6 per 100,000 women in 1994. Most of the tumors are diagnosed in advanced stages with little chance of cure. METHODS: To determine the age of patients in Mexico at presentation of breast carcinoma, the authors analyzed the cases registered from 1993 to 1996 from the database of the Histopathological Registry of Malignant Neoplasms in Mexico. RESULTS: There were 29,075 cases of breast carcinoma. The median age of Mexican women with breast carcinoma is 51 years, and 45.5% of all breast carcinomas develop before patients reach age 50 years. The most frequently affected age group is that of 40-49 years (29.5%), whereas the groups from 30 to 39 and from 60 to 69 years of age have a similar percentage (14%) of frequency. This contrasts with women from the United States, as well as with women from European countries, where the median age at presentation is 63 years, and only one-fourth of the patients are younger than 50 years of age, and three-fourths are postmenopausal. Similar to Mexico, in Venezuela and in Japan nearly one-half of women with breast carcinoma are younger than 50 years of age, and this resembles rates in many Latin American countries. CONCLUSIONS: It is necessary to change the guidelines of breast carcinoma screening in Mexican women, to increase the possibility of early diagnosis and better survival.
RADIATION EXPOSURE	Risk increases with younger age of exposure and higher radiation doses Mantle radiation for Hodgkin's disease have 20-30% increased risk 10-20 yrs following radiation
SEX
Male Versus Female Breast Cancers. Muir D, Kanthan R, Kanthan SC. Departments of Pathology (Drs Muir and R. Kanthan) and Surgery (Dr S. C. Kanthan), College of Medicine, University of Saskatchewan, Saskatoon.	Arch Pathol Lab Med 2003 Jan;127(1):36-41 Abstract quote Context.-The rate of male breast cancer is a small fraction of that observed in females, thus severely limiting our understanding of the pathogenesis of this condition. It remains unclear whether the biological behavior and tumor progression associated with male breast cancer parallel that of the female form. Objectives.-To evaluate the immunohistochemical profile of male breast carcinomas and to compare this profile with that of stage-matched female breast cancers. Design.-Seventy-five cases of primary male breast cancer were identified using the records of the Saskatchewan Cancer Foundation over a period of 26 years (1970-1996). Fifty-nine of these cases had formalin-fixed, paraffin-embedded tissue blocks available for the purposes of this study. All cases were reviewed and a standardized modified Bloom-Richardson grading criterion was applied. Estrogen receptor status, progesterone receptor status, c-Erb-B2 expression, p53 expression, and Bcl-2 expression were evaluated by immunohistochemistry. Results from 240 consecutive cases of stage-matched female breast cancers analyzed in the same laboratory were used as a standard set for comparison. Results.-Male breast cancers tended to be high grade (85% grade 3) in comparison with the female breast cancers (50% grade 3). In descriptive analysis across all stages of disease, male carcinomas were more frequently estrogen receptor positive (81% vs 69%) than their female counterparts. Despite their high grade, they were less likely to overexpress p53 (9% vs 28%) and Erb-B2 (5% vs 17%) than the female counterparts. There was no significant difference in either progesterone receptor (63% vs 56%) or Bcl-2 (79% vs 76%) overexpression. Stratified analysis by stage-matched controls showed no statistically significant differences among the men and women with stage I disease. However, in stage II-matched samples, statistically significant differences were observed between the 2 groups. The male cancers were more likely to overexpress estrogen receptor (81.6% vs 64.4%, P =.04), progesterone receptor (71.1% vs 47.5%, P =.01), and Bcl-2 (78.9% vs 69.4%, P =.20). They also showed statistically significant lower expression of p53 (7.9% vs 36.3%, P =.001) and Erb-B2 (5.3% vs 23.8% P =.01). Conclusion.-Male breast cancers display distinct immunophenotypic differences from those occurring in women, implying a different pathogenesis in the evolution and progression of this disease. Such differences may play key roles in therapeutic management, warranting different treatment strategies in comparison to female breast cancers.

 

DISEASE ASSOCIATIONS	CHARACTERIZATION
ANGIOSARCOMA
Cutaneous angiosarcoma following breast-conserving surgery and radiation: an analysis of 27 cases. Billings SD, McKenney JK, Folpe AL, Hardacre MC, Weiss SW. Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA	Am J Surg Pathol. 2004 Jun;28(6):781-8. Abstract quote   Iatrogenic angiosarcomas (AS), following treatment of breast carcinomas and attributed to chronic lymphedema, were first described by Stewart and Treves. With emphasis on breast-conserving therapy combined with adjuvant radiation, a recently recognized form of cutaneous postradiation angiosarcoma of the breast (CPRASB) has emerged. To more completely characterize CPRASB, 27 cases were analyzed. Histologic features studied included pattern of growth (vasoformative, sieve-like, or solid), nuclear grade, necrosis, and mitotic rate. Clinical and follow-up information was obtained. The patients received relatively standard radiation treatment. The median interval to diagnosis of CPRASB was 59 months; 5 occurred in less than 3 years. Lymphedema was largely absent, and when present was only mild in nature. CPRASB was frequently multifocal at presentation (13 of 27). All tumors had a vasoformative pattern of growth; the majority (16 of 27) had areas with a sieve-like pattern. The solid pattern was less frequent (7 of 27). The majority had high-grade nuclear features (16 grade 3, 8 grade 2, 3 grade1). The mean mitotic rate was 9/10 HPF. Necrosis was rare (2 of 27). All were treated with wide excision or mastectomy. Follow-up was available on 22 of 27 cases (median 44 months). Fourteen experienced local recurrence and 6 had multiple recurrences. Metastasis was documented in 9 of 22 patients and involved lungs (6), contralateral breast (3), skeleton (2), lymph nodes (1), and soft tissue (1). Eight patients died of disease, 2 died with disease, 4 were alive with disease, and 8 are alive without disease. The median interval to death was 33.5 months. All 4 patients with disease have documented metastasis. CPRASB differs from Stewart-Treves AS by its shorter latency period and lack of association with lymphedema.
COWDEN'S SYNDROME
Clinical and pathological features of breast disease in Cowden's syndrome: an underrecognized syndrome with an increased risk of breast cancer. Schrager CA, Schneider D, Gruener AC, Tsou HC, Peacocke M. Department of Pathology, Tufts University School of Medicine, Boston, MA, USA.	Hum Pathol 1998 Jan;29(1):47-53 Abstract quote Cowden's syndrome (CS), or multiple hamartoma syndrome, is an autosomal dominant disorder associated with benign skin tumors and an increased risk of breast cancer. In an effort to understand the basic mechanisms regulating the development of breast cancer in this patient population, as well as to define diagnostic aspects of the disorder, we describe for the first time the clinical and pathological spectrum of breast disease in CS. We obtained the clinical histories and examined the histopathology of 59 cases from 19 women with CS sent to us from a variety of institutions. The 19 women showed a spectrum of benign histopathological findings, including ductal hyperplasia, intraductal papillomatosis, adenosis, lobular atrophy, fibroadenomas, and fibrocystic change. Seventeen (89%) showed features suggestive of a breast hamartoma. Fourteen women (74%) showed malignant disease, most of which was ductal carcinoma. Twelve patients (86%) showed ductal carcinoma in situ (DCIS), and 12 (86%) showed infiltrating ductal carcinoma. One patient had only DCIS and another patient showed both infiltrating tubular carcinoma and lobular carcinoma in situ. Ten patients (71%) actually showed foci of tumor involving densely fibrotic, hamartomatous areas. In summary, we show that women with CS have a spectrum of exuberant benign and malignant breast pathology. A common benign breast lesion in CS is a densely fibrotic hyalinized nodule, whereas the most frequent breast malignancy is ductal carcinoma.
ENDOMETRIAL CARCINOMA	Increased risk of breast cancer
GRANULAR CELL TUMOR
Colocalized granular cell tumor and infiltrating ductal carcinoma of the breast. Al-Ahmadie H, Hasselgren PO, Yassin R, Mutema G. Departments of Pathology (Drs Al-Ahmadie, Yassin, and Mutema) and Surgery (Dr Hasselgren), University of Cincinnati Medical Center, Cincinnati, Ohio.	Arch Pathol Lab Med 2002 Jun;126(6):731-3 Abstract quote A 57-year-old woman presented with a 2-year history of a palpable mass in the upper inner quadrant of the right breast. A 1.1-cm, poorly circumscribed, firm tumor nodule was noted, consisting of 2 histologically distinct lesions in the same location, with some areas showing purely well-differentiated invasive ductal carcinoma and others composed of granular cell tumor. In 1 area, the 2 tumors collided and infiltrated each other. The invasive ductal carcinoma was admixed with ductal carcinoma in situ of solid and cribriform types. To our knowledge, this is the first case report demonstrating colocalization of these 2 neoplasms, which raises questions regarding causal relationship. We also review the literature on granular cell tumor of the breast.
HODGKIN DISEASE
Breast cancer following radiotherapy and chemotherapy among young women with hodgkin disease. Travis LB, Hill DA, Dores GM, Gospodarowicz M, Van Leeuwen FE, Holowaty E, Glimelius B, Andersson M, Wiklund T, Lynch CF, Van't Veer MB, Glimelius I, Storm H, Pukkala E, Stovall M, Curtis R, Boice JD Jr, Gilbert E. Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, Bethesda, Md.	JAMA. 2003 Jul 23;290(4):465-75. Abstract quote CONTEXT: Second cancer is the leading cause of death in long-term survivors of Hodgkin disease (HD), with exceptionally high risks of breast cancer among women treated at a young age. Quantitative associations between radiotherapy dose delivered to the breast and administered chemotherapy have not been reported to date in large series, nor has the influence of ovarian exposures on subsequent risk. OBJECTIVE: To quantify the long-term risk of breast cancer associated with use of radiotherapy and chemotherapy to treat young women with HD. DESIGN, SETTING, AND SUBJECTS: Matched case-control study of breast cancer within a cohort of 3817 female 1-year survivors of HD diagnosed at age 30 years or younger, between January 1, 1965, and December 31, 1994, and within 6 population-based cancer registries. The study was conducted March 1, 1996, through September 30, 1998. MAIN OUTCOME MEASURES: Relative risk (RR) of breast cancer associated with radiation dose delivered to site of breast cancer or to ovaries and with cumulative dose of alkylating agents. RESULTS: Breast cancer occurred in 105 patients with HD who were matched to 266 patients with HD but without breast cancer. A radiation dose of 4 Gy or more delivered to the breast was associated with a 3.2-fold (95% confidence interval [CI], 1.4-8.2) increased risk, compared with the risk in patients who received lower doses and no alkylating agents. Risk increased to 8-fold (95% CI, 2.6-26.4) with a dose of more than 40 Gy (P<.001 for trend). Radiation risk did not vary appreciably by age at exposure or reproductive history. Increased risks persisted for 25 or more years following radiotherapy (RR, 2.3; 95% CI, 0.5-16.5; P =.03 for trend with dose). Treatment with alkylating agents alone resulted in a reduced risk (RR, 0.6; 95% CI, 0.2-2.0) of breast cancer, and combined alkylating agents and radiotherapy in a 1.4-fold (95% CI, 0.6-3.5) increased risk. Risk of breast cancer decreased with increasing number of alkylating agent cycles (P =.003 for trend). Risk also was low (RR, 0.4; 95% CI, 0.1-1.1) among women who received 5 Gy or more delivered to ovaries compared with those who received lower doses. CONCLUSIONS: Hormonal stimulation appears important for the development of radiation-induced breast cancer, as evidenced by the reduced risk associated with ovarian damage from alkylating agents or radiation. The high radiation-related risk, which did not diminish at the highest doses or the longest follow-up, however, suggests the need for lifetime surveillance and programs of patient and public awareness.
OVARIAN ADENOFIBROMAS
The association of benign and malignant ovarian adenofibromas with breast cancer and thyroid disorders. Silva EG, Tornos C, Malpica A, Deavers MT, Tortolero-Luna G, Gershenson DM. Department of Pathology, The University of Texas M. D. Anderson Cancer Center, Houston, TX.	Int J Surg Pathol 2002 Jan;10(1):33-9 Abstract quote An unexpected association with breast cancer and thyroid disorders was found during a review of 91 cases of benign and malignant ovarian adenofibromas. Sixty-three tumors were benign, 11 had areas of borderline neoplasms, and 17 had a component of carcinoma. Such tumors were divided into glandular/cystic (61 cases) and papillary (30 cases) according to their gross and microscopic appearance. Among the 61 patients with glandular/cystic adenofibromas, 13 (21%) had breast cancer and 19 (31%) also had thyroid disorders. Among the 30 patients with papillary adenofibromas there were no cases of breast cancer and only 2 patients had thyroid disorders. The average age of the patients with ovarian adenofibroma and breast cancer or thyroid disorders was higher (66 years) than that of patients without breast cancer or thyroid disorders (55 years). More patients with breast cancer and thyroid disorders had bilateral adenofibromas than patients without breast cancer or thyroid disorders. We also reviewed the medical records of 100 patients with ovarian cancer without adenofibroma component, 100 patients with breast cancer, and 100 patients with ovarian and breast cancer. Six percent of patients with ovarian cancer had breast cancer and 16% of each one of these groups had thyroid disorders. This unexpected association found between glandular/cystic adenofibromas, breast cancer, and thyroid disorders might be explained by defects common to these organs. Disorders of some of these organs have been linked by common genetic changes and it is known that these organs are under the influence of similar hormones. Mutations of PTEN have been found in breast and thyroid cancer. The thyroid and ovaries are controlled by glycoprotein hormones of the pituitary gland, which have common alpha subunits.
PROLACTINOMA
Two case reports of breast carcinoma associated with prolactinoma. Strungs I, Gray RA, Rigby HB, Strutton G. Department of Pathology, Toowoomba Base Hospital, Qld, Australia.	Pathology 1997 Aug;29(3):320-3 Abstract quote Two cases of breast carcinoma associated with prolactinoma are presented. Literature review reveals only five previous case reports of this association. Both of our cases occurred in women, aged 55 and 34. Both were typical of the reported cases in that they had long histories of amenorrhea before diagnosis of prolactinomas and breast carcinomas. One patient had a three and a half year history of atypical ductal hyperplasia and a prominent intraduct component in the invasive tumor. Both had axillary lymph node metastases. The significance of the association of breast carcinoma with prolactinoma is discussed. Whereas studies in animals have shown prolactin to be an initiator and promoter of breast carcinoma, studies in humans have been inconclusive. Some studies have shown raised levels of prolactin in patients with breast carcinoma and their daughters, while others have not. The paucity of case reports linking breast carcinoma and prolactinoma may indicate that the association is mere coincidence, but studies evaluating the relationship between breast carcinoma and all forms of hyperprolactinemia need to be conducted before a causal link is dismissed. Prolactin may act as a cofactor with, for example, estrogen or stress, to induce breast carcinoma.
THYROID CANCER
The development of breast carcinoma in women with thyroid carcinoma. Chen AY, Levy L, Goepfert H, Brown BW, Spitz MR, Vassilopoulou-Sellin R. Department of Head and Neck Surgery, University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA.	Cancer 2001 Jul 15;92(2):225-31 Abstract quote BACKGROUND: Breast carcinoma and thyroid carcinoma are two malignancies that occur most commonly in women. An association between the incidence rates of thyroid and breast carcinoma in women after a diagnosis of the other malignancy has been suggested in a retrospective analysis of a single institution's tumor registry. In that study, an increased incidence of breast carcinoma in premenopausal women previously treated for thyroid carcinoma was observed. METHODS: The purpose of this study was to investigate further this relation utilizing a large database, the National Cancer Institute's Surveillance, Epidemiology and End Results (SEER) database. The SEER database is maintained by the National Cancer Institute, and it represents 11 population-based cancer registries covering approximately 14% of the United States population. The study was a population-based retrospective cohort analysis using external comparisons. From 1973 to 1994, 365 women in the SEER database were identified as having both thyroid and breast carcinomas. The SEER database from 1973 to 1994 was utilized to calculate age specific and calendar year specific incidence rates for each year for thyroid and breast carcinomas. The expected number of second cancers for each age group, calendar year, and follow-up period were determined by multiplying these incidence rates by the age specific and calendar year specific number of person-years at risk. The risk ratio (RR) was calculated by dividing the observed by the expected number of second cancers. Statistical significance was determined by the Poisson test. RESULTS: A total of 1,333,115 person-years were available for analysis. One hundred thirteen thyroid carcinoma cases were diagnosed after breast carcinoma cases (RR, 0.99; P = 0.576). Two hundred fifty-two breast carcinoma cases were diagnosed after thyroid carcinoma cases (RR, 1.18; P = 0.007). Premenopausal women (age 20-49 years) with an index thyroid carcinoma have a significantly increased risk of developing subsequent breast carcinoma (RR, 1.42; P = 0.001). Black premenopausal women with an index thyroid carcinoma do not have an increased risk of developing breast carcinoma, but the statistical power is lower due to low numbers. No women with index breast carcinoma have an increased risk of developing thyroid carcinoma. CONCLUSIONS: Women with a history of thyroid carcinoma have a greater than expected risk of developing breast carcinoma. This risk is most pronounced in premenopausal white women. The implications of this observation with respect to breast carcinoma screening guidelines and thyroid carcinoma treatment guidelines deserve further investigation.

 

PATHOGENESIS	CHARACTERIZATION
ANIMAL MODEL
Histopathologic Characterization of Mammary Neoplastic Lesions Induced With 7,12 Dimethylbenz(alpha)anthracene in the Rat. Costa I, Solanas M, Escrich E. Department of Pathology, Hospital General de Granollers, Barcelona, Spain (Dr Costa); and the Department of Cell Biology, Physiology and Immunology, Medical Physiology Unit, Universitat Autonoma de Barcelona, Barcelona, Spain (Drs Costa, Solanas, and Escrich).	Arch Pathol Lab Med 2002 Aug;126(8):915-927 Abstract quote Context.-The dimethylbenz(alpha)anthracene (DMBA) breast cancer model induced in the rat is used for the study of mammary carcinogenesis because it closely mimics human breast disease. Objective.-To analyze the histopathologic features of mammary carcinomas induced in the DMBA experimental model, in a manner similar to that used in human pathology, to allow a comparative analysis between both systems. Design.-Three experimental series of 20 animals were used. At 53 days of age, a single dose of 5 mg of DMBA per rat was given. Mammary tumors were collected when the rats were killed. Several histopathologic parameters were studied. For grading, the parameters described in the modified Scarff-Bloom-Richardson scheme were used, adapted to rat mammary tumors. Results.-More than 50% of the carcinomas presented a pattern grade I, a nuclear grade I or II, and fewer than 10 mitoses/10 high-power fields (P <.05). Although the tumors were generally well differentiated, they showed a range of differentiation. More than 85% of carcinomas did not display tumoral necrosis (P <.05). This feature was observed mostly in high-grade carcinomas. There was no or scanty lymphoplasmacytic infiltration in more than 70% of carcinomas (P <.05). The degree of infiltration increased with the histologic grade. Microcalcifications were found rarely (P <.05). The carcinomas exhibited a mixed structural pattern, most with a predominant cribriform pattern (P <.05). No or light (+) stromal response was seen in most cases (P <.05). Some carcinomas, especially when poorly differentiated, presented a desmoplastic reaction. Most carcinomas presented scanty mast cell infiltration (P <.05), no features of secretion (P <.05), and absence of microcribriform pattern (P <.05). These features were seen more often in low-grade carcinomas. Conclusions.-Despite the presence of some structural differences, rat mammary adenocarcinomas and the most common human breast carcinomas share several morphologic similarities. Moreover, some features could be related to the aggressive behavior of the tumor. The analysis carried out in this study, similar to that done in human pathology, allows a more extensive understanding of mammary tumors in rats, as well as a more accurate use of this animal model, and has made it possible to develop an innovative classification of rat mammary lesions.
APOPTOSIS
Major histocompatibility complex status in breast carcinogenesis and relationship to apoptosis. Redondo M, Garcia J, Villar E, Rodrigo I, Perea-Milla E, Serrano A, Morell M. Department of Biochemistry, Hospital Costa del Sol, Marbella, Spain.	Hum Pathol. 2003 Dec;34(12):1283-9 Abstract quote.   Major histocompatibility complex (MHC) molecules are of central importance in regulating the immune response against tumors. In this study we used immunohistochemistry to study human leukocyte antigen (HLA) class I and II antigen expression in normal breast tissues and benign, preneoplastic, primary, and metastatic breast lesions using antibodies against beta-2-microglobulin (beta2-m), heavy-chain, and HLA-DR antigens. Whereas all normal tissues and benign lesions were positive for beta2-m and HLA-A, -B, and -C antigens, total loss of HLA class I antigens was found in 37% (11 of 30) of in situ carcinomas, in 43% (56 of 131) of the primary tumors, and in 70% (31 of 45) of the lymph node metastases. HLA-DR was also underexpressed in breast cancer cells; thus 20% (6 of 30) of in situ carcinomas, 15% of invasive carcinomas (20 of 131), and only 1 metastatic case were positive for this antigen. Both HLA class I and II antigen expression were more frequently down-regulated in metastatic lesions than in primary breast lesions (P <0.05), and a tendency toward a simultaneous defective expression of HLA class I and II antigens was observed in primary carcinomas (P = 0.07). However, no correlation was found between the expression of any of the aforementioned molecules and pathological parameters or survival. Interestingly, HLA class I expression was expressed more frequently in tissues with high apoptotic activity and was significantly associated with the expression of the proapoptotic bax gene (P = 0.02), and was inversely associated with expression of the antiapoptotic bcl-2 gene (P = 0.03). We conclude that alterations in HLA class I and II antigen expression are early events in breast carcinogenesis and play significant roles in metastatic progression. In addition, their expression is correlated with apoptosis-regulating proteins, which may influence the cytotoxicity of T cells against HLA class I-specific tumor antigens.
ESTROGEN RECEPTOR BETA EXPRESSION
Declining estrogen receptor-beta expression defines malignant progression of human breast neoplasia. Shaaban AM, O'Neill PA, Davies MP, Sibson R, West CR, Smith PH, Foster CS. Department of Cellular and Molecular Pathology, University of Liverpool, UK.	Am J Surg Pathol. 2003 Dec;27(12):1502-12. Abstract quote   It has been shown that the risk of breast cancer developing in certain morphologically identifiable benign breast lesions correlates with expression of estrogen receptor alpha (ER-alpha). Although ER-alpha and ER-beta genes share a large degree of homology, it is generally thought that their distribution and functions are substantially different in many tissues. Recent development of reliable antibodies to ER-beta has provided this first opportunity to test the hypothesis that the likelihood of malignant transformation in morphologically benign breast lesions can be accurately defined by the distribution and level of ER-beta expression relative to that of ER-alpha. Using a monoclonal antibody, ER-beta protein expression has been analyzed in 53 normal breasts and compared with a cohort of histologically distinct breast lesions of different prognostic risk (54 hyperplasia of usual type, 35 ductal carcinoma in situ, and 141 invasive cancers). All of these tissues were also assessed for ER-alpha. Expression of ER-beta protein was also analyzed in an additional spectrum of benign breast lesions with low or negligible risk of progression to malignancy. The median proportion of cells expressing ER-beta was highest in normal breast lobules (median 94.33%, interquartile range 78.25-99.00) but declined significantly through usual ductal hyperplasia (median 76.67, interquartile range 49.17-95.00, P = 0.002) and ductal carcinoma in situ (median 70.00, interquartile range 59.00-85.00, P = 0.009) to invasive cancer (median 60.00, interquartile range 50.00-80.00, P < 0.001). An appreciable proportion (33.81%) of ER-alpha-negative invasive cancers expressed ER-beta. A high but variable level of ER-beta expression occurred in the benign lesions. The data from the intact histologic tissues were evaluated with respect to the relative expression of ER-alpha and ER-beta in five mammary cell lines of different behavioral phenotype (MCF7, ZR-75, T47D, MDAMB231, HUMA121). The highly significant differences in expression and distinct tissue distributions of ER-alpha and ER-beta within the histologic lesions of defined risk, together with the data from the cell lines, support the original hypothesis that the tissue concentration, relative occurrence, and/or interaction of these two types of estrogen receptor may play an important role in modulating mammary tumorigenesis.
LOSS OF HETEROZYGOSITY
Loss of heterozygosity associated with uniparental disomy in breast carcinoma. Murthy SK, DiFrancesco LM, Ogilvie RT, Demetrick DJ. Departments of Pathology and Laboratory Medicine (SKM, LMD, RTO, DJD), Oncology (LMD, RTO, DJD), and Biochemistry and Molecular Biology (DJD), The University of Calgary.	Mod Pathol 2002 Dec;15(12):1241-50 Abstract quote Loss of heterozygosity is commonly assumed to be due to deletion of the appropriate genomic region in one chromosome within a neoplastic cell but may be due to other mechanisms such as mitotic non-disjunction or somatic recombination leading to uniparental heterodisomy. We chose to study the genomic regions surrounding the p53 and RB1 tumor suppressor genes in breast carcinoma to evaluate the different mechanisms that could mediate loss of heterozygosity. A microsatellite analysis of polymorphic markers in 50 breast cancer samples showed loss of heterozygosity for at least 1 of the 10 markers analyzed in 50% of the tumors studied, and an overall 8.47% of the informative loci showed loss of heterozygosity. All of the cases with loss of heterozygosity were further analyzed for gene copy number of the tumor suppressor genes RB1 and p53 by fluorescence in situ hybridization of either tumor touch preparations or microdissected tumor nuclei with specific genomic probes. Surprisingly, all samples showed the presence of both copies of tumor suppressor genes, including 4/50 cases showing loss of heterozygosity of tumor suppressor gene-spanning markers. One of the 4 cases showed loss of heterozygosity of markers spanning a distance of 6 cM over the RB1 gene, with normal copy numbers of the gene. Three other cases showed loss of heterozygosity of markers within the tumor suppressor gene (RBI or p53) and at least one other spanning marker. No cases showed a simultaneous reduction to homozygosity of markers both near the tumor suppressor gene and distal loci. We suggest that the presence of both copies of the tumor suppressor gene in the cases with loss of heterozygosity of spanning markers and internal markers for that tumor suppressor gene could be explained by somatic recombination resulting in uniparental disomy, but not mitotic nondisjunction or deletion. As the mechanism for physical deletion of a chromosome may be different from those mediating somatic recombination, study of this phenomenon may identify different pathways of genomic instability that may be of diagnostic or treatment significance in breast or other cancers, particularly in those treatments based upon DNA-altering agents.
PROGRESSION
Different proliferative activity of the glandular and myoepithelial lineages in benign proliferative and early malignant breast diseases. Bankfalvi A, Ludwig A, De-Hesselle B, Buerger H, Buchwalow IB, Boecker W. Institute of Pathology, Munster University Hospital, Munster, Germany.	Mod Pathol. 2004 Sep;17(9):1051-61. Abstract quote   The aim of the present study was to explore cell biological characteristics of normal breast, benign proliferative breast diseases and noninvasive breast malignancies based on the recently published adult progenitor cell concept from our group. Here, we investigated the proliferative activity of CK5/14(+), CK8/18/19(+) and alpha-smooth muscle actin(+) cellular phenotypes encountered in normal mammary gland, in a series of usual ductal hyperplasias and early malignant breast diseases, such as atypical ductal and lobular hyperplasias, as well as ductal and lobular in situ carcinomas. Immunohistochemical double labeling was performed on frozen sections from diagnostic breast biopsies by using antibodies to basal cytokeratins (CK5/14), glandular cytokeratins (CK8/18/19), smooth muscle actin and the Ki-67 antigen (MIB1). Normal breast tissues and usual ductal hyperplasias were characterized by a heterogeneous cellular composition of the growth fraction. The proliferative cell compartment consisted of CK8/18/19(+) glandular and, in a variable proportion, CK5/14(+) progenitor phenotypes. In contrast, noninvasive breast malignancies were composed of a monotonous proliferation of CK 8/18/19(+) neoplastic glandular cells. These findings indicate a significant role of progenitor cells in the development of benign proliferative breast diseases and lend support to the view that malignant transformation in the human breast usually occurs in a cell committed to the glandular lineage. Our results provide cell kinetic support to the functional progenitor cell hypothesis, and we propose this concept as an operative model for understanding benign proliferative and malignant breast diseases.
Genetic heterogeneity and clonal evolution underlying development of asynchronous metastasis in human breast cancer. Kuukasjarvi T, Karhu R, Tanner M, Kahkonen M, Schaffer A, Nupponen N, Pennanen S, Kallioniemi A, Kallioniemi OP, Isola J. Department of Pathology, Tampere University Hospital, University of Tampere, Finland.	Cancer Res 1997 Apr 15;57(8):1597-604 Abstract quote To understand the genetic basis and clonal evolution underlying metastatic progression of human breast cancer in vivo, we analyzed the genetic composition of 29 primary breast carcinomas and their paired asynchronous metastases by comparative genomic hybridization and fluorescence in situ hybridization. The mean number of genetic changes by comparative genomic hybridization was 8.7 +/- 5.3 in primary tumors and 9.0 +/- 5.7 in their metastases. Although most of the genetic changes occurred equally often in the two groups, gains of the Xq12-q22 region were enriched in the metastases. According to a statistical analysis of shared genetic changes and breakpoints in paired specimens, 20 of the metastases (69%) showed a high degree of clonal relationship with the corresponding primary tumor, whereas the genetic composition of 9 metastases (31%) differed almost completely from that of the paired primary tumors. In both groups, however, chromosome X inactivation patterns suggested that the metastatic lesions originated from the same clone as the primary tumor. Fluorescence in situ hybridization analysis with probes specific to metastatic clones usually failed to find such cells in the primary tumor sample. In conclusion, detailed characterization of the in vivo progression pathways of metastatic breast cancer indicates that a linear progression model is unlikely to account for the progression of primary tumors to metastases. An early stem line clone apparently evolves independently in the primary tumor and its metastasis, eventually leading to multiple, genetically almost completely different, clones in the various tumor locations in a given patient. The resulting heterogeneity of metastatic breast cancer may underlie its poor responsiveness to therapy and explain why biomarkers of prognosis or therapy responsiveness measured exclusively from primary tumors give a restricted view of the biological properties of metastatic breast cancer.
	Am J Clin Pathol 2001;115:362-369 A linear stepwise progression of breast tumorigenesis has been postulated, from usual ductal hyperplasia through atypical hyperplasia, ductal carcinoma in situ (DCIS), and invasive carcinoma Likely that at least 2 pathways for the development of invasive breast carcinoma exist Low-grade invasive carcinoma may arise from low-grade DCIS, which in turn is related closely to atypical ductal hyperplasia (ADH) Or, high-grade invasive carcinoma may arise from high-grade DCIS, but the immediate precursor of high-grade DCIS is not clear
Quantitative Study of Breast Cancer Progression: Different Pathways for Various In Situ Cancers L. Mariuzzi, M.D., A. Mombello, M.D., G. Granchelli, M.D., V. Rucco, M.D., E. Tarocco, M.D., D. Frank, Ph.D., J. Davis, M.D., D. Thompson, M.Sc., H. Bartels, M.SIE., G. M. Mariuzzi, M.D. and P. H. Bartels, Ph.D., F.I.A.C.(Hon), M.D. (Hon) Departments of Pathology of the University of Udine (LM) and the University of Verona (AM, GG, VR, ET, GMM), Verona, Italy; and Department of Pathology (JD), Arizona Cancer Center (DF), and Optical Sciences Center (DT, HB, PHB), University of Arizona, Tucson, Arizona	Mod Pathol 2002;15:18-25 Abstract quote The chromatin pattern in nuclei from breast ductal proliferative lesions was quantitatively evaluated with the objective of deriving measures of tumor progression. A total of 110 cases were analyzed. There were 38 cases of normal tissue or benign proliferative lesions, 41 cases of ductal carcinoma in situ (DCIS), and 31 cases of microinfiltrating DCIS and of infiltrating cancer. A total of 9424 nuclei were analyzed. High-resolution images were digitally recorded. For each nucleus, 93 karyometric features descriptive of the spatial and statistical distribution of the nuclear chromatin were computed. Data analysis included establishing a profile of relative deviations of each feature from "normal," called the nuclear signature, and of lesion signatures as well as of trends of lesion progression. Two trends of evolution could be discerned: one from normal to hyperplasia, atypical hyperplasia, and comedo DCIS as representative of high-grade lesions; and the other from normal to hyperplasia to cribriform DCIS, solid DCIS, and infiltrating cancer, representing lower grade lesions. The nuclei in microinfiltrating foci are distinctly different from nuclei in high-grade comedo DCIS. The nuclei in microinfiltrating foci have a statistically significantly lower nuclear abnormality. They may represent outgrowing clones.
ONCOGENES
ras oncogene	Mutations present in 10-30%
Her2-neu
BRCA1 and BRCA2
c-myc	Ampflication of 17% of cancers Altered expression had significantly shorter disease free survival
Immunohistochemical Expression of Human Erythrocyte Glucose Transporter and Fatty Acid Synthase in Infiltrating Breast Carcinomas and Adjacent Typical/Atypical Hyperplastic or Normal Breast Tissue Piero L. Alò, MD, Paolo Visca, MD, Claudio Botti, MD, Gregorio M. Galati, MD, Valeria Sebastiani, MD, Tiziana Andreano, MD, Ugo Di Tondo, MD, and Ellen S. Pizer, MD, PhD	Am J Clin Pathol 2001;116:129-134 Abstract quote To evaluate the immunohistochemical expression of GLUT1, human erythrocyte glucose transporter 1, and fatty acid synthase (FAS), 66 human breast carcinomas and adjacent peritumoral tissue were studied. GLUT1 and FAS were expressed in 53 and 61 carcinomas, in 17 and 14 typical/atypical hyperplastic tissues, and in 16 and 13 tissues adjacent to tumor normal breast tissue, respectively. Statistical analysis revealed association between invasive carcinomas, invasive carcinomas with in situ component and GLUT1 immunostaining. GLUT1 staining was associated with tumor grade, FAS with tumor stage, and GLUT1 and FAS coexpression with tumor grade. Controls expressed no immunostaining. GLUT1 and FAS are new markers involved in the biologic activities of cancer cells. GLUT1 and FAS coexpression may indicate increased use of energy by the neoplastic cells correlated with poorly differentiated features and aggressive behavior. The innovative finding that GLUT1 and FAS are observed in mammary carcinoma adjacent nonneoplastic tissues may suggest a role in detecting initial phases of breast carcinogenesis.
Evidence for further breast cancer susceptibility genes in addition to BRCA1 and BRCA2 in a population-based study. Antoniou AC, Pharoah PD, McMullan G, Day NE, Ponder BA, Easton D. CRC Genetic Epidemiology Unit, University of Cambridge, Cambridge, United Kingdom.	Genet Epidemiol 2001 Jul;21(1):1-18 Abstract quote We used data from a population based series of breast cancer patients to investigate the genetic models that can best explain familial breast cancer not due to the BRCA1 and BRCA2 genes. The data set consisted of 1,484 women diagnosed with breast cancer under age 55 registered in the East Anglia Cancer registry between 1991-1996. Blood samples taken from the patients were analysed for mutations in BRCA1 and BRCA2. The genetic models were constructed using information on breast and ovarian cancer history in first-degree relatives and on the mutation status of the index patients. We estimated the simultaneous effects of BRCA1, BRCA2, a third hypothetical gene BRCA3, and a polygenic effect. The models were assessed by likelihood comparisons and by comparison of the observed numbers of mutations and affected relatives with the predicted numbers. BRCA1 and BRCA2 could not explain all the familial clustering of breast cancer. The best-fitting single gene model for BRCA3 was a recessive model with a disease allele frequency 24% and penetrance 42% by age 70. However, a polygenic model gave a similarly good fit. The estimated population frequencies for BRCA1 and BRCA2 mutations were similar under both recessive and polygenic models, 0.024 and 0.041%, respectively. A dominant model for BRCA3 gave a somewhat worse fit, although the difference was not significant. The mixed recessive model was identical to the recessive model and the mixed dominant very similar to the polygenic model. The BRCA3 genetic models were robust to the BRCA1 and BRCA2 penetrance assumptions. The overall fit of all models was improved when the known effects of parity on breast and ovarian cancer risks were included in the model-in this case a polygenic model fits best. These findings suggest that a number of common, low-penetrance genes with additive effects may account for the residual non-BRCA1/2 familial aggregation of breast cancer, but Mendelian inheritance of an autosomal recessive allele cannot be ruled out.
PTEN
Reduced expression of PTEN correlates with breast cancer progression. Bose S, Crane A, Hibshoosh H, Mansukhani M, Sandweis L, Parsons R. Department of Pathology, University of California, Los Angeles, California 90048, USA.	Hum Pathol 2002 Apr;33(4):405-9 Abstract quote PTEN is a tumor-suppressor gene with phosphatase activity that is mutated in a variety of cancers. We analyzed a series of 34 invasive and 18 in situ breast cancers with known molecular status of the PTEN genotype using immunohistochemistry. Reduced PTEN protein expression was seen in 38% of invasive cancers and in 11% of in situ cancers. The frequency of reduced expression was highest in stage II and III cancers. Reduced expression also correlated with aneuploidy. In addition, in tumors with both in situ and invasive components, expression within the ductal carcinoma in situ portion tended to reflect the expression pattern of the invasive component. These data suggest that PTEN expression is frequently reduced in advanced breast cancers.

 

LABORATORY/ RADIOLOGIC/ OTHER TESTS	CHARACTERIZATION
SCREENING MAMMOGRAPHY	Yearly screening for women over 40 years of age
Influence of annual mammography from age 40 on breast cancer pathology. Anderson TJ, Waller M, Ellis IO, Bobrow L, Moss S.	Hum Pathol. 2004 Oct;35(10):1252-9 Abstract quote.   The objective of this study was to determine the influence of annual mammography on pathology features of breast cancers in an invited population. We conducted a randomized trial of 53,890 invited and 106,971 control United Kingdom women who were recruited only from those aged 40 years, with central review of cancer histology. We compare the invasive cancer distribution for the categories of size, histological type, grade, and node status in subgroups of the invited population with that of controls. Among 1287 cancers identified in the total population through the end of December 1999, there are major differences among prevalence, incidence, interval, and lapsed-attender and nonattender subgroups for the distribution of cancer numbers in categories of chosen qualitative histological features. These reflect the biases known to affect a population exposed to screening. Comparing cancers from the unbiased group of the invited population with controls shows significant differences in distributions for size, grade, and node status but not histological type. Multivariate logistic regression shows significant reduction (odds ratio, 0.73; P = 0.043) in node-positive status for the unbiased group. We conclude that annual mammography from age 40 years significantly reduces size and positive-node status of invasive cancers in the invited population. The potential for phenotypic drift of grade emphasizes the relevance of screen detection of all grades at sizes smaller than 10 mm.
Breast cancers in women 35 years of age and younger: mammographic findings. Shaw de Paredes E, Marsteller LP, Eden BV. Department of Radiology, University of Virginia Health Sciences Center, Charlottesville 22908.	Radiology 1990 Oct;177(1):117-9 Abstract quote During an 8-year period, 74 breast cancers were diagnosed in 66 patients 35 years of age and younger who underwent preoperative mammography. Mammograms and clinical data in these women were reviewed retrospectively to evaluate the mammographic findings and the efficacy of mammography. In 58 cases the cancer was detected by means of both clinical examination and mammography; in eight cases, mammography alone enabled readers to find the lesion; in seven cases, the lesion was found by means of clinical examination, but mammograms were negative; and in one case a cancer was found by means of incidental biopsy of the contralateral breast. Although 34 patients (52%) had dense breasts, mammography demonstrated the lesion in 66 cases (89%); the most common mammographic finding was microcalcifications, with or without associated masses (n = 28 [38%]). The authors do not suggest that screening of women younger than 35 years be performed routinely, but they believe that mammography can be valuable in screening young women at high risk for breast cancer or in confirming and suggesting prompt biopsy of a suspicious lesion.
Relationship between mammographic and histological risk factors for breast cancer. Boyd NF, Jensen HM, Cooke G, Han HL. Division of Epidemiology and Statistics, Ontario Cancer Institute, Canada.	J Natl Cancer Inst 1992 Aug 5;84(15):1170-9 Abstract quote BACKGROUND: Information on breast cancer risk can be obtained both from the histological appearance of the breast epithelium in biopsy specimens and from the pattern of parenchymal densities in the breast revealed by mammography. It is not understood, however, how parenchymal densities influence breast cancer risk or whether these densities are associated with histological risk factors. PURPOSE: We have estimated, in a large cohort of women, the relative risk of detecting carcinoma in situ, atypical hyperplasia, hyperplasia without atypia, or nonproliferative disease in biopsy specimens from women with different extents of mammographic density. We also examined the association between these histological classifications and radiological features present specifically at the biopsy site. METHODS: The source of study material was a population of women aged 40-49 years who were enrolled in the Canadian National Breast Screening Study (NBSS). Mammograms from women who had undergone a biopsy (n = 441) and from a comparison group of women (n = 501) randomly selected from the mammography arm of the NBSS were classified according to the extent of mammographic density. The corresponding histological slides were independently classified by a review pathologist. RESULTS: Compared with women showing no mammographic densities, women with the most extensive densities (i.e., occupying greater than 75% of the breast volume) had a 9.7 times greater risk of developing carcinoma in situ or atypical hyperplasia (95% confidence interval [CI] = 1.75-53.97), a 12.2 times greater risk of developing hyperplasia without atypia (95% CI = 2.97-50.14), and a 3.1 times greater risk of developing non-proliferative disease (95% CI = 1.20-8.11). The gradients in risk were not monotonic across the five classifications of mammographic density. The association could not be explained by the presence of mammographic densities at the biopsy site, but calcification at the biopsy site was strongly associated with high-risk histological changes (relative risk = 24; 95% CI = 5.0-156.0). CONCLUSIONS: These results suggest that the radiological patterns referred to as mammographic dysplasia may influence breast cancer risk by virtue of their association with high-risk histological changes in the breast epithelium. IMPLICATIONS: Identification of the factors responsible for high-risk histological changes may offer new insights into the etiology of breast cancer and potentially lead to the development of methods for its prevention.
National Institutes of Health Consensus Development Conference Statement: Breast Cancer Screening for Women Ages 40-49, January 21-23, 1997. National Institutes of Health Consensus Development Panel.	J Natl Cancer Inst 1997 Jul 16;89(14):1015-26 Abstract quote OBJECTIVE: To provide health care providers, patients, and the general public with a responsible assessment of currently available data regarding the effectiveness of mammography screening for women ages 40-49. PARTICIPANTS: A non-Federal, nonadvocate, 12-member panel representing the fields of oncology, radiology, obstetrics and gynecology, geriatrics, public health, and epidemiology and including patient representatives. In addition, 32 experts in oncology, surgical oncology, radiology, public health, and epidemiology, presented data to the panel and to a conference audience of 1,100. EVIDENCE: The literature was searched through Medline and an extensive bibliography of references was provided to the panel and the conference audience. Experts prepared abstracts with relevant citations from the literature. Scientific evidence was given precedence over clinical anecdotal experience. CONSENSUS PROCESS: The panel, answering predefined questions, developed its conclusions based on the scientific evidence presented in open forum and the scientific literature. The panel composed a draft statement that was read in its entirety and circulated to the experts and the audience for comment. Thereafter, the panel resolved conflicting recommendations and released a revised draft statement at the end of the conference. The final statement with a minority report was completed within several weeks after the conference. CONCLUSIONS: The Panel concludes that the data currently available do not warrant a universal recommendation for mammography for all women in their forties. Each woman should decide for herself whether to undergo mammography. Her decision may be based not only on an objective analysis of the scientific evidence and consideration of her individual medical history, but also on how she perceives and weighs each potential risk and benefit, the values she places on each, and how she deals with uncertainty. However, it is not sufficient just to advise a woman to make her own decision about mammograms. Given both the importance and the complexity of the issues involved in assessing the evidence, a woman should have access to the best possible relevant information regarding both benefits and risks, presented in an understandable and usable form. Information should be developed for women in their forties regarding potential benefits and risks to be provided to enable each woman to make the most appropriate decision. In addition, educational material to accompany this information should be prepared that will lead women step by step through the process of using such information in the best possible way for reaching a decision. For women in their forties who choose to have mammography performed, the costs of the mammograms should be reimbursed by third-party payors or covered by health maintenance organizations so that financial impediments will not influence a woman's decision. Additionally, a woman's health care provider must be equipped with sufficient information to facilitate her decisionmaking process. Therefore, educational material for physicians should be developed to assist them in providing the guidance and support needed by the women in their care who are making difficult decisions regarding mammography. The two panel members writing a minority report believed the risks of mammography to be overemphasized by the majority and concluded that the data did support a recommendation for mammography screening for all women in this age group and that the survival benefit and diagnosis at an earlier stage outweigh the potential risks.
Women with breast cancer: histologic findings in the contralateral breast. Roubidoux MA, Helvie MA, Wilson TE, Lai NE, Paramagul C. Department of Radiology, University of Michigan Medical Center, Ann Arbor 48109-0326, USA.	Radiology 1997 Jun;203(3):691-4 Abstract quote PURPOSE: To investigate contralateral breast biopsy histologic findings in women with breast cancer. MATERIALS AND METHODS: Histologic findings in 237 patients with breast cancer who underwent contralateral breast biopsy for clinically or mammographically detected abnormalities were retrospectively reviewed. Malignant findings were categorized by histologic type. Benign findings were categorized by risk of breast cancer. Comparison was made with mammographically guided breast biopsy results in 1,294 patients without breast cancer. RESULTS: Of the 237 patients, 168 (70.9%) had either malignancy or high-risk histologic findings. One hundred thirty-nine patients (58.6%) had malignant findings; 98 (41.4%) had benign findings. Of the 98 with benign findings, 29 (30%) had high-risk histologic findings. Thirty (33%) of the 91 patients with invasive cancer had invasive lobular carcinoma. Forty-seven (45.6%) of the 103 patients with malignant lesions at mammographically guided biopsies had ductal carcinoma in situ alone. CONCLUSION: Compared with biopsy in women without breast cancer, contralateral biopsy in women with breast cancer was more likely to show malignancy, invasive lobular carcinoma, or ductal carcinoma in situ alone (P < .001) or to show high-risk histologic benign findings (P < .001). Mammographic and clinical findings in the contralateral breast should be regarded as more suspicious than those in patients without known breast cancer.
BREAST DUCTAL LAVAGE
Assessment of utility of ductal lavage and ductoscopy in breast cancer-a retrospective analysis of mastectomy specimens. Badve S, Wiley E, Rodriguez N. Northwestern University Medical School, Chicago, Illinois (SB, EW, NR) and Indiana University School of Medicine, Indianapolis, Indiana (SB).	Mod Pathol 2003 Mar;16(3):206-9 Abstract quote Early detection of breast lesions continues to be an important goal in the management of breast cancer. At present, mammographic imaging in addition to physical examination is the main screening method for the detection of cancer. Fiberoptic ductoscopy and duct lavage are being recently used to evaluate patients at risk for breast cancer. Both techniques examine the nipple and central duct area to identify intraductal lesions. In this study, we examined the frequency of involvement of these structures in mastectomy specimens as a surrogate marker to estimate the utility of these methods in breast cancer patients. The presence and type of involvement of the nipple and central duct area was retrospectively evaluated in 801 mastectomy specimens from a 4-year period that had been performed for infiltrating or in situ carcinoma. Atypical proliferation or cells, when seen in the ducts of this region, was considered as evidence of nipple involvement, even if definite evidence of malignancy was lacking. The review of 801 mastectomies showed nipple and central duct involvement in 179 (22%) cases. Among the 665 cases of infiltrating carcinoma, 17% did not have an intraductal component. The relative rarity of nipple and central duct in mastectomy specimens and the lack of an in situ component in many cases raise questions about the utility of fiberoptic ductoscopy and duct lavage as methods for screening of breast cancer. Additionally, as these methods examine only 1-2 ducts of the 15-20 ducts that open at the nipple, they might fail to detect focal abnormalities.
Cellular characteristics of nipple aspiration fluid during the menstrual cycle in healthy premenopausal women. Mitchell G, Trott PA, Morris L, Coleman N, Sauter E, Eeles RA. Section of Cancer Genetics, Institute of Cancer Research, Cotswold Road, Sutton, Surrey SM2 5NG, UK.	Cytopathology 2001 Jun;12(3):184-96 Abstract quote Cellular characteristics of nipple aspiration fluid during the menstrual cycle in healthy premenopausal women. Fifteen healthy premenopausal female volunteers underwent weekly nipple aspiration of ductal fluid from both breasts during two menstrual cycles to investigate the variability of the cellular profile of the ductal fluid. Ductal fluid was successfully obtained using breast massage and nipple-areolar suction from 247/280 (89%) breasts. 83% of samples available for cytological analysis were cellular and 30% of cellular aspirates contained ductal epithelial cells identified using standard morphological criteria. No significant variation in cell number or cell type was identified during the menstrual cycle. All samples tested had an 'H' score of zero for oestrogen receptor. Seven out of 14 women expressed the proliferation marker Mcm-2 in the cells of at least one of the specimens, with no evidence of a menstrual cycle influence on expression. In conclusion, the cellular profile of breast ductal fluid did not vary consistently during the menstrual cycle, permitting future breast cancer screening studies incorporating serial nipple aspirations to be performed independent of the phase of the cycle.
Breast cancer risk in women with abnormal cytology in nipple aspirates of breast fluid. Wrensch MR, Petrakis NL, Miike R, King EB, Chew K, Neuhaus J, Lee MM, Rhys M. Dept. of Epidemiology and Biostatistics, School of Medicine, Box 1215, University of California San Francisco, San Francisco, CA 94143, USA.	J Natl Cancer Inst 2001 Dec 5;93(23):1791-8 Abstract quote BACKGROUND: We previously showed that women with abnormal cytology in breast fluid obtained by nipple aspiration had an increased relative risk (RR) of breast cancer compared with women from whom fluid was not obtained and with women whose fluid had normal cytology. This study extends the follow-up in the original study group (n = 4046) and presents the first follow-up for a second group of women (n = 3627). METHODS: We collected nipple aspirate fluid from women in the San Francisco Bay Area during the period from 1972 through 1991, classified the women according to the most severe epithelial cytology observed in fluid specimens, and determined breast cancer incidence through March 1999. We estimated RRs for breast cancer using Cox regressions, adjusting for age and year of study entry. All statistical tests were two-sided. RESULTS: For women in the first and second study groups, the median years of follow-up were 21 years and 9 years, respectively, and breast cancer incidences were 7.8% (285 cases in the 3633 women for whom breast cancer status could be determined) and 3.5% (115 of 3271), respectively. Compared with women from whom no fluid was obtained, whose incidences of breast cancer were 4.7% (39 of 825) and 3.3% (65 of 1950) for those in group 1 and group 2, respectively, incidences and adjusted RRs were 8.1% (34 of 422), with RR = 1.4 (95% confidence interval [CI] = 0.9 to 2.3), and 0% (0 of 31), respectively, for those with unsatisfactory aspirate specimens and 8.2% (148 of 1816), with RR = 1.6 (95% CI = 1.1 to 2.3), and 3.1% (25 of 811), with RR = 1.2 (95% CI = 0.8 to 2.0), respectively, for those with normal cytology in aspirates. Compared with women from whom no fluid was obtained, incidences and adjusted RRs for women in group 1 with epithelial hyperplasia and atypical hyperplasia in aspirates were 10.8% (52 of 483), with RR = 2.4 (95% CI = 1.6 to 3.7), and 13.8% (12 of 87), with RR = 2.8 (95% CI = 1.5 to 5.5), respectively, while those for women in group 2 were 5.5% (25 of 457) and 0% (0 of 22), respectively, with a combined RR = 2.0 (95% CI = 1.3 to 3.3). CONCLUSION: The results obtained with the newly followed women independently confirmed previous findings that women with abnormal cytology in nipple aspirates of breast fluid have an increased risk of breast cancer.
Ductal lavage for detection of cellular atypia in women at high risk for breast cancer. Dooley WC, Ljung BM, Veronesi U, Cazzaniga M, Elledge RM, O'Shaughnessy JA, Kuerer HM, Hung DT, Khan SA, Phillips RF, Ganz PA, Euhus DM, Esserman LJ, Haffty BG, King BL, Kelley MC, Anderson MM, Schmit PJ, Clark RR, Kass FC, Anderson BO, Troyan SL, Arias RD, Quiring JN, Love SM, Page DL, King EB. Institute for Breast Health, University of Oklahoma Health Sciences Center, Oklahoma City, 73104, USA.	J Natl Cancer Inst 2001 Nov 7;93(21):1624-32 Abstract quote BACKGROUND: Breast cancer originates in breast epithelium and is associated with progressive molecular and morphologic changes. Women with atypical breast ductal epithelial cells have an increased relative risk of breast cancer. In this study, ductal lavage, a new procedure for collecting ductal cells with a microcatheter, was compared with nipple aspiration with regard to safety, tolerability, and the ability to detect abnormal breast epithelial cells. METHODS: Women at high risk for breast cancer who had nonsuspicious mammograms and clinical breast examinations underwent nipple aspiration followed by lavage of fluid-yielding ducts. All statistical tests were two-sided. RESULTS: The 507 women enrolled included 291 (57%) with a history of breast cancer and 199 (39%) with a 5-year Gail risk for breast cancer of 1.7% or more. Nipple aspirate fluid (NAF) samples were evaluated cytologically for 417 women, and ductal lavage samples were evaluated for 383 women. Adequate samples for diagnosis were collected from 111 (27%) and 299 (78%) women, respectively. A median of 13,500 epithelial cells per duct (range, 43-492,000 cells) was collected by ductal lavage compared with a median of 120 epithelial cells per breast (range, 10-74,300) collected by nipple aspiration. For ductal lavage, 92 (24%) subjects had abnormal cells that were mildly (17%) or markedly (6%) atypical or malignant (<1%). For NAF, corresponding percentages were 6%, 3%, and fewer than 1%. Ductal lavage detected abnormal intraductal breast cells 3.2 times more often than nipple aspiration (79 versus 25 breasts; McNemar's test, P<.001). No serious procedure-related adverse events were reported. CONCLUSIONS: Large numbers of ductal cells can be collected by ductal lavage to detect atypical cellular changes within the breast. Ductal lavage is a safe and well-tolerated procedure and is a more sensitive method of detecting cellular atypia than nipple aspiration.
IMAGE GUIDED BIOPSIES
Diagnostic Agreement in the Evaluation of Image-guided Breast Core Needle Biopsies: Results from a Randomized Clinical Trial. Collins LC, Connolly JL, Page DL, Goulart RA, Pisano ED, Fajardo LL, Berg WA, Caudry DJ, McNeil BJ, Schnitt SJ. Department of Pathology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts; dagger Department of Pathology, Vanderbilt University School of Medicine, Nashville, Tennessee; double dagger Department of Radiology, University of North Carolina School of Medicine, Chapel Hill, North Carolina; section sign Department of Radiology, University of Virginia Health Sciences Center, Charlottesville, Virginia; paragraph sign Department of Radiology, University of Maryland School of Medicine, Baltimore, Maryland; and Department of Health Care Policy, Harvard Medical School, and Department of Radiology, Brigham and Women's Hospital, Boston, Massachusetts.	Am J Surg Pathol. 2004 Jan; 28(1): 126-131. Abstract quote   SUMMARY: BACKGROUND Image-guided core needle biopsies (CNBs) are commonly used as the initial sampling method for nonpalpable, mammographically detected breast lesions. Although prior studies have shown that this procedure is a highly sensitive and accurate method for the detection of breast cancer, the level of diagnostic agreement between pathologists in the analysis of CNB has not been previously studied in detail.METHODS To address this, we reviewed the pathologic findings in 2004 CNB from patients enrolled in the Radiologic Diagnostic Oncology Group 5 study, a randomized, multicenter trial designed to determine the role of CNB and fine needle aspiration biopsy in the evaluation of nonpalpable breast lesions. Slides of CNB specimens were initially diagnosed by pathologists at the 22 participating institutions (local diagnosis) and were then sent to the study pathologists for central review (central diagnosis). Local and central diagnoses were compared.RESULTS Overall, the central diagnosis and local diagnosis were concordant in 1925 cases (96%), indicating an excellent level of agreement by kappa statistic analysis (kappa = 0.90; 95% confidence interval 0.88-0.92). The level of agreement between local and central pathologists did not vary with the image guidance system (stereotactic mammography vs. ultrasound) or with the mammographic findings (soft tissue density vs. microcalcifications). The level of diagnostic agreement observed for CNB was comparable to that observed among 596 open surgical biopsies obtained from patients in this study and subjected to central pathology review (93% agreement; kappa = 0.89, 95% confidence interval 0.86-0.92). CONCLUSIONS The level of diagnostic agreement in interpretation of breast CNB is extremely high among pathologists and is comparable to that seen for open surgical biopsy.
MRI
Human breast lesions: characterization with contrast-enhanced in vivo proton MR spectroscopy--initial results. Yeung DK, Cheung HS, Tse GM. Department of Clinical Oncology, Medical Physics Division, Prince of Wales Hospital, 30-32 Ngan Shing St, Shatin, Hong Kong, China.	Radiology 2001 Jul;220(1):40-6 Abstract quote PURPOSE: To assess the clinical usefulness of localized proton (hydrogen 1) magnetic resonance (MR) spectroscopy in the characterization of contrast material-enhanced breast lesions on the basis of choline detection. MATERIALS AND METHODS: Examinations were performed at 1.5 T with use of a standard breast coil. Contrast-enhanced MR imaging was performed in 30 consecutive patients (mean age, 50 years; age range, 20--80 years) who had nonspecific lesions (>1.5 cm in diameter) on sonograms or mammograms. Single-voxel (1)H MR spectroscopy was performed in the enhancing lesions by using a point-resolved spectroscopic sequence with echo times of 38, 135, and 270 msec. MR spectroscopic and histopathologic findings were determined in blinded fashion and compared. RESULTS: Twenty-four patients had carcinoma of the breast (tumor size, 2.0--11.2 cm; mean, 4.7 cm), and six had benign lesions (lesion size, 1.8--3.8 cm; mean, 2.7 cm). Choline was detected in 22 patients with carcinoma. Choline was not detected in five patients with benign lesions and in two patients with carcinoma. The preliminary results indicate that this technique had a sensitivity of 92%, specificity of 83%, and accuracy of 90%. CONCLUSION: Choline can be reliably detected in less than 45 minutes in large contrast-enhanced breast lesions by using a multiecho point-resolved spectroscopic protocol. The presence of water-soluble choline metabolites obtainable with (1)H MR spectroscopy could complement MR imaging findings to improve specificity and to reduce the number of unnecessary biopsies.
Occult Contralateral Breast Carcinoma Incidentally Detected by Breast Magnetic Resonance Imaging Priscilla J. Slanetz, MD, MPH,* Whitney B. Edmister, AB, Eren D. Yeh, MD, Anjali C. Talele, AB, and Daniel B. Kopans, MD	Breast J 2002;8:145 Abstract quote The incidence of synchronous bilateral breast cancers has been reported to be between 3.4 and 7.4, as detected on mammography, physical examination, or both. We undertook a study to determine how often magnetic resonance (MR) imaging detects a contralateral abnormality in patients with known breast carcinoma. As part of an institutional review board (IRB) -approved research protocol, 17 patients with pathologically proven invasive carcinoma underwent preoperative MR imaging of both breasts using a T1-weighted, high-resolution gradient echo sequence (precontrast and postcontrast), an echo-planar sequence during administration of gadolinium, and a T2-weighted, fast-spin echo sequence. The morphology and dynamic enhancement of lesions in both breasts were assessed. Biopsy was recommended for any lesion meeting set criteria. MR imaging identified all 17 known invasive cancers in the breast of concern on mammography or physical examination. Five of 17 patients (29) had 10 contralateral lesions identified on MR, for which biopsy was recommended. One of these lesions proved to represent a fibroadenoma. The other 9 lesions proved to represent a malignancy (6 invasive lobular, 2 infiltrating ductal, and 1 tubular). Four of the 17 patients (24) with invasive cancer had contralateral synchronous cancers occult to physical examination, mammography, and ultrasonography