Benign breast disease and cancer risk

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1 Critical Reviews in ONCOLOGY1 HEMA TOLOG Y Critical Reviews in Oncology/Hematology 15 ( 1993) 22 I-242 Benign breast disease and cancer risk Simonetta Bianchi*, Domenico Palli b, Monica Galli, Giancarlo Zampia Istituto di Anatomia e lstologia Patologica, Universita degli Studi di Firense, Florence. Ital> hu.o. di Epidemiologia, Centro per lo Studio e la Prevenzione Oncologica. Florence, Ita!, Se:ione Distacrata IST, Florence. Ita!& (Accepted 16 June 1993) Contents Introduction BBD consensus statement Page s histological classification Non-proliferative BBD Proliferative disease without atypia Atypical hyperplasia I. Atypical ductal hyperplasia (ADH) Atypical lobular hyperplasia (ALH) A comparison of BBD histological classifications BBD and cancer risk: a review of epidemiological studies Case-control studies Cohort studies Nested case-control studies Gross cysts and BC risk Clinical significance of AH BBD and mammographic patterns BBDand cytologicexamination Reproducibility of histological diagnosis of proliferative disease IO. Role of ancillary techniques to histological diagnosis II. Biological profile of AH Conclusions Acknowledgements Biographies Reviewer References * Corresponding author, lstituto di Anatomia e lstologia hto]ogica. Policlinico Careggi. Viale Morgagni Florence. Italy 1040~8428/93/$ Elsevier Scientific Publishers Ireland Ltd. All rights reserved. SSDl (93)00086-U

2 222 S. Bianchi et al. /Cd. Rev. Oncol. Hematol. I5 (1993) Introduction Breast cancer (BC) is the most common tumor and the leading cause of cancer death in the female population in developed countries. There is therefore considerable interest in investigating factors associated with increased breast cancer risk. For a long time benign breast disease (BBD) has been considered a condition at increased risk of developing a breast cancer. BBD is sometimes used as a term vaguely referred to clinical features such as pain, a breast lump or a cyst possibly leading to a biopsy to exclude the presence of a carcinoma. In contrast, several epidemiologic studies have used BBD more specifically to indicate any condition for which a woman has undergone a surgical biopsy with a histologically confirmed benign diagnostic outcome [ 11. Although various histologic types of BBD can be distinguished, often they are not clearly specified in the pathology report. Fibrocystic disease (FCD) and mammary displasia have also been used as synonyms of BBD by both clinicians and pathologists. It is important to understand that these terms do not represent a distinct entity for either the clinician or the pathologist and do not provide any clear information although they have been in use for several decades, generally implying a breast disease but lacking a precise definition. The term fibrocystic disease has been used to describe a heterogeneous group of abnormalities that clinically appear as a condition in which there are palpable breast masses that undergo changes during the menstrual cycle. These palpable masses probably represent physiologic changes rather than a pathologic process. Hughes has also suggested the generic term aberrations of normal development and involution (ANDI) to indicate the dynamic changes occurring in the normal breast during reproductive life [2]. Some irregular mammary density, due to stromal fibrosis, cysts and proliferative lesions, is present in at least 50% of premenopausal women and autopsy studies have shown that such changes are found almost in every female breast. On the basis of these observations Love Abbreviations: ADH, atypical ductal hyperplasia; AFIP, Armed Forces Institute of Pathology; AH, atypical hyperplasia; AIDH. atypical intraductal hyperplasia; AL, atypical lobule; ALA, atypical lobule type A; ALB, atypical lobule type B; ALH. atypical lobular hyperplasia; ANDI, aberrations of normal development and involution; BBD, benign breast disease; BC. breast cancer; Cl, confidence interval; CIS, carcinoma in situ; DCIS. ductal carcinoma in situ; FA, fibroadenoma: FCD, fibrocystic disease; FNA. line needle aspiration; LCIS, lobular carcinoma in situ; MIN. mammary intraepithelial neoplasia; NPD, non-proliferative disease; PBD, proliferative breast disease; PDWA, proliferative disease without atypia; RR, relative risk: TDLU, terminal duct lobular unit; TGF-ol, transforming growth factor-a. et al. [3] considered unreasonable to define as a disease any process occurring clinically in 50%) and histologically in 90% of women. They concluded that: the term librocystic disease has lost its specificity and therefore should be abandoned. Lumpy breasts or physiologic nodularity are more descriptive of the clinical situation, and specific histologic designations are more useful in describing the pathology. as well as the prognosis. Elimination of the charged term fibrocystic disease may finally allow us to study the clinical and histologic manifestations of hormonal variations in the breast and to determine. through large, well-controlled prospective studies, the real importance of librocystic changes in terms of future malignant disease... In 1985 Hutter [4] published a paper entitled Good bye to fibrocystic disease in which the author stated:...lt is time to empty the fibrocystic disease wastebasket and thereby mitigate the anxiety of a large number of women who no longer need to be concerned about a high risk for breast cancer. 2. BBD consensus statement In 1985 a meeting on the precancerous significance of BBD was organized in New York by the Cancer Committee of the College of American Pathologist with the aim of reaching a consensus on the diagnostic terms to be used in surgical pathology reports of BBD and to categorize the lesions by their degree of BC risk. On the basis of the results of previous studies [5], the meeting developed a consensus statement [6] concerning different histological types of BBD and emphasized the differing risks associated with various morphological features, subdividing them into three categories according to the risk for subsequent invasive BC (Table. 1): (i) no increased risk when there is no evidence of epithelial proliferation; (ii) slightly increased risk ( times) based upon presence of epithelial proliferation without atypia, i.e., proliferative disease without atypia (PDWA); (iii) moderately increased risk (5 times) resulting from epithelial proliferation with atypia i.e., atypical hyperplasia (AH) or so called borderline lesions. The consensus statement placed sclerosing adenosis in the non-proliferative BBD category. A more recent study has provided support for the reassignement of sclerosing adenosis to the category of proliferative BBD [7]. The authors considered sclerosing adenosis as an independent risk factor for subsequent invasive BC apart from its association with atipical lobular hyperplasia (ALH) with a risk of about 1.7, justifying the inclusion of sclerosing adenosis in the group of proliferative BBD without atypia. Other studies reported an elevated risk for fibroadenoma (FA) [8,9] with a slightly increased risk of 1.7. However FA is considered an abnormality of development rather than a benign neoplasm so that the epithelium of fibroadenoma is subject to the same changes as

3 S. Bianchi et al. /Cd. Rev. Oncol. Hematol. 1.5 (1993) Table I with hyperplastic alterations within lobular units as Consensus BBD histological classification shown by Ohuchi et al. [14] and Salhany et al. [15]. Benign breast tissue removed from women with clini- (1) Non-proliferative BBD Ductal ectasia Fibroadenoma Adenosis (florid or sclerosing) Fibrosis Cysts (macro and/or micro) Mild hyperplasia Mastitis Fat necrosis (2) Proliferative BBD without atypia (PDWA) Ductal hyperplasia (moderate or florid) Lobular hyperplasia (moderate or florid) Papilloma with tibrovascular core (3) Atypical hyperplasia (AH) - (Borderline lesion) Atypical ductal hyperplasia Atypical lobular hyperplasia Entities such as radial scar. ductal adenoma and juvenile papillomatosis are classified according to the characteristics of the epithelial component. Modified from Hutter (1986) [6] the remaining breast tissue, i.e., epithelial hyperplasia. It is considered therefore that a breast carcinoma arising in a FA occurs by chance [lo]. Gross cystic disease has also been associated with subsequent breast cancer, but the published literature is still confusing and conflicting. Page and his colleagues IS,1 l] have suggested that it is not the cyst in itself but the associated hyperplastic atypical lesions to be at increased risk of subsequent breast cancer. The consensus document [6] considered cysts in the category with no risk increase. The major problem with histological studies is that only a small minority of patients with palpable cysts undergo a surgical biopsy so that any conclusion drawn from such studies may not be relevant when assessing the breast cancer risk of all patients with palpable breast cysts [lo]. Clinical follow-up studies of women with palpable breast cysts reported an increased risk of subsequent breast carcinoma ranging between 2.5 and 7.5 [IO]. There is some evidence that BC risk is enhanced in women reporting also a positive family history. Cyst fluid composition has been classified according to biochemical characteristics or to apocrine cytology: at present, however, biochemical measurements in cyst fluids cannot accurately. identify women likely to develop breast cancer [ 121. A follow-up study of women with a solitary papilloma showed an increased risk of subsequent development of carcinoma [13], for this reason papilloma with a Iibrovascular core was placed in the slightly increased risk category. It was recently suggested that the simultaneous occurrence of epithelial hyperplasia of various degree was responsible for the increased risk. In fact. particularly peripheral papillary lesions are continuous cal fibrocystic disease is characterized, according to WHO classification [16], by a spectrum of proliferative and regressive alterations of mammary tissues, whose defining elements are represented by cysts, apocrine changes, stromal fibrosis, adenosis and epithelial proliferation of various degrees. It is now evident that the most important histologic variable is the degree of the hyperplastic epithelial proliferation, ranging from minimal hyperplasia to neoplasia even though there is evidence that in many cases breast cancer can arise de novo, without any premalignant phase [6]. Terms such as papillomatosis and epitheliosis have been used as synonyms of epithelial hyperplasia. The term papillomatosis has been used by many authors, particularly in the United States [17,18], to describe benign intraductal epithelial proliferations exhibiting solid intraluminal budding and fingerlike projections, This term, however, is potentially confusing because of the evident derivation from the term papilloma, and actually papillomatosis is sometimes used to indicate multiple intraductal papillomas. In addition, many cases of common type epithelial hyperplasia do not show any papillary pattern. Papillomatosis is commonly applied to examples of moderate and florid epithelial hyperplasia. The use of the term epitheliosis is similarly confusing because some authors, particularly in English literature, use it for severe forms of epithelial hyperplasia that have some resemblance to carcinoma in situ, others advocate its use to distinguish a confluent hypercellularity that is not cancer [19]. Because the specificity of the terms papillomatosis and epitheliosis has been reduced by the inclusion of many different entities, the simpler term of epithelial hyperplasia has been recommended [20,211. The term proliferative breast disease (PBD) has been specifically proposed by DuPont and Page [5] to indicate histological hyperplastic lesions which have implications for elevated risk of breast carcinoma and to distinguish them from proliferative changes without such implications. 3. Page s histological classification The system for classifying benign breast lesions originally proposed by DuPont and Page [5,22] and supported at the consensus meeting of the College of American Pathologists [6], provides a prognostic, clinically relevant approach. This system separates the histologic lesions of excised benign breast tissue into three categories with different prognostic significance according to relative risks for the subsequent development of breast cancer: non-proliferative benign breast disease, proliferative disease without atypia (PDWA) and atypical hyperplasia (AH).

4 S. Biundzi tv ul. / Crit. Rev. Oncol. Hematol. Fig. 1 (A.B) Sclerosing adenosis characterized by proliferation of acinar structures of the lobular units. and myoepithelial elements 15 (1993) with enlargement and distorsion 3.1. Non-proliferative BBD The category of non-proliferative BBD includes several entities traditionally grouped under the name of tibrocystic disease, such as cysts, apocrine metaplasia, fibrosis, florid and/or sclerosing adenosis (Fig. la.b), mild epithelial hyperplasia. Mild epithelial hyperplasia of usual type is defined as an increase in the number of epithelial cells within a duct with a 3/4-cell layer above the basement membrane (instead of a 2-cell layer as usual) with no evidence of occlusion, enlargement or distension of the glandular lumen (Fig. 2). Inflammatory conditions like duct ectasia, mastitis, fat necrosis, and other benign conditions, such as fibroadenoma, are also considered in this category Proliferative disease without atypia In the PDWA category moderate and florid ductal or lobular hyperplasias are included. In moderate and florid hyperplasia (Fig. 3) five or more cell layers above the basement membrane are evident, with luminal occlusion and distension. There is also a tendency to bridge and often distend the involved space. The proliferation may have a solid, fenestrated or papillary pattern. The spaces that remain within the duct lumen are irregular, differently shaped Fig. 2. Mild epithelial hyperplasia with a 3-4 cell layer above the basement membrane.

5 S. Bianchi et al. / Crir. Rev. Oncol. Hemarol. 15 (1993) and often slit-like. The luminal aspect of the cells frequently shows a protrusion into the lumen, termed apical snout. Neighbouring cells relate to each other keeping parallel orientation. This phenomenon has been termed streaming (Fig. 4A,B) or swirling (Fig. 5A.B) [ 191and its presence is usually considered as strong evidence for a benign lesion (Fig. 6A,B). The current terminology divides epithelial hyperplasia into two groups: ductal and lobular. Although this terminology is widely accepted, the histological differentiation of these lesions is mainly based on cytological and architectural criteria rather than on histogenesis. In fact it is supposed that almost all proliferative breast lesions arise in the terminal duct lobular unit (TDLU). When proliferative lesions are present in extralobular duct they are referred to as ductal hyperplasia. In contrast when proliferative changes are present in intralobular ducts the term lobular hyperplasia is used A fypical hyperplasia Atypical hyperplasia is defined as a proliferative lesion in which either cytological and architectural criteria of carcinoma in situ are met but are not represented in a full degree. AH is therefore also known as borderline lesion. According to other authors atypical hyperplasia is also diagnosed if criteria of carcinoma in situ are present but not uniformly so throughout at least two spaces Fig. 4 (A.B) Florid epithelial hyperplasia: the cells show parallel orientation (termed streaming )

6 S. Bianchi PI ul. / Crir. Rev. Oncol. Hematol. I5 (1993) Fig. 5 (A,B) Florid epithelial Fig. 6 (A,B) Florid hyperplasia epithelial characterized hyperplasia showing by a proliferation a proliferation showing of cytologically a solid or fenestrated architecture benign cells that till and distend (cell swirling ) the ducts.

7 221 S. Bianchi et al. /Crit. Rev. Oncol. Hematol. 15 (1993) [20]. In 1985 the same authors defined atypical lesions as those having some, but not all, of the histologic and the cytologic features of lesions recognized as carcinoma in situ. Atypical hyperplasias can be categorized as either ductal or lobular in type. Many criticisms have been moved to these definitions mostly because of the lack of precise and reproducible criteria. Identification of the histologic features of atypical hyperplasia requires familiarity with the histologic features of in situ carcinoma. Even among experienced pathologists, there are often diagnostic difficulties, particularly for the ductal lesions. It may be difficult to determine whether a proliferative lesion represents an example of florid hyperplasia of the usual type or atypical hyperplasia. At the other end of the spectrum, it may be difficult to decide whether a lesion represents a highly atypical hyperplasia or an in situ carcinoma. Considering these problems Page and Rogers [23] have recently published a paper focused on three different sets of criteria for diagnosing atypical hyperplasia: cytologic features, histologic pattern and anatomic extent of lesion Atypical ductal hyperplasia (ADH) Cytologic features. ADH exhibits a partial involve- Fig. 7 (A,B) Atypical ductal hyperplasia with cribriform as in DCIS pattern. and irregular ment of the basement membrane-bound space by two types of cell populations. A first type is composed of evenly spaced, uniform cells with uniformly hyperchromatic oval to rounded nuclei like ductal carcinoma in situ non-comedo type. Cytoplasm is usually pale and intercellular borders are usually distinct. The second cell population (non-atypical) consists of columnar polarized cells of the type usually seen in the ductal lamina positions immediately above the basement membrane. Histologic pattern. The predominant pattern is cribriform (Fig. 7A,B). Secondary spaces are both regular with smooth, rounded punched-out borders and rigid, non-tapering bars, as in non-comedo type ductal carcinoma in situ (DCIS); and irregular as in florid hyperplasia without atypia (Fig. 8A-D). To qualify for ADH (as opposed to florid hyperplasia without atypia) both cell populations should present at least six or seven cell layers (Fig. 9A,B). Anatomic extent of lesion. It is discriminant between ADH and DCIS. At least two basement membranebound spaces need to be completely involved by a cell population with the cytologic and histologic features of DCIS for a diagnosis of DCIS. Therefore, a lesion with only a single space with diagnostic features of DCIS is diagnosed as ADH. Secondary spaces are both regular with smooth, rounded punched-out as in florid hyperplasia without atypia. borders

8 S. Biunlhi Fig, 8 (A-D) Atypical et ul. / Crit. Rev. Oncol. Hemarol. ductal hyperplasia, the proliferation is composed m part of evenly spaced uniform cells with regularly nuclei. In other areas the proliferating cells maintain their orientation. 15 (1993) 221-,242 placed monomorphic

9 S. Bianchi et al. / Crir. Rev. Oncol. Hematol. 1.5 (1993) Fig. 9 (A,B) Atypical 229 ductal hyperplasia with micropapillary pattern showing hypercromatic areas of the spaces lack this rigidity and cells mantain A typical lobular hyperplasia (A LH) When changes within lobular units lack the complete criteria for lobular carcinoma in situ (LCIS) but have similar cytologic features, ALH is diagnosed [24]. Cytologic features. Cells in ALH are quite normal with round, frequently somewhat lightly stained nuclei and cytoplasm evenly spaced one from another without evident pattern or polarity. Small nucleoli may be present. Uniformity and roundness of the cell population are indicative for a diagnosis of ALH. Histologic pattern. Mild acinar distension and distorsion of involved acinar spaces and preservation of central lumen are present (Fig. loa,b). Anatomic extent of lesion. Less than one-half of the acini in a unit are filled with the characteristic cells. The same characterising cells of ALH may be seen within ducts separated from lobular units; in this case a diagnosis of involvement within ducts is suggested, similarly to the pagetoid changes described by Foote and Stewart [25]. When ductal involvement of these cells is at least two-cell thick and the abnormal cells are clearly distinguishable from local cells, particularly if undermining a separate superficial or luminal cell population, a diagnosis of ductal involvement,of ALH cells is made ]261. cells in rigid configuration normal orientation. that bridge the lumen. Other 4. A comparison of BBD histological classifications Several studies have attempted to define the relationship between BBD and the subsequent risk of breast cancer, but often without a precise morphological definition of the lesions underlying. Therefore only a few well designed prospective or retrospective studies are available to clarify the magnitude of risk for the various types of BBD. Studies concerned with this problem date from the first decades of this century. In 1931, the precancerous significance of some benign breast alterations was suggested by Cheatle and Cutler [27]. In 1940 Warren reported that women with hyperplasia and intraductal papillomas showed a risk of developing carcinoma times higher than that of the normal population [28]. In 1945, Foote and Stewart suggested a relevant role of the precancerous potential of hyperplasia reported as five times more frequently in breast cancer [29]. Several clinical studies from 1940 through to 1960 recognized that patients diagnosed histologically as affected by BBD were at increased risk of developing invasive carcinoma. By the 1970s there were major attempts to separate the histologic components of BBD in terms of the risk

10 S. Bianchi 230 Fig. 10 (A,B) Atypical lobular hyperplasia: partial filling and mild acinar of subsequent cancer. Kern and Brooks in 1969 reported that atypical epithelial hyperplasia is more often associated with breast cancer than with fibrocystic disease and concluded that hyperplasia is an important feature in the development of breast cancer. Hyperplasia was graded on the basis of the degree, extent of stratitication, hyperchomasia, cellular pleomorphism and presence of mitoses, as l-3 (grade 1 for relatively slight Table 2 Comparison of proposed histological classifications Grade of benign II ALA/AL9 disease with epithelial Hemarol. with focal preservation 15 (1993) of luminal spaces proliferation III Distinct I-11 distension Rev. Oncol. changes, grade 2 for cases with marked atypia and grade 3 for those of a borderline nature) [30]. Wellings et al. [31] studying uninvolved breast tissue excised at the time of resection for breast carcinoma identified an increased incidence of hyperplastic ductular lesions in patients with breast cancer compared to women without cancer. The main limitation in comparing the numerous Grade Hyperplasia Black and Chabon 1969 [32] Welling et al., 1975 breast et al. / Crir. ALA/AL9 but minimal atypia 111 Grade IV Atypia suggestive ALA/AL9 in situ carcinoma IV [311 Hutchinson et al., 1980 Epithelial hyperplasia I331 Cook and Rohan, 1985 Mild hyperplasia l341 DuPont and Page, 1985 Mild hyperplasia ]51 Fechner and Mills, Tavassoli and Norris, 1361 McDivitt et al., 1992 [91 Mild hyperplasia 1990 Hyperplasia atypia without or papillomatosis without atypia Moderate hyperplasia Moderate and florid hyperplasia Moderate and florid hyperplasia Hyperplasia (intraductal) Hyperplasia with moderate atypia Epithelial hyperplasia or papillomatosis with atypia Severe hyperplasia Atypical ductal or lobular Mild to severe atypial hyperplasia hyperplasia Atypical hyperplasia (intraductal) Hyperplasia with marked atypia

11 S. Bianchi et al. /Crit. Rev. Oncol. Hematol. 15 (1993) studies concerning the risk of developing a breast carcinoma in patients with BBD is the lack of uniform criteria in the histologic classification and the high interobserver variation among pathologists. The reproducibility of histologic classification should be measured before assessing the clinical relevance of any association. The grading systems which have been used by different authors are summarized in Table 2. The scheme proposed by Black and Chabon [32] classifies the lesions by their degree of proliferation and by their location in the breast. They used a numerical grade from 1-5, representative of cellular changes suggesting the proliferative sequence: grade 1, normal epithelium; grade 2, hyperplasia; grades 3 and 4, different degrees of atypia; and grade 5, in situ carcinoma. According to the location in the breast gland there are four sites in which the changes can occur: primary ducts, terminal interlobular ducts, intralobular ducts, individual acini. The grouping of lesions by location has not proved to be useful in assessing different levels of breast cancer risk. Moreover this grading system does not take into account the different types of hyperplasia that can be observed. Wellings et al. [31] considering that most breast lesions arise in terminal duct-lobular units (TDLU) or in the lobules themselves, classified hyperplastic changes as atypical lobule (AL) type A (ALA) or type B (ALB) on the basis of morphological features. ALA shows variable degrees of anaplasia, moderate and severe in grades III and IV respectively, forming an arbitrary continuum from normal lobules to DCIS. ALB may give rise to LCIS. The grading system for ALA and ALB, based on both histologic and cytologic patterns, was divided into four grades. Hutchinson et al. [33] used a system of histological classification which does not detail grading but merely reports the presence or absence of epithelial atypia. Cook and Rohan [34] classified hyperplasia in three grades: mild, moderate or severe. Their mild hyperplasia corresponds to mild epithelial hyperplasia as defined by DuPont and Page; the moderate hyperplasia corresponds to moderate or florid epithelial hyperplasia as described by DuPont and Page while the severe hyperplasia corresponds to atypical hyperplasia. The classification criteria proposed by DuPont and Page have been already described [5]. Fechner and Mills [35] defined atypical hyperplasia by both qualitative and quantitative criteria. The qualitative criteria require a combination of predominantly cytologic abnormalities, in association with an appropriate growth pattern. Atypia can be graded as mild to severe, mostly on the basis of cytological abnormalities. If the number of abnormal cells in a duct involved with hyperplasia is minimal, this can be viewed as mild atypia. In contrast, in severe atypia most of the duct is involved. The diagnosis of atypical hyperplasia can be made when there is partial involvement of a duct by alterations architecturally and cytologically indistinguishable from cribriform in situ carcinoma. Cytologic abnormalities include enlarged hyperchromatic nuclei, irregular shape and high nuclear cytoplasmic ratio. In any case architectural and quantitative criteria are poorly defined in that atypical ductal hyperplasia is defined as such even when these cells are present focally along with typical hyperplasia with no specific architecture. Tavassoli and Norris [36] used other criteria (known as AFIP criteria) for atypical intraductal hyperplasia (AIDH) similar to those of DuPont and Page but they also emphasized specific cytologic architectural and quantitative aspects of the epithelial proliferation:...aidh is defined as a lesion in which the proliferating epithelial cells display a cytologic atypia similar to the cytologic features of one of the non-necrotic variants of ductal carcinoma in situ (DCIS) in which monotonous, rounded epithelial cells show a subtly increased nu- clearicytoplasmic ratio with round, often centrally located nuclei. not necessarily displaying appreciable nuclear hyperchromasia but lacking the typical architectural growth pattern of these non-necrotic car- cinomas. Alternatively, a proliferation may have both the cytologic and architectural features of one of the non-necrotic forms of DCIS and the changes may involve two or more ducts or ductules: however. if the involved ductsiductules measure less than 2 mm in aggregate di- ameter, the lesion is regarded as AIDH... They pointed out that AFIP criteria were necessary because the previous definition of AIDH was rather vague and emphasized the cytologic features as particularly important in separating AIDH from intraductal hyperplasia. Furthermore, the requirement of Page et al. that two spaces be involved by atypical changes for a diagnosis of DCIS can cause confusion because there is no size limit provided for the spaces. Unquestionable DCIS may involve a single duct or space, expanding to 1 cm or more, and no one would hesitate to designate it as carcinoma. The requirement that two spaces be involved is not reasonable in such a situation. The authors proposed a 2 mm cumulative diameter prerequisite because they believe it is at the level of these small ductules that the quantity assumes importance in the assessment of atypical proliferations. McDivitt et al. [9] used a modilication of the Black- Chabon cytologic grading system to classify hyperplasia and atypia. Atypical epithelial proliferation, graded in moderate and marked, include grades 3 and 4 of Black and Chabon [32]. Atypia grade 3 is associated with monomorphic proliferation which obliterates the lumen. Progressive loss of cell polarity occurs with increased nuclear prominence in grade BBD and cancer risk: a review of epidemiological studies The relationship between BBD and BC has been

12 232 S. Biunchi et (11./Cril. Rev. Oncol. Hematol. 15 (1993) evaluated and confirmed in several epidemiological studies. We reviewed results from three types of epidemiological studies: case-control, cohort and nested casecontrol studies. Case-control studies are based on the comparison of a general series of BC patients and a group of hospitalized or healthy subjects. Information is collected at interview and a high prevalence of BBD often is reported among study subjects because both biopsy-proven BBD and clinical lumps are included. In contrast, cohort studies and nested case-control studies are based only on histologically confirmed BBD but different histological classification criteria have been used (Page and DuPont or Black and Chabon classifications). All of these epidemiological studies evaluated the risk of developing breast cancer having a positive history of BBD in terms of RR but it is not easy to compare the results because of differences in the BBD classifications. All of the identified cohort studies reported the risk of developing a breast cancer having a previous hystologically confirmed history of BBD in comparison with the general population. BC risk, however, could vary with time since the diagnosis of BBD: this factor has been well considered by DuPont and Page [37]. They evaluated the BC risk associated with both AH and PDWA and found it is greater in the first 10 years after benign breast biopsy. Women with PDWA who remain free of breast cancer for 10 years are at no greater risk of breast cancer than women of similar age who do not have such a history. BC risk in women with AH is reduced if they remain free of BC for 10 years following the initial biopsy. This supports the hypothesis that the AHs are not obligate precursor lesion for breast cancer, and that these lesions may either progress to cancer, remain unchanged, or possibly regress over a substantial period of time. This time-dependent analysis suggests that follow-up of women with AH must be most vigilant during the first 10 years following diagnosis. At the end of this review four epidemiological studies evaluating the role of gross breast cysts are also reported. All showed a significant risk of developing cancer although other studies suggest that the cytologic examination of cyst fluids should be limited to those blood-stained. 5. I. Case-control studies Six case-control studies were identified evaluating the role of BBD as a risk factor for BC in the general population. Usually cases were women affected with histologically confirmed BC while controls were sampled among hospitalized patients. Cases and controls were generally matched by age and other sociodemographical characteristics. Most studies were not primarily focused on the role of BBD in BC risk but at interview, information about a previous history of BBD was collected. In one study [9] a histologic confirmation of reported BBD history was sought; in the other studies BBD was simply considered as a clinical entity (a breast lump or a cyst). All the studies calculated the relative risk of developing BC for women reporting BBD at interview (in comparison to women not reporting BBD) using multiple logistic regression analysis. La Vecchia et al. [38] conducted a hospital-based study in Northern Italy to evaluate the role of the most important risk factors for BC, in which 1108 cases and 1281 controls were identified below the age of 75 and interviewed. The risk of BC for those reporting a previous positive history of BBD was 1.9 (CI, ). BBD was defined as a clinical entity and was reported by 13.2 % of cases and by 6.6% of controls. Shatzkin et al. [39] examined risk factors for BC in US black women. In a hospital-based case-control study 522 BC cases and 583 controls were identified: a RR of 3.5 (CI, ) was found analyzing the data obtained by a questionnaire for those reporting BBD at interview. In the study of Tao et al. [40], 497 histologically confirmed incident BC cases were identified through a Cancer Registry and an equal number of controls were sampled from the general population in China. A selfadministered questionnaire was completed by both cases and controls. Tao found a RR of 3.2 (CL ); 28% of cases and 1 l % of controls reported a BBD history. Graham et al conducted a nutritional study in postmenopausal women (439 hospitalized BC cases and 492 controls) to evaluate the general risk factors of BC. Data were obtained by personal interview and in this frame information about a previous history of BBD (defined as lumps, cysts, and/or Iibrocystic disease) was also collected (24% of cases and 19 /;1 of controls reported a positive previous history of BBD). A RR of 1.4 (CI, ) was found. Pm-Bureau et al. [42] conducted a hospitalized matched case-control study in a population of urban, premenopausal women living in Paris between (cases had a BC diagnosis before their 45th birthday); 24% of 210 cases and 5.7% of an equal number of controls reported a previous history of BBD. The associated RR was 5.5 (CL ). McDivitt [9] analyzed data collected from a population-based case-control study of women aged years with BC diagnosis and control subjects ramdomly selected from the general population of six cities of USA between 1980 and Women were classified as having BBD only if the information given in a interview had a surgical biopsy confirmation. The original BBD biopsy were reviewed by three patologists and classified in three cathegories (not proliferative or Black Chabon grade 1; proliferative without atypia or Black Chabon grade 2; atypical hyperplasia or Black Chabon grade 3 or 4). An overall risk of 1.7 (CI, ) was found for all women with BBD according to specific histologic

13 S. Bianchi et al. / Crit. Rev. Oncol. Hematol. I5 (1993) Table 3 Results of 6 case-control studies on BBD (as reported at interview) and breast cancer risk Study Country Breast cancer Controls RR (95% CI) N /u with BBD N A, with BBD La Vecchia, 1987 [38] Schatzkin [39] Tao, 1988 [40] Graham, 1991 [41] Plu-Bureau, McDivitt [9] Italy USA China USA France USA (I.4-2.6) ( I.9-6.2) 497 II ( ) I.4 (1.o- I.9) (2.6-l 1.9) ( ) types the risk was 1.5 (CI, ) for non-proliferative, 1.8 (CI, ) for proliferative without atypia and 2.6 (Cl, ) for atypical hyperplasia. Overall, these case-control studies found a signilicantly increased risk of BC for women reporting a loosely defined BBD ranging between 1.4 and 5.5. These results, showed in Table 3, however, were based on information obtained only by questionnaire, except one study Cohort studies We identified 9 cohort studies on BBD as a BC risk factor. Women were included as cohort members only after receiving a diagnosis of BBD on a surgical biopsy; all the studies reported precise indications about the enrollement period and details about calculation of person-years. The risk of developing a BC having a histologic type of BBD was reported as a RR except in one mortality study in which a standardized mortality ratio (SMR) for BC was calculated. Usually the reference group was the general population, but in two studies it was an healthy sample of the general population. RRs are reported in Table 4 separately for non- proliferative disease (NPD), proliferative disease without atypia (PDWA) and atypical hyperplasia (AH), but only 5 studies reported all these results. Ashikari et al. [43] studied a cohort of 296 women diagnosed as having an atypical lesion of the breast in a surgical biopsy from 1960 to 1972 in USA. The expected number of BC cases was derived applying the age-specific incidence rate for BC reported for the year 1969 to the accumulated person-years at risk. The estimated risk of BC for women with atypical lobular hyperplasia and duct papillomatosis was almost 18 times than in the general population. Monson et al, [44] followed 733 women for an average of 30.3 years. These women had a biopsy diagnosis of chronic mastitis or chronic cystic mastitis at a Massachussetts hospital between 1915 and The SMRs for all causes of death were calculated: the number of deaths from BC was higher than in the general population showing an increased risk of 2.6. Kodlin et al. [45] conducted a follow-up study on 2411 cases of BBD diagnosed by biopsy between 1948 and 1973 in a hospital of Oakland. All the biopsies were classified in three classes using the Black-Chabon Table 4 Results of 9 cohort studies on hystologic type of BBD and breast cancer risk Study Country BBD cohort N Breast cancer cases N RR General population NPD PDWA AH Ashikari [43] USA Monson (441 USA Kodlin, 1977 [45] USA Moskowitz, 1980 [46] USA Hutchinson [33] USA o Roberts, 1984 [47] UK I.0 3.lb DuPont and Page, 1985 [5] USA I.o Carter, 1988 [8] USA I I.O I.5 I Nomura [48] Japan I.oc A standardized mortality ratio was calculated. brr estimated for all BBD types. Creference is a group of healthy women.

14 234 S. Bianchi et al. /Cd. Rev. Oncol. Hematol. 15 (1993) classification (1 or 2 corresponding to non-proliferative disease; 3 to proliferative without atypia; 4 to atypical hyperplasia). For all the three classes RRs were calculated: 2.3 for classes 1 and 2, 2.4 for class 3, and 6 for class 4. Moskowitz et al. [46] classified 1408 biopsies from 1978 as having bland fibrocystic disease or hyperplastic disorder, in which cases with atypical hyperplasia were identified. Patients were followed for a total of 3542 person-years. At first, BC risk was calculated for all types of hyperplasia and for atypical hyperplasia using as a reference category the bland fibrocystic group (RR 7.9 and 27, respectively). Then risks were calculated comparing BC incidence in the 3 groups (bland breast disease, all the hyperplasias and the atypical hyperplasia) relatively to BC incidence in the general population (RR: 0.4, 3.0 and 13 respectively). Hutchinson et al. [33] identified a cohort of 1,441 white women from 1940 through 1975 with biopsyproved BBD. In 1976 the original BBD slides were reviewed and a follow-up showed that 66 subjects had developed breast cancer. RRs were calculated for various types of benign lesion: 2.5 for non-proliferative lesion and 2.8 for both hyperplasia with and without atypia. Roberts et al. [47] identified 770 women from 1967 to 1970 in Wales (for a total of 8470 person-years at risk), 22 of these developed cancer (RR 2.7). However only 326 out of 770 subjects had slides available for review and 11 had subsequently developed BC (RR 3.1); the other women had only a combination of mammography, clinical or cyst aspiration diagnosis. The paper did not present RRs specifically calculated for each type of BBD among the 326 BBD patients with histological confirmation. DuPont and Page [5] published numerous studies about BBD and BC risk, in which they reviewed and reclassified according to specific pathologic criteria BBD biopsies of 3303 USA women selected from a larger group of about patients. The series was analyzed in terms of BC risk and a long-term follow-up was performed. The risk was estimated for each category as follows: 0.9 for non-proliferative, 1.6 for proliferative without atypia and 4.4 for proliferative with atypia. Carter et al. [8] identified BBD cases and women free from recognized breast disease (normal subjects) in a screening project in USA. Follow-up began in 1973 (6 months after the first biopsy for cases and 5.5 years after the screening for healthy subjects) and ended in BBD were classified into five categories: atypical hyperplasia, proliferative disease without atypia, non-proliferative, fibroadenoma and other BBD. RR calculated for NP, PDWA and AH was 1.5, 1.9, 3.0, respectively. The reference population for BC risk comparison was the normal women group. Nomura et al. [48] recently published preliminary results from the analysis of a retrospective cohort in Japan, in which a total of 428 patients with biopsied BBD were followed for a median period of 8 years. All the BBD biopsies were classified into three categories on the basis of epithelial proliferation and/or atypia according to the classification of Page and DuPont. BC risk was calculated using as reference a cohort of 856 healthy women followed as BBD subjects, it was 0.7 for NPD, 4.0 for PDWA and 25.2 for AH. Overall, all the results of the cohort studies presented in Table 4 show a significant risk increase for both types of proliferative disease (with or without atypia) in comparison to the general population. This increase in risk is generally higher for AH (ranging from 2.8 to 25.2). A similar increase in risk was not found for NPD: different results were reported with three studies showing no significantly increased risk [5,47,49]. RRs for the NPD category were never higher than 2.6, as reported in the mortality study of Monson [44] Nested case-control studies Four case-control studies nested within a cohort study Table 5 Results of 4 nested case-control studies on hystologic type of BBD and breast cancer risk Study Country Controls Breast cancer RR N cases N NPD PD AH (Cl) (Cl) Black, 1972 [49] Canada I.0 5.0b Palli, 1991 [SO] Italy I ( ) ( ) London, 1992 [51] USA 488 I ( ) (2.1 ~ 6.8) DuPont, 1993 [52] USA ( ) ( ) 95% Confidence interval. bci not available, P <

15 S. Bianchi et al. / Crii. Rev. Oncol. Hematol. I5 (1993) have been reported. The original cohorts including all women having a biopsy BBD diagnosis were the study populations in which BC cases and controls were identified. Cases were women with breast cancer who had a prior biopsy for BBD. Controls were randomly selected (matched on year of biopsy and year of birth) among women in the same cohort who had a benign breast biopsy but who had not developed BC. RRs for specific BBD histologic types were usually reported in comparison to the reference group of subjects having a NPD. Table 5 reports the results of these studies. In Canada, Black et al. [49] identified 155 controls and 60 BC cases and, using the numerical grading system for assessing duct epitelial proliferation described previously by Black and Chabon [32], reported that a woman with some ductal atypia had a risk of developing BC 5-fold greater than that of a woman with no evidence of atypical changes. In the study of Palli et al. [50] 62 cases of BC were identified in Italy in a large cohort of women previously treated for biopsy-proven BBD along with a group of 315 controls, strictly matched by age and year of diagnosis. All of the original slides were reclassified according to the classification of Page and DuPont. An adjusted RR of 1.3 was found for PDWA and of 13.0 for AH. London selected 121 cases with BC and 488 controls in a US cohort [511. After a review of the slides from the first benign breast biopsy the RRs were calculated for PDWA and AH (1.6 and 3.7 respectively). In a recent nested case-control study DuPont et al. [52] evaluated the role of proliferative breast disease as a determinant of risk of BC among participants into a multicentric screening program. Overall, 227 controls and 95 BC cases were identified: a relative risk of 1.3 was found for PDWA and of 4.3 for AH. They also reported the comparison of histological diagnoses of the two study pathologists in which reproducibility was quite low. These four studies reported high RR for AH while risk was near unity for PDWA. Differences are evident when comparing results of cohort studies with those of nested case-control studies but both reported a higher RR for AH than for PDWA providing evidence that AH is an important risk factor for BC Gross cysts and BC risk Because breast cysts are a relatively frequent finding in clinical practice, with clinical and mammographic diagnosis usually confirmed by needle aspiration of the cyst fluid, results from several studies of series of patients, in whom a cyst was aspirated, have been reported. Four follow-up studies evaluated the risk of developing BC for women having a previous diagnosis of gross cyst by line needle aspiration (FNA). A total of 322 cases of macroscopic breast cysts were followed after aspiration for a minimum follow-up period of 5 years from Jones et al. [53] in the UK. Seven patients developed a carcinoma arising in either the same or the opposite breast (4 and 3 respectively). BC risk for women with a diagnosis of FNA gross cyst disease was more than twice that which would be expected in the general population. Ciatto et al. [54] evaluated the risk of subsequent BC in 3809 women for whom the diagnostic workup of a gross cystic disease included also FNA. Thirty-four developed a BC and a risk of 1.7 was found in comparison with the general female population of Florence. Bundred et al. [55] identified 352 women in Wales with aspirated cysts between 1976 and Fourteen of these developed BC. Women included in this cohort were significantly more likely to develop BC than women in the general population. and a RR of 4.4 was found. In the study of Bodian et al. [56] a cohort of 1501 women was identified between 1936 and 1982 in USA. All subjects had a diagnosis of gross cystic disease confirmed by aspiration. During the follow-up, 162 of these cases developed BC. The risk of developing BC was 3- fold of that in the general population. The results of these studies are reported in Table Clinical significance of AH An increased breast cancer risk in a small group of women with BBD can be reliably determined on the basis of histologic criteria, i.e., AH of the epithelial proliferation. Long-term follow-up results reported by DuPont and Page [37] showed that BC risk in women with AH is reduced if they remain free of BC for 10 years, following the initial biopsy. More recently, studies, considering the laterality of subsequent breast cancer in patients with AH, reported that overall cancer risk was approximately the same for the two breasts [50,57]. These data would suggest that AH must be considered as a marker for the subsequent development of breast cancer rather than a precursor Table 6 Results of 4 cohort and breast cancer studies on gross cystic disease (as defined by FNA) Study Country BBD Breast RR cohort cancer cases Jones, 1980 [53] UK >2 Ciatto, Italy Bundren, 1991 [55] UK Bodian, USA

16 236 S. Bianchi et al. / Crit. Rev. Oncol. Hematol. 15 (1993) Evolution of breast cancer risk will improve as more specific information about possible interactions between histologic parameters and epidemiologic risk factors (family history, number of pregnancies, age at menarche and first birth, smoking history, dietary factors, menopausal status, etc.) will become available. It is clear, however, that patients with AH should be examined at closer follow-up in comparison to other women with BBD. Currently, women with a diagnosis of AH should follow a program including a physical examination and a mammography test every 12 months. Patients with PDWA or NPD should be invited to follow the guidelines issued for the generale female population of similar age, including a regular program of mammographic surveillance for those over 50 years of age. Mammographic surveillance is, at present, the most widely accepted strategy for most women with increased BC risk and prophylactic surgery does not represent a practical alternative [59]. 7. BBD and mammographic patterns Several studies have attempted to correlate BBD with mammographic patterns. Rubin et al. [60] reviewed 100 consecutive non-palpable lesions detected mammographically in a series of patients with documented risk factors. The pathologic specimens of breast biopsies were reviewed and classified according to the criteria of DuPont and Page [5]. The results showed carcinomas in 20% of the biopsies (55% of which were non-invasive). AH was found in 10% of the biopsy specimens, whereas proliferative disease without atypia occurred in 21% of the biopsies, 49% of the biopsies showed non-proliferative changes. On the basis of these results, the authors concluded that mammography is able to identify a high percentage of women with pathologic lesions known to have an elevated risk for subsequent breast cancer. The high incidence of AH with respect to the data reported by Dupont and Page [5] (10% versus 3.6%) could be explained by the fact that Rubin s study [60] refers to a selected group of patients with other risk factors such as family history, controlateral breast cancer and nulliparity. These results, however, showing that biopsies performed for lesions discovered mammographically can detect a high percentage of women at elevated risk for subsequent development of breast cancer have not been confirmed in other studies [61]. In our own experience, in a large series of nonpalpable lesions (1173 cases) the prevalence of AH was 3.3%) overall and increased to 6.5% in the group of 557 benign non-palpable lesions [62]. Bartow et al. [63] in an autopsy series of 486 women examined the correlation between radiographic para- meters and histologic pattern: in women over 50 years of age the P2/DY Wolfe parenchymal pattern was significantly associated with the presence of both lobular microcalcifications and marked intraductal epithelial hyperplasia. Other studies correlating biopsy tissue with mammographic patterns [46, had previously found an increased prevalence of these epithelial hyperplasias in breasts with high-risk Wolfe patterns (P2 and DY). Other studies, however [68] carried out also in postmenopausal women [65,66] found no strong correlation between hyperplastic lesions and high-risk parenchymal patterns. Boyd et al. [69] reported that women with densities in more than 75 /;, of the breast volume were more likely to develop histological changes associated with a substantially increased risk of breast cancer than women without densities. Women with densities occupying more than 75% of the breast volume had a 9.7 times greater risk of developing carcinoma in situ or atypical hyperplasia, a 12.2 times greater risk of developing hyperplasia without atypia and a 3.1 times greater risk of developing non-proliferative disease. Nevertheless the authors did not find any association between mammographic density at the biopsy site and the high-risk histological lesions, but calcifications at the biopsy site were strongly associated with high-risk histological changes. Although there is a correlation between histological and radiological indicators of breast cancer risk, the high-risk histological changes do not necessarily occur in regions of the breast showing mammographic densities. Mammographic densities are considered to be associated with changes in the breast stroma, not in the epithelium. Calcifications have recently been shown to be associated with atypical hyperplasia [70] and specifically with ADH but not ALH; this finding is consistent with the frequent association of microcalcifications with ductal in situ carcinoma but almost never with lobular in situ carcinoma. In LCIS microcalcifications when present, are found in adjacent tissue. It must be underlined, however, that in Helvie s study [70] the indication to surgical biopsy in the majority of cases was based on mammographic, not clinical, findings. It would be desirable to be able to use mammographic features such as Wolfe patterns and microcalcifications to select those women for whom frequent screening mammography and physical examination are necessary because of increased BC risk. At present further studies are necessary to demonstrate the relationship, if any, between epithelial hyperplasia and mammographic patterns considering that no pathognomonic mammographic appearance of AH has been determined. It is our opinion that the diagnosis of AH in a breast