Anatomic markers of human premalignancy and risk of breast cancer

Anatomic Markers of Human Premalignancy and Risk of Breast Cancer David L. Page, MD, and William D. Dupont, PhD

Epithelial hyperplasia of the breast carries an increased likelihood of carcinoma development, with most lesions best understood as markers of higher risk. The indication of increased cancer risk for more worrisome or complex histologic patterns has been supported in many studies. About 25% of women who underwent biopsies in the premammographic era had well-developed hyperplastic changes associated with an elevated risk of 1.5 to 2.0 times that of the general population when age and length of time of follow-up were considered. Somewhat fewer than 5% of women had specific patterns of atypical hyperplasia (AH) that approached the criteria of carcinoma in situ (CIS). These women with AH had a risk of cancer four to five times that of the general population, or about one half the risk associated with microscopic CIS. Only ductal CIS should be considered without question to be an intrinsic precancerous lesion because of its regular association with recurrence at the site of its initial diagnosis. Further studies indicated an appreciable interaction between AH and other nonanatomic risk factors, particularly a family history of breast cancer. Also, lower dosage estrogen replacement after menopause does not affect risk in any histologically defined group. The atypical hyperplastic lesions are more common in women undergoing biopsies on the indication of mammographic calcifications than because of palpable masses. The primary therapeutic implications of these premalignant lesions are intensified breast cancer surveillance and screening for these patients. Cancer 66:1326-1335,1990,

ONSIDERATIONS OF PREMALIGNANCY often begin C with the supposition that there are anatomically identifiable lesions that may eventually progress in some fashion into life-threatening neoplastic disease. In ac- tuality, most lesions that we recognize as such have their premalignant implication as indicators of increased risk. It would be useful to recognize at least two categories of premalignancy. One would be indicators or markers of increased risk, and the other would be lesions that are themselves committed in a large percentage of cases to result in invasion and metastasis.

Presented at the American Cancer Society National Conference on Breast Cancer, Chicago Westin Hotel, Chicago, Illinois, July 19-2 I , 1989.

From the Departments of Pathology and Preventive Medicine, Van- derbilt University Medical Center, Nashville, Tennessee.

Supported by National Cancer Institute Contract NO1-CB-74098 and grants R01 CA-28223, ROI-CA31698, and ACS RD22 from the Amer- ican Cancer Society.

Address for reprints: David L. Page, MD, Department of Pathology, Vanderbilt University Medical Center, Room (2-332 1, MCN Nashville, TN 37232.

Accepted for publication February 16, 1990.

Both of these theoretic constructs may be united in the important phrase and concept “nonobligate precursors.”’ However, even this approach, which accepts premalignant lesions as less than fully committed, is more relevant to some lesions than to others. Thus, the microscopic examples of noncomedo ductal carcinoma in situ (DCIS) should be regarded as more likely to become carcinomas later. The evidence of a more determinate nature of these lesions derives from two sources. These lesions are indicators of high risk for cancer and indicate the likely site of later cancer development. Both recurrence of nonin- vasive as well as evolution to invasive carcinoma regularly occur at the same site as that found at previous biopsy to contain the small DCIS l e ~ i o n . ~ . ~ This was the consistent finding of two large studies, which found a remarkably similar incidence of these lesions (about 0.25%) and each of which documented the later developing carcinomas as occurring in the region of the original b i o p ~ y . ~ , ~ In sharp contrast, no other high-risk indicator lesions were associated with regional occurrence of subsequent carcinomas. Rather, the subsequently developing invasive cancers after

1326

No. 6 RISK OF BREAST CANCER - Page and Dupont 1327

lobular carcinoma in situ or the AH discussed below may occur in either breast.6 Some further support for this con- clusion is forthcoming from a recent follow-up study of more than 4000 women after breast biopsies done in Northern Italy.’

A stratification of lesions with premalignant significance has been recognized before by James Ewing, who titled his 19 14 paper, “Precancerous Diseases and Precancerous Lesions, Especially in the breast.”8 Ewing wrote, “. . . certain pathological conditions are followed in a variable but high proportion of cases by carcinoma . . . but it should be emphasized that these diseases possess in themselves not a single essential element of the cancerous pro- cess. They are merely observed to precede and favor the development of cancer.” One intent of his review was to separate precancerous diseases (also termed precancerous conditions) from the cellular populations that pass “by the many transitional stages . . . into cancer.” Thus, chronic mastitis is a condition believed to be precancerous and separable from the morphologically defined “. . . suspicious changes suggesting carcinoma.” He further distinguished another condition: “I believe, further, that a distinction should be made between precancerous lesions and miniature carcinomas. Only in size do such miniature carcinomas differ from the established disease. Such lesions cannot properly be called precancerous since they exhibit the essential features of fully developed carcinoma, only on a small scale.”

Most of Ewing’s own observations and citations from the work of others included concurrent observations only, i.e., lesions associated with established cancers present at the time of cancer diagnosis. Although these studies have given us a great deal of fundamental information? and established most of the diagnostic terms and concepts in general US^,^,'^ they cannot indicate the predictive power for cancer of any lesions or conditions that are discovered without cancer.’’ Cohort studies with a follow-up design provide information on the predictive power of risk indicators. These studies are prospective in design with regard to histologic data because that information is eval- uated in its original form. Despite some differences in histologic criteria, agreement is uniform in general prin- ciples in these studies, and they have consistently supported the assignment of increasing risk of breast cancer to more extensive and complex examples of epithelial hyperplasia. Our estimates6312 of both the incidence and relative risk of AH are in rough agreement with those reported by Kodlin et af.I3 for lesions with a Black-Chabon atypiat4 score of 4 (the designation closest to atypical hyperplasia in our studies). The incidence of 2% for Grade 4 lesions found by Kodlin et aZ.I3 compares relatively closely with our incidence of AH in 3.6% of 10,366 benign breast biopsies. This latter study reevaluated biopsies performed in Nashville’s largest hospitals between 1950 and

1968, obtained an 85% successful follow-up with a median of 17 years, and found 135 women who developed invasive carcinoma of the breast.I2 Carter et a1.,15 using truly ret- rospective histologic data (from original surgical pathology reports) from the National Cancer Institute (NCI) and American Cancer Society (ACS) Breast Cancer Detection Demonstration Project, found a greater clustering or less separation of risk for histologic categories (see Table 1). This latter finding would be expected from less rigorous histologic analysis. The trend is evident, however, and family history of breast cancer also significantly increased breast cancer risk over that identified by histologic category alone in both the Carter et af.” and Dupont and Page’* follow-up studies.

Even this risk-assessment approach must be tempered with judgment; all of the risks described here should be greatly increased if the comparison population were at low risk. This only serves to emphasize that any statement about relative risk indicates a comparison of one population to another.

Proliferative Breast Disease

Many definitions and terms have been used for conditions in the breast other than carcinoma. Benign breast disease has served some well, but is a term largely based on clinical features such as pain or lumpiness that some- times lead to biopsy because of suspicion that carcinoma may be present. Some epidemiologic studies have taken benign breast disease to indicate any woman who underwent a biopsy with a diagnostic outcome of benign.I6 Mammography has further confounded the use of these imprecise terms by adding another diagnostic modality. Thus, terms should be used that are defined by the modalities by which they are detected. This is because there is no correlative term that relates a clearly defined group of clinical signs, symptoms, mammographic findings, and histology in a consistent way. There is a positive, but in- direct association between mammographic density and epithelial hyperplasia. ” It is likely that hyperplastic lesions are more common in the benign breasts that are surgically biopsied on clinical suspicion of carcinoma, as compared with forensic autopsy examination of women.”

TABLE 1. Breast Cancer Risk and Epithelial Hyperplasia

No or Slight Moderate Incidence of Risk group low risk risk risk AH (%)

Kodlin el a/.13 2.3 2.4* 6.0 2 Carter et I .5 1.9t 3.0 5.6 Dupont and Page” 0.9 1.6 4.4 3.6

AH: atypical hyperplasia. *Used Black and Chabon’s14 categories. t Used original pathology report.

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Our use of the term disease in the diagnostic phrase “proliferative breast disease” is predicated on the notion that pain, lumpiness mimicking carcinoma, nipple dis- charge, or reliable indications of subsequent cancer risk elevation should be present. Without these disturbances the usual negative and harmful implications of the term “disease” should be understood to be absent. Therefore, the use of the term “fibrocystic disease” as an all-inclusive term for breast discomfort, lumpiness, or both seems in- appropriate. One reason is that irregular mammary density due to fibrosis, cysts, or both is present in at least 60% of North American and European women in the immediate premenopausal era of their lives. It seems inappro- priate to designate such a condition as a “disease,” although the analogous phrase fibrocystic change is useful. The diagnostic phrase proliferative breast disease indicates that there are proliferative alterations noted by histology, and that they indicate a disease by their demonstrated link to an increased risk of subsequent carcinoma development. The risk categories may be stratified into slight, moderate, and marked, with “slight” indicating a risk ap- proaching double that of the general population and “marked” indicating about a tenfold increased risk. The attempt to link rigorously defined categories with risk statements leads to some apparent inconsistencies in that the variety of alternatives is not reducible to an even spec- trum. It is, however, our intention to recognize entities and seek their risk assessment individually. The current status of these assignments of histologic parameters to risk groups is presented in Table 2, and is little changed from that assigned by a consensus conference that was

TABLE 2. Relative Risk for Invasive Breast Carcinoma Based on Histologic Examination of Breast Tissue Without Carcinoma*

No increased risk (no proliferative disease) Adenosis including florid Apocrine change Duct estasia Mild epithelial hyperplasia of usual type

Hyperplasia of usual type, moderate or florid Sclerosing adenosis, papilloma

ADH and ALH

Lobular CIS and noncomedo DCIS

Slightly increased risk (1.5 to 2 times)

Moderately increased risk (4 to 5 times) (AH or borderline lesions)

High risk (8 to 10 times (C1S)t

AH: atypical hyperplasia; CIS: carcinoma in situ; DCIS: ductal carcinoma in situ; ADH: atypical ductal hyperplasia; ALH: atypical lobular hyperplasia.

* Modified from Hutter et al.j9 Women in each category are compared with women matched for age who have had no breast biopsy with regard to risk of invasive breast cancer in the ensuing 10 to 20 years. Note: These risks are not lifetime risks.

t Note that only smaller examples of noncomedo ductal carcinoma have been consistently assessed as risk indicators after biopsy only.

supported by the ACS and the College of American Pa- thologists. l 9

Slightly Increased Risk Risk in this slightly elevated group is reliably increased

more than 50% over that of women of similar age from the general population. However, risk of developing invasive carcinoma in the next 10 to 15 years does not reliably attain the magnitude of 100% greater or double that of the reference population. This range of risk may be recorded as 1.5 to 2.0 times that of the general population, and indicates that the risk assessment or assignment is not specific, but rather probabilistic. The magnitude of the relative risk depends largely on the populations used for comparison. Thus, we found a risk elevation of 1.6 times when the general population was used as a comparison group, and 1.9 when women from our study with only mild or no hyperplasia were the comparison population. l 2

The major histologic patterns and categories contained in this slight elevation of risk category are the more developed, usual, or common types of epithelial hyperplasia. The terms “papillomatosis” and “epitheliosis” have been used for these changes.’0320221 These later terms are still useful, but have caused confusion and are inconsistently applied, at least among countries. The intent of the term “usual” is to relay the idea that these are the commonly found patterns of cytology and cell relationships seen when cell numbers are increased within the basement membrane-bound spaces within the human breast. These alterations are most common in the immediate premenopausal ages.

Hyperplastic lesions indicating a slight cancer risk should be further understood to mean proliferative disease without atypia (PDWA), to separate them from the next group characterized by a greater magnitude of risk. Of course, PDWA lesions also lack the qualitative and quan- titative histologic features of atypical hyperplasia.6%22

The positive histologic features of PDWA follow. First, a mild variation of size and shape of cells, and, more specifically, nuclei is found (Fig. 1). This feature is of great defining importance in differentiating these lesions from those of AH and noncomedo DCIS. They are most commonly present within lobular units and terminal ducts.’ Second, the cells are frequently related to each other by a pattern of swirling or streaming.20 Third, there is a varied shape of secondary lumina that are often slit-like and are present between the cells within individual spaces (Fig. 2). Fourth, the secondary lumina, particularly in larger more cellular lesions, may be present peripherally, that is, they are present immediately above the cells that sur- mount the basement membrane of the containing space. Finally, the cells appear to be varied, not only in their

No. 6 RISK OF BREAST CANCER * Page and Dupont 1329

FIG. 1 . Pleomorphism of nuclear size and shape in mild degree is demonstrated here. No- tice the central part of the primary lumen in this involved spaced has foam cells. Secondary spaces between the involved cells comprising this hyperplastic lesion of florid degree are irregular and frequently slit-like.

cytologic appearance but in their placement. Thus, nuclei are not evenly separated from one another. This feature may be understood as concomitant to the swirling or streaming change noted above.

The histologic diagnoses of sclerosing adenosis and papilloma are also indicators of slightly increased breast cancer risk. The consensus conference in 198619 was re- luctant to accept sclerosing adenosis because it was not a reliable indicator of increased risk. Also, although it was initially included in the group of PDWA lesions,12 careful analyses of associated and confounding elements had not been performed. Since that time we have completed an analysis of sclerosing adenosis and its various associations. When rigorously defined histologically, sclerosing adenosis

is an indicator of slightly increased risk of subsequent breast carcinoma, apart from its association with other risk indicator^.^^ McDivitt and associatesz4 also found sclerosing adenosis to be an indicator of increased risk of a magnitude double that of the general population.

The solitary papilloma has been thought to have little concern relative to subsequent breast cancer risk, and this is probably consistent with its placement within the slight risk category. Carter25 indicated that follow-up of women after removal of papillomas indicated the disease carries a somewhat increased risk. Our studies confirmed this link of papillomas with an increased risk of slight magnitude. l 2 We also analyzed atypical features within the epithelium of papillomas and found that such patterns

FIG. 2. A swirling pattern of cells, following one after the other, in somewhat subtle for- mation is present. Variations in size and shape of the spaces between the cells is also evident, a feature characteristic of hyperplasia without atypia.

1330 CANCER September I 5 Supplement 1990 Vol. 66

add to the magnitude of later cancer risk.26 It is possible that more complex or multiple papillomas (usually found distant from the nipple) more frequently contain atypical hyperplastic changes and features of carcinoma in sit^.^'

Moderately Increased Risk

This term was chosen by a consensus conference” to place these lesions in perspective between those noted above and microscopic examples of CIS. The relative risk for subsequent invasive carcinoma after AH is four to five times that of the general population. This is approximately half the risk experienced by women with microscopic CIS (see below).

The recognition that a woman has a cancer risk relative to the general population of an approximate magnitude of four times demands clarification because it is easily misunderstood. These relative risk figures compare two groups for purposes of statistical evaluation, and are not readily transferrable directly to clinical practice. Any relative risk figure is bound by the experience of the groups studied and is thus here confined to a follow-up period

of approximately 15 years. It is also somewhat confined to the group of women who most frequently undergo biopsies in usual clinical practice, that is, those women about age 50. Few women younger than 30 or older than 60 were present in our studies, and risk figures for atypical lesions must be understood to be less certain for women in these age groups.28

The atypical hyperplastic lesions that comprised this moderate risk group are recognized histologically by their close resemblance to lesions long recognized as CIS. They are named by analogy to lobular carcinoma in situ and DCIS. The AH, atypical lobular hyperplasia (ALH), and atypical ductal hyperplasia (ADH), as defined in this manner, may be viewed as having some of the same features as the CIS lesions, but in less than a fully developed form.63’2,22 Histologic rules for separating the atypical hyperplastic lesions from CIS are not the same as those separating the atypical hyperplastic lesions from hyperplasia without atypia because the histologic categories are not a continuum of alteration (Figs. 3 and 4). Rather than being a continuum or range of change, these histologic defini-

FIG. 3. ADH is seen here with rigid bars of similar hyperchromatic cells between regular, rounded secondary spaces. Note that the cells at the outer portion of this involved space are quite different and show normal polarization and prevents more cytoplasm. This latter feature prevents this from being recognized as DCIS.

No. 6 RISK OF BREAST CANCER Page and Dupont 1331

FIG. 4. This example of lobular carcinoma in situ, with distension and filling more than 50% of the acinar spaces, also serves to illustrate ALH. If only the smaller, nondistended spaces were present, this could be recognized as ALH.

tions attempt to recognize natural groupings of patterns in the complex array of histologic mammary alterations. However, when no natural grouping was found, an arbitrary one was applied. Thus, the separation of ALH from lobular carcinoma in situ {Fig. 4) is based on an arbitrary rule that we found most conducive to reproducibility in diagnosk6 The categories produced by this separation were then tested in a prospective, epidemiologic setting and found to indicate different levels of risk (Table 2). Lobular carcinoma in situ is recognized at times when there is a well-developed example of filling, distention, and distortion of more than half the acini of a lobular unit by a uniform population of characteristic cells. This follows the approach of the original de~c r ip t ion .~~ ALH is recognized when less than half the acini are completely distended, are filled by the uniform population of characteristic cells, or both. Further stratification of risk is attained by citing the phenomenon of involvement by ducts of these uniform, round cells of the “lobular” series. This phenomenon has been long recognized as pagetoid spread into When the lobular units involved only attain the features of ALH, this ductal involvement has been termed ductal involvement by cells of ALH.3‘ Ductal involvement in cases that otherwise qualify as ALH pro- duces a subsequently increased risk of breast carcinoma approximately intermediate between that indicated by ALH alone and that of lobular carcinoma in sit^.^'

A category with minimal features of ALH was accepted in our cohort study12 to establish a definition with few criteria for this range of histologic lesions. It is recognized when a lobular unit has the general appearance of ALH but an increased number of cells cannot be reliably iden-

tified within a ~ i n i . ~ ’ This point of recognition of ALH is present when it is not possible to identify readily more than four cells when counting nuclei from one basement membrane to the opposite basement membrane within an acinus. In other words, the normal cell population of two cells above the basement membrane would produce the total count of four cells when counting the full com- plement of cells across the diameter of an acinus. Mimicry of ALH is often produced by poorly fixed specimens, and has been cited as mimicking lobular carcinoma in sitx2’

Atypical ductal hyperplasia (ADH) lesions should be understood to indicate a somewhat lesser degree of cer- tainty with regard to anatomic pattern recognition and risk assignment than the lobular series lesions. The reasons for this are simply that ( I ) the ductal lesions have a greater variety of patterns and therefore reproducibility of diagnosis is somewhat more difficult to obtain; and (2) they have not been demonstrated to be lesions indicating increased risk in as many studies. This is well demonstrated by comparing our own initial and subsequent studies. The first of these Nashville studies32 included approximately 1000 women and had an incidence of ADH higher than subsequent studies with a demonstration of only a slightly increased risk of later carcinomas. The reason for this is that flagrant or extensive examples of florid hyperplasia of usual type were included as “atypical.” In the ensuing studies, much more restrictive criteria requiring patterns and cytology reminiscent of CIS were applied. This reduced the incidence of these lesions found in benign breast biopsies and elevated the subsequent risk determination to the same range as that of ALH.I2 These two studies were completely consistent with regard to anatomic def-

1332 CANCER September 15 Supplement 1990 Vol. 66

initions and determinations of subsequent breast cancer risk with regard to ALH of lobular type. Thus, ALH has a more consistent record as a risk indicator. Note that most cases of ADH demonstrate some well-developed features of DCIS. However, there is a cell population re- maining within the involved spaces that appears normal. These nonatypical cells demonstrate a polarity and ori- entation toward the lumen, and, most important, have no nuclear pattern similarity to the cells of the atypical cell population (Fig. 3).

Each type of AH was found during follow-up to indicate an increased risk of breast cancer in the range of four to five times that of the general population. There was such a strong interaction with family history in this study that it is relevant to consider women with AH who have a positive family history of breast cancer separately from those who do not (Fig. 5). Absolute risk figures that express likelihood for cancer development over a definite time are more useful in the clinical setting. Experience for pre- diction is limited to comparable women studied over comparable periods, ie., limited to about 15 years when derived from the Nashville studies. A further proscription against applying relative risks to a longer period is evident because relative risk falls when determined from 10 years after initial biopsy.33 The absolute risk of breast cancer development in women with AH without a family history of the disease was 8% in 10 years, whereas those with a positive family history experienced a risk of about 25% at 15 years. This strong interaction with family history

has been supported in one recent studyI5 but not in another.24 The risk of subsequent breast carcinoma development is equally distributed between either breast for both lesions of ALH and ADH.

Lesions of Greatly Increased Risk

Histologic lesions qualifying for this category are microscopic examples of DCIS and lobular carcinoma in situ. Note that mass lesions produced by DCIS, particularly comedo DCIS, are excepted from this category of high-risk lesions.

A recently reported study from Northern Italy noted a four times greater risk for later invasive carcinoma in women with CIS at biopsy,’ with a mean length of follow- up of 16 years. With slight allowances for differences in study design and histologic criteria, this evidence is in keeping with that noted above. Only 0.18% of more than 4000 biopsy samples originally diagnosed as benign were reviewed and diagnosed as DCIS with another 0.48% diagnosed as “clinging carcinoma.” This last category appears to overlap considerably with ADH as defined in our studies. Clinging carcinoma, with an incidence of somewhat less than one half that of ADH in our studies (0.48% vs 2. 1%),6 however, is evidently not completely comparable with ADH.

Lobular carcinoma in situ is the classic example of a greatly increased risk lesion identifying a high risk of subsequent carcinoma development in either breast. The predictive value of lobular carcinoma in situ is recorded

YO CUMULATIVE BREAST CANCER INCIDENCE

C 45

u 40 M 35 L

A 30 T I 25 V

20

15 0 R 10 B ‘ 5 D 1 0 T Y

-.------------- Atypical hyperplasia -i plus family history i

i !

,J

1 ! r” Atypical hyperpfasia

i r---- U

FIG. 5. The absolute risk of subsequent breast carcinoma, developed from the study by Dupont and Page,” is demonstrated. Note that at 15 years women with either atypical hyperplastic lesion (ALH or ADH) and family history of breast cancer in a first degree relative have a 20% chance of having developed invasive breast carcinoma. This risk is only 8% to 10% in the 10- to 15- year period after biopsy for women with AH and no such history. The absolute risks for the other categories are also demonstrated.


in several studies, and recognizes increased risk in the range of seven to ten times that of the general population. No interaction to increase the magnitude of risk has been recognized, even for the concurrence of a positive family history of breast cancer.34

The presence of ductal involvement (pagetoid spread) in the presence of ALH indicates an increase in risk ap- proaching the magnitude of lobular carcinoma in sit^.^^

Our understanding of the natural history of microscopic examples of DCIS comes largely from two studies published in 1978 and 1982.4,5 Each study reviewed a large number of breast biopsy specimens previously recognized as benign and identified nearly 60 cases between them of microscopic and noncomedo DCIS. Follow-up of these women demonstrated an absolute risk of breast cancer development between 25% and 30% in 15 years. The relative risk of this experience was about ten times that of the general population. Of importance, both studies were in total agreement that subsequent invasive carcinoma occurred in the same area of the breast as the originally identified CIS lesions. This strongly indicates that such lesions are predominantly monofocal as tested by the bi- ology of long-term follow-up.

These studies of CIS have demonstrated the great dif- ference between the ductal and lobular categories with regard to their indications for clinical management. It seems likely that relatively small and noncomedo ductal examples of DCIS may be cured by local excision. Only further experience will prove precisely when in the range of size and histology this conservative approach might be most a p p r ~ p r i a t e . ' ~ ~ ~ ~ ~ ~ There is a mounting experience with conservative treatment of DCIS, however, which seems quite satisfactory for the microscopic lesions.'

Lobular carcinoma in situ must be considered an indicator of risk anywhere within both breasts. The experience of Haagensen er aL3' demonstrated that women who were closely followed after the demonstration of high- risk lesions of lobular type were consistently alive and well after treatment with mastectomy of invasive breast cancers that subsequently developed. This observation supports the clinical posture of close follow-up with the addition of mammography, which was not available to Haagensen et al, in the early detection of curable breast carcinomas in this setting. Thus, many physicians use mammography to follow women with lobular carcinoma in situ, although extirpative surgery is also used.38

Lesions Without Increased Risk

This category encompasses many changes that char- acterize most benign breast biopsy specimens, including cysts of any size, mild hyperplasia of usual type, and apocrine change. It is likely that radial scars, without the co- existence of epithelial hyperplasia as found in elevated

risk categories, should also be in this group, although for- mal prospective analysis of those lesions is not yet forthcoming except in studies of limited s ~ o p e . ~ ~ - ~ '

Mild epithelial hyperplasia of usual type is extremely common in breast biopsy specimens. It is understood to indicate an increase in the numbers of cells above the basement membrane area to a thickness of three or four, with the normal cell thickness understood to be two. These mild changes are also understood to lack features noted for moderate and florid hyperplasia of usual type, particularly distention of involved spaces and tendency for cells to cross the individual space (acinus, ductule, or duct). These mild changes are analogous to the Type 2, Series A change described by Wellings and J e n ~ e n . ~

Lesions in the category without risk may be viewed as defined by exclusion, that is, risk indicator lesions are absent. Seventy percent of breast biopsy specimens from the premammographic era were included in this group.12 There is, actually, some indication that women having this group of histologic alterations are at slightly decreased risk compared with the general population because their overall risk, controlled for age and follow-up, was 10% less than that of the general population. Although this decrease is not statistically significant, it adds credibility to the finding that these women, defined solely as those who have undergone surgical biopsy, are not at increased risk of subsequently developing carcinoma.

Other Associations (Nonanatomic, With Risk)

An important and practical consideration concerns the relation of these histologic markers of cancer risk to other nonanatomic indicators of breast cancer risk. We recently published the experience of Nashville women with estrogen replacement after menopause who, after 1956, had no elevation of breast cancer risk, at least beyond that recognized by histologic risk categories. This lack of risk elevation after 1956 is presumably related to a dosage effect, as this was the time that the lower doses currently in use were introduced. Breast cancer risk was not affected. Risk was slightly reduced for women within each of the histologically defined risk groups, but was not statistically significant4'

Age at first birth also interacts with anatomic risk fac- t o r ~ . ~ * Women who experience first childbirth at an early age have a decreased risk of breast cancer within each histologic risk group, particularly within the AH group (Table 3).

Conclusions

Clinical assessment of breast cancer risk is an endeavor unfamiliar to most physicians. The usefulness of risk as-

1334 CANCER September 15 Supplemen2 1990 Vol. 66

TABLE 3. Effect of Reproductive History and Proliferative Disease on Breast Cancer Risk*

Variable No. of women Relative risk P-value

With atypia AFB 520 AFB >20 Nulliperous

Without atypia AFB 1 2 0

AFB 230 Nulliperous

520 21-29 230 Nulliperous

AFB 2 1-29

All

42 110 68

330 720 156 379

689 1,380

289 74 1

1.6 4.5 4.9

0.95 1.3 1.5 I .4

0.8 1.3 I .4 1.6

0.52 <0.0001 <0.0001

0.89 0.17 0.22 0.13

0.39 0.04 0.24 0.005

AFB: age at first birth. * Adapted from Dupont and Page.43

sessment will grow as more specific information about determinants of risk and their interaction with screening and therapeutic modalities becomes available. We are not a full professional generation removed from a time when the answer to the question of whether malignancy existed in the breast was absolute, yes or no. Now special types of breast cancer are recognized that pose little threat to life, and some benign conditions indicate a greatly increased risk of cancer. Thus, the simple dichotomy of benign versus malignant disease has been replaced by a complex stratification of categories with varying indications of likelihood of morbidity.

Perhaps the greatest practical importance of these risk assessments is that upwards of 70% of women undergoing biopsy of a benign breast lesion are not at increased risk of breast cancer development. A recent reviewI5 of the follow-up data from the Breast Cancer Detection Dem- onstration Project of the ACS and NCI supports this. This study by Carter rt ~ 1 . ‘ ~ also supports the association of more extensive and complex examples of hyperplasia with elevated risk.

Currently, women who are at slightly increased risk should be encouraged to follow a regular (yearly) program of mammographic surveillance, whereas women with lesions associated with a moderately increased risk should follow such a program without fail. AH is rare and occurred in only 4% of breast biopsy specimens before the mammographic era. This incidence is currently higher with the existence of mamrnographically directed biopsy.43,44 Other considerations such as mammographic density, family history, and patient anxiety will affect clinical management decisions. In most of these patients,37 however, extirpative surgery is probably not a practical consideration.

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Anatomic markers of human premalignancy and risk of breast cancer

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