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These changes in the breast are associated with an increased risk for breast cancer. The following table lists the relative risks. This category comprises the following conditions moderate or florid epithelial hyperplasia, with or without atypica, sclerosing adenosis, and small duct papillomas.

Histologic Changes Relative Risk
Mild ductal hyperplasia, adenosis, cystic changes, apocrine metaplasia No increased risk
Sclerosing adenosis, moderate to florid epithelial hyperplasia, papillomas (Proliferative breast disease without atypia) 1.5-2x
Atypical ductal and atypical lobular hyperplasia 4-5x
DCIS and LCIS 11x

The stratification of risk is an important advance in the understanding of breast disease. Overall, however, these changes are still uncommon. If a cohort of women undergoing breast biopsies for benign disease are examined, 50% will have proliferative changes. Of these 50%, 5-10% will have atypical hyperplasia. Of this latter category, 15% will develop invasive carcinoma (JAMA 1992;267:941).


Disease Associations  
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Gross Appearance and Clinical Variants  
Histopathological Features and Variants  
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The increasing prevalence of benign proliferative breast lesions in Japanese women.

Schnitt SJ, Jimi A, Kojiro M.

Department of Pathology, Beth Israel Hospital, Boston, Massachusetts 02215.

Cancer 1993 Apr 15;71(8):2528-31 Abstract quote

BACKGROUND. Although the increasing incidence of breast cancer in Japan has been well-documented, the possibility that there also has been an increase in the frequency of benign proliferative breast disease in Japanese women has not been previously studied.

METHODS. The authors compared the histologic findings in a series of 266 consecutive benign breast biopsy specimens from 1974 to 1975 (Group I) to those in a series of 266 similar biopsy specimens accessioned at the same institution in Japan one decade later (i.e., 1984 to 1985; Group II). The extent of sampling was similar in both groups. The specimens were categorized as showing nonproliferative lesions, proliferative lesions without atypia, or atypical hyperplasia using the criteria of Dupont and Page.

RESULTS. Proliferative lesions without atypia were significantly more common in biopsy specimens from Group II than those from Group I (16.2% versus 9%; P = 0.01). Although atypical hyperplasias were twice as common in Group II as in Group I, these lesions were uncommon in both groups (2% in Group II versus 1% in Group I, p = NS). The differences in pathologic findings between the two groups were most evident in younger women. For patients younger than 40 years of age, the prevalence of proliferative lesions (with or without atypia) was 18% for Group II and 6% for Group I (P = 0.003). For patients 40 years of age or older, proliferative lesions were seen in 17% of patients in Group II and 13% in Group I (P value, not significant).

CONCLUSIONS. The frequency of benign proliferative breast lesions in Japanese women, particularly among women younger than 40 years of age, is increasing. These observations are consistent with the results of previous studies in North America that have demonstrated a relationship between benign proliferative breast lesions and the development of breast cancer.



Comparative genomic hybridization analysis of lobular carcinoma in situ and atypical lobular hyperplasia and potential roles for gains and losses of genetic material in breast neoplasia.

Lu YJ, Osin P, Lakhani SR, Di Palma S, Gusterson BA, Shipley JM.

Section of Cell Biology and Experimental Pathology, Institute of Cancer Research, Surrey, United Kingdom.

Cancer Res 1998 Oct 15;58(20):4721-7 Abstract quote

Lobular carcinoma in situ (LCIS) and atypical lobular hyperplasia (ALH) of the breast are cytologically similar breast lesions that reportedly carry different relative risks of subsequent development of invasive carcinoma. They are frequently multifocal and bilateral.

We have identified the chromosomal copy number changes in 31 LCIS and 14 ALH lesions from 28 cases and also the 7 invasive carcinomas that subsequently developed in 6 of these cases. This was achieved by comparative genomic hybridization analysis of microdissected formalin-fixed, paraffin-embedded material. There was no significant difference between the aberrations found in the unilateral versus the bilateral cases of LCIS. Loss of material from 16p, 16q, 17p, and 22q and also gain of material from 6q were found at a similar high frequency in LCIS and ALH.

Loss of these genomic regions may indicate the locations of genes that predispose to the development of the lesions, and the results are consistent with LCIS and ALH representing the same genetic stage of development. Comparison of the comparative genomic hybridization results from LCIS/ALH with those from ductal carcinoma in situ and invasive cancer showed some similarities at the chromosomal level, but it also showed significant differences, including gain of 1q and 8q and evidence for genomic amplification, which were not found in LCIS/ALH.

A genetic model is postulated for the possible relationships between noninvasive lobular lesions and invasive breast carcinoma, delineating potential roles for specific chromosome copy number changes.

Pattern of Chromosome 16q Loss Differs between an Atypical Proliferative Lesion and an Intraductal or Invasive Ductal Carcinoma Occurring Subsequently in the Same Area of the Breast

Hitoshi Tsuda, etal.

Mod Pathol 2001;14:382-388 Abstract quote

Atypical proliferative lesions of the breast, such as atypical ductal hyperplasia and atypical papilloma, are considered to be precursors of breast carcinomas and have frequently been shown to have loss of heterozygosity (LOH) on chromosome 16q at the DNA level.

We evaluated whether an atypical proliferative lesion and a carcinoma that subsequently occurred in the same area of the ipsilateral breast were of identical clonal origin in seven patients.

Using DNA isolated from microdissected archival tissue of epithelial components of both the biopsy specimen of the atypical proliferative lesion and the mastectomy specimen of the carcinoma, the pattern of LOH on 16q was compared between these two lesions using polymerase chain reaction –microsatellite LOH analysis. As a control, LOH on 16q was examined in 13 cases of usual ductal hyperplasia, 10 usual papillomas, and 6 atypical ductal hyperplasias.

In the seven cases, LOH on 16q was detected in three of the six atypical proliferative lesions and in five of the seven carcinomas, but the allele with LOH or a deleted region always differed between the two. LOH was detected in both atypical proliferative lesions and carcinomas in one case, only in the atypical proliferative lesion in two cases, and only in carcinomas in three cases. In the controls, LOH on 16q was absent in usual ductal hyperplasias or usual papillomas but was detected in two of six atypical ductal hyperplasias.

Although atypical proliferative lesions were frequently confirmed to be of clonal nature with LOH on 16q, these lesions and carcinomas were considered to be clones, probably originated from a field with these clones.


The timing and characterization of p53 mutations in progression from atypical ductal hyperplasia to invasive lesions in the breast cancer.

Kang JH, Kim SJ, Noh DY, Choe KJ, Lee ES, Kang HS.

Department of Biological Science, BioMedical Research Center, Korea Advanced Institute of Science and Technology, Taejon 305-701, Korea.

J Mol Med 2001 Nov;79(11):648-55 Abstract quote

The main reason for the recent interest in p53 is that almost 50% of human cancers contain p53 gene mutations. The majority of studies on p53 alterations in breast cancer have been limited to the isolated cases of ductal carcinoma in situ and infiltrating ductal carcinoma.

The aims of this study were to determine the status and timing of p53 mutation in the progression from atypical ductal hyperplasia to invasive cancer, and to evaluate the patterns of p53 mutations in noninvasive and invasive lesions. Available lesions of invasive (n=88) and noninvasive (n=76) lesions were microdissected in 107 paraffin-embedded tissues (19 ductal carcinomas in situ, 57 invasive carcinomas with intraductal components, and 31 pure invasive carcinomas) and double-strand DNA sequencing was performed in exon 4-9 of the p53 gene.

Among in situ cancers without invasive disease 36.8% had p53 mutations whereas in situ cancer with concurrent invasive disease showed p53 mutations in 33.3% of cases. In particular, two of seven atypical ductal hyperplasias harbored p53 alterations (one insertion and one missense mutation) in exon 8. The invasive component harbored p53 mutations in 30 of 88 cases (34.1%).

We also discovered a novel deletion of 14 bp in exon 6 of two invasive lesions. The invasive component (1.33+/-0.13) carried a greater number of p53 mutations than its counterparts (1.19+/-0.10) and demonstrated more frequent multiple mutations (23.3% vs. 15.4%), but without statistical significance. Moreover, no statistical significance could be attached to the mutation frequency in the zinc-binding domains (26.7% vs. 15.4%), the directly DNA contact region (13.3% vs. 15.4%) and the missense mutation of p53 (50.0% vs. 57.7%) of the two groups.

Based on our results, in spite of the small number of the lesions investigated, p53 mutation can occur at the stage of atypical ductal hyperplasia. The hypermutability and the specific p53 mutations involving the biologically functional domain (e.g., zinc binding domain or DNA contact region) have an insignificant influence on invasive progression in the breast cancer.



Atypical ductal hyperplasia in stereotactic breast biopsies: enhanced accuracy of diagnosis with the mammotome.

Joshi M, Duva-Frissora A, Padmanabhan R, Greeley J, Ranjan A, Ferrucci F, Kwon J, Khettry U.

Breast Care Center, Holy Family Hospital, Methuen, Massachusetts, and Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts.

Breast J 2001 Jul-Aug;7(4):207-13 Abstract quote

There is little literature assessing the incidence of subsequent carcinoma in patients diagnosed with atypical ductal hyperplasia (ADH) by mammotome.

We reviewed 216 stereotactic mammotome biopsies (SMBs) and compared the results to the 121 automated tru-cut biopsies (ATC) performed at our breast care center from June 1994 to July 1998. The median age in the mammotome series was 57 years, compared to 56 years in the ATC group. An increase in biopsies for microcalcifications (49% versus 41%) was noted in the SMB series. This was accompanied by an increase in the number of cases with a diagnosis of pure ductal carcinoma in situ (DCIS) (10% versus 4%). Compared to the tru-cut, in which 38% (3 of 8) of the cases diagnosed as atypical hyperplasia (AH) showed DCIS and/or invasive carcinoma on open biopsy, none of the cases diagnosed as AH on mammotome revealed carcinoma on open biopsy.

ADH is more accurately diagnosed with SMB than by the ATC method and may not be an indication for subsequent open biopsy.


Atypical ductal hyperplasia diagnosis by directional vacuum-assisted stereotactic biopsy of breast microcalcifications. Considerations for surgical excision.

Sneige N, Lim SC, Whitman GJ, Krishnamurthy S, Sahin AA, Smith TL, Stelling CB.

Department of Pathology, University of Texas M.D. Anderson Cancer Center, Unit 53, 1515 Holcombe Blvd, Houston, TX 77030, USA.


Am J Clin Pathol 2003 Feb;119(2):248-53 Abstract quote

In 824 patients who underwent directional vacuum-assisted biopsies (DVABs) of breast microcalcifications, 61 (7.4%) showed atypical ductal hyperplasia (ADH). The 42 who subsequently underwent excision were the subjects of this study.

Cases were evaluated for the mammographic characteristics of the lesion, the percentage of lesion removed according to mammography, and histologic findings (including number of large ducts and/or terminal duct-lobular units involved with ADH) in DVAB specimens. Pathologic findings in the surgical specimens in the area of the biopsy site also were recorded. In the DVAB specimens, ADH was confined to an average of 1.5 large ducts or lobular units and was associated with microcalcifications in all of the patients. Surgical specimens showed ADH in 15 cases, no residual lesion in 24 cases, and ductal carcinoma in situ in 3 cases.

We found that microcalcifications that contain ADH in less than 3 lobules or ducts and/or that are removed completely by DVAB do not reveal higher-risk lesions on excision; thus, removal is unnecessary.

When assessing microcalcifications with ADH, clinicians should consider the percentage of microcalcifications removed by DVAB and the extent of lobular involvement to better assess the need for excision.


EPITHELIAL HYPERPLASIA Proliferation of epithelial layers usually three or more layers in thickness
ATYPICAL DUCTAL HYPERPLASIA Proliferation of ductal epithelial cells sharing some but not all the features of ductal carcinoma in situ (DCIS)
ATYPICAL LOBULAR HYPERPLASIA Proliferation of lobular cells sharing features of lobular carcinoma in situ (LCIS) but filling or distending less than 50% of the acini within the lobule
SCLEROSING ADENOSIS Increased numbers of benign ducts distorted by sclerosis. Complex sclerosing areas with abundant fibrosis and elastosis are called radical scars or complex sclerosing lesions
PAPILLOMAS Papillomas composed of bland epithelial cells with a well defined fibrovascular core, a basal myoepithelial layer, and intact basement membrane
An Analysis of Breast Cancer Risk in Women With Single, Multiple, and Atypical Papilloma.

Lewis JT, Hartmann LC, Vierkant RA, Maloney SD, Shane Pankratz V, Allers TM, Frost MH, Visscher DW.

Divisions of *Anatomic Pathology daggerMedical Oncology double daggerBiostatistics, Mayo Clinic, Rochester, MN 55905.
Am J Surg Pathol. 2006 Jun;30(6):665-672. Abstract quote  

Breast papillomas may be single or multiple and associated with atypical ductal or lobular hyperplasias (ADH/ALH). The risk of breast carcinoma development in patients with papillomas, particularly those with multiple or atypical lesions, is incompletely defined.

Fibrocystic lesions were histopathologically classified in a benign breast disease cohort of 9155 who underwent biopsy from 1967 to 1991, with papilloma assessment in 9108. Individuals with papillomas (N=480) were classified into 4 groups: single papilloma (SP, N=372), single papilloma with ADH or ALH (SP+A, N=54), multiple (>5) papillomas (MP, N=41), and multiple papillomas with ADH or ALH (MP+A, N=13). Those without papillomas were classified as nonproliferative (NP, N=6053), proliferative without atypia (PDWA, N=2308), and ADH/ALH [atypical hyperplasia (AH), N=267]. The relative risk of cancer development within our cohort was compared to that expected in the general population using standardized incidence ratios. The relative risk of breast cancer development associated with SP [2.04, 95% confidence interval (CI) 1.43-2.81] was greater than NP (1.28, 95% CI 1.16-1.42) but similar to PDWA (1.90, 95% CI 1.66-2.16). The risk associated with SP+A (5.11, 95% CI 2.64-8.92) was highly elevated but not substantively different than atypical hyperplasia (4.17, 95% CI 3.10-5.50). Patients with MP are at increased risk compared with PDWA or SP (3.01, 95% CI 1.10-6.55), particularly those with MP+A (7.01, 95% CI 1.91-17.97). There was a marginal increase in breast cancer risk (16%) among patients with proliferative disease if a papilloma was present, but this did not reach statistical significance (P=0.29). The observed frequency of ipsilateral (vs. contralateral) breast cancer development in papilloma subsets was not significantly different than other patient groups.

We conclude that SP imparts a cancer risk similar to conventional proliferative fibrocystic change. The presence of papilloma in, or associated with, atypia does not modify the risk connotation of ADH/ALH overall. MP constitutes a proliferative breast disease subset having unique clinical and biologic behavior.
Papillary Lesions of the Breast With and Without Atypical Ductal Hyperplasia
Can We Accurately Predict Benign Behavior From Core Needle Biopsy?

S. Nicholas Agoff, MD, and Thomas J. Lawton, MD
Am J Clin Pathol 2004;122:440-443 Abstract quote

Evaluation of papillary lesions of the breast can be difficult, and in core needle biopsy specimens, accurate diagnosis is challenging. Initial studies suggested that all papillary lesions revealed by core biopsy required surgical excision. Recent data suggest that only papillary lesions with atypical ductal hyperplasia (ADH) revealed by core biopsy need surgical excision.

We evaluated our experience at the University of Washington Medical Center, Seattle, with papillary lesions with and without ADH on core biopsy to determine whether diagnostic accuracy can be achieved. In 51 core biopsy specimens, we evaluated the presence or absence of ADH: 25 were benign papillomas; 26 were papillomas with ADH. Surgical follow-up was available for 36 cases (11 papillomas and 25 papillomas with ADH). Clinical (radiologic) follow-up was available in 5 papilloma cases (average follow-up, 35.6 months). Follow-up revealed that all papillomas on core biopsy were benign. Excisional biopsy revealed ductal carcinoma in situ or invasive carcinoma in 12 (48%) of 25 papillary lesions with ADH.

Benign papillomas can be adequately diagnosed with core biopsy. All papillary lesions with ADH require surgical excision owing to the high rate of associated neoplasia.

Improved reporting methods for atypia and atypical ductal hyperplasia in breast core needle biopsy specimens. Potential for interlaboratory comparisons.

Renshaw AA.

Dept of Pathology, Baptist Hospital of Miami, 8900 N Kendall Dr, Miami, FL 33176, USA.

Am J Clin Pathol 2001 Jul;116(1):87-91 Abstract quote

The incidence of atypia and atypical ductal hyperplasia (ADH) in breast core needle biopsies varies widely (900%).

I sought to identify methods to reduce the dependence of this measure on variability in the patient population. The results of all breast core needle biopsies with a diagnosis of ADH or atypia not otherwise specified for a 50-month period were reviewed. These were separated into different groups by age, and the variability of different reporting methods was compared. Of 3,026 cases, 216 were diagnosed as ADH or atypia not otherwise specified.

The overall incidence of atypia by age group varied significantly from 0.029 to 0.10. The variability was reduced when atypia was expressed in relation to ductal carcinoma in situ (range, 1.0-2.1) or fibrocystic changes (range, 0.15-0.28). However, variability by age was the least when atypia was expressed in relation to the number of cases performed for calcifications (range, 0.13-0.17). Variability in atypia rates associated with age is reduced significantly when atypia is expressed in relation to the number of biopsies done for calcifications.

This method of reporting atypia may allow interlaboratory comparisons with less dependence on the characteristics of the patient population.


Pathologic Review of Atypical Hyperplasia Identified by Image-Guided Breast Needle Core Biopsy.

Yeh IT, Dimitrov D, Otto P, Miller AR, Kahlenberg MS, Cruz A.

Departments of Pathology (Drs Yeh and Dimitrov), Radiology (Dr Otto), and Surgery (Drs Miller, Kahlenberg, and Cruz), University of Texas Health Science Center, San Antonio.


Arch Pathol Lab Med 2003 Jan;127(1):49-54 Abstract quote

Context.-Management of breast needle core biopsies diagnosed as atypical ductal hyperplasia, atypical lobular hyperplasia, and lobular carcinoma in situ is controversial. Current recommendations involve excisional biopsy to rule out ductal carcinoma in situ and/or invasive carcinoma, which have been reported in more than 50% of cases in some series.

Objective.-To determine how frequently these diagnoses made on needle core biopsy are ultimately found to represent in situ or invasive carcinoma based on excisional biopsy specimens, in order to identify predictive factors.

Design.-One thousand eight hundred thirty-six image-guided needle core biopsies were performed between January 1, 1995 and May 1, 2001. Fifty-four (2.9%) patients diagnosed with atypical ductal hyperplasia (n = 36), atypical lobular hyperplasia (n = 12), atypical ductal hyperplasia + atypical lobular hyperplasia (n = 3), or lobular carcinoma in situ (n = 3) subsequently underwent breast excisions. Pathologic features were reviewed in each of the needle core biopsies using Page's criteria and were then correlated with excision specimens.

Setting.-University medical center.

Results.-Review of the needle core biopsy cases with either ductal carcinoma in situ or invasive carcinoma + ductal carcinoma in situ on final excision showed that nucleoli were evident in most of the needle core cases, with foci of nuclear pleomorphism and individual cell necrosis or apoptosis.

Conclusion.-A more precise diagnosis can be made by using strict criteria for atypical ductal hyperplasia versus ductal carcinoma in situ on needle core biopsy. Cytologic atypia, even if in a small area, particularly when there is apoptosis/individual cell necrosis, correlates with the finding of a more serious lesion on excision.


Cancerization of lobules and atypical ductal hyperplasia adjacent to ductal carcinoma in situ of the breast.

Goldstein NS, Lacerna M, Vicini F.

Department of Anatomic Pathology, William Beaumont Hospital, Royal Oak, Michigan 48073, USA.

Am J Clin Pathol 1998 Sep;110(3):357-67 Abstract quote

Recurrent carcinoma develops in approximately 10% of patients with ductal carcinoma in situ (DCIS) of the breast treated with local excision and radiation therapy. Cancerization of lobules (COL) and atypical ductal hyperplasia (ADH)frequently occur at the edge of DCIS.

We postulated that recurrent carcinoma is associated with ADH or COL near the DCIS excision margin, and the amount of DCIS left in the breast may be too large for eradication by radiation therapy.

To identify histologic features associated with recurrence, we retrospectively studied specimens of 94 patients with DCIS treated by local excision and radiation. We analyzed the rim of tissue near the final margin for the amount of COL, ADH, and DCIS. During a median follow-up of 78 months, local recurrence developed in 9 patients. COL or ADH with DCIS near the final margin was associated with recurrence; the strongest relationship was with recurrences in the same site as the lumpectomy bed. DCIS with ADH was significantly associated with recurrence in the low-grade DCIS group; DCIS with COL was associated with recurrence in the high-grade group. Other features were not associated with outcome.

We believe that ADH composed of cells identified as those of DCIS should be considered part of the DCIS lesion. DCIS may be inadequately excised if ADH and DCIS or COL and DCIS are near the margin.

Interobserver reproducibility in the diagnosis of flat epithelial atypia of the breast.

O'malley FP, Mohsin SK, Badve S, Bose S, Collins LC, Ennis M, Kleer CG, Pinder SE, Schnitt SJ.

1Mount Sinai Hospital and University of Toronto, Toronto, Ontario, Canada.

Mod Pathol. 2006 Feb;19(2):172-9. Abstract quote  

Columnar cell lesions (CCLs) of the breast with low-grade/monomorphic-type cytologic atypia are being identified increasingly in biopsies performed owing to mammographic microcalcifications. The WHO Working Group on the Pathology and Genetics of Tumours of the Breast recently introduced the term 'flat epithelial atypia' (FEA) for these lesions. However, the ability of pathologists to reproducibly diagnose FEA and to distinguish it from CCLs without atypia has not been previously evaluated. Eight pathologists with an interest in breast pathology participated in a study to address this issue.

The study reference pathologist provided the other seven study pathologists with a Powerpoint tutorial that included written criteria for, and representative images of, FEA and CCLs without atypia (ie, columnar cell change and columnar cell hyperplasia). Following review of the tutorial, the study pathologists examined images in Powerpoint format from 30 CCLs and were instructed to categorize each as either 'FEA' or 'not atypical'. Overall agreement among the eight pathologists was 91.8% (95% CI, 84.0-96.9%), and the multi-rater kappa value was 0.83 (95% CI, 0.67-0.94), which is within the 'excellent agreement' range. Agreement was slightly better for determining absence of FEA (92.8%: 95% CI, 84.1-97.4%), than for determining its presence (90.4%: 95% CI, 79.9-96.7%).

We conclude that the diagnosis of FEA and its distinction from CCLs without atypia is highly reproducible with the use of available diagnostic criteria.
Columnar Cell Lesions of the Breast: The Missing Link in Breast Cancer Progression?: A Morphological and Molecular Analysis.

Simpson PT, Gale T, Reis-Filho JS, Jones C, Parry S, Sloane JP, Hanby A, Pinder SE, Lee AH, Humphreys S, Ellis IO, Lakhani SR.

From the *Breakthrough Toby Robins Breast Cancer Research Centre, Institute of Cancer Research, London, UK; daggerPaediatric Oncology, Institute of Cancer Research, London, UK; double daggerDepartment of Pathology, University of Liverpool, Liverpool, UK; section signDepartment of Histopathology, St James' Hospital, Leeds, UK; parallelDepartment of Histopathology, City Hospital NHS Trust Hospital, Nottingham, UK; paragraph signMedical Solutions, London, UK; #Royal Marsden Hospital, London, UK; and **Molecular & Cellular Pathology, Mayne Medical School, University of Queensland, Queensland Institute of Medical Research and Royal Brisbane and Women's Hospital, Brisbane, Australia.
Am J Surg Pathol. 2005 Jun;29(6):734-746. Abstract quote  

Columnar cell lesions (CCLs) of the breast are a spectrum of lesions that have posed difficulties to pathologists for many years, prompting discussion concerning their biologic and clinical significance.

We present a study of CCL in context with hyperplasia of usual type (HUT) and the more advanced lesions ductal carcinoma in situ (DCIS) and invasive ductal carcinoma. A total of 81 lesions from 18 patients were subjected to a comprehensive morphologic review based upon a modified version of Schnitt's classification system for CCL, immunophenotypic analysis (estrogen receptor [ER], progesterone receptor [PgR], Her2/neu, cytokeratin 5/6 [CK5/6], cytokeratin 14 [CK14], E-cadherin, p53) and for the first time, a whole genome molecular analysis by comparative genomic hybridization. Multiple CCLs from 3 patients were studied in particular detail, with topographic information and/or showing a morphologic spectrum of CCL within individual terminal duct lobular units. CCLs were ER and PgR positive, CK5/6 and CK14 negative, exhibit low numbers of genetic alterations and recurrent 16q loss, features that are similar to those of low grade in situ and invasive carcinoma.

The molecular genetic profiles closely reflect the degree of proliferation and atypia in CCL, indicating some of these lesions represent both a morphologic and molecular continuum. In addition, overlapping chromosomal alterations between CCL and more advanced lesions within individual terminal duct lobular units suggest a commonality in molecular evolution.

These data further support the hypothesis that CCLs are a nonobligate, intermediary step in the development of some forms of low grade in situ and invasive carcinoma.

Atypical ductal hyperplasia and ductal carcinoma in situ of the breast associated with perineural invasion.

Gobbi H, Jensen RA, Simpson JF, Olson SJ, Page DL.

Division of Anatomical Pathology, Vanderbilt University Medical Center, Nashville, TN 37232-2561, USA.

Hum Pathol 2001 Aug;32(8):785-90 Abstract quote

Perineural invasion is a histologic feature usually diagnostic of invasion in malignancies. In the breast, however, it has been associated with benign lesions such as sclerosing adenosis (SA), complex sclerosing lesion/radial scar (CSL/RS), and ductal carcinoma in situ (DCIS).

This article describes perineural invasion associated with atypical ductal hyperplasia (ADH), florid hyperplasia without atypia (FH), and DCIS. All cases with a diagnosis of perineural invasion were selected from a series of 10,000 breast consult cases. Invasive mammary carcinomas were excluded.

Fourteen cases of perineural invasion were found and associated with the following diagnoses: ADH (5), DCIS (3), FH (5), and ductal adenoma (1). Nine cases developed in CSL/RS, 4 cases in SA, and 1 case in a previous biopsy site of ductal adenoma; lesions were all less than 3 mm. The glands involving nerves showed cytologic and architectural features of the adjacent ADH, DCIS, and FH. Immunostaining for protein gene product (PGP) 9.5 marked nerves, and smooth muscle actin antibody highlighted the myoepithelial cells around glands.

Perineural invasion seen in association with DCIS and ADH, in a background of CSL/RS and SA, may pose difficulty in diagnosis, especially in small biopsy specimens. It should be assessed with care to avoid misinterpretation as invasive mammary carcinoma.


CYCLIN D1/Ki-67  
Immunohistochemical Staining for Cyclin D1 and Ki-67 Aids in the Stratification of Atypical Ductal Hyperplasia Diagnosed on Breast Core Biopsy

Omar Hameed, MBChB, etal
Am J Clin Pathol 2005;124:862-872
Abstract quote

A diagnosis of atypical ductal hyperplasia (ADH) after breast core biopsy usually is followed by an excisional biopsy to exclude the presence of a more significant lesion. To determine whether the immunohistochemical expression of cyclin D1 (CyD1) and Ki-67 can aid in case stratification for the likelihood of finding ductal carcinoma in situ (DCIS) on subsequent excision, we immunohistochemically stained 21 consecutive ADH cases diagnosed by core biopsy, and proliferation indices (PIs) were calculated for each case.

Fluorescence in situ hybridization to detect CCND1 amplification was performed in 10 cases. In 5 cases, DCIS (with or without invasive carcinoma) was identified in the subsequent excision. The mean PICyD1 and PIKi-67 for these cases were significantly higher than in the remainder (P = .03 and P = .05, respectively). The sensitivities of PICyD1 and PIKi-67 for the presence of DCIS on subsequent excision were 100%, and the specificities were 75% and 69%, respectively. The specificity of the 2 markers combined was 88%. The number of cells with CCND1 amplification was higher in cases with DCIS or ADH on subsequent excision.

Immunostaining for CyD1 and Ki-67 might help stratify cases of ADH on core biopsy and identify patients unlikely to have DCIS found on excision.


Histopathologic analysis of atypical lesions in image-guided core breast biopsies.

Bonnett M, Wallis T, Rossmann M, Pernick NL, Bouwman D, Carolin KA, Visscher D.

Departments of Pathology (MB, TW), Surgery (DB, KAC), and Radiology (MR), Karmanos Cancer Institute and Wayne State University School of Medicine, Detroit, Michigan.


Mod Pathol 2003 Feb;16(2):154-60 Abstract quote

Appropriate follow-up of patients with needle core breast biopsies (NCBB) showing atypical hyperplasia remains unclear because previous studies show that subsequent open biopsies in variable proportions of these patients reveal ductal carcinoma in situ (DCIS) or even invasive carcinoma, indicating significant sampling artifact. NCBB with diagnoses of atypia were morphologically classified into groups as follows: I, ALH (n = 24); II, ADH with minimal cytologic atypism (n = 90); III, atypia, other (9 columnar, 2 apocrine, 11 atypical papillary); IV, severe ADH/borderline DCIS (n = 31). Mammographic and histologic features, including the number of foci of atypia in the NCBB and the calcification span, were then correlated with presence of DCIS or invasive tumor in subsequent open excisions.

Open excisional biopsies showed more severe lesions in 12% of Group I-III cases (8% in Group I, 9% in Group II, and 27% in Group III), of which 15 were DCIS and one was an invasive tubular carcinoma (0.3 cm). Of the DCIS, 60% (n = 9) were </=5 mm, and 13 of 15 (87%) were low grade. The NCBB cavity was immediately adjacent to the more severe lesions in 88% (n = 14) of cases, in keeping with sampling error. The subset showing severe ADH with borderline nuclear features in contrast was associated with a high likelihood (63%) of DCIS in follow-up excisions. NCBB with atypical papillary features also showed a high frequency of DCIS (4/11, 36%) in subsequent open excisions. Other factors associated with more severe lesions on open biopsy included the number of atypical foci in the NCBB (>4, P <.05) and the mammographic calcification span (>2.0 cm, P <.0001).

Atypical lesions diagnosed in NCBB samples are radiographically and morphologically heterogeneous, accounting for the variable frequency of DCIS or invasive neoplasm identified in subsequent open excisions, which are usually focal, low grade, and a consequence of sampling artifact (i.e., adjacent to the NCBB cavity). DCIS is more likely if microcalcifications are mammographically extensive or if atypia is multifocal or is associated with borderline cytologic features.

Risk factors for breast cancer in women with proliferative breast disease.

Dupont WD, Page DL.

N Engl J Med 1985 Jan 17;312(3):146-51 Abstract quote

To assess the importance of various risk factors for breast cancer in women with benign proliferative breast lesions, we reevaluated 10,366 consecutive breast biopsies performed in women who had presented at three Nashville hospitals.

The median duration of follow-up was 17 years for 3303 women, 1925 of whom had proliferative disease. This sample contained 84.4 per cent of the patients originally selected for follow-up.

Women having proliferative disease without atypical hyperplasia had a risk of cancer that was 1.9 times the risk in women with nonproliferative lesions (95 per cent confidence interval, 1.2 to 2.9). The risk in women with atypical hyperplasia (atypia) was 5.3 times that in women with nonproliferative lesions (95 per cent confidence interval, 3.1 to 8.8). A family history of breast cancer had little effect on the risk in women with nonproliferative lesions. However, the risk in women with atypia and a family history of breast cancer was 11 times that in women who had nonproliferative lesions without a family history (95 per cent confidence interval, 5.5 to 24). Calcification elevated the cancer risk in patients with proliferative disease. Although cysts alone did not substantially elevate the risk, women with both cysts and a family history of breast cancer had a risk 2.7 times higher than that for women without either of these risk factors (95 per cent confidence interval, 1.5 to 4.6).

This study demonstrates that the majority of women (70 per cent) who undergo breast biopsy for benign disease are not at increased risk of cancer. However, patients with a clinically meaningful elevation in cancer risk can be identified on the basis of atypical hyperplasia and a family history of breast cancer.

Atypical hyperplastic lesions of the female breast. A long-term follow-up study.

Page DL, Dupont WD, Rogers LW, Rados MS.

Cancer 1985 Jun 1;55(11):2698-708 Abstract quote

A total of 10,542 breast biopsy specimens obtained between 1950 and 1968 were studied.

Examples of atypical "ductal" (ADH) and atypical lobular hyperplasia (ALH), defined as having only some features of carcinoma in situ (CIS), were diagnosed in 3.6% of these specimens. In the same series, CIS was diagnosed in 1.7% of biopsy specimens excluding those with invasive cancer.

The subsequent risk of invasive breast carcinoma after ALH or ADH was 4-5 times that of the general population. Follow-up was 90% successful and extended 17 years after biopsy. History of breast cancer in a mother, sister, or daughter doubled the risk of subsequent invasive carcinoma development (to 8 times for ALH and 10 times for ADH).

The authors conclude that among the epithelial hyperplastic lesions of the human breast, a minority may be recognized by their resemblance to CIS which have a clinically significant elevation of subsequent breast cancer risk. This risk is one-half that of CIS.

Breast cancer risk associated with proliferative disease, age at first birth, and a family history of breast cancer.

Dupont WD, Page DL.

Am J Epidemiol 1987 May;125(5):769-79 Abstract quote

The authors reevaluated 10,542 consecutive breast biopsies of women who presented at three Nashville hospitals.

Median follow-up was 17 years for 3,398 women (84.4% of patients originally selected for follow-up). Breast cancer relative risks associated with no proliferative disease, proliferative disease without atypia, and atypical hyperplasia were 0.80, 1.4, and 4.0 times that for women from the Cancer in Connecticut data base, respectively (adjusted for age at biopsy, year of biopsy, and length of follow-up).

Nulliparous women were at increased risk of breast cancer (relative risk = 1.6; 95% confidence interval (CI) = 1.1-2.2). Women who gave birth to their first child before age 21 years had a relative risk of 0.80, with higher cancer risks associated with later age at first birth. The effect of age at first birth on cancer risk followed a similar pattern within the no proliferative disease, proliferative disease without atypia, and atypical hyperplasia groups. Nulliparous women with atypical hyperplasia had a relative risk of 4.9 (95% CI = 2.7-8.9), while women with no proliferative disease who gave birth before age 21 years had a relative risk of 0.50 (95% CI = 0.19-1.3). Nulliparous women with a family history of breast cancer had a relative risk of 2.7 (95% CI = 1.4-5.2). Women with a family history who first gave birth by age 20, between ages 21 and 29, and after age 30 years had relative risks of 0.53, 2.1, and 4.0, respectively (95% CI = 0.08-3.8, 1.1-3.9, and 1.8-9.6, respectively). Breast size had no effect on cancer risk in women without proliferative disease. However, in women with proliferative disease, small, medium, and large breasts were associated with relative risks of 1.2, 1.4, and 2.1, respectively.

A prospective study of the development of breast cancer in 16,692 women with benign breast disease.

Carter CL, Corle DK, Micozzi MS, Schatzkin A, Taylor PR.

Cancer Prevention Studies Branch, National Cancer Institute, Bethesda, MD 20892-4200.

Am J Epidemiol 1988 Sep;128(3):467-77 Abstract quote

The authors studied the relation between benign breast disease and subsequent breast cancer in 16,692 women with biopsy-diagnosed benign breast disease who had participated in the Breast Cancer Detection Demonstration Project throughout the United States.

Women were classified into one of five benign breast disease categories: atypical hyperplasia, proliferative disease without atypia, nonproliferative disease, fibroadenoma, and other benign breast disease. A total of 485 incident cases of breast cancer were identified in the women from August 1973 to February 1986 after a median follow-up period of 8.3 years from the diagnosis of benign breast disease. Age-adjusted incidence rates were calculated for benign breast disease types stratified by family history and calcification status. Relative risk (RR) estimates of breast cancer for women in the five benign breast disease categories, compared with the screened women who did not develop recognizable breast disease (normal subjects), were computed using the proportional hazards model. Results indicated that risk was associated with the degree of epithelial atypia.

Over all age groups, women with nonproliferative disease, proliferative disease without atypia, and atypical hyperplasia displayed progressively increasing risks of 1.5, 1.9, and 3.0, respectively, compared with normal subjects, with 95% confidence intervals (CI) exceeding unity. Particularly high risk was seen among women under age 46 years with atypical hyperplasia (RR = 5.7, 95% CI 3.0-10.6). Women with fibroadenoma as the only indication of their benign breast disease had a relative risk of 1.7, with a lower 95% confidence limit of 1.0. No increased risk was seen for women with other benign breast disease. Positive family history (RR = 1.8) and calcification (RR = 1.2) significantly increased a woman's risk proportionately over the risk associated with each benign breast disease subtype.

The authors conclude that the risk of developing breast cancer varies by category of benign breast disease and is directly related to the degree of epithelial atypia.

Invasive breast cancer risk in women with sclerosing adenosis.

Jensen RA, Page DL, Dupont WD, Rogers LW.

Department of Pathology, Vanderbilt University Medical School, Nashville, Tennessee 37232.

Cancer 1989 Nov 15;64(10):1977-83 Abstract quote

To assess sclerosing adenosis (SA) as an independent risk factor for subsequent invasive breast cancer (IBC), the authors reviewed 10,366 benign breast biopsy specimens (BB) obtained between 1950 and 1968 and identified 547 cases of SA meeting strict histologic criteria of expanded lobular units with whorled compressed acini. Of those women targeted for follow-up (3303, of whom 349 had SA), 84% were successfully followed for an average of 17 years.

The relative risk for IBC among patients with SA regardless of the presence of atypical hyperplasia (AH) was 2.1. This risk decreased to 1.7 when patients with AH were excluded, and rose to 6.7 when only those patients with SA and AH were analyzed. The coexistence of a family history of IBC in a first-degree relative did not further elevate risk above that of SA alone when women with AH were excluded.

Sclerosing adenosis was found to be positively associated with atypical lobular hyperplasia (ALH) as ALH was present in biopsy specimens with SA 2.7 times more frequently than in other biopsy specimens.

Perimenopausal age, histologic calcification, and family history of IBC (FH) were also positively associated with SA. Sclerosing adenosis was most frequent in the perimenopausal period and had a weak association with family history of IBC. No association with atypical ductal hyperplasia (ADH) was identified.

The authors conclude sclerosing adenosis represents an independent risk factor for subsequent invasive breast cancer apart from its association with ALH, and the risk (excluding patients with coexistent atypical hyperplasia) is in the range of 1.7, times thereby justifying inclusion of sclerosing adenosis as a component of a group of histopathologically defined lesions termed "proliferative breast disease without atypia" which implies a relative cancer risk of 1.5 to 2.0.

A comparison of the results of long-term follow-up for atypical intraductal hyperplasia and intraductal hyperplasia of the breast.

Tavassoli FA, Norris HJ.

Department of Gynecologic and Breast Pathology, Armed Forces Institute of Pathology, Washington, D.C. 20306-6000.

Cancer 1990 Feb 1;65(3):518-29 Abstract quote

Follow-up information was obtained on 199 women with breast biopsy specimens containing intraductal epithelial proliferation.

The proliferations were divided into regular or ordinary intraductal hyperplasia (IDH) (117 cases) and atypical intraductal hyperplasia (AIDH) (82 cases). The average length of follow-up was 14 years for the patients with IDH and 12.4 years for the patients with AIDH.

Of the 117 patients with ordinary IDH, carcinoma subsequently developed in six (5%); three of these were invasive carcinomas (2.6%). All three invasive carcinomas were in the ipsilateral breast, but of the three intraductal carcinomas (IDCa), two were in the contralateral breast. Of the 82 patients with AIDH, invasive carcinoma subsequently developed in eight (9.8%); six of these were located in the ipsilateral breast and two in the contralateral breast. One of these six patients died of disseminated carcinoma.

The average interval to the subsequent carcinoma (intraductal and invasive carcinoma) was about the same in the two groups (8.3 years for AIDH and 8.8 years for IDH lacking atypia). When considering only subsequent invasive carcinomas, the interval was 8.3 years for the AIDH and 14.3 years for the IDH lacking atypia. Of the 14 patients with IDH and a family history of breast carcinoma, invasive carcinoma subsequently developed in one (7%) as compared with two (2%) of the 91 with a negative family history. Among patients with AIDH, invasive carcinoma subsequently developed in two of the 13 (15%) of those with a family history of breast carcinoma as compared with one of 57 (1.8%) of the women with a negative family history.

The presence of atypia in epithelial hyperplasia is a significant factor in increasing the likelihood of the development of subsequent invasive carcinoma (P = 0.03; two-tailed test).

Of women with AIDH, invasive carcinoma subsequently developed in 17% of those with sclerosing adenosis (SA) as compared with 4.2% of those without it.

Therefore, SA may be a contributing factor to increased risk. A positive family history also appears to increase the likelihood of the subsequent development of invasive carcinoma, particularly in patients with AIDH.

Histologic types of benign breast disease and the risk for breast cancer.

The Cancer and Steroid Hormone Study Group.

McDivitt RW, Stevens JA, Lee NC, Wingo PA, Rubin GL, Gersell D.

Division of Anatomic Pathology, Washington School of Medicine, St. Louis, Missouri.

Cancer 1992 Mar 15;69(6):1408-14 Abstract quote

Specific histologic types of benign breast disease (BBD) may increase breast cancer risk.

The authors analyzed data from a population-based, case-control study of women aged 20 to 54 with newly diagnosed breast cancer and control subjects randomly selected from the general population. A panel of pathologists classified the histologic findings of biopsy slides for 433 women with breast cancer and 261 control subjects, all of whom had a history of biopsy for BBD, as to the presence of epithelial hyperplasia, atypia, and other histologic features.

When compared with women who had never had a breast biopsy, women with BBD without hyperplasia had an odds ratio of 1.5 (95% confidence limits [CL] 1.3 to 1.9), women with hyperplasia without atypia had an odds ratio of 1.8 (CL = 1.3, 2.4), and women with hyperplasia and atypia had an odds ratio of 2.6 (CL = 1.6, 4.1). Fibroadenoma was an independent risk factor for breast cancer (odds ratio = 1.7; CL = 1.1, 2.5).

These findings suggest that women with BBD with epithelial hyperplasia either with or without atypia and women with fibroadenoma should be monitored carefully because of their elevated risk for breast cancer.

Breast cancer risk associated with proliferative breast disease and atypical hyperplasia.

Dupont WD, Parl FF, Hartmann WH, Brinton LA, Winfield AC, Worrell JA, Schuyler PA, Plummer WD.

Department of Preventive Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-2637.

Cancer 1993 Feb 15;71(4):1258-65 Abstract quote

BACKGROUND. Women with proliferative breast disease (PD) have been observed to have an increased risk of breast cancer. The authors evaluated the effect of PD on breast cancer risk in a case-control study among participants of the Breast Cancer Detection Demonstration Project (BCDDP).

METHODS. More than 280,000 women were screened in the BCDDP at 29 centers. Study subjects were selected from BCDDP participants who underwent biopsy that revealed benign breast tissue. There were five BCDDP centers for which histologic slides were available on more than 85% of the benign biopsy specimens. Case patients for this study were the 95 women from these five centers who had breast cancer develop during follow-up. Two matched control patients who did not have breast cancer develop were selected for each case. The biopsy slides were reviewed by two pathologists who were blinded with regard to cancer outcome.

RESULTS. Women with atypical hyperplasia (AH) had 4.3 times the breast cancer risk of women without PD (95% confidence interval [CI], 1.7-11). In women with PD lacking AH, the relative risk was 1.3 (95% CI, 0.77-2.2). A family history of breast cancer (FH) increased breast cancer risk 2.4 times (95% CI, 1.4-4.3). The joint occurrence of FH and AH had a strong synergistic effect on breast cancer risk.

CONCLUSIONS. AH is a reliable marker of increased breast cancer risk among women undergoing breast biopsy.

Prognostic significance of benign proliferative breast disease.

Bodian CA, Perzin KH, Lattes R, Hoffmann P, Abernathy TG.

Department of Biomethematical Sciences, Mount Sinai Medical Center, New York, New York 10029.

Cancer 1993 Jun 15;71(12):3896-907 Abstract quote

BACKGROUND. Recent studies concerning an association between benign breast diseases and risk of subsequent breast cancer have focused on benign proliferative lesions recognized in biopsy specimens. Some have implicated atypical hyperplasia as being associated with the greatest risk.

METHODS. The histologic sections of specified benign breast lesions from 1799 women were reviewed and reclassified, using published criteria for proliferative disease. Prognostic significance was assessed by relating the pathologic findings to the development of breast cancer observed during an average 21 years of follow-up, in which time 157 women developed the disease.

RESULTS. Benign proliferative changes were recognized in 85% of the patients, with a corresponding relative risk of subsequent carcinoma equal to 2.2 times population rates (95% confidence limits, 1.9 and 2.6). Increasing levels of hyperplasia and atypia in lobules or ducts were associated with modest increases in risk, ranging from 2.1 to 2.3 to 3.0 for proliferative changes with no atypia, mild atypia, and moderate to severe atypia, respectively. This trend was not statistically significant. The most significant risk indicators in this study were the presence of adenosis (relative risk, 3.7), and moderate or severe atypia in ducts (relative risk, 3.9).

CONCLUSIONS. Benign proliferative breast disease recognized in biopsy specimens is associated with an increased risk of future breast cancer, but fine distinctions among levels of hyperplasia and atypia did not significantly distinguish risk among patients in this study.


Atypical apocrine adenosis of the breast: a clinicopathologic study of 37 patients with 8.7-year follow-up.

Seidman JD, Ashton M, Lefkowitz M.

Department of Gynecologic and Breast Pathology, Armed Forces Institute of Pathology, Washington, DC, USA.

Cancer 1996 Jun 15;77(12):2529-37 Abstract quote

BACKGROUND: Apocrine metaplasia is occasionally superimposed on sclerosing adenosis (apocrine adenosis) in breast biopsies, and cytologic atypia is sometimes present (atypical apocrine adenosis). The long term risk of patients developing breast carcinoma subsequent to the diagnosis of this lesion is unknown.

METHODS: Atypical apocrine adenosis was defined as apocrine adenosis with enlarged nucleoli and a greater than threefold variation in nuclear area. Lesions with recognizable cytoarchitectural patterns of intraductal carcinoma were excluded. Surveillance, Epidemiology and End Results (SEER) data were used as the reference population for calculations of relative risk.

RESULTS: Thirty-seven women with atypical apocrine adenosis had a mean follow-up of 8.7 years. Four patients developed invasive ductal carcinoma of the breast (3 ipsilateral, 1 contralateral) after a mean of 5.6 years. The relative risk of developing carcinoma was 5.5 (95% confidence interval [CI], 1.9-16). All patients who developed carcinoma were older than age 60 at the time of breast biopsy showing atypical apocrine adenosis, and carcinoma developed at a mean age of 70 years. In the older than 60 years age group (11 patients), the relative risk of developing carcinoma was 14 (95% CI, 4.1-48).

CONCLUSIONS: Atypical apocrine adenosis confers an increased risk of developing breast carcinoma in women older than age 60, and the risk in younger women is probably low. Some cases of atypical apocrine adenosis may represent in situ apocrine carcinomas that are difficult to diagnose because of the absence of the usual architectural features of intraductal carcinoma.


Carcinoma and atypical hyperplasia in radial scars and complex sclerosing lesions: importance of lesion size and patient age.

Sloane JP, Mayers MM.

Department of Histopathology, Royal Marsden Hospital, Sutton, Surrey, UK.

Histopathology 1993 Sep;23(3):225-31 Abstract quote

One hundred and twenty-six radial scars and complex sclerosing lesions from 91 women were examined to determine the incidence of and the clinical and pathological factors associated with the development of carcinoma and atypical hyperplasia within them.

There was a clear relationship between the presence of carcinoma and atypical hyperplasia and the size of the lesion. This was not, however, a progressive relationship, there being a cut-off point about 6-7 mm, below which carcinoma was very uncommon and above which it was relatively frequent. A similar relationship was seen with patient age. Carcinoma was not seen in lesions removed from women under 40, was rare in the decade 41-50 and was relatively common above this age but with no further increase in the over 60s.

A significantly higher incidence of carcinoma and atypical hyperplasia was encountered in scars detected by mammographic screening and could be explained by lesion size and the ages of the patients from which they were removed.

No relationship was found between the presence of carcinoma within radial scars and complex sclerosing lesions and the existence of carcinoma in the residual breast tissue when direct extension was excluded.

The carcinomas identified in the scars were of variable type and included small and large cell ductal carcinoma in situ, lobular carcinoma in situ and invasive carcinoma of tubular and ductal types. In situ carcinoma and atypical hyperplasia involved a very variable percentage of the epithelium of the lesions with mean values for ductal carcinoma in situ of 32%, lobular carcinoma in situ 25% and atypical hyperplasia 25%.


Ductal involvement by cells of atypical lobular hyperplasia in the breast: a long-term follow-up study of cancer risk.

Page DL, Dupont WD, Rogers LW.

Department of Pathology, Vanderbilt University Medical Center, Nashville, TN 37232.

Hum Pathol 1988 Feb;19(2):201-7 Abstract quote

A cohort study of women with ductal involvement by cells of atypical lobular hyperplasia (DIALH) revealed an incidence of 1.4% in benign biopsy specimens.

When combined with diagnostic lobular unit alterations of atypical lobular hyperplasia (ALH), a consequent risk of invasive carcinoma of 6.8 times that in the general population was found. This relative risk for women with ALH and DIALH approaches the risk for lobular carcinoma in situ, whereas the risk for ALH with or without DIALH is 4.3 and the risk for ALH without DIALH is reduced to 2.7. Only definitive changes of DIALH with an insinuated characteristic population of cells between attenuated luminal cells and basement membrane should be so diagnosed.

DIALH in association with lobular alterations that are borderline with regard to a diagnosis of lobular carcinoma in situ will increase the certainty that a medically meaningful increased risk for subsequent invasive cancer is indicated.

Prognostic Significance of Estrogen Receptor Beta in Epithelial Hyperplasia of Usual Type With Known Outcome.

Shaaban AM, Jarvis C, Moore F, West C, Dodson A, Foster CS.

From the Departments of *Cellular and Molecular Pathology and daggerPublic Health, University of Liverpool, Liverpool, U.K.

Am J Surg Pathol. 2005 Dec;29(12):1593-1599. Abstract quote  

The prognostic significance of ER-alpha expression in benign proliferative breast disease has been confirmed in epithelial hyperplasia of usual type (HUT). However, little is known about the role of ER-beta in these lesions.

Therefore, this study was performed to test the hypothesis that, in HUT lesions, the ratio of ER-alpha:ER-beta is an accurate determinant of breast cancer risk and of predicting subsequent progression to invasive breast cancer.

This case-control study analyzed a cohort of benign proliferative breast lesions and foci of ductal HUT in 117 patients with long follow-up (20 years). These foci were analyzed by morphometric image analysis together with immunohistochemistry using monoclonal antibodies to ER-beta1 and to ER-alpha. The data were compared with ER-beta expression in all breast carcinomas that subsequently developed in the same patients as well as to ER-alpha expression in the corresponding tissues. In cases that progressed to carcinoma, the ratio of ER-alpha to ER-beta in HUT was significantly higher (P < 0.001) than in those that did not progress. None of the HUT foci from patients who progressed to breast cancer were simultaneously ER-alpha negative and ER-beta positive. Using both ER-beta and ER-alpha in a logistic model demonstrated a 75% correct classification rate for the cohort studied.

These findings confirm the diagnostic and prognostic value of defining the ER-alpha and ER-beta status of HUT lesions identified morphologically. The data support the hypothesis that high ER-alpha:ER-beta levels characterize those cases within HUT likely to progress to breast cancer. The data also reveal that a reduced level of ER-beta relative to ER-alpha is an accurate predictor of individual cases of HUT likely to progress to invasive breast carcinoma, thus supporting the concept that ER-alpha transcriptional activity is directly modulated by ER-beta.

No elevation in long-term breast carcinoma risk for women with fibroadenomas that contain atypical hyperplasia.

Carter BA, Page DL, Schuyler P, Parl FF, Simpson JF, Jensen RA, Dupont WD.

Department of Laboratory and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada.

Cancer 2001 Jul 1;92(1):30-6 Abstract quote

BACKGROUND: The authors previously showed that women with a fibroadenoma have a relative risk of invasive breast carcinoma of approximately 2.0 compared with women of similar age from the general population. This relative risk approaches 1.0 when family history and proliferative changes in the adjacent parenchyma are removed and rises to > 3.0 if the fibroadenoma has complex histology. The risk for developing breast carcinoma in women with atypical lobular hyperplasia (ALH) and atypical ductal hyperplasia (ADH) or their minimal variants within a fibroadenoma is unknown.

METHODS: The authors conducted a long-term, retrospective cohort study of 1834 women with adequate follow-up who presented with fibroadenoma at three local hospitals between 1950 and 1968. Histology was reviewed using established criteria, and the patients were categorized with ALH, ADH, minimal atypia, or no atypia.

RESULTS: The overall prevalence of ALH or ADH within fibroadenomas was 0.81%. Minimal or true atypia within a fibroadenoma appeared to be correlated with proliferative disease in the adjacent parenchyma but could not predict for the presence there of well-established atypia. Only 7% of women with well-developed atypia developed invasive carcinoma on follow-up. Three women with minimal atypia developed invasive carcinoma.

CONCLUSIONS: In this study of a large cohort of women with fibroadenoma, the authors found that atypia within a fibroadenoma cannot predict for the presence of atypia within adjacent breast parenchyma. They also found that atypia confined to a fibroadenoma does not incur a clinically meaningful risk of future breast carcinoma development greater than that of fibroadenoma alone.


Estrogen replacement therapy in women with a history of proliferative breast disease.

Dupont WD, Page DL, Parl FF, Plummer WD Jr, Schuyler PA, Kasami M, Jensen RA.

Department of Preventive Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-2637, USA.

Cancer 1999 Mar 15;85(6):1277-83 Abstract quote

BACKGROUND: Little information is available regarding the invasive breast carcinoma risk associated with estrogen replacement therapy (ERT) in women with histories of histologically defined breast lesions.

METHODS: A retrospective cohort study of a consecutive series of women who underwent breast biopsies that proved to be benign between 1952-1978 was conducted. Follow-up data were obtained for 9494 women (87.6% of women eligible for follow-up). To investigate the effect of ERT on invasive breast carcinoma risk, the analysis was restricted to women with premenopausal breast disease whose follow-up extended through menopause and who did not develop premenopausal breast carcinoma. Relative risks were calculated with respect to women who took ERT but whose benign breast biopsies had neither atypical hyperplasia (AH), complex fibroadenoma (CFA), nor proliferative disease without atypia (PDWA).

RESULTS: During 190,845 woman-years of follow-up there were 444 confirmed cases of invasive breast carcinoma in the entire cohort. Women with a history of AH had relative risks of invasive breast carcinoma of 2.87 (95% confidence interval [95% CI], 1.3-6.3) and 2.53 (95% CI, 1.0-6.3) if they did or did not take ERT, respectively. For women with a history of CFA these risks were 1.57 (95% CI, 0.72-3.4) and 1.46 (95% CI, 0.53-4.0), respectively, whereas for women with a history of PDWA they were 1.37 (95% CI, 0.88-2.1) and 1.13 (95% CI, 0.69-1.9), respectively.

CONCLUSIONS: ERT does not significantly elevate the risk of invasive breast carcinoma in women with previous histologically defined benign breast disease. Therefore, ERT is not contraindicated in these women.

Biopsy confirmed benign breast disease, postmenopausal use of exogenous female hormones, and breast carcinoma risk.

Byrne C, Connolly JL, Colditz GA, Schnitt SJ.

Channing Laboratory, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA.

Cancer 2000 Nov 15;89(10):2046-52 Abstract quote

BACKGROUND: A history of proliferative benign breast disease has been shown to increase the risk of developing breast carcinoma, but, to the authors' knowledge, how postmenopausal exogenous female hormone use, in general, has affected breast carcinoma risk among women with a history of proliferative breast disease with or without atypia has not been well established.

METHODS: In the current case-control study, nested within the Nurses' Health Study, benign breast biopsy slides of 133 postmenopausal breast carcinoma cases and 610 controls with a history of benign breast disease, were reviewed. Reviewers had no knowledge of case status.

RESULTS: Women with proliferative disease without atypia had a relative risk for postmenopausal breast carcinoma of 1.8 (95%, confidence interval [CI]: 1.1 to 2.8), and women with atypical hyperplasia had a relative risk of 3.6 (95%, CI: 2.0 to 6.4) compared with women who had nonproliferative benign histology. Neither current postmenopausal use of exogenous female hormones nor long term use for 5 or more years further increased the risk of breast carcinoma in the study population beyond that already associated with their benign histology.

CONCLUSIONS: Women who had proliferative benign breast disease, with or without atypia, were at moderately to substantially increased risk of developing postmenopausal breast carcinoma compared with women who had nonproliferative benign conditions. In the current study, postmenopausal exogenous female hormone use in general did not further increase the breast carcinoma risk for women with proliferative benign breast disease. However, the analysis did not exclude the possibility of increased risk with a particular hormone combination or dosage.

Atypical hyperplasia, proliferative fibrocystic change, and exogenous hormone use.

Zera RT, Danielson D, Van Camp JM, Schmidt-Steinbrunn B, Hong J, McCoy M, Anderson WR, Linzie BM, Rodriguez JL.

Departments of Surgery and Pathology, Hennepin County Medical Center, affiliated with the University of Minnesota Medical School, Minneapolis, Minn.

Surgery 2001 Oct;130(4):732-7 Abstract quote

Background. The association between breast cancer development and exogenous hormone use (EHU) is suggested by indirect clinical evidence. We undertook this study to better define the relationship that EHU has with proliferative fibrocystic change (PFC) and atypical hyperplasia (AH).

Methods. Women diagnosed with AH without associated carcinoma from January 1990 to December 1999 were compared with control subjects who underwent breast biopsy procedures during the same interval and who were diagnosed with either a proliferative fibrocystic change (PFC) or a nonproliferative fibrocystic change (NPFC). EHU was defined as the use of estrogen or progesterone taken together or separately within 3 months of biopsy.

Results. EHU was significantly higher in patients with AH compared with women with NPFC (P =.01). This observation was also significant if all proliferative change (both AH and PFC) was compared with NPFC (P =.03); it was not significant when PFC alone was compared with NPFC. No significant difference in EHU was demonstrated between women with AH and those with PFC.

Conclusions. There is strong association between AH and EHU. These results support the theory that a continuum exists between hyperplasia and carcinoma and that EHU may influence the transition from one to the other in an undefined subset of women. We encourage our patients with AH to discontinue EHU.


Invasive Mammary Carcinoma After Immediate and Short-Term Follow-up for Lobular Neoplasia on Core Biopsy.

Crisi GM, Mandavilli S, Cronin E, Ricci Jr A.


Am J Surg Pathol 2003 Mar;27(3):325-33 Abstract quote

Lobular neoplasia (LN), including atypical lobular hyperplasia (ALH) and lobular carcinoma in situ, may be encountered in breast core biopsies performed for mammographic abnormalities even though LN is often not, in itself, responsible for the abnormal mammogram. The need for surgical excision following a diagnosis of LN on core biopsy is not well defined.

We examined pathologic and mammographic findings in a consecutive series of cases diagnosed as LN to address this issue. Radiology/pathology records were reviewed for cases with a pathology diagnosis of pure LN during the period 1998-2001. Specifically excluded were cases with associated atypical ductal hyperplasia, ductal carcinoma in situ, invasive mammary carcinoma, or any history of breast malignancy.

Thirty-five women 39-76 years of age (mean 52 years) were identified. Specimens were obtained as stereotactic core (31) or limited wire-guided biopsy (four). The diagnoses were lobular carcinoma in situ (12), lobular carcinoma in situ/ALH (10), and ALH (13). Fourteen patients did not undergo excisional biopsy and had no subsequent clinical follow-up to warrant additional biopsy (follow-up 6 months to 3 years). Five patients had no immediate excision, but eventually during clinical follow-up for LN (1 month to 3 years), two developed mammographic lesions in the ipsilateral (one patient) or contralateral breast (one patient) that led to diagnoses of invasive mammary carcinoma (lobular and composite ductal-lobular types, 10 and 8 mm, respectively); three patients had subsequent mammographic findings in the ipsilateral or contralateral breast leading to biopsies showing only LN (two patients) or no neoplastic pathology (one patient). The remaining 16 patients (all core biopsied) underwent immediate wire-guided excisions. Thirteen (81%) showed additional foci of LN, one (6.3%) with atypical ductal hyperplasia, and two (12.5%) with invasive lobular carcinoma (3 mm and <1 mm). Three (19%) had no residual disease; however, additional clinical follow-up in one of these patients revealed an invasive mammary carcinoma in the contralateral breast (false-negative mammography). Radiographic findings were calcifications and density/mass lesions in 27 and 8 cases, respectively. Of 27 cases presenting with Ca, 10 showed colocalization of LN and Ca.

In the eight cases presenting with density/mass, incidental microscopic microcalcifications colocalized to LN were found in two cases. When present, histologic Ca was associated with LN in 12 of 29 cases studied (41%). Of the 21 patients with immediate or subsequent excision, five (24%) were found to have an associated invasive mammary carcinoma (two on immediate excision and three after short-term follow-up of up to 3 years). The bilaterality of cancer risk was expected; however, the number of invasive carcinomas was not. That the invasive carcinomas detected at follow-up were small implies that they might have been present (but occult) at initial presentation.

We conclude that lobular carcinoma in situ detected on core biopsy is potentially a significant marker for concurrent and near-term breast pathology requiring complete intensive multidisciplinary clinical follow-up with specific individualization of patient care.

Lobular neoplasia of the breast: higher risk for subsequent invasive cancer predicted by more extensive disease.

Page DL, Kidd TE Jr, Dupont WD, Simpson JF, Rogers LW.

Department of Pathology, Vanderbilt University School of Medicine, Nashville, TN 37232.

Hum Pathol 1991 Dec;22(12):1232-9 Abstract quote

We have stratified the cancer risk implications of lobular pattern in situ neoplasias of the breast by separating marked examples of this histologic spectrum (lobular carcinoma in situ [LCIS]) from lesser examples (atypical lobular hyperplasia). The lesser-developed examples have been shown previously to have a lower relative risk (RR) of later invasive carcinoma of the breast (IBC).

Forty-eight examples of LCIS were found in 10,542 otherwise benign breast biopsies, representing an incidence of 0.5%. Nine patients were excluded from follow-up because of bilateral mastectomy within 6 months of entry biopsy, IBC within 6 months of entry biopsy, or prior IBC.

Follow-up of the remaining 39 patients was complete, averaged 18 years, and revealed an RR of subsequent IBC of 6.9 (P less than .00001). Average overall follow-up for LCIS patients was 19 years; it was 25 years for those alive and free of IBC at the time of their follow-up interview. Neither family history of IBC nor postmenopausal estrogen therapy further affected risk. The absolute risk of IBC after LCIS was 17% at 15 years (adjusted for withdrawals), and the RR was 8.0 in the first 15 years of follow-up compared with the general population. An analysis based on a time-dependent hazards model found that during the first 15 years following biopsy women with LCIS had 10.8 times the risk of breast cancer compared with biopsied women of comparable age who lacked proliferative disease. Some previously published articles reporting lobular neoplasia (LN) suggest that those series with the greatest incidences of LN (whether termed LN or LCIS) have the lowest RR of subsequent breast cancer. Those series with higher incidences of LN include less well-developed histologic patterns of LN (atypical lobular hyperplasia).

We conclude that our study of LN and studies performed by others support the higher risk of IBC after histologically flagrant examples (LCIS, about nine times higher) and a relatively lower but definable risk after more histologically subtle examples (atypical lobular hyperplasia, four to five times lower). This relative cancer risk is probably not constant over more than 15 years; thus, cancer risk 15 to 25 years after initial diagnosis of LCIS is uncertain.


Clinicopathologic analysis of breast lesions associated with multiple papillomas.

Ali-Fehmi R, Carolin K, Wallis T, Visscher DW.

Departments of Pathology and Surgery, Karmanos Cancer Institute and Wayne State University School of Medicine, Detroit, MI. Accepted for publication October 28, 2002.


Hum Pathol 2003 Mar;34(3):234-9 Abstract quote

We performed a retrospective clinicopathologic study of 28 patients with breast lesions characterized by the presence of multiple (at least 5) papillomas (MPs) in at least 2 nonconsecutive blocks. All histologic sections were assessed for the presence of coexisting fibrocystic lesions, including atypical hyperplasia (atypical ductal hyperplasia [ADH] or atypical lobular hyperplasia [ALH]), lobular carcinoma in situ (LCIS), and papillary atypia (defined as nuclear hyperchromatism, stratification, and architectural complexity of a lesser degree than in papillary carcinoma).

All of the lesions were compared with a set of cases in which ductal carcinoma in situ (DCIS) (n = 20) or invasive carcinoma (INV)(n = 13) was accompanied by MPs. The MP cases had a characteristic morphologic appearance, typically presenting as a mass comprising multiple adjacent ducts filled by papillomas, accompanied by dense fibrosis and intermingled with various proliferative fibrocystic lesions, particularly florid adenosis.

Atypical hyperplasia was a frequent finding (in 12 of 28 cases; 43%), particularly in cases with atypical papillomas (7 of 11; 63.6%). Although contralateral lesions occurred in 4 of 28 patients (14.2%; 3 MPs and 1 INV), only 1 patient (4%) has developed ipsilateral breast carcinoma (mean follow-up, 47 months). DCIS associated with MP was typically low grade (17 of 20; 85%) and arose from areas within or immediately adjacent to preexisting benign lesions. None has recurred (mean follow-up, 41 months), although 1 patient has contralateral MP and 3 patients (23%) have developed carcinomas in the opposite breast. INVs developing in a background of (ipsilateral) MPs were mostly small (8 of 11 <2.0 cm), node negative (7 of 10), and estrogen receptor (ER) positive (8 of 8). Only 1 of 13 patients (8%) has died from disease (mean follow-up, 59 months), but 5 (38%) have developed contralateral breast lesions (including 1 MP, 1 MP-DCIS, 1 DCIS, 1 LCIS, and 1 INV).

We conclude that the frequent associations with ADH, ALH/LCIS, malignant lesions, and bilaterality imply that MP may represent a marker of constitutionally increased breast cancer risk.

Because carcinomas arose within or close to areas involved by preexisting benign MP lesions, it may also be appropriate to excise segments of tissue involved by MP, particularly cases with atypia, and closely monitor for contralateral disease.

Subsequent breast carcinoma risk after biopsy with atypia in a breast papilloma.

Page DL, Salhany KE, Jensen RA, Dupont WD.

Department of Pathology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, USA.

Cancer 1996 Jul 15;78(2):258-66 Abstract quote

BACKGROUND. Risk of breast cancer after biopsy demonstrating a papilloma has long been variously interpreted on the basis of histologic pattern of multiplicity of papillomas.

METHODS. A nested case control study was performed on women with surgical breast biopsies evidencing papillomas; cases who subsequently developed invasive carcinoma were compared with controls who did not. Presence of atypical hyperplasia (AH) within the papilloma as well as areas of AH in the surrounding parenchyma were evaluated in both cases and controls. The entire cohort (not tested) was separately evaluated for all variables except for atypia within papillomas.

RESULTS. The relative risk of invasive carcinoma for women with papillomas containing AH was > 4x that of papillomas without AH within or surrounding the papilloma. This risk may be greater with added atypical hyperplasia outside the papilloma and most strikingly, most of the subsequent invasive carcinomas developed in the same breast and probably near the site of the original papilloma. However, ordinary patterns of epithelial hyperplasia lacking specific features of AH within the papilloma do not add to the risk of subsequent carcinoma development over papillomas without hyperplasia.

CONCLUSIONS. This study indicates that women having papillomas with AH have a similar or greater cancer risk than others with specifically defined patterns of atypical hyperplasia within the breast parenchyma (4-5x relative risk). Most importantly, this risk is largely local in the region of the original papilloma.

Breast papillomas with atypical ductal hyperplasia: a clinicopathologic study.

Raju U, Vertes D.

Department of Pathology, Henry Ford Hospital, Detroit, MI, USA.

Hum Pathol 1996 Nov;27(11):1231-8 Abstract quote

Breast papillomas with areas of atypical proliferation reminiscent of ductal carcinoma in situ (DCIS) and atypical ductal hyperplasia (ADH) are rare, but pose considerable diagnostic difficulty when encountered.

The clinicopathologic features of 20 women 27 to 78 years of age with papillomas having atypical proliferations are reviewed. They presented with palpable masses or nipple discharge.

Histologically, parts of all lesions had features of papillomas with a biphasic proliferation of benign epithelial cells and myoepithelial (ME) cells. Part of the lesion in each papilloma also had an expansile proliferation of larger uniform cells having evenly spaced, round nuclei and a solid to subtle cribriform growth pattern, similar to ADH or DCIS. These lesions tended to be large, complex or multiple.

Twelve patients had 4 to 20 years of follow-up after biopsy only. One each had concurrent and previous contralateral breast carcinoma. Two developed invasive carcinoma of the contralateral breast in 15 and 18 years, respectively. Two developed DCIS on the same side in 2 and 8 years. Six had recurrent papillomas with (5) or without (1) ADH in 1 to 7 years all of whom had no further problems. Only 3 of 12 patients are event free. In contrast, only 8 recurrent papillomas, and 1 ipsilateral invasive carcinoma and 2 contralateral carcinomas occurred in 60 patients with papillomas without ADH in 4 to 18 years.

Thus, the patients having ADH within papillomas seem to have greater likelihood of subsequent disease such as recurrences or overt neoplasia, but the length of follow-up and number of patients are not large enough to provide definitive answers. Because none of the patients developed invasive carcinoma on the same side, conservative management with close observation similar to that following a diagnosis of ADH seems to be appropriate.

Papillomatosis and breast cancer: a case report and a review of the literature.

Batori M, Gallinaro LS, D'Urso A, Ruggeri M, Lorusso R, Forte A, Fierro N.

Dipartimento di Scienze Chirurgiche e Tecnologie Mediche Applicate, University La Sapienza, Rome, Italy.

Eur Rev Med Pharmacol Sci 2000 Jul-Aug;4(4):99-103 Abstract quote

Papillomatosis is a relatively common (22%) benign microscopic lesion in the breast and rarely seen in women less than 30 years old. It is a papillary proliferation of the ductal epithelium which partly fills up smaller ducts and to degree distends them. The histological classification of this entity is controversial because similar or identical lesions have been classified using different terms such as epitheliosis and epithelial hyperplasia, and interpretation of published series has been difficult due to imprecise definition of this term. Clinical, radiological and histological patterns of this entity are often sufficient to raise concern as to possible malignancy.

Moderate or florid hyperplasia without atypia is considered to carry slight (1,5-2 times) increase in risk of later developing cancer, while in the atypical hyperplasia the risk is four to five times that of the general population.

The authors describe a case of papillonlatosis recentely observed in a 67 years old female patient and, confirmed the importance to establish an accurate preoperative diagnosis. It is important that the surgeon works with the pathologist to produce clear descriptive report of epithelial changes from normal through hyperplasia to atypias in order to establish a precise surgical indication.


Adequate histologic sampling of breast core needle biopsies.

Renshaw AA.

Department of Pathology, Baptist Hospital of Miami, 8900 N Kendall Dr, Miami, FL 33176, USA.

Arch Pathol Lab Med 2001 Aug;125(8):1055-7 Abstract quote

OBJECTIVE: To determine the degree of histologic sampling necessary for adequate examination of breast core needle biopsy specimens.

DESIGN: The results of all breast core needle biopsies (11 and 14 gauge) with a diagnosis of atypical small acinar proliferation or atypical ductal hyperplasia and subsequent excisional biopsies, for a 50-month period were reviewed. Blocks of all cores were sectioned entirely in 8 slides to determine the amount of sectioning needed to detect these foci, and the results were correlated with those from the excision specimen.

SETTING: Large community hospital practice.

RESULTS: Of 3026 cases, 216 (7.1%) were diagnosed as atypical ductal hyperplasia or atypia not otherwise specified. Subsequent resections were available in 105 (49%) cases, and after review, 95 (92%) qualified as atypical ductal hyperplasia and 2 were determined to be atypical small acinar proliferations. The 2 small acinar proliferations were first detected on the second and fourth slides. Of the atypical ductal hyperplasia cases, 43% were detected on the first slide, 17% on the second, 23% on the third, 8% on the fourth, and 8% on the fifth. No lesions were initially detected after this level. Ductal carcinoma in situ was detected in the excision specimens from 1 case each of those detected initially on the fourth and fifth slides.

CONCLUSION: Five sections of breast core needle biopsy specimens are necessary to ensure that all atypical small acinar proliferations and atypical ductal hyperplasia lesions are sampled.

Core biopsy of the breast with atypical ductal hyperplasia: a probabilistic approach to reporting.

Ely KA, Carter BA, Jensen RA, Simpson JF, Page DL.

Division of Anatomic Pathology, Vanderbilt University Medical Center, Nashville, Tennessee 37232, USA.

Am J Surg Pathol 2001 Aug;25(8):1017-21 Abstract quote

The diagnosis of atypical ductal hyperplasia (ADH) at needle core breast biopsy (NCB) is typically regarded as an indication for surgical excision. Although ADH is an intermediate risk nonobligate precursor lesion, the rationale for further therapy is the result of a reported high prevalence of a concomitant more advanced lesion (typically ductal carcinoma in situ) as the index lesion.

To assess whether certain histopathologic features of ADH in NCB are predictive of open biopsy outcomes, the authors correlated the extent and pattern of ADH in 47 core biopsies (11-or 14-gauge) with the subsequent surgical specimen. Extent of ADH on NCB was ascertained by determining the number of large ducts and/or terminal duct-lobular units affected, with involvement of one large duct or one terminal duct-lobular unit representing a single focus, involvement of one duct and one terminal duct-lobular unit as two foci, and so on.

Of the 47 cases, ADH was restricted to < or =2 foci in 24 cases (51.1%), confined to 3 foci in 8 cases (17.0%), and involved > or =4 foci in 15 cases (31.9%). The corresponding histopathologic findings at excision were benign lesions without atypia (n = 14), focal residual ADH (n = 13), atypical lobular hyperplasia (n = 3), ductal carcinoma in situ (n = 15), and invasive mammary carcinoma (n = 2).

When the number of foci of involvement by ADH on NCB (based on an average of 11.6 cores per case) was correlated with the open biopsy results, all cases of ADH limited to < or =2 foci had no worse lesion on excision, whereas ADH present in > or =4 foci was found to be a strong predictor of a more advanced lesion on excision (p <0.0001, chi2). When histologic pattern was evaluated, all cases of pure micropapillary ADH on NCB showed pure micropapillary ductal carcinoma in situ on excision.

Atypical Ductal Hyperplasia in Breast Core Needle Biopsies Correlation of Size of the Lesion, Complete Removal of the Lesion, and the Incidence of Carcinoma in Follow-up Biopsies

Andrew A. Renshaw, MD, Norberto Cartagena, MD, Randy H. Schenkman, MD, Robert P. Derhagopian, MD, and Edwin W. Gould, MD

Am J Clin Pathol 2001;116:92-96 Abstract quote

We reviewed the results of all breast core needle biopsies with a diagnosis of atypical ductal hyperplasia (ADH) or atypia not otherwise specified and subsequent excisional biopsies for a 50-month period and correlated the results.

Of 3,026 biopsies, 216 were diagnosed as ADH or atypia not otherwise specified, and subsequent resection was available for 105. After review, 95 qualified as ADH. Subsequent resection showed ductal carcinoma in situ (DCIS) in 13 excisions, ADH in 31, lobular carcinoma in situ in 6, and benign proliferative lesions in the remaining 45. In none of the 8 biopsies in which DCIS was found and radiographs were available for review was the radiographic lesion entirely removed. For comparison, the incidence of carcinoma in resections done for a diagnosis of DCIS, low or intermediate grade (solid, cribriform, or micropapillary type), on core needle biopsy was significantly greater (8 of 10 cases). However, the size of the lesions diagnosed as carcinoma also was significantly greater than that of the lesions diagnosed as ADH, and in none of the 8 biopsies with DCIS at excision was the lesion entirely removed at the time of biopsy.

The incidence of carcinoma in excisional biopsies done for a diagnosis of ADH in core needle biopsies in our institution is relatively low, while the incidence of ADH is relatively high. Possible reasons for this include total removal of small lesions at the time of biopsy and use of the diagnostic term ADH for lesions that are not associated with coexistent DCIS.

Follow-up Surgical Excision Is Indicated When Breast Core Needle Biopsies Show Atypical Lobular Hyperplasia or Lobular Carcinoma In Situ: A Correlative Study of 33 Patients With Review of the Literature.

Elsheikh TM, Silverman JF.

From *Pathologists Associated/Ball Memorial Hospital Muncie, IN; and daggerDepartment of Pathology, Allegheny General Hospital, Pittsburgh, PA.
Am J Surg Pathol. 2005 Apr;29(4):534-543. Abstract quote  

Atypical lobular hyperplasia (ALH) and lobular carcinoma in situ (LCIS) diagnosed in core needle biopsy (CNB) are generally regarded as risk indicators for developing invasive ductal or lobular carcinoma in either breast. Currently, there are no well-established guidelines for management of these patients. The most common management options are careful observation and endocrine chemoprophylaxis for high-risk patients. Previous studies had contradicting recommendations regarding follow-up surgical excision (FSE) of CNB yielding ALH or LCIS. These studies, unfortunately, have been limited by their retrospective nature, small number of patients examined, and association with other high-risk lesions. Only CNB diagnosed as pure LCIS or ALH (not associated with other high-risk lesions such as ADH, radial scar, or papilloma) were included in the study.

We reviewed 33 CNB (20 ALH and 13 LCIS) with subsequent FSE from 33 patients (age range, 30-83 years; mean, 58 years). Eighteen of these patients were prospectively analyzed, where FSE was performed in an unselected fashion. All CNBs were obtained by mammotome (11-gauge, 30 cases; and 14-gauge, 3 cases). Mammography identified calcifications in 29 cases (88%) and a mass in 4 cases (12%). FSE revealed infiltrating ductal and/or lobular carcinoma in 4 of 13 LCIS (31%). FSE of 20 ALH revealed cancer in 5 cases (25%), including 4 ductal carcinoma in situ (DCIS) and 1 invasive lobular carcinoma. Seven of these nine cancers were associated with calcifications, and two presented as masses. Sampling error and underestimation of cancer (DCIS or invasive carcinoma) was associated with CNB diagnosis of LCIS or ALH in 27% of all cases. Underestimation of cancer was seen in 28% of prospectively examined patients, including 20% of ALH and 38% of LCIS. CNB associated with mass lesions or that showed histologic features of pleomorphic LCIS or extensive classic LCIS had a higher rate of cancer underestimation. Despite removal of all abnormal mammographic calcifications by CNB in 6 patients, one cancer was detected on FSE.

To the best of our knowledge, this is the largest study reported to date, and the only one to include prospectively examined patients with no pre-selection bias. Our data strongly suggests that subsequent FSE is warranted in all patients with CNB diagnoses of LCIS or ALH, to exclude the presence of cancer.

Lobular carcinoma in situ diagnosed by core needle biopsy: when should it be excised?

Middleton LP, Grant S, Stephens T, Stelling CB, Sneige N, Sahin AA.

Departments of Pathology (LPMSG, NS, AAS) and Radiology (TS, CBS), The University of Texas MD Anderson Cancer Center, Houston, Texas.


Mod Pathol 2003 Feb;16(2):120-9 Abstract quote

Core needle biopsy is the preferred technique for evaluating breast masses and abnormal mammographic findings. The frequency of detection of noninvasive lobular lesions by core needle biopsy is increasing. Historically, the diagnosis of lobular carcinoma in situ has been considered a risk factor for the development of invasive carcinoma, and treatment has consisted of careful clinical follow-up with or without chemopreventive therapeutic agents such as tamoxifen citrate.

We retrospectively reviewed core needle biopsy material with the primary diagnoses of lobular carcinoma in situ, atypical lobular hyperplasia, and lobular neoplasia in conjunction with clinical and radiographic findings to make recommendations as to when excision may be merited. We searched our database for core needle biopsy cases with lobular carcinoma in situ, atypical lobular hyperplasia, and lobular neoplasia as the primary diagnosis. Microcalcifications had been sampled with a stereotactically guided, 11 G Mammotome biopsy device, and masses had been sampled with an ultrasound guided, 18 G core needle. Glass slides were reviewed and histological parameters assessed. Mammographic findings were reviewed, and clinical information was obtained from the medical record. When available, excisional biopsy material was reviewed. The 2337 breast core needle biopsies performed from January 1995 to December 2001 included 35 (1.5%) with classic lobular carcinoma in situ (14), lobular neoplasia (4), and atypical lobular hyperplasia (17) as the primary diagnosis. Twelve of these 35 cases (34%) had histological evidence of microcalcifications directly associated with the lobular carcinoma in situ, lobular neoplasia, atypical lobular hyperplasia. Radiologic review revealed 21 calcifications, 6 ultrasonographic masses, and 8 mammographic masses and/or architectural distortions. Excisional biopsy had been performed in 17 cases (49%). In six cases diagnosed as in situ on core needle biopsy, excisional biopsy revealed invasive carcinoma. All of these patients had radiographically detectable masses. Eleven cases had excisional biopsies that showed histology similar to that of the core needle biopsies.

The most important predictor of invasive carcinoma on excision was a synchronous mass lesion. Lobular carcinoma in situ involving adenosis and lobular carcinoma in situ with pagetoid spread on core needle biopsies did not show a histologically more aggressive lesion on excision and, therefore, may not require additional surgery. Histologically identified calcifications were associated with lobular lesions 34% of the time; however, their presence inside an in situ lobular lesion did not portend worse pathology on re-excision and should not be a criterion for excision.

Based on these findings, we recommend excisional biopsy of lobular carcinoma in situ, atypical lobular hyperplasia or lobular neoplasia only when it is associated with a synchronous mass lesion.

Mild ductal atypia after large-core needle biopsy of the breast: is surgical excision always necessary?

O'hea BJ, Tornos C.

Department of Surgery, University Hospital and Medical Center, State University of New York at Stony Brook, Stony Brook, NY 11794-8191, USA.

Surgery 2000 Oct;128(4):738-43 Abstract quote

BACKGROUND: The aim of the current study was to identify a select group of patients with mild atypia who do not need surgical excision after large-core needle biopsy (LCNB) of the breast.

METHODS: Nineteen (70%) of 27 patients with ductal atypia found on LCNB had subsequent surgical excision. These 19 patients were retrospectively assigned to 3 groups according to the severity of the atypia found, which was compared with the final pathologic specimen after surgical biopsy.

RESULTS: Cancer was identified through surgical biopsy in 6 (32%) of 19 patients. The severity of atypia seen on the LCNB specimen strongly correlated with subsequent cancer identification (P<.01). Two (33%) of 6 patients in group 2 (true atypical ductal hyperplasia [ADH]) and 4 (80%) of 5 patients in group 3 (severe ADH, borderline ductal carcinoma in situ) had cancer after surgical biopsy. No cancer was found after surgical biopsy in 8 patients in group 1 (mild atypia, not meeting criteria for ADH).

CONCLUSIONS: The results of this study suggest that surgical excision can be avoided after LCNB of the breast in patients with only mildly atypical lesions that do not meet criteria for ADH. Patients with true ADH should continue to have surgical excision.

Nonmalignant lesions in breast core needle biopsies: to excise or not to excise?

Jacobs TW, Connolly JL, Schnitt SJ.

Am J Surg Pathol 2002 Sep;26(9):1095-110 Abstract quote

Large core needle biopsies using stereotactic mammography or ultrasound guidance are now commonly performed as the initial diagnostic approach to nonpalpable breast lesions. Although the subsequent management of patients with invasive cancer, ductal carcinoma in situ, and most benign lesions diagnosed on core needle biopsy specimens is straightforward, certain nonmalignant lesions pose dilemmas with regard to the most appropriate clinical management following core needle biopsy.

The purpose of this article is to review the available data regarding several nonmalignant breast lesions, which when encountered in core needle biopsy specimens raise repeated management questions. These include atypical ductal hyperplasia, lobular neoplasia (atypical lobular hyperplasia and lobular carcinoma in situ), papillary lesions, radial scars, fibroepithelial lesions, mucocele-like lesions, and columnar cell lesions.

Appropriate management of atypical ductal hyperplasia diagnosed by stereotactic core needle breast biopsy.

Gadzala DE, Cederbom GJ, Bolton JS, McKinnon WM, Farr GH Jr, Champaign J, Ordoyne K, Chung K, Fuhrman GM.

Department of Surgery, Ochsner Clinic, New Orleans, LA 70121, USA.

Ann Surg Oncol 1997 Jun;4(4):283-6 Abstract quote

BACKGROUND: Stereotactic core needle breast biopsy (SCNBB) is a minimally invasive technique used to sample nonpalpable mammographic abnormalities. The optimal management of atypical ductal hyperplasia (ADH) diagnosed by SCNBB is unknown. We hypothesized that ADH diagnosed by SCNBB should be evaluated by excisional breast biopsy (EBB) because of the risk of identifying carcinoma in association with ADH that would be missed if a diagnostic sampling technique alone was utilized.

METHODS: To test this hypothesis, a prospective diagnostic protocol was created which called for SCNBB instead of EBB for patients with mammographic abnormalities considered suspicious for malignancy. If ADH was noted on histologic evaluation of the cores, patients were advised to undergo an EBB.

RESULTS: A review of the initial 900 patients evaluated by SCNBB yielded 39 patients (4.3%) with ADH detected by SCNBB. Thirty-six of these 39 patients agreed to proceed with EBB: 19 patients demonstrated benign findings including atypical ductal hyperplasia, 13 patients demonstrated noninvasive ductal carcinoma, and 4 patients had evidence of invasive carcinoma.

CONCLUSIONS: A 47% rate of detecting noninvasive or invasive breast carcinoma supports the hypothesis that ADH detected by a sampling technique, such as SCNBB, should be managed by EBB.

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Commonly Used Terms

Epitheliosis-British term for epithelial hyperplasia.

Fenestrations-Irregular lumens present within ducts.

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