Benign breast disease and cancer risk

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

4.

5.

6.

7.

8.

9.

IO.

II.

12.

13.

14.

15.

16.

Introduction ...........................................................................

BBD consensus statement ...............................................................

Page’s histological classification ..........................................................

3.1. Non-proliferative BBD ............................................................ 3.2. Proliferative disease without atypia ................................................. 3.3. Atypical hyperplasia ..............................................................

3.3. I. Atypical ductal hyperplasia (ADH) ......................................... 3.3.2. Atypical lobular hyperplasia (ALH) .........................................

A comparison of BBD histological classifications ...........................................

BBD and cancer risk: a review of epidemiological studies ................................... 5.1. Case-control studies ..............................................................

5.2. Cohort studies ...................................................................

5.3. Nested case-control studies ........................................................

5.4. Gross cysts and BC risk ..........................................................

Clinical significance of AH ..............................................................

BBD and mammographic patterns ........................................................

BBDand cytologicexamination ..........................................................

Reproducibility of histological diagnosis of proliferative disease ..............................

Role of ancillary techniques to histological diagnosis .......................................

Biological profile of AH ................................................................

Conclusions ...........................................................................

Acknowledgements .....................................................................

Biographies ............................................................................

Reviewer ..............................................................................

References ............................................................................

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* Corresponding author, lstituto di Anatomia e lstologia htO]OgiCa. Policlinico Careggi. Viale Morgagni 85. 50134 Florence. Italy

1040~8428/93/$24.00 0 1993 Elsevier Scientific Publishers Ireland Ltd. All rights reserved.

SSDl 1040-8428(93)00086-U

222 S. Bianchi et al. /Cd. Rev. Oncol. Hematol. I5 (1993) 221-242

1. 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 hy-

perplasia; ANDI, aberrations of normal development and involution;

BBD, benign breast disease; BC. breast cancer; Cl, confidence inter-

val; 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 neo-

plasia; 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 Com- mittee 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 dif- fering 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 ( 1.5-2 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

S. Bianchi et al. /Cd. Rev. Oncol. Hematol. 1.5 (1993) 221-242 223

Table I with hyperplastic alterations within lobular units as Consensus BBD histological classification shown by Ohuchi et al. [14] and Salhany et al. [15].

(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 papillo-

matosis’ 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 simul- taneous occurrence of epithelial hyperplasia of various degree was responsible for the increased risk. In fact. particularly peripheral papillary lesions are continuous

Benign breast tissue removed from women with clinical ‘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 deriva- tion 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 [20,2 11.

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 Amer- ican 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).

S. Biundzi tv ul. / Crit. Rev. Oncol. Hematol. 15 (1993) 221-242

Fig. 1 (A.B) Sclerosing adenosis characterized by proliferation of acinar structures and myoepithelial elements with enlargement and distorsion of the lobular units.

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.

3.2. 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 occlu-

sion 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 base-

ment membrane.

S. Bianchi et al. / Crir. Rev. Oncol. Hemarol. 15 (1993) 221-242 225

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) [ 191 and 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 differentia- tion 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.

3.3. 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’)

226 S. Bianchi PI ul. / Crir. Rev. Oncol. Hematol. I5 (1993) 221-242

Fig. 5 (A,B) Florid epithelial hyperplasia characterized by a proliferation showing a solid or fenestrated architecture (cell ‘swirling’)

Fig. 6 (A,B) Florid epithelial hyperplasia showing a proliferation of cytologically benign cells that till and distend the ducts.

S. Bianchi et al. /Crit. Rev. Oncol. Hematol. 15 (1993) 221-242

[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.

3.3.1. Atypical ductal hyperplasia (ADH) Cytologic features. ADH exhibits a partial involve-

221

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 hyper- chromatic 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 polar- ized 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 membrane- bound 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.

Fig. 7 (A,B) Atypical ductal hyperplasia with cribriform pattern. Secondary spaces are both regular with smooth, rounded ‘punched-out’ borders

as in DCIS and irregular as in florid hyperplasia without atypia.

S. Biunlhi et ul. / Crit. Rev. Oncol. Hemarol. 15 (1993) 221- ,242

Fig, 8 (A-D) Atypical ductal hyperplasia, the proliferation is composed m part of evenly spaced uniform cells with regularly placed monomorphic

nuclei. In other areas the proliferating cells maintain their orientation.

S. Bianchi et al. / Crir. Rev. Oncol. Hematol. 1.5 (1993) 221-242 229

Fig. 9 (A,B) Atypical ductal hyperplasia with micropapillary pattern showing hypercromatic cells in rigid configuration that bridge the lumen. Other

areas of the spaces lack this rigidity and cells mantain normal orientation.

3.3.2. 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 cen- tral 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 under- mining a separate superficial or luminal cell population, a diagnosis of ductal involvement ,of ALH cells is made

]261.

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 193 1, 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 3-4.5 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

230 S. Bianchi et al. / Crir. Rev. Oncol. Hemarol. 15 (1993) 221-2 42

Fig. 10 (A,B) Atypical lobular hyperplasia: partial filling and mild acinar distension with focal preservation of luminal spaces

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 stratitica- tion, hyperchomasia, cellular pleomorphism and presence of mitoses, as l-3 (grade 1 for relatively slight

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 duc- tular lesions in patients with breast cancer compared to women without cancer.

The main limitation in comparing the numerous

Table 2

Comparison of proposed histological classifications of benign breast disease with epithelial proliferation

Black and Chabon

1969 [32]

Welling et al., 1975

[311 Hutchinson et al., 1980

I331 Cook and Rohan, 1985

l341 DuPont and Page, 1985

]51 Fechner and Mills, 1990

1351 Tavassoli and Norris, 1990

1361 McDivitt et al., 1992

[91

Grade II Grade III

Hyperplasia Distinct but minimal atypia

ALA/AL9 I-11 ALA/AL9 111

Epithelial hyperplasia or papillomatosis without

atypia

Mild hyperplasia Moderate hyperplasia

Mild hyperplasia Moderate and florid

hyperplasia

Mild hyperplasia Moderate and florid

hyperplasia

Hyperplasia

(intraductal)

Hyperplasia without Hyperplasia with moderate

atypia atypia

Grade IV

Atypia suggestive in situ carcinoma

ALA/AL9 IV

Epithelial hyperplasia or papillomatosis

with atypia

Severe hyperplasia

Atypical ductal or lobular hyperplasia

Mild to severe atypial hyperplasia

Atypical hyperplasia

(intraductal)

Hyperplasia with marked atypia

S. Bianchi et al. /Crit. Rev. Oncol. Hematol. 15 (1993) 221-242 731

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, individu- al 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 predomin- antly 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 indis- tinguishable from cribriform in situ carcinoma. Cytologic abnormalities include enlarged hyper- chromatic nuclei, irregular shape and high nuclear cyto- plasmic 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 prere- quisite 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 4.

5. BBD and cancer risk: a review of epidemiological studies

The relationship between BBD and BC has been

232

evaluated and confirmed in several epidemiological studies.

We reviewed results from three types of epidemiological studies: case-control, cohort and nested case-

control 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 dif-

ferent 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, informa-

tion about a previous history of BBD was collected. In

S. Biunchi et (11. /Cril. Rev. Oncol. Hematol. 15 (1993) 221-242

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 in-

terviewed. The risk of BC for those reporting a previous positive history of BBD was 1.9 (CI, 1.4-2.6). 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, 1.6-6.2) 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 con-

firmed incident BC cases were identified through a Cancer Registry and an equal number of controls were

sampled from the general population in China. A self- administered questionnaire was completed by both cases and controls. Tao found a RR of 3.2 (CL 2.2-4.7); 28% of cases and 1 l”% of controls reported a BBD history.

Graham et al. 1411 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, 1.0-1.9) was found. Pm-Bureau et al. [42] conducted a hospitalized mat-

ched case-control study in a population of urban, premenopausal women living in Paris between 1982-1985

(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 2.6-11.9).

McDivitt [9] analyzed data collected from a population-based case-control study of women aged 20-54 years with BC diagnosis and control subjects ramdomly selected from the general population of six cities of USA between 1980 and 1982. 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, 1.5-2.0) was found for

all women with BBD according to specific histologic

S. Bianchi et al. / Crit. Rev. Oncol. Hematol. I5 (1993) 221-242 233

Table 3 Results of 6 case-control studies on BBD (as reported at interview) and breast cancer risk

Study

La Vecchia, 1987 [38]

Schatzkin. 1987 [39]

Tao, 1988 [40]

Graham, 1991 [41]

Plu-Bureau, 1992 1421

McDivitt. 1992 [9]

Country

Italy

USA

China

USA

France

USA

Breast cancer

N “/u with

BBD

1108 13.2

522 13.8 497 28.4

437 25.4 210 24.3

3891 10.7

Controls RR (95% CI)

N “A, with

BBD

1281 6.6 1.9 (I .4-2.6)

563 7.6 3.5 ( I .9-6.2) 497 II.1 3.2 (2.2-4.7) 492 19.3 I .4 (1 .o- I .9) 210 5.7 5.5 (2.6-l 1.9)

3923 6.3 1.7 (1.5-2.0)

types the risk was 1.5 (CI, 1.3- 1.9) for non-proliferative, 1.8 (CI, 1.3-2.4) for proliferative without atypia and 2.6 (Cl, 1.6-4.1) for atypical hyperplasia.

Overall, these case-control studies found a signilicant- ly 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.

5.2. 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 1939. 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. 1974 [43] USA 296 20 1.0 - - 18.0 Monson. 1976 (441” USA 773 49 1.0 2.6 - Kodlin, 1977 [45] USA 2411 46 1.0 2.3 2.4 6.0 Moskowitz, 1980 [46] USA 1408 13 1.0 0.4 3.0 13.0 Hutchinson. 1980 [33] USA 1441 66 1 .o 2.5 2.8 2.8 Roberts, 1984 [47] UK 326 11 I.0 3.lb DuPont and Page, 1985 [5] USA 3303 134 I .o 0.9 1.6 4.4 Carter, 1988 [8] USA I6 692 485 I .O’ I.5 I.9 3.0 Nomura. 1992 [48] Japan 428 21 I .oc 0.7 4.0 25.2

“A standardized mortality ratio was calculated.

bRR estimated for all BBD types.

Creference is a group of healthy women.

234 S. Bianchi et al. /Cd. Rev. Oncol. Hematol. 15 (1993) 221-242

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.

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.

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).

Carter et al. [8] identified 16 692 BBD cases and 23 862 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 1986. 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.

Hutchinson et al. [33] identified a cohort of 1,441 white women from 1940 through 1975 with biopsy- proved 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.

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.

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 10 000 patients. The series was

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].

5.3. 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 155 60 I.0 5.0b

Palli, 1991 [SO] Italy 315 62 I.0 1.3 13.0

(0.5 - 3.5) (4.1 - 41.7)

London, 1992 [51] USA 488 I21 1.0 1.6 3.7

(1.0 - 2.5) (2.1 ~ 6.8)

DuPont, 1993 [52] USA 227 95 1.0 1.3 4.3 (0.8 - 2.2) (1.7 - 11.0)

‘95% Confidence interval.

bCI not available, P < 0.005.

S. Bianchi et al. / Crii. Rev. Oncol. Hematol. I5 (1993) 221-242 235

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 3 15 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 [5 11. 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.

5.4. 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 1982. 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 6.

6. 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’ 1581.

Table 6

Results of 4 cohort studies on gross cystic disease (as defined by FNA)

and breast cancer

Study Country BBD Breast RR

cohort cancer

cases

Jones, 1980 [53] UK 322 7 >2

Ciatto, 1990 1541 Italy 3809 34 1.7

Bundren, 1991 [55] UK 352 14 4.4

Bodian, 1992 1561 USA 1501 162 3.0

236 S. Bianchi et al. / Crit. Rev. Oncol. Hematol. 15 (1993) 221-242

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, meno-

pausal 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 pop-

ulation 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 Du-

pont 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 non-

palpable 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 [46,64-671 had

previously found an increased prevalence of these epithelial hyperplasias in breasts with high-risk Wolfe

patterns’(P2 and DY). Other studies, however [68] car-

ried 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 substan- tially 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 hy-

perplasia 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 associ-

ated with changes in the breast stroma, not in the epithelium.

Calcifications have recently been shown to be associ-

ated 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

S. Bianchi er al. / Crit. Rev. Oncol. Hematol. 15 (1993) 221-242 231

biopsy is in most cases a random event, because of the lack of specific mammographic or clinical patterns as lobular in situ carcinoma. Specificity of mammography in diagnosing BC has increased and currently the benign/malignant ratio is considered acceptable only if less than 1: many women with benign lesions are now spared a surgical biopsy and therefore can not be included in a histologically defined BBD group.

Absolute numbers of newly diagnosed BBD cases can be considered stable also in areas with increasing mammography examinations.

8. BBD and cytologic examination

Some studies have tested the hypothesis that system- atic sampling of breast tissue by fine-needle aspiration yields sufficient material for detection of proliferative changes. King et al. [71] analyzed 108 cases with FNA and 39 related surgical biopsies. In addition a cytometric study was carried out blind to cytologic or histologic classification. Grading of proliferative changes in surgical biopsies followed the Wellings’ system. Each FNA sample was assigned a final classification as follows: benign without proliferation, mild hyperplasia, atypical hyperplasia in&ding moderate hyperplasia, or malignant. Criteria for moderate and atypical hyperplasia in FNA have not been previously described. Cytometric analysis correctly classified six out of seven cases of moderate and atypical hyperplasia as abnormal, while conventional FNA evaluation failed to distinguish these cases from mild hyperplasia.

Skolnick et al. [72] examined the frequency of proliferative breast disease (PBD) performing four-quadrant FNA in families that were ascertained by two first degree relatives with breast cancer in order to test the hypothesis that PBD and breast cancer are inherited jointly in these families. Cytologic analysis of FNA revealed PBD in 35% of clinically normal female tirst- degree relatives of breast cancer cases and in 13% of controls. Genetic analysis suggested that genetic susceptibility was increased for both PBD and breast cancer in these kindreds. Page and DuPont [73] criticized the latter study considering PBD as a well-defined histologic condition ‘bearing only a slight and untested resemblance to the cytologic findings’ reported in Skolnick’s study [72].

Marshall et al. [74] used blind multiple FNAs to determine the frequency of clinically inapparent proliferative breast disease in women with a family history of breast cancer. Proliferative breast disease was identified in 20 of 51 study subjects (39.2%); in 16 women (31.4%) benign hyperplasia was reported while in 4 (7.9%) the diagnosis was atypical hyperplasia. Although these findings show that FNA sampling and computerized image analysis can be useful in the detection and characterization of clinically inapparent PBD, they must be viewed

as preliminary evidence; validation of this technique requires correlational histologic studies on mastectomy specimens. Overall the diagnosis of PBD by FNA is still considered controversial, the identitication and characterization of PBD in tissue sections relies heavily on the overall architectural pattern and cytologic features of proliferation which cannot be assessed in cytologic specimens.

Bibbo et al. [75] stated that the limitations of FNA for diagnosing mild to moderate atypical hyperplasia appear to be greater than those of surgical biopsy since diagnostic cytologic changes for this lesion have not been precisely defined. Also Ducatman et al. [76] stated that Marshall’s study does not prove that FNA is useful in screening asymptomatic women for clinically inapparent PBD. Validation of cytologic criteria is needed before considering FNA as a tool for diagnosing PBD.

Atypical cells could also be sampled from a DCIS and differential diagnosis between DCIS and ADH is prac- tically impossible using FNA. Abendroth et al. [77], suggested that the only DCIS cases easily distinguishable from ADH are represented by comedo-type lesions or large-cell carcinomas; in contrast to this cribriform and other small cell DCIS variants would share cytologic features with ADH. Salhany and Page 1781 stated that no cytologic features were noted that could differentiate the FNA samples with ALH from those of LCIS.

ALH and LCIS are histologically defined lesions with different clinical and prognostic implications, but cannot be differentiated on cytologic grounds. These results suggest that an excisional biopsy should be performed in cases of suspected atypical lobular hyperplasia and lobular carcinoma in situ.

At present the evaluation of premalignant changes with FNA can not be recommended in clinical practice until further evidence of its clinical relevance is provided.

9. Reproducibility of histological diagnosis of proliferative disease

A number of studies have shown that the risk of developing an invasive carcinoma correlates with the degree of epithelial proliferation and atypia. To date, however, the ability of pathologists to categorize proliferative breast lesions in a reproducible way has not been adequately evaluated. Only a few surveys have been carried out in order to test the degree of interobserver variability among pathologists.

Recently Rosai considering the wide disparity among pathologists in the use of the term atypical hyperplasia submitted ten cases of proliferative ductal lesions and seven cases of proliferative lobular lesions for a diagnostic opinion to five highly respected pathologists with a large experience in breast pathology [79]. The diagnostic

238 S. Bianchi et al. iCrir. Rev. Oncot. Hematoi. IS (1993) 221-242

categories available for classification were hyperplasia, atypical hyperplasia, carcinoma in situ (CIS) and ‘other’. The pathologists were asked to use the same diagnostic criteria as in their daily practice. The study showed that there was not a single case in which all five pathologists agreed on a diagnosis (only in three cases four of the five pathologists agreed). In six cases

diagnoses ranged between hyperplasia and CIS. On the basis of these results the author concluded that uniform diagnostic criteria in this field have not been reached. The basic problem is that it is impossible to eradicate

completely the role of subjectivity in this diagnostic field. Considering that the current terminology (atypical hyperplasia vs. carcinoma in situ) tends to separate clearly what is actually histologically similar [SO], Rosai

also proposed to drop the hyperplasia/CIS dichotomy and suggested to introduce the concept of mammary intraepithelial neoplasia (MIN) of either ductal or lobular

type, together with a grading system. The proposed terminology, however, would not solve the interpretation problems of these lesions and the problem of interobserver variability,

Raju (811, commenting on Rosai’s proposal, recommended a limited utilization of the term atypical hyperplasia in order to avoid an additional ‘wastebasket’ term with little meaning when used too loosely.

The results of a recent reproducibility study concerning 24 proliferative breast lesions [82] suggested that interobserver reproducibility in the classification of proliferative breast lesions can be improved using stan-

dardized diagnostic criteria. The criteria for categorizing proliferative lesions used in this study were those

developed by Page so that his diagnoses were assumed as the ‘reference diagnosis’. Agreement ranged from 71

to 92% with an average value of 83%. Overall, 10 diagnostic discrepancies were found, including atypical hyperplasia versus carcinoma in situ in six cases, usual versus atypical hyperplsia in two cases and usual and

atypical hyperplasia versus carcinoma in situ in two. Furthermore, the importance of distinguishing between atypical hyperplasia and small cell carcinoma in situ is unknown since the natural history of such ductal car-

cinoma in situ is poorly understood; nevertheless the current management of patients with atypical hyperplasia differs from that of patients with small cell carcinoma in situ. If clinical studies will be able to show that natural history of small cell carcinoma in situ does not differ considerably from that of atypical hyperplasia, the need to distinguish between these two lesions will be eliminated and the possibility of adopting a classification system that groups these two types of lesions, as proposed by Rosai, could be considered.

The difficulty in carrying out studies concerning interobserver reproducibility in surgical pathology derives also from the lack of a ‘gold standard’. Rosen [83] has recently proposed that one potentially valuable method

to overcome this difficulty is to perform a study in which a panel of pathologists examines a series of breast biop-

sies with non-invasive proliferative lesions from patients with available follow-up data. Only the comparison of these diagnoses with the subsequent clinical evolution will bring out those criteria with the best predictive

value in terms of breast cancer risk.

10. Role of ancillary techniques to histological diagnosis

AH shares several histological features with in situ carcinoma making a clear differential diagnosis difficult.

A possible approach to overcome the histopatho- logical diagnostic difficulties could be the analysis of

these lesions with ancillary techniques in an attempt to obtain a more reproducible separation between the various groups. Unfortunately, this goal has not yet been achieved. Ultrastructural studies have failed to

provide more accurate diagnostic criteria than the light microscope to differentiate atypical hyperplastic lesions from in situ carcinoma. Electron microscopic findings have shown that cellular atypia in hyperplastic lesions

seen with the traditional light microscope is paralleled by ultrastructural alterations which, in many instances, approximate those seen in mammary carcinoma cells

[84,85]. Immunohistochemical studies investigating the anti-

genie profile of the cellular proliferation in mild/ moderate ductal hyperplasia, atypical ductal hyper-

plasia and intraductal carcinoma have demonstrated distinct differences in high-molecular-weight cytokeratin expression of mild/moderate ductal hyperplasia and intraductal carcinoma but it has failed to provide

evidence that would be helpful for distinguishing atypical ductal hyperplasia from intraductal carcinoma. All examples of atypical ductal hyperplasia showed the same antigenic profile of intraductal carcinoma, i.e.,

non-reactivity to high molecular weight cytokeratin

WI. Various ‘tumor-associated antigens’ detected im-

munohistochemically with monoclonal antibodies have

failed to show statistically significant differences between CIS and atypical hyperplasia [87-891. Mor- phometric studies have shown that a measure of nuclear area is the best discrimination between ductal hyperplasia without atypia and intraductal carcinoma but further studies are required to determine whether mor- phometric parameters provide useful information in assessing lesions such as atypical ductal hyperplasia.

Overlapping of these parameters should be expected when atypical hyperplasia and in situ carcinoma are compared [90].

Determination of nuclear DNA content, either by cytophotometry or flow cytometry yielded disappoin- ting results. De Potter et al. [91] in a study carried out with the aim of establishing objective criteria for

S. Bianchi et al. /Crit. Rev. Oncol. Hematol. IS (1993) 221-242 239

distinguishing between atypical hyperplasia and ductal

carcinoma in situ, observed an increased number of tetraploid nuclei in atypical hyperplasia as well as in ductal carcinoma in situ reached the conclusion that DNA measurement is of limited value in the differential

diagnosis between proliferative lesions with atypia and intraductal carcinoma.

In contrast, other authors recently found a significantly higher incidence of aneuploidy in intraduc-

tal carcinoma versus atypical hyperplasia using image cytophotometric DNA analysis, (DCIS 71% vs. AH 30%) [92]. Abnormal DNA content also correlated with higher nuclear grade within the DCIS groups (moderate

63% vs. poor 93% aneuploid). This pattern of abnormal DNA content appears to represent a continuum that reflects biological aggressivity because large cell DCIS

like comedocarcinoma are more likely to progress to in-

vasive carcinoma. It must be observed however, that the only two small cell DCIS cases showed a diploid DNA content.

Recently, a study has been carried out to determine if

expression of transforming growth factor alpha (TGFcY) would assist in the histological diagnosis of different intraductal epithelial proliferations. The results showed that evaluation of TGF-CY expression in epithelial proliferation of the breast does not help the histopathologist in distinguishing atypical ductal hyperplasia from ductal hyperplasia without atypia or DCIS [93].

11. Biological profile of atypical hyperplasia

A detailed analysis of the biological profile of AH is

beyond the scope of the present review.

Only a few studies attempted to investigate the biological profile of atypical hyperplasia. The ras oncogene p21 expression was demonstrated progressively stronger and more extensive from normal through hyperplastic

and atypical epithelium to non-invasive carcinoma [94,95]. In an immunohistochemical study investigating c-e&B-2 overexpression in benign and malignant breast disease, none of the 13 cases of atypical ductal prolifera-

tion demonstrated the pattern of staining associated with overexpression [96]. The same results have been obtained recently by Allred’s study in which overexpression of HER-2/neu was not observed in any of the

hyperplastic lesions classified as proliferative disease without atypia or atypical ductal hyperplasia [97]. De Potter et al. [98] have described similar findings in their seven cases of ADH, while Lodato et al. [99] recently reported two positive cases out of 21 ADHs, but they pointed out that both cases showed only weak focal im- munostaining and that one was difficult to distinguish from DCIS. Thus, it appears that ADH are rarely associated with overexpression of HER-Zlneu. Other studies will be required to determine wether HER-~/MU and ras p21 are markers for progression of AH to car-

cinoma.

A DNA study testing the hypothesis of whether

women with both breast cancer and a history of atypical hyperplasia have an increased frequency of germline p.53

mutation, as well as whether atypical hyperplasias ex- hibit somatic p.53 mutations has been performed. The very preliminary results showed no germline or somatic cell mutations in these patients suggesting that the ~53

mutations occurred during late stages in the pathogenesis of cancer [ 1001.

Immunohistochemical studies have shown an increased and homogeneous expression of estrogen receptors in some proliferative breast lesions [IO]-1031. This could

lead to an increased activation of genes regulating proliferative activity [ 104,105] and to an increased size of the cell population in the proliferative compartment.

The proliferative lesions showing this alterated expres-

sion of estrogen receptor include ALH, LCIS. ADH and DCIS non-comedo type with small cells [loll.

Nenci et al. [106] pointed out that promotion is the

step of the carcinogenetic process whereby an initiated tissue develops focal proliferation as a ‘proximate’

precursor. The increased and homogeneous expression

of estrogen receptor in atypical hyperplasia suggests that a continuous estrogen stimulus may be critical in sus- taining the growth of mammary preneoplastic lesions and their progression to invasive cancer.

A study concerning the expression of a structural pro-

tein (fodrin) within epithelial proliferative lesion of the breast showed that one evident histologic characteristic of epithelial hyperplasia is the partial or complete loss of normal cellular polarity. In fact in normal epithelium, fodrin, whose function is related to maintenance of cellular polarity, appears to be localized along the later- al cell membrane between adjacent cells, whereas in hy-

perplasia fodrin is present around the entire cellular membrane [107].

New biological markers as oncogenes, growth factors, structural proteins or hormone receptors have not yet

provided new elements in order to understand the natural history of proliferative epithelial lesions. Although there is no known clinical or therapeutic correlate. the demonstration that estrogen receptor is present in the

majority of atypical hyperplasia appears to be an ex- citing area for future research.

12. Conclusions

Several studies have investigated the relationship between BBD and increased breast cancer risk and have reported that among different histologic types of BBD, epithelial proliferative lesions and in particular proliferative lesions with atypia, the so called ductal and/or lobular atypical hyperplasia are at increased risk of development of breast cancer.

The use of specific histologic diagnoses in surgical

pathology reports of benign lesions found in breast tis-

240

sue specimens is recommended and the non-specific and generic terms like BBD and FCD should be avoided.

For women with histologically diagnosed AH a physical examination and a mammography test every 12 months are recommended.

For women with PDWA or non-proliferataive disease who are over 50 years old, a mammography every 2 years is recommended.

Atypical hyperplasia is rare, occurring in about 2-4X of breast biopsy specimens. It is likely that this propor- tion will not increase with more widespread utilization of mammography because of a lack of specific mammographic patterns. Actually it can be considered as a random finding in a surgical biopsy performed to exclude BC.

Although a combination of histologic and cytologic criteria for the diagnosis of atypical hyperplasia have been provided, AH remains a diagnosis with a certain degree of interobserver variability with the possibility either to be underdiagnosed as a proliferative lesion without atypia or to be overdiagnosed as in situ carcinoma. At present routine histologic evaluation is the only tool available for the classification of these lesions as a highly specific biologic marker has yet been identified to evaluate proliferative lesions of the breast. A diagnosis of PBD or AH can not be supported by FNA alone.

The biological meaning of AH is still not well understood: AH could be an intermediate step in the progression to invasive carcinoma or could be simply considered as a ‘marker’ of increased risk for the whole breast gland.

13. Acknowledgements

This work was supported by a grant from ‘Consiglio Nazionale Delle Ricerche (CNR)’ - finalised project ACRO, Rome, Italy.

The co-operation of Mrs. L. Soini in typing the manu- script is gratefully acknowledged.

14. Biographies

Simonetta Biunchi, M.D. is an assistant Professor at the Pathology Department, Florence University, Italy. Domenico Palli, M.D. is a medical epidemiologist at the Epidemiology Unit, C.S.P.O., Florence, Italy. Monica Galli, B.Sc. is an epidemiologist at the Epidemiology Unit, C.S.P.O., Florence, Italy. Professor Giancarlo Zampi, M.D. is the Director of the Pathology Depart- ment, Florence University, Italy.

15. Reviewer

This paper was reviewed by Juan Rosai, M.D., Memorial Sloan Kettering Cancer Center, New York, USA.


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Benign breast disease and cancer risk