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ABC Amber CHM Viewer 1.03, 17.05.2011

:Title: Breast Imaging, 3rd Edition

Copyright Â©2007 Lippincott Williams & Wilkins> Table of Contents > 2A - Breast Anatomy and Basic Histology,Physiology, and Pathology

2ABreast Anatomy and BasicHistology, Physiology, andPathologyAs with all organ systems, an understanding of the anatomy, histology,and pathology of the breast leads to an enhanced ability to interpretimaging studies. Breast imaging primarily involves the assessment ofthe morphology of macroscopically visible breast structures. A basicunderstanding of the anatomy and histology of the breast, and of thecomplex underlying microscopic structures in which changes take place,is important for an understanding of the pathologic processes thatoccur. All are helpful for image interpretation.

Radiologists are all pattern readers. However, rather than justsearching for patterns, the interpreter should try to understand theunderlying processes that produce the morphologic changes that arevisible on the various imaging studies. Although different processesmay produce similar findings, in many cases the imaging morphologyreflects histologic and pathologic changes. The anatomy of the breastand the organization and distribution of the histologic elements shapethe imaging findings. Ideally the interpreter should be able to explain,using specific criteria, why a finding is judged benign or potentiallymalignant by being able to explain the specific characteristics of thefinding that led to the particular assessment.

Anatomy OverviewThe breast is a modified skin gland that develops from the mammaryridge in the embryo. It generally lies on the chest wall between theclavicle and the sixth to eighth ribs. Breast tissue can be found as far

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medially as the sternum and laterally to the midaxillary line. Breasttissue is frequently found high in the axilla, occasionally reaching to itsapex.

The breast lies on top of and lateral to the pectoralis major muscle,whose muscle fibers course obliquely from the ribs to the humerus.Since breast tissue frequently wraps around the lateral margin of thepectoralis major muscle (Fig. 2A-1), imaging the breast is bestaccomplished using the mediolateral oblique projection. The best wayto image the most tissue is by positioning the breast such that theplane of compression is parallel to the oblique fibers of the free marginof the muscle. This permits maximum traction on the breast so that itcan be fully positioned over the detector and comfortably compressed.It also permits evaluation of the portion of the breast that lies lateral tothe muscle and extends up into the axilla.

Recent work at the MGH by Jennifer Rusby, MD, suggests that there areusually more than 20 lobes or segments that are defined by the majorlactiferous ducts that open on the nipple. A lobe (segment) can bethought of as a tree whose trunk, branches, and leaves are hollow.These arborizing networks conduct milk from the lobules (the trueglands of the breast) to the nipple. The lobule is actually the mostproximal of the structures if direction is the flow of breast secretions(milk), but it is called the terminal portion of the duct system. Thelobule consists of multiple blunt-ending ductules in a cluster like thefingers of a glove. These fingers form the glandular acini of the lobule.They are surrounded by specialized connective tissue that differshistologically

P.8from the stromal connective tissue found in the rest of the breast. Theacini and specialized connective tissue together form the lobule. Aterminal duct and its lobule are collectively called the terminal ductlobular unit (TDLU) (Fig. 2A-2). TDLUs can be found as immediatebranches of the major ducts and are not always at the periphery of theductal networks. Breast cancer is thought to originate in the terminalduct in the lobule. One theory is that this is the location of stem cellsand that these undifferentiated cells are the most likely to developmalignant transformations.

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Figure 2A-1 Orientation of the pectoralis major and minor muscles.

The breast is held together by varying amounts of connective tissuethat form varying volumes of sheets of tissue known as Cooper'sligaments. Fat is interspersed throughout the breast and surrounds it assubcutaneous and retromammary adipose deposits.

Breast DevelopmentLittle detail is available on the actual development of the humanbreast. Much of the information that we have is based on mousemodels, which differ significantly from the human breast. The breastshave the same ectodermal origin as skin glands. They develop from themammary ridges, which begin as ventral â€śstreaksâ€ť found in thefifth week of gestation. The mammary ridges extend longitudinally from

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the base of the forelimb bud (the primitive axilla) along the ventralsurface of the embryo (the chest and abdomen to be) to an area medialto the base of the hindlimb bud (the primitive inguinal region). Ifdevelopment proceeds normally, the middle portion of the upper thirdof the mammary ridge persists to form the breast bud on the chest walland eventually the tail of Spence, extending into the axilla, while theremainder of the structure disappears. Failure of portions of the ridge toinvolute may result in accessory breast tissue anywhere along theâ€śmilk line,â€ť extending from the axilla to the inguinal region (1,2).

The axilla is the most common area in which accessory breast tissuecan be found. Accessory breast tissue may be in continuity with themain breast tissue (Fig. 2A-3A), it may appear as a separatediscontinuous structure (Fig. 2A-3B), or it may actually form acomplete breast (Fig. 2A-3C). Accessory nipples are occasionallypresent (see Fig. 2A-3D). These are most common in the anteriorsuperior abdominal wall just caudal to the usual breast location andmay be mistaken for nevi.

Although very rare, breast cancer can occur anywhere there is a rest ofbreast tissue (3,4). We have seen a case where breast cancerdeveloped in a rest of tissue in the upper anterior abdominal wall. Sincethe most common location for accessory breast tissue is in the axilla,imaging should include as much axillary tissue as possible.

During the first trimester of intrauterine growth, the primitiveepidermal bud in the embryo begins to produce

P.9cords of epithelial cells that penetrate down into the dermis. Researchindicates that there are factors that are produced in the underlyingmammary mesenchyme that stimulate this growth (5). Interactionsbetween the glandular tissues of the breast and its supporting stromaappear to continue throughout life. In the full-term fetus there isalready a simple network of branching ducts, and although lobules (theglandular elements) do not appear until adolescence, secretion mayoccur under the stimulation of maternal hormones and the newbornmay have a nipple discharge.

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Figure 2A-2 (A) This schematic representation of the basic anatomy ofthe breast can be compared to the lateral view (B) from a negativemode radiograph using the Xerox technique.

Thelarche (breast development) usually precedes menarche, and underhormonal stimulation the breast buds enlarge, becoming palpable discsbeneath the nipple. The ducts grow back into the soft tissues, which arealso stimulated to increase, and lobular development (differentiation)begins. This growth may proceed asymmetrically because of thefluctuating hormonal environment and a variable sensitivity of theend-organ tissues to the stimulation (Fig. 2A-4). In my experience theonly reason for one breast to be larger than the other is due todevelopmental asymmetry (Fig. 2A-5). On the rare occasion when onebreast becomes larger due to cancer, the reason is obvious, since abreast full of tumor becomes extremely hard.

I have been unable to determine the true developmental sequence ofthe breast in the subcutaneous tissue. The breast develops in thesuperficial layer of fascia that lies just beneath the skin. It is not clearwhether the superficial layer splits into a deep and superficial layer toform an incomplete envelope around the gland, or whether theelongating ducts invaginate the fascia, which then ends up enveloping

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the gland (Fig. 2A-6). One of our senior surgeons often spoke of adefinable â€ścapsuleâ€ť that is often present around the glandularportion of the breast, suggesting the latter. With digital mammographyand image processing I believe that this â€ścapsuleâ€ť can be seen onmany mammograms (Fig. 2A-7).

Since the breast buds may develop asymmetrically, the detection of anasymmetric lump beneath the nipple before puberty should not because for concern (see Fig. 2A-4). Biopsy should rarely be considered,since the inadvertent removal of the breast bud will result in failure ofbreast development. Only the rarest forms of breast cancer occur inprepubertal and pubertal girls, and these are usually indolent. Whenthey do occur, they are likely to grow eccentrically

P.10P.11from the nipple, unlike the breast bud, which is centered under thenipple. Asymmetry at this stage almost always resolves in ultimatefairly symmetrical breast development.

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Figure 2A-3 Accessory breast tissue can form anywhere along theâ€śmilk line.â€ť Breast tissue can be found extending high into theaxilla. It may be in continuity with the breast, as seen on thesemediolateral mammograms (A). Accessory tissue may also beseparate from the main breast tissue (arrow), as seen on leftmediolateral oblique view (B). Accessory tissue may even form aseparate, ectopic breast, as seen in this third individual (C), who had aseparate breast mound in her right axilla (arrow). Accessory nipplesmay be seen, as in this lateral xeromammogram where a separate

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nipple was visible at the bottom of the breast (D) (arrow).

Figure 2A-4 Ultrasound demonstrates asymmetric development of thenormal breast buds in a 9-year-old girl. The breast buds are thehypoechoic, triangular areas that lie beneath the nipple.

Asymmetric Breast SizeAlthough adult breasts frequently differ in size, marked asymmetry isrelatively unusual (see Fig. 2A-5). Without skin or other changes tosuggest inflammation or neoplasia, asymmetric breast size is virtuallyalways a developmental phenomenon. On the rare occasion where thebreast enlarges due to cancer, the problem is obvious: the breastbecomes extremely hard and the skin is usually thickened. If onebreast is considerably larger than the other but there is no thickening,then the enlargement is virtually always

P.12P.13developmental. I suspect that developmental asymmetry may becomemore obvious if a patient gains weight. Since the breast is a repositoryfor fat, if the breasts are asymmetric to begin with, the expansion ofthe adipose tissue in the breast may result in what appears to be onebreast that is enlarging.

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Figure 2A-5 This is a developmental anomaly where the left breast ismuch larger than the right, as seen on the craniocaudal projection.

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Figure 2A-6 It is unclear how the breast develops with respect to thesuperficial fascia, which runs just under the skin (A). The fascia maysplit, forming a deep and superficial layer with the breast forming inbetween (insinuation) (Bâ€“D). The other possibility is that as the

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ducts elongate and grow back into the soft tissues, they may beenveloped by the fascia, like pushing a finger into plastic wrap(invagination) (E,F).

Figure 2A-7 On digital mammography it is possible to see whatappears to be a capsule around the parenchymal cone of thefibro-glandular tissue.

Male breasts also contain primitive ducts. Probably as a result of thefluctuating hormonal environment in adolescent males, gynecomastia isfairly common during puberty (see Chapter 19, â€śThe Male Breastâ€ť).This too may be asymmetric and almost always corrects itself withoutthe need for intervention.

Breast Size and Risk of Breast CancerIt is not clear that a larger breast means that there are a greaternumber of TDLUs. Since this is the location for the development ofmost breast cancers, one could speculate that women with more TDLUsmight be at higher risk. However, I suspect that breast size and trueâ€śglandularityâ€ť are independent of one another. There are no goodstudies that have demonstrated any significant relationship between

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breast size and risk for cancer.

Terminal DifferentiationAs the breast grows, the subcutaneous adipose and connective tissuesincrease in volume and ductal elements proliferate, elongating andextending deeper into the subcutaneous tissues. Over a variable periodof time, terminal buds at the ends of the branching ducts differentiateinto tufts of blunt-ending ductules that form the glandular acini of theTDLUs. The exact cells responsible for duct elongation and lobulardifferentiation have not been identified. The evidence suggests thatthere are â€śstemâ€ť cells at the terminal end of the duct that areresponsible for this growth. Studies suggest that it may be theundifferentiated stem cell that is transformed and results in breastcancer (6). It is likely that the rapid cell proliferation and DNAreplication that take place in this area account for the fact that mostcancers appear to develop in the terminal duct as it enters, or along itscourse within, the lobule. Increased cellular proliferation increases thechance that DNA will not be copied properly and that mutations willoccur.

Deng et al (7) found that there were similar genetic defects (loss ofheterozygosity) in the cells of normal lobules that were adjacent tolobules that contained breast cancer cells, while cells in lobules furtheraway did not have the same genetic changes. This suggests that theremay be a common progenitor for both the benign and malignant cells ofthe affected duct network. If there is a stem cell responsible for thedevelopment of the ducts and lobules, then an alteration in its DNAearly in life, prior to duct elongation and terminal lobulardifferentiation, could be distributed into every cell in the segment. Thiswould place the cells throughout the segment at risk for further geneticchange, increasing the likelihood that one of the cells might ultimatelybecome a cancer. This would explain the findings of Deng et al. Itmight also be the explanation for the so-called field phenomenon, inwhich the cells in an area of the breast have a similar abnormalitywhile other areas of the breast are normal. This is the likelyexplanation for diffuse adenosis, atypical hyperplasia, and lobularcarcinoma in situ (LCIS).

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It would be very unlikely that a carcinogen or mutagen could damageall of the cells in a segment while sparing cells in other segments of themature breast. However, if a stem cell were altered in the immaturebreast, the damage would be distributed to all of the cells of thedeveloping segment, and only the cells of that segment would beaffected (Fig. 2A-8). This is the likely explanation for segmentallydistributed abnormalities.

Our attention in preventing breast cancer is often directed toward olderwomen. However, if there is a stem cell, its presence would suggest theimportance of exposure

P.14P.15to carcinogens at an early age, prior to terminal differentiation. This isalso supported by the fact that cancers with long doubling times (180days) may take as long as 30 years to reach 2 cm in size (8),suggesting that malignant transformation for a woman who isdiagnosed with cancer in her forties may have been initiated while shewas in her teens or twenties. Data in mice suggest that the breast issusceptible to carcinogens during development. In mice, the period ofend-bud differentiation is a time during which a carcinogen is morelikely to initiate malignancy (9). A similar phenomenon may occur inhumans. The data showing that radiation is a carcinogen in the breastshow that the breast is more sensitive to radiation while it isdeveloping, during adolescence and for women in their early twenties,while the mature (differentiated) breast of women in their early fortiesand older is not at increased risk from radiation. The maturation of thebreast may take place over many years and may not be complete untilthe third decade of life, or it may proceed rapidly with an early firstfull-term pregnancy. It is likely that the terminal differentiation thattakes place with a full-term pregnancy protects the breast from futurecarcinogens. Breast cancer prevention might include protecting thebreast from carcinogens while it is developing.

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Figure 2A-8 Breast cancer may be initiated very early in life. (A)This diagram represents three primitive ducts in the infant breast. Ifthere are breast stem cells, then each duct's stem cells will eventuallydevelop that duct network separate from the others. (B) When thebreast develops, the DNA from that stem cell is distributed throughoutthat segment and none of the other segments (C). If cancer develops inseparate duct networks (D), then this could happen due to damageafter thecducts developed. A carcinogen could affect separate segments.If multiple cancers develop separately in one duct network (D), thismay be due to DCIS bridging several (E) branches and invasive cancersgrowing simultaneously. However, if there were no DCIS bridges, thiswould imply that there was damaged DNA throughout the segment and

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not any other segments, and the only way this could happen is if theDNA was damaged before the ducts developed so that the damaged DNAwas spread throughout the segment but not in any of the segments (F).This would be likely if a carcinogen damaged a stem cell before the ductdeveloped and would be unlikely to occur from a carcinogen thataffected the ducts after they had developed.

Additional lobular development may take place in preparation forlactation. After the cessation of lactation, many of the lobules involute.Since the breast must be complete for lactation, a full-term pregnancylikely causes rapid lobular differentiation. It is likely, however, thatcomplete maturation does not occur until after a full-term pregnancy.This may explain why women who have a first full-term pregnancy bythe age of 18 have a much lower risk of subsequently developingcancer than women who remain nulliparous or have their first childafter age 30. An early full-term pregnancy offers some protectionpossibly by narrowing the period of time over which differentiationtakes place and, consequently, the â€świndow of opportunityâ€ť duringwhich a carcinogen may be most effective in causing lasting damage.If, as appears to be the case, the mature breast (differentiated terminalbuds into lobules) is less susceptible to carcinogens (e.g., radiation),this might account for the diminished risk of breast cancer amongwomen who bear a child early in life.

Breast AnatomyIn most individuals, the bulk of the breast extends from the second tothe seventh rib. Since breast tissues often curve around the lateralmargin of the pectoralis major muscle (Fig. 2A-9), the orientation ofthe muscle is important for optimal mammographic positioning. Thepectoralis major muscle spreads like a fan across the chest wall.Portions of the pectoralis major muscle attach to the clavicle, thelateral margin of the scapula, costal cartilage, and the aponeurosis ofthe external oblique muscles of the abdomen. All these fibers convergeon and attach to the greater tubercle of the humerus. The free fiberspredominantly run obliquely over the chest from the medial portion ofthe thorax toward the humerus (see Fig. 2A-1). The relationship of thebreast to the pectoralis major muscle influences two-dimensional

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projectional imaging, such as mammography. Since the breast tissue isclosely applied to the muscle, some of the lateral tissues can be imagedonly through the muscle. As with any soft-tissue structure overlyingmuscle, it is easier to project the breast into the field of view by pullingit away from the chest wall and compressing it with the plane ofcompression paralleling the obliquely oriented muscle fibers of thepectoralis major muscle. To maximize the tissue imaged, the freeportion of the muscle should be included in the field of view.

Figure 2A-9 Breast CT with the breasts in the pendent position showsbreast tissue on the left adjacent to the pectoralis major muscleextending up toward the axilla. This would be behind the pectoralis onthe mediolateral oblique projection. In this individual the tissue isabsent on the right after surgery for breast cancer.

Although it has not been directly studied, there is likely a variableattachment of the pectoralis major muscle medially to the thoracic wall.I believe that in approximately 1% of women, a small tongue of muscleadjacent to the sternum is sufficiently free to be pulled into the field ofview of the mammogram in the craniocaudal projection (Fig. 2A-10).This is not seen on the mediolateral oblique, since it is very difficult topull this portion of the muscle into the machine in this projection. Wehave seen what we believe to be a variant of the muscle on achest-wall lateral xeromammogram (Fig. 2A-11). This variable portionof the muscle (Fig. 2A-12) may be round, triangular, or flame-shapedand should not be mistaken for a mass.

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When a flame-shaped structure that is almost completely

P.16separate from the chest wall is seen medially (Fig. 2A-13A), it is likelythe sternalis muscle that is being imaged (Fig. 2A-13B). The sternalismuscle is a thin muscle that runs parallel to the sternum and is foundin 4% to 11% of individuals (10). It has been speculated that it wasonce an extension of the rectus abdominis, but it is not connected tothis or any other muscle, and its origin and use are unknown. Itappears to be of no functional value and can be unilateral or bilateral.

Figure 2A-10 The density seen medially (arrow) on this craniocaudalprojection is the pectoralis major muscle pulled into the field of viewby the compression system.

Although either pectoralis major or sternalis muscles can project intothe craniocaudal mammographic image, care must be exercised toavoid dismissing a true medial mass as muscle, since breast cancerscan occur in this portion of the breast. If there is any doubt, computedtomography (CT; Fig. 2A-13C) (11), magnetic resonance imaging (MRI;Fig. 2A-13D), or ultrasound can be used to confirm or exclude a mass.By placing a patient on her side in the CT scanner so that the breast onthe side in question pulls toward the table (Fig. 2A-14), the sternalismuscle will be pulled by the breast, and a definitive diagnosis can bemade if this is needed.

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Figure 2A-11 These chest wall lateral xeromammograms show whatis likely a variation of the pectoralis major attachment to the thoraciccage with a free margin of what is likely the inferomedial attachment (arrows).

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Figure 2A-12 The tissue densities seen at the edge of the film onthese craniocaudal projections, medially, are the pectoralis majormuscles.

P.17The pectoralis minor muscle lies beneath the pectoralis major muscle,extending from the third, fourth, and fifth ribs to the coracoid processof the scapula. Occasionally it is seen on the mediolateral obliqueprojection as a second triangle of muscle high in the axilla above thepectoralis major muscle in the corner of the film (Fig. 2A-15). This isnot the latissimus dorsi muscle, as some have speculated. In lymphnode dissection of the axilla, lymph nodes beneath the pectoralis minormuscle are called level II lymph nodes.

The Vascular Supply of the BreastArterial blood flows from the axillary artery through the lateral thoracicartery to supply the upper outer quadrant of the breast. The central andmedial portions of the breast are supplied from perforating branches of

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the internal mammary artery, which lies adjacent to and beneath thesternal border. Branches of the intercostal arteries provide blood to thelateral breast tissues, with some blood coming from the subscapularand thoracodorsal arteries.

Venous drainage is back through the axillary, internal mammary, andintercostal veins, providing three major routes for hematogenousmetastasis.

EnervationNerves supplying the breast originate primarily from the anterior andlateral cutaneous branches of the thoracic intercostal nerves, with someenervation from the cervical plexus to the upper breast. The deep painsensors in the breast appear to be variable. In many women, needleaspiration or needle localization with 20-gauge or smaller needles canbe performed with a minimum of discomfort without the use of localanesthesia (12). In some women, however, it is extremely difficult toestablish deep anesthesia. In our experience this is more likely if thebreasts are extremely dense radiographically, which usually is due tofibrous connective tissue. It is merely speculation, but perhaps thenerves are more tightly tethered in these women and are not displacedfrom the needle path. Fibrous connective tissue may also prevent theanesthetic from reaching the nerves.

Breast pain is a fairly common symptom and is likely due to edema andswelling that occurs in many women with the normal hormone cycle.Mammography is rarely able to demonstrate the cause of breast pain.Although pain is almost always due to benign processes and breastcancer is usually painless, malignancy occasionally causes breast pain.Focal pain and, in our experience, a drawing sensation are the types ofpain that can be associated, on rare occasions, with breast cancer.Some physicians believe that some types of breast pain are actuallychest wall in origin and referred to the breast. The discomfort ofcostochondritis, for example, can be perceived as breast pain. This isapparent when pushing the breast against the chest wall causes painbut squeezing it side to side does not.

The Lymphatics of the Breast

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The lymphatic drainage of the breast has diagnostic and therapeuticimplications. Tumor can spread through the lymphatic vessels. Thelymphatic system is also a route for access to the vascular system aslymph is eventually returned to the venous system through the thoracicduct and other anastomoses. Although breast cancer likely spreadsprimarily hematogenously, the presence of tumor in the lymphatics orin the lymph nodes indicates that the tumor has developed a metastaticpotential. This increases the likelihood that tumor is elsewhere in thebody.

Not all breast cancers have the ability to metastasize. Although it is notyet possible to determine which do have the ability to spread to otherorgans, lymph node involvement indicates that the tumor has achieveda metastatic capability and that the disease should be consideredsystemic and no longer confined to the breast. Some studies suggestthat spread through the lymphatics may be the primary route for accessto the vascular system, although pathologists

P.18P.19describe direct invasion of blood vessels within the breast. Lymphnodes containing tumor are usually either excised or treated withradiation to prevent recurrence, although treating the lymph nodesdoes not appear to influence overall survival. The lymphatics havegained increasing importance as sentinel lymph node biopsy (detectionand removal of the first lymph nodes in the chain that drain the tissuecontaining cancer) has replaced full axillary dissection as the methodof choice for assessing the status of the lymph nodes.

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Figure 2A-13 (A) The appearance of the sternalis muscle on thecraniocaudal projection and a schematic of the sternalis muscle (B).When in doubt, CT can demonstrate the sternalis muscle. Here thepatient is oblique in the scanner and the breast pulls the muscle awayfrom the chest wall (C). On this MRI the full course of the muscle isdemonstrated (D) (arrows).

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Figure 2A-14 With the patient on her back in a CT scanner, the muscleis barely evident (A), but when she rolls on her side, the breast can pullon the sternalis muscle (B), pulling it away from the chest wall andmaking it more evident.

Figure 2A-15 (A) The pectoralis major muscle (M) is visible anterior tothe pectoralis minor muscle (m) seen on this mediolateral obliquemammogram. The two muscles are evident on this CT reconstruction ofthe left breast of another patient reformatted at an oblique angle,simulating the mediolateral oblique projection. The slice is through theupper outer left breast (B).

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The lymphatic drainage of the breast has been extensively studied, yetsignificant uncertainty continues as to its distribution and how itactually functions. There are clearly significant variations betweenindividuals. Some

P.20investigators have suggested that the lymphatic drainage comes fromthe deeper tissues of the breast flowing toward the surface throughlymphatic channels to the skin. These then drain into a subareolarplexus and then to the axilla. There is a small percentage of drainageto the upper abdomen and medially to the internal mammarylymphatic chain, but the primary lymphatic drainage from all parts ofthe breast (including the medial tissues) is to the axilla. That there issignificant variation is clear in a small number of cases in whichinvestigators injected an iodinated contrast into the tumor bed ofwomen with cancer and into the tissues around the cancer and thenimaged the lymphatics with multi-slice CT (13). Lymphatics are clearlyvisible coursing directly from these areas through the breast itself tothe axilla; in one case there was drainage both toward the axilla andtoward the internal mammary chain. These drainage routes areincreasingly important as surgeons rely increasingly on sentinel lymphnode identification and biopsy. The most common method foridentifying the sentinel nodes at this time is to inject radioactivetechnetium sulfur colloid followed by the injection of a vital dye so thatthese are picked up by the lymphatics and flow toward the first lymphnode in the drainage of the breast. Using a collimated Geiger counter,the radioactive lymph node is identified, and then the blue dye helpsto make it visible during the limited dissection. The goal is to facilitatethe passage of these materials to the sentinel or first lymph nodes inthe lymphatic drainage of the breast.There has been great debate as to the best site in which to inject thesematerials. There are proponents of injection around the tumor andthose who favor injection into the subcutaneous tissue; others favor anintradermal injection, and still others believe a subareolar injection isthe best. Each has its proponents, and it only depends on the publishedseries as to which one adheres. I suspect that most injection sites workas long as they are in the correct breast! There is certainly a variationthat is based on the individual, and there is no one injection site that

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appears to be the best for all situations.

Although the concept of staging breast cancer is changing, the presenceof tumor in the lymphatics within the breast as well as in the axilla is ofimportant prognostic significance. Treatment may be modified based onanalysis of the lymphatics and axillary nodes. For staging purposes andprognostication, axillary lymph nodes are divided into three levels (Fig.2A-16). Level I lymph nodes are lateral to the lateral margin of thepectoralis major muscle and extend down into the tail of the breast.Mammography can frequently demonstrate the lowest lymph nodes inthis portion of the lymphatic chain. Level II lymph nodes are beneaththe pectoralis minor muscle. When an axillary dissection is performed,the free margin of the pectoralis major muscle is retracted out of theway and preserved, and the pectoralis minor muscle is transected toremove these lymph nodes. This is also performed when a modifiedradical mastectomy is used to treat breast cancer. The level III lymphnodes are medial and superior to the pectoralis minor muscle, up to theclavicle. Data suggest that the higher the level of nodal involvementwith cancer, the worse the prognosis.

Figure 2A-16 The axillary nodes are divided into three levels, asdemonstrated schematically.

Sentinel NodeMost of the lymphatic drainage of the breast usually converges on the

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chain of lymph nodes described above. There are often one or twolymph nodes in the axilla through which most of the lymph drainagefrom the breast passes (Fig. 2A-17). These have been called thesentinel nodes. Sentinel nodes were first demonstrated in patients withmelanoma: technetium-99m sulfur colloid, injected at the periphery ofthe melanoma, concentrated in the first lymph nodes that drained thearea of the tumor (14), making them identifiable using a gamma probe(15,16). Removal and examination of these nodes was predictive forthe presence or absence of metastatic disease. By reducing the need formore complex nodal dissection, morbidity and expense were reduced.

Krag (17) and Giuliano (18) pioneered the evaluation of the sentinelnodes in the axilla in women with breast cancer. In Krag's preliminaryreport, 0.4 mCi technetium-99m sulfur colloid mixed in 0.5 mL salinewas injected into the tissue in a 180-degree arc around the tumor alongits axillary perimeter, and a probe was held over the axilla. The sentinelnode was found where there were at least 30 counts in 10 seconds. Thenode was removed and evaluated for the presence of metastaticdisease and compared to the results of the full axillary dissection. In astudy of 22

P.21women, a sentinel node was identified in 18 women who had fullaxillary dissections (all three levels) following radionuclide injections 1to 9 hours before surgery. Among the 18 women, 62 radioactive and170 nonradioactive nodes were removed. In all seven of the womenwho had positive nodes, the sentinel node contained tumor. In three ofthe patients, only this node contained tumor.

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Figure 2A-17 These diagrams depict the fact that a radioactive traceror vital dye injected near a tumor (actually almost anywhere in thesame breast) will be picked up by the same lymphatics thatpresumably conduct cancer cells to the axillary lymph nodes. Byfinding where the radioactivity begins to concentrate in the axilla andlooking for the dye, the surgeon can find the first nodes in thedrainage pattern, known as the sentinel nodes. The absence of tumorin the sentinel node is a fairly accurate indication that the axilla isâ€śnegative.â€ť If tumor cells are found in the sentinel node, then thetherapeutic approach may change and an axillary dissection may beundertaken.

Although we originally injected around the tumor, injections in theperiaveolar region appears to be just as effective and keeps tracer atthe injection site away from axilla where it could hide signals from thenodes (18a). The predictive value of the sentinel node biopsy has beenvalidated in other trials. Its use reduces the need for a full axillarydissection. This greatly facilitates the surgical approach to breastcancer and thus far appears to reduce the morbidity that has beenassociated with axillary dissection. The use of imaging-guided needlebiopsy has reduced the need for open surgical excision to make adiagnosis of breast cancer. With this knowledge and the use of sentinel

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node biopsy, the surgeon can often perform the surgical tumor excisionand stage the axilla in a single operative procedure.

Some prefer to have a map of the lymphatic drainage usinglymphoscintigraphy. We have never done this. Although I have noproof, I suspect that the sentinel nodes are usually the lymph nodesthat we see routinely in the low axilla by mammography. Anenterprising investigator could prove this and facilitate the biopsy ofthese lymph nodes without the need for injecting dye and radioactivetracers.

P.22

Intramammary Lymph NodesLymph nodes are found not only in the axilla but also in the breastitself. In at least 5% of normal women (Massachusetts GeneralHospital, unpublished data), intramammary lymph nodes can be seenon mammograms. Although Egan stated that whole breast dissectionsrevealed lymph nodes throughout the breast (19), in our experiencethey are rarely, if ever, imaged anywhere but in the lateral half of thebreast and are invariably along the surface of the parenchymal conejust under the subcutaneous fat. We have, on rare occasion, biopsiedlesions that were described by the pathologist as â€ślymphoid tissueâ€ťelsewhere in the breast, but we have never biopsied a complete lymphnode elsewhere in the breast. Meyer et al described three cases inwhich apparently complete lymph nodes were confirmed histologicallyin the central and medial portion of the breast (20) (nophotomicrographs were included in the article). Based on the thousandsof biopsies that they performed to find these few lymph nodes, it wouldappear that lymph nodes in locations other than the lateral portions ofthe breast are extremely uncommon. Virtually all intramammary nodes,visible by mammography, are in the lateral half of the breast along themargin of the breast parenchyma. They have been found as far anterioras two thirds to three fourths of the way to the nipple. The majority ofintramammary nodes are associated with the upper outer breast tissue,although they can be found in the lower outer part of the breast or canappear to be in this area by rolling the breast when performing lateralmammograms.

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Supporting Structures of the BreastI believe that the breast is almost completely supported by the skin.There are only loose connections (arteries, veins, and lymphatics) atthe back of the breast to the muscles of the chest wall. The breast isgiven structure by the fibrous tissues that surround and course throughit. Surrounded by a fascial shell that is sometimes obvious andsometimes nonexistent, the stromal, epithelial, and glandular elementsof the breast are held together by a highly variable interlacing networkof fibrous connective tissue. This supporting network, when present,forms planar sheets of varying thickness from fibrous tissue that coursebetween the deep and superficial layers of fascia, incompletelycompartmentalizing the structures of the breast (Fig. 2A-18). Theseligaments, described by Cooper in the 1800s, form crisscrossing andoverlapping structures that can be seen on two-dimensional imagingthat project as irregular and often spiculated shapes, frequentlycomplicating image analysis of the breast (Figs. 2A-19 and 2A-20).These fibrous structures form around and support the developing ductnetwork as it grows back into the soft tissues of the chest wall. In somewomen Cooper's ligaments form an extremely

P.23tough network of fibrous connective tissue, while in other women thereis little if any of this connective tissue. Work by Prechtel suggests thatthere is a progressive decrease in the percentage of connective tissuein the breast that occurs with aging (21). This coincides with aprogressive increase in the percentage of fat contained in the breast.Contrary to popular belief, this fatty replacement does not occursuddenly at menopause, but is a progressive change that seems tooccur in different women at different ages and never occurs in somewomen. In our unpublished analysis of over 70,000 mammograms, itappears that the percentage of women who have dense breast tissues(corresponding to a high fibroglandular content) is approximately 90%at age 30 and decreases fairly steadily to approximately 45% ofwomen by the age of 65 (Fig. 2A-21).

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Figure 2A-18 If the glandular and fat portions of the breast areremoved, what remains are Cooper's ligaments. This schematic depictsthe fibrous connective tissues that support the ductal, glandular, andfat tissues of the breast. (Adapted from

Barth V, Prechtel K. Atlas of breast disease. Philadelphia: BC Decker;1991.)

Figure 2A-19 Fibrous connective tissue courses through the breast invarious amounts that differ from individual to individual. These werefirst described by Sir Astley Cooper and are known as Cooper'sligaments. They attach to the skin by the retinacula cutis, which arelike the peaks of mountains suspending the breast from the skin.Ducts can follow the retinacula cutis to the skin so that breast cancer

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can develop in the subcutaneous fat. I believe this is why some womenwho have extensive DCIS and skin-sparing mastectomies developrecurrences. It may be impossible to dissect close enough to the skinto remove these very peripheral ducts, and if they contain cancer,recurrences can occur.

Figure 2A-20 The curvilinear structures are Cooper's ligaments, seenin tangent to the x-ray beam on this mediolateral xerogram.

Intralobular and Interlobular ConnectiveTissueThere are two general types of connective tissue in the breast: thenonspecialized connective tissue that holds the breast together and isfound throughout the breast between the lobules (interlobularconnective tissue), and the specialized connective tissue that iscontained with and surrounds the terminal duct lobular unit (Fig.2A-22). Histologic staining shows a clear difference between theinterlobular, or stromal, connective tissue described above and thespecialized, loosely arranged connective tissue that surrounds and is

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intimately related to the terminal ducts and lobules forming theintralobular connective tissue (Fig. 2A-23). Together, these fibrouselements produce a cohesive structure that resists surgical dissectionalong tissue planes and often requires the surgeon to employ cuttingtechniques when operating on the breast. The fibrous connectivetissues of the breast can be so tough that they make it very difficult tointroduce and position needles for diagnostic aspiration or corebiopsies. The stromal connective tissue can be so firm that it isimpossible to pass a 20-gauge or thinner needle into the breast withoutbending it.

The superficial extensions of Cooper's ligaments, known as theretinacula cutis, attach the breast to its primary support, the skin (Fig.2A-24). The deep layer of superficial fascia, which is often notdetectable at surgery, demarcates the back of the breast. Thisretromammary fascia lies immediately against the pectoralis fascia thatlies on the pectoralis major muscle. These fascial planes permit adegree of mobility for the breast to slide on the muscles of the chestwall.

Surrounding the parenchymal cone of the breast is a layer ofsubcutaneous fat of variable thickness. Perforated by the fibrousattachments to the skin, this fat layer does not isolate the breast, andductal epithelium can be found directly beneath the dermis inassociation with the retinacula cutis. These extensions make itimpossible to perform complete removal of the breast with anyprocedure less than a total mastectomy, as ducts may extend to theskin (Fig. 2A-25). To avoid devascularization and sloughing of the skin,epithelial elements that can undergo malignant change are likely leftbehind with a subcutaneous mastectomy, making this procedure animperfect method for eliminating the risk of breast cancer. Even acomplete mastectomy cannot remove all of the ducts that attach closeto the skin without devascularization and loss of the skin. It is theresidual tumor extension into these ducts or the development of newcancer in these residual structures that is probably the cause ofrecurrent breast cancer following even a modified radical mastectomy.

At the back of the breast, but within the retromammary fascia, isanother layer of fat of varying volume forming the retromammary fat.

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The retromammary fascia slides on the prepectoral fascia, permittingsome mobility of the breast on the chest wall. Unfortunately, theretromammary space between the retromammary fascia and thepectoralis fascia is a potential space that does not completely isolatethe breast. There are projections through the deep layer of

P.24P.25fascia that traverse the retromammary space into the pectoralis majormuscle, and cancer can spread through the vessels and lymphaticsthat penetrate to the chest wall. It was this lack of complete isolationof the breast from the pectoralis fascia that led to the surgicalprinciples on which radical mastectomy (removal of the pectoralismajor muscle) was based.

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Figure 2A-21 This graph demonstrates the steady decrease in thepercentage of women with dense breasts that occurs with age amongwomen who are not using hormone replacement therapy (A). Thepercentages are moderated (B) by the use of hormone replacementtherapy, suggesting that two effects are in play: age and hormonelevels.

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Figure 2A-22 The specialized connective tissue within the lobule(intralobular) surrounds the acini like a haze. It is distinct from thetough fibrous tissue that supports and holds the breast together,forming the connective tissue between the lobules(interlobularconnective tissue).

We have shown that the majority of breast cancers develop in theparenchyma in a zone 1 cm wide that lies immediately beneath thesubcutaneous fat, or anterior to the retromammary fat (Fig. 2A-26). Itis also possible that the majority of the TDLUs are in this zone or even,as some have speculated, that the fat acts as a reservoir forcarcinogens (hence the propensity for cancers to develop adjacent tothese fat areas) (22), but this is purely speculative. The most likelyexplanation is simply that this is, geometrically, where most of thebreast tissue is found (23).

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Figure 2A-23 There are two kinds of connective tissue in thebreast. The connective tissue between the lobules that supports andholds the breast together can be seen in this drawing. The specializedconnective tissue surrounds the acini of the lobule.

Figure 2A-24 The curvilinear structures seen on this mediolateraloblique digital mammogram are the retinacula cutis that attach thebreast to the skin.

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Figure 2A-25 Branches of this duct that was injected with contrastmaterial go right to the skin of the breast.

P.26

The Skin and Fascia of the BreastThe skin of the breast is usually 0.5 to 2 mm thick. It becomes thickerto form the areola surrounding the nipple. Just beneath the skin lies thesuperficial layer of fascia (see Fig. 2A-2) that, at the level of the breast,divides into superficial and deep layers. The breast develops betweenthis split layer of fascia and is enveloped by it. It is not clear exactlyhow the breast develops in this split layer. I have heard one theory thatsuggests that the breast tissue develops anterior to the fascia, and as itgrows, it pushes the fascia back and is enveloped by it, like pushingyour hand into plastic wrap (see Fig. 2A-6). The deep layer of thesuperficial fascia forms the retromammary fascia that, as far as I cantell, is variably present. It lies immediately on the fascia that overliesthe pectoralis major muscle, providing surfaces that permit somemovement of the breast on the chest wall. With the exception of thepectoralis fascia, the other fascial layers are often quite delicate andmay not be apparent at surgery or even to the pathologist. They do notcompletely isolate the breast from the pectoralis major. Blood vesselsand lymphatics penetrate the fascial layers, coursing between themuscle and the breast.

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Figure 2A-26 Cancers are most commonly found at the periphery ofthe parenchyma. This schematic demonstrates the volume of tissue atthe periphery of the parenchyma in a zone 1 cm wide that lies justbeneath the subcutaneous fat and in front of the retromammary fat.More than 70% of breast cancers develop in this zone.

Adipose Tissue in the BreastImmediately beneath the skin is a layer of subcutaneous fat. This layervaries with individuals: in some women it is clearly separate from theparenchymal cone of the breast, while in others the subcutaneous fatcannot be distinguished from fat that is present between the glandularstructures. The amount of fat in the breast varies with each individualand with the weight of the individual. The breast is a repository for fat,and the amount of intramammary fat can vary as the individual gainsand loses weight (Fig. 2A-27).

The nipple is usually centered in the lower portion of the breast.Accessory nipples are not uncommon. These may be found anywherealong the course of the embryologic mammary ridge but are mostcommon as small, dark, raised structures below the breast on the upperabdomen. The nipple is designed for nursing. It contains smoothmuscles that form erectile tissue to facilitate suckling. It contains manysensory nerve endings as well. The studies of the nipple are not ascomplete as one might hope, but various sources suggest that there are

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anywhere from 6 to over 20

P.27ducts that open on the surface of the nipple. Even Love's extensiveevaluation failed to demonstrate any reproducible number ororganization of the mammary ducts (24). Recent work at the MGHevaluating over 50 mastectomies shows an average of over 20 ductsopening in the nipple (personal communication, Jennifer Rusby, MD).Each duct opening defines the culmination of an arborizing structure ofducts that form a lobe or segment as they extend from the lobules thatform the glandular structures of the breast to the nipple surface. Theskin of the nipple is continuous with the epithelium of the ducts.Cancer in the ducts can extend out into the skin of the nipple, formingPaget's disease of the nipple.

Figure 2A-27 The tissue density of the breast reflects the bodyfat of the patient. This patient had a large amount of breast fat (A).When she lost weight, her breasts became much denser (B).

The surface of the nipple itself is irregular, with a cobblestone texture(Fig. 2A-28). This is appearance is produced by numerous crevices in

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its surface. The duct orifices are usually at the bottom of thesecrevices. With magnification, the duct openings can be seen asglistening gray specks in the tissue of the nipple. Each duct and itstributaries defines a lobe or segment of the gland. Beneath the nippleopenings, the major ducts dilate into their ampullary portions. Theseare the lactiferous sinuses. The deeper segmental ducts divide intosubsegmental structures and may branch further until they form theterminal duct that enters the lobule.

The pigmented tissues of the areola contain numerous apocrine sweatglands and sebaceous glands, as well as hair follicles. The glands helpto lubricate the nipple/areolar surface during nursing to reduceirritation. The skin of the areola is thicker than the rest of the skin ofthe breast, tapering down toward the limbus of the areola where it joinsthe regular skin. The small, raised nodular structures that aredistributed over the areola (Morgagni's tubercles)

P.28define the openings of Montgomery's (sebaceous) glands (Fig. 2A-29).

Figure 2A-28 In this close-up, the nipple surface has a cobblestoneappearance. Cellular debris can be found in the crevices, and the ductopenings are usually in these crevices.

Nipple and Lactiferous DuctsThe nipple and areola contain erectile smooth muscle as well assebaceous glands. There are hair follicles in the areola, and on occasion

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the glands or follicles contain calcifications that rarely pose a diagnosticproblem when seen on the mammogram. It appears that 20 or morelactiferous ducts have orifices in the nipple. Each major duct extendsback into the breast in a branching network of smaller segmental andsubsegmental ducts, culminating in the terminal ducts and theblunt-ending acini of the lobules.

Figure 2A-29 The nippleâ€“areolar complex includes raised structureson the surface of the areola known as Montgomery's tubercules. Notethe verrucoid surface of the nipple. The duct openings are generallydown in the crevices of the nipple surface.

Segmental Anatomy of the BreastEach major duct and its tributaries is considered a lobe or segment ofthe breast. The volume and geography drained by each duct network isextremely variable (Fig. 2A-30). One segment can be very extensive;another can be extremely small. TDLUs can be found as immediatebranches beneath the nipple (probably the location of subareolarcancers) as well as deep within the breast at the ends of multiplebranches. The segmental anatomy of the breast is poorly understood.The lobes are not recognizable as histologically defined entities, sincethere are no boundaries separating one from another. Branches from agiven duct network do not always conform to a predictable distribution.Although the major ducts tend to branch into the portion of the breastthat corresponds to the quadrant of the nipple on which they open,branches can extend in unexpected directions and even branch into twocompletely different quadrants. Breast cancer appears to be a process

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that is initially confined to the cells of a single duct network.Theoretically, the removal of the entire segment (a major duct and itstributaries) should prevent recurrence. However, the segments are notevident at surgery, and since branches of the same duct may extendinto two or more quadrants (Fig. 2A-31), branches of the duct andtumor within it may remain after resecting even an entire quadrant ofthe breast.

Branches from different primary ducts likely overlap and interdigitatewith branches from other segmental ducts. Although it was originallythought that the ducts in one segment were isolated from the ducts ofanother, work by Ohtake et al (25), in their three-dimensional studiesof the ducts, suggest that there may be anastomoses betweensegmental networks, and this may be an additional way in whichcancer, spreading through the duct system, involves other segmentsand quadrants of the breast. Some are skeptical of this observation.

The mechanism of some breast cancer recurrences is likely due to thefact that the duct containing the tumor is transected and since thepathologist evaluates only a small portion of the entire excised tissue,the extension of tumor into another part of the breast may not beappreciated. In this way, undetected and unsuspected, tumor may beleft behind at surgery. Adjuvant radiation therapy is intended to kill anyresidual tumor; however, if the residual tumor burden is too high,radiation may not eradicate the residual disease. Cancer that hasspread into those branches and has not been eliminated by radiation islikely the source for some cases of recurrent disease. If techniques canbe devised to accurately delineate a segment or eliminate the samplingerror of the pathologic tissue evaluation, therapy

P.29could be more accurately tailored to permit complete tumordestruction.

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Figure 2A-30 (A) The breast is composed of lobes or segments thatare defined by the major lactiferous ducts that open on the nipple. Thisis evident in this reproduction of the painting done by Cooper's artistfollowing the injection of the ducts with paraffin. (B) Frequently asegment occupies a wedge of breast tissue, as seen in this duct injectionimaged by xeroradiography in the craniocaudal projection. (C) Somesegments are very small, as seen in this galactogram in thecraniocaudal projection.

An understanding of the development of a cancer in relationship to theduct system may have important etiologic implications. At present, itappears that most breast cancer is unifocal and arises from a singlecell. The presence of true multifocal cancer would raise doubt about thistheory. Research, however, suggests that multifocal cancers areactually connected through intraductal bridges of tumor, and thissuggests that multiple foci likely represent areas where intraductalcancer cells that have spread to different portions of the involved ducthave developed invasive capability.

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Figure 2A-31 A major duct can branch in two directions and actuallyinvolve two separate quadrants. This duct branches medially andlaterally. On the craniocaudal projection the injected duct has branchesthat spread across the entire upper breast, so that if this patient wereto have cancer and it was a segmental process, a quadrant resectionwould likely miss branches and possible cancer that had spread withinthe ducts. It is likely, for this reason, that quadrant resection does notpreclude recurrent cancer. (Courtesy of Norman Sadowsky, MD)

The ducts of the breast are lined by an inner layer of epithelial cellssurrounded by a thinner, and often discontinuous-appearing, layer ofmyoepithelial cells (Fig. 2A-32). The myoepithelial cells presumablyplay a role in the propulsion and expression of milk during lactation.The presence of both cell types in a lesion such as a papilloma is usedby the pathologist to determine that it is benign, since only theepithelial cells are involved in cancer formation. Because terminalbranches are not only found deep

P.30in the breast tissue but may also form immediately off a major ductanywhere in the breast, cancers may occur immediately beneath thenipple as well as anywhere else in the breast.

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Figure 2A-32 Schematic of a cross-section of a duct lined byepithelial cells and surrounding myoepithelial cells.

The Terminal Duct Lobular UnitBranching continues until the distal duct ultimately ends in a groupingof blunt-ending ductules (like the fingers of a glove) that form acollection of glandular acini defined as a lobule arrayed at the end andaround a terminal duct (Fig. 2A-33) like hollow grapes in a stem. Aportion of the terminal duct and its ductules (acini) is surrounded bythe intralobular, more loosely organized, specialized connective tissue.

The final branch from the segmental duct as it enters the lobule istermed the extralobular terminal duct. The portion of the terminal ductwithin the lobule is termed the intralobular terminal duct. Theblunt-ending tubes, or ductules, that extend like fingers into the lobule,form from 10 to 100 acini that empty into the intralobular terminalduct. Following the work done by Wellings et al (26), histologists havetermed the extralobular terminal duct and its lobule the terminal ductallobular unit (TDLU). The TDLU is the most important structure in thebreast. It is the glandular unit that produces milk, and it is postulatedthat most cancers arise in the terminal duct (Fig. 2A-34) either insideor just proximal to the lobule (27). It may be significant that this is thesite where the elastic tissue that surrounds the extralobular terminalduct ends, but any relationship remains to be determined. The lobuleitself is usually, although not always, clearly distinguishable from thesurrounding stroma and larger ducts. Its own stromal matrix(intralobular connective tissue), which some believe is derived from the

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dermis, contains very fine collagen fibers and reticulum and is morecellular than the extralobular connective tissue. It is also quitevascular. Although there is no demarcating membrane, the intralobularstroma stains distinctively differently from the extralobular stroma onhistologic section. There are likely important chemical communicationsthat occur between the acini and the specialized connective tissue thatsurround them.

Unlike the larger ducts, the lobule contains no elastic tissue. Althoughmost malignant tumors in the breast are epithelial in origin, interesthas been focused on the role of the contiguous, nonepithelial elementsof the supporting stroma. The complex stromalâ€“epithelial interactionsand the micronutrients that bathe the terminal duct are thought bysome to have a bearing on cell transformation and cancer promotion.

In addition to cancer, most of the benign lesions, such as cysts andfibroadenomas, that develop in the breast, develop in the TDLU.

Stem Cells in the Breast?Some have postulated that there are stem cells in the breast that areresponsible for its development. If there are stem cells, they wouldlikely be concentrated in the TDLU, since this is the portion of thebreast that undergoes growth during puberty, â€śterminaldifferentiation,â€ť as well as periodic proliferation and apoptosis.Although they have not yet been isolated, it is likely that theseundifferentiated cells would be more susceptible to malignanttransformation, and this might account for why most breast cancersappear to originate in the TDLU. If the undeveloped and developingbreast has a large number of stem cells, this might explain why theimmature breast is more susceptible to radiation carcinogenesis thanthe fully differentiated adult breast.

The Normal Breast: Menstrual Variation,Lactation, and Aging InvolutionCancer is clearly the most significant pathologic process affecting thebreast. Its early detection is the paramount reason for performingbreast evaluation. Other abnormalities that occur in the breast are

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important primarily because they cause concern to the patient orphysician and must be differentiated from malignancy. Of less clinicalsignificance but potentially greater epidemiologic value has been aneffort by investigators to predict which women are more likely todevelop breast cancer by identifying histologic changes that mayindicate a higher risk for subsequent malignancy (28). These effortshave been complicated by difficulty distinguishing pathologic processesfrom the wide range of physiologic processes that occur. At a cellularlevel, the breast is a dynamic organ that is continually changing withcyclic hormonal fluctuations. Although these primarily microscopicalterations are often not visible by any currently available imagingtechnique, they are reflected clinically in many women by cyclic painand swelling. Histologically the breast involutes with age, and theperiodic variations are superimposed on long-term involutionalchanges. There is a lack of clear understanding of what constitutes theâ€śnormalâ€ť breast, and this has been

P.31P.32reflected in the frequently unsatisfactory terminology that has beencoined to describe various, probably physiologic, changes that occur aspart of a spectrum of normal variation. Such terms asâ€śmastopathy,â€ť â€ścystic mastitis,â€ť â€śdysplasia,â€ť and theall-encompassing â€śfibrocystic diseaseâ€ť are synonymous with a lackof true understanding of where normal physiology ends and truepathology begins. Autopsy studies have shown that as many as 50% ofwomen have changes that most pathologists would characterize asfibrocystic disease (29). Similar changes were noted in reductionmammoplasty tissue and subcutaneous mastectomies performed onhealthy women (30). As is discussed in the section on the normalbreast, a satisfactory definition of the normal breast by imagingcriteria is also lacking.

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Figure 2A-33 (A) This is a thick section of tissue that has beendefatted so that the three-dimensional terminal ducts and lobules arevisible at 40Ă— magnification. (B) The appearance of TDLUs is seen onthis optically enlarged craniocaudal galactogram (C) in which thelobules (the small â€śfluffyâ€ť densities at the ends of the ducts) havefilled with contrast. (D) This histologic section demonstrates theterminal duct and lobular acini of a TDLU. The large arrow points to theintralobular terminal duct. The TDLU is composed of the terminal duct(extralobular and intralobular portion), the ductules, or acini, of thelobule, and the specialized connective tissue that surrounds the aciniand is distinct from the surrounding fat and the interlobular connectivetissue. (E) Multiple lobules and their specialized connective tissue, aswell as the interlobular, nonspecialized connective tissues, are visible inthis lower-magnification section.

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Figure 2A-34 Cancers are thought to arise in the intralobular portionof the terminal duct in the location suggested by this schematic.

The breast is a heterogeneous organ. Further complicating breastanalysis is the variable â€śend-organâ€ť response of its cellularconstituents to fluctuations in hormone levels. One volume of breasttissue may be very sensitive to hormonal variations, while otherportions of the same breast and the contralateral breast may have littleor no reaction. This heterogeneous response can result in clinicallyapparent â€ślumpsâ€ť that may merely reflect disproportionatestimulation of a volume of breast tissue, resulting in a prominence thatdistinguishes the particular tissue volume from the surrounding lessaffected tissues. The distribution of fibroglandular elements is notuniform; neither is the distribution of fat. Islands of these varioustissues may feel, on clinical breast examination, as thickened areas oreven lumps, while by mammography the heterogeneous distribution ofnormal breast tissue elements may produce suspicious densities.

â€śFibrocystic Diseaseâ€ť andâ€śMammary Dysplasiaâ€ťFibrosis and cystic changes are extremely common in the breast. Asnoted above, at autopsy as many as 50% of women have breastelements that can be termed fibrocystic (31). The question that hasnever been satisfactorily answered is whether these changes are part ofa normal spectrum or part of a pathologic process. The lack of uniformdefinitions has only added to the confusion. Any lump that is excised

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for whatever reason becomes, by definition, abnormal tissue.Pathologists faced with these biopsies needed to find the pathology andthus developed â€śwastebasketâ€ť categories. The terms â€śfibrocysticdiseaseâ€ť and â€śmammary dysplasiaâ€ť have unfortunately beenused to categorize histologic variations that range from normalphysiologic responses to true premalignant proliferative growth.Clinicians and radiologists optimistically trying to assure themselvesthat they could predict histopathology adopted these terms with littlejustification. The examining fingers feel tissue inhomogeneities that aremore often than not the normal variations of a heterogeneous organ.The mammogram reflects the x-ray attenuation of the tissuesproducing shadows that relate more to the water content of thestructures than the histology. With the exception of the ultrasounddiagnosis of a cyst, the calcification of an involuting fibroadenoma, orthe spiculated margins of some cancers, imaging techniques are rarelyable to accurately define true histology due to the overlappingappearance of many processes. The normal and the neoplastic mayproduce identical morphologic changes, and inferring specific histologyfrom physical examination or imaging is a statistical guess in mostinstances. Terms such as â€śfibrocystic diseaseâ€ť and â€śmammarydysplasiaâ€ť should be eliminated because they have becomecompromised by lack of specificity. Dupont and Page have shown that itis only the small subcategory of proliferative histologies within thecategory of fibrocystic disease that carries a higher risk for futuremalignant change (32), and within the proliferative changes theatypical proliferative changes are most important; this has beenacknowledged by the College of American Pathologists (28).

Cysts, for example, are of no consequence unless they occur in womenwith a family history of breast cancer. Dupont and Page found that thiscombination, for unexplained reasons, increases a woman's risk two tothree times. The most significant histologic risk factor among benignchanges appears to be atypical epithelial hyperplasia (ductal andlobular). Women who have had biopsies showing these atypicalproliferative changes are at 5 times the risk of developing breast canceras women whose biopsies showed no proliferative changes, and whenthese changes are found among women with a family history of breastcancer, the relative risk increases to 11 times that of the woman with

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no proliferative changes. Aside from these significant exceptions, nouseful correlations exist between the broad category of fibrocysticdisease and breast cancer risk. Furthermore, atypical hyperplasia canbe diagnosed only by breast biopsy and as yet cannot be predicted bymammography, although the process may produce calcifications thatinstigate a biopsy. The terms â€śfibrocystic diseaseâ€ť andâ€śmammary dysplasiaâ€ť cause unnecessary fear and carry anunsubstantiated prejudicial connotation. They certainly

P.33do not belong in an imaging lexicon and should probably be eliminatedaltogether and replaced by specific histologic categories, as suggestedby the College of American Pathologists (28).

Breast Tissue Changes With the MenstrualCycleThe breast is a dynamic organ. Although this is not readily evident atthe present level of imaging, histologic variation over the short term ofthe menstrual cycle is superimposed on the long-term changes of theaging process. Based on normal tissues derived from subcutaneousmastectomies and reduction mammoplasty material, Vogel et al (30)have reconstructed and detailed the monthly cellular changes occurringduring the menstrual cycle.

During the estrogen-stimulated proliferative phase of the menstrualcycle (days 3 to 7) (Fig. 2A-35), the mitotic rate in the acinar cells ofthe lobule increases, indicating cell proliferation in the breast as well.No secretions are seen, and the lobules are defined by a dense cellularmantle. During the follicular phase, between day 8 and day 14, twodistinct cell types, along with more collagen, are visible in the acini,while mitotic activity is diminished. The luteal phase occurs betweenday 15 and day 20, and the pathologist can recognize three distinctivecell types in the breast. The cells of the lobule develop vacuoles, andsecretions are visible in the ducts. Vogel et al noted loosening of thestroma within the lobule, followed by true apocrine secretion into thedistended duct lumen, during the secretory phase. The tissues withinthe lobule become edematous and there is venous congestion, whichprobably accounts for some of the discomfort many women experience

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premenstrually. Active secretion appears to end during the menstrualphase of day 28 to day 2, and then the cycle repeats itself. During thelater phases there is likely apoptosis, or programmed cell death. Somehave estimated that as many as two thirds of the cells are reabsorbedin this fashion. This process ensures that a certain percentage of cellsthat had been formed earlier in the cycle are removed to prepare forthe proliferative changes of the next hormone cycle. The role ofapoptosis in breast cancer remains to be determined. I suspect,however, that with every cycle of proliferation, DNA must be copiedaccurately. Errors in DNA synthesis are corrected if cell repairmechanisms function correctly, and if they cannot be repaired, the cellusually dies. I suspect that failure of either of these two mechanismscould lead to the preservation of erroneous sections of DNA. These maynot be significant, but I suspect that the accumulation of errors overtime could be one of the mechanisms involved in malignanttransformation. This might be why the increased exposure of women totheir own hormone cycles (with earlier menarche and later menopause)may lead to an increased risk of breast cancer.

These microscopic changes have never been clearly documented at themacroscopic imaging level. A few studies have suggested, notunexpectedly, possible increased water in the breast in thepremenstrual portion of the cycle (33,34), but there has been no goodcorroboration of importance of these observations with regard toimaging. Some suggest that mammography should be performed beforeovulation. This is primarily to reduce the discomfort for some womenwhen compressing the edematous breast in the premenstrual phase.One study suggested that the sensitivity of mammography is reducedwhen performed in the luteal phase of the menstrual cycle; however,this involved data from the National Breast Screening Study of

P.34Canada, which had notoriously bad mammograms, and it is unclearwhether there was a true problem or simply that women did not permittheir sore breasts to be compressed as needed (35). There are no gooddata that determine what, if any, effect the phase of the menstrualcycle has on mammographic cancer detection, but it makes sense toencourage women to be imaged in the first part of the cycle, whentheir breasts can be compressed with less discomfort. There are clear

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problems with performing contrast-enhanced MRI in the second part ofthe cycle, and this should be avoided whenever possible due to themarked increase in contrast enhancement that occurs in the normaltissues in the luteal phase of the cycle (see Chapter 20, â€śMagneticResonance Imaging of the Breastâ€ť).

Figure 2A-35 The breast is highly sensitive to the hormone changesduring the menstrual cycle. Just as with the endometrium, there is cellproliferation in the first part of the menstrual cycle. There are two celltypes visible during the middle of the cycle (follicular phase), and thecells become vacuolated and secretions accumulate during the luteal

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phase of the cycle, also associated with edema and venous congestionin the breast. The cycle begins again after apoptosis (programmed celldeath) reduces the cell population at the end of the cycle. (Reprintedwith permission from

Scott J, DiSaia PJ, Hammond C, et al, eds. Danforth's obstetrics andgynecology, 7th ed. Philadelphia: Lippincott, 1994:30.)

LactationPregnancy clearly has a profound effect on the breast. The epithelialcells begin to demonstrate changes in the first trimester. During thesecond trimester, the lobules increase in size and there is a generalizedproliferation of lobular acini, many of which begin to contain secretedmaterial. Continued increase in the size of the lobules in the thirdtrimester leads to replacement (crowding out) of the intralobular andinterlobular connective tissue, until by the onset of lactation only thinfibrous septa separate the enlarged, secretion-distended lobules. Themyoepithelial cells elongate. These are thought to be the contractilecells of the breast that aid in expressing milk. When lactation takesplace, membrane-encapsulated fat globules are secreted from theepithelial cells. The membranes of these milk fat globules have beenstudied for their antigenic components in the search for tumor markersin nonlactating women.

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Figure 2A-36 The tissues of the lactating breast are often extremelyand heterogeneously dense, as seen on this mediolateral obliqueprojection (A). The density often regresses after the cessation oflactation, as seen in the same patient 1 year later postlactation (B).

When lactation ceases, the breast undergoes a degree of involution, butlarge lobules may persist. A return to a new baseline takesapproximately 3 months following the cessation of lactation. Becauselactation causes a marked increase in the radiographic density of thebreast (Fig. 2A-36) that

P.35could obscure pathology, we recommend that routine screeningmammography not be performed for at least 3 months following thecessation of lactation. If diagnostic mammography is needed when apatient is lactating, we recommend that the woman nurse or pump herbreasts prior to the mammogram. True involution occurs with age.

Aging Changes and InvolutionPathologists seem in general agreement that the breast undergoesinvolutional changes as women age, but the timing of this involution is

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not clear. It is clear from our data at the Massachusetts GeneralHospital that many women show little change in their mammographicpatterns with increasing age. Over a long period of time, andapparently unrelated to ovarian activity, atrophic changes occur, butthe process is not uniform throughout the breast and the timing ofchanges varies with individuals. The acinar lining cells of the lobulesdiminish, and the lobules themselves shrink in size. Connective tissuein the lobule becomes densely fibrotic or replaced by fat. Small cystsmay form as the acini coalesce, but these eventually fibrose anddisappear. The ductal epithelium also undergoes atrophy, and this maylead to obliteration of many of the ducts.

Intuitively, involution would be most likely associated with hormonalalterations at the time of the menopause, but at least one studyquestions this chronology. Aging studies, of necessity, must relatedifferent women at varying ages, since it is not possible to follow onewoman over time at the microscopic level. A British investigation byHuston et al (36) suggests that involution begins earlier than thegenerally assumed perimenopausal years. On the basis of whole breaststudies, these researchers concluded that involution probably begins asearly as the third or fourth decade of life and is fairly advanced by thetime of menopause. This agrees with the work of Prechtel (37), cited inmany pathology textbooks (38), which shows that the percentage offibroglandular tissue decreases steadily with age but that the decreaseis variable among individuals, with no abrupt change at any age (Fig.2A-37). In a single longitudinal study of mammographic parenchymalpatterns Wolfe (39) suggested that noticeable fatty replacement occursaround the time of menopause. It is not clear how much of theobserved change was technical artifact (Wolfe comparedhigher-contrast film-screen studies of the 1960s with low-contrastxeroradiographic images of the 1970s) and whether radiographicallyvisible change actually occurs; nor is it clear how much fattyreplacement is a function of general weight gain rather than a truereflection of histologic change. Our own experience suggests that themammographic appearance of the breast changes gradually in somebut not all women with increasing age, and that the most visiblechanges occur with fluctuations in the patient's weight. Our datasuggest that approximately 90% of women have dense breast tissue

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(glands and connective tissue) evident by mammography at age 30,with the percentage of dense versus fatty tissue changing graduallywith increasing age. There appears to be some acceleration of theprocess that occurs between ages 45 and 60, but this is superimposedon the gradual change that occurs from age 30 to age 70. Based onmammographic patterns, it appears that many women do not everundergo fatty involution at any age.

Figure 2A-37 The percentage of the breast that is collagen decreaseswith age, while the percentage of fat increases with age, as seen inthis schematic adapted from Prechtel. (Adapted from

Prechtel K. Mastopathic und altersabbangige brustdrusenverandernagen. Fortschr Med 1971;89:1312â€“1315.)

The lack of a uniform definition of what constitutes the normal breastcomplicates determination of the abnormal. Furthermore, in allprobability, host responses are important in the development ofpathology. Breast evaluation is further complicated by the variableresponse of the end organ. This variability is suggested not only by theinhomogeneous monthly changes seen histologically, but also by thevarying rate at which different parts of the breast undergo involutionalchange. The breast is a relatively disordered organ that lacks uniformarchitectural landmarks. The inhomogeneities found in varying degreesin all breasts compromise the ability of imaging studies to detect theearly epithelial changes that may indicate a malignant process.

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Histology and PathologyUnderstanding the benign and malignant changes that develop in thebreast is facilitated by dividing the breast into its major componentsand evaluating the changes that can occur in each, as summarized inTable 2A-1.

Relationship of Pathology to the Duct andLobuleBenign and malignant lesions of the breast may be categorized by thelevel within the duct network in which they occur. Some processes arecategorized as if they arose from the cells of the ducts, while others arebelieved to have arisen from the components of the lobules. There areonly

P.36a few significant lesions that arise in the interlobular stroma.Fibroadenomas and phylloides tumors appear to arise from theintralobular, specialized connective tissue.

TABLE 2A-1 THE MOST COMMON BENIGN AND MALIGNANTLESIONS OF THE DUCT SYSTEM

Lesions of the major ducts Duct ectasia Cystic dilatation of the large duct (large duct cyst) Large duct papilloma Intraductal carcinoma extending from the terminal ductLesions of the minor and terminal ducts Hyperplasia Peripheral duct papillomas Ductal carcinomaLesions of the lobule Cyst Fibroadenoma Adenosis Phylloides tumor Lobular carcinoma

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Lesions of the interlobular connective tissue Sarcoma

The following is a summary of the histologic and pathologic changesthat can occur in the breast. For a more complete description ofpathologic changes, see Chapter 2B.

Lesions of the Major Ducts

Duct EctasiaNonspecific ectatic dilatation of the major collecting ducts can be seenby mammography and ultrasound as tubular structures beneath thenipple. Ectatic ducts may be found deeper in the breast as well. Theetiology of duct ectasia has not been clearly elucidated. Periductalinflammation is either the result of duct dilatation and the extrusion ofirritating materials into the surrounding stroma or the cause of ductwall weakening and dilatation. Duct ectasia is a process that generallyinvolves the major collecting ducts.

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Figure 2A-38 Histologic cross-section of an intraductal papilloma.

Large Duct PapillomaSolitary benign papillomas occur in the major ducts. These areepithelial proliferations on a fibrovascular stalk (Fig. 2A-38). They areusually found within a few centimeters of the nipple, growing within theduct and sometimes distending it. They may produce a nipple dischargethat may be serous or sanguineous. Intraductal papillomas may beassociated with a solitary duct enlargement. Some believe this is due toduct obstruction. Since the dilatation is frequently both proximal anddistal to the papilloma, and since the normal ducts are usually blockedby keratin in the nipple orifices, obstruction is probably not the cause ofthe dilatation. As with cyst formation, it is likely that the papillomacauses or is associated with increased fluid secretion that is notbalanced by the normal resorption mechanisms of the duct, and thefluid imbalance causes distention of the duct. Although previously thelarge duct papilloma was thought not to represent a breast cancer riskfactor, some studies have suggested that women with solitary ductpapillomas are at a very small increased risk for developing breastcancer (40,41).

Paget's DiseasePaget described a form of ductal cancer that involves the large ducts.Although there is disagreement as to the exact progression of Paget'sdisease, these are likely ductal carcinomas that spread down the duct

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and out onto the nipple, where characteristic Paget's cells are found inthe dermis, associated with an eczematoid, crusting nipple lesion. Thisform of ductal carcinoma often has a favorable prognosis due to itsoften early clinical presentation, although it may be found inconjunction with a more advanced, invasive lesion deeper in the breast.

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Lesions of the Minor and Terminal Ducts

HyperplasiaHyperplasia likely occurs at all levels in the duct system, but theterminal duct appears to be the most significant breast structure.Wellings has postulated, and most agree, that the terminal duct is thesite where most cancers develop. Hyperplasia of the epithelium in thissegment is relatively common. Several layers of otherwisenormal-appearing epithelial cells form in the duct. The frequentassociation of hyperplasia with cysts may be the cause-and-effectrelationship of a benign obliteration of the duct blocking lobulardrainage and leading to cyst formation, although I do not believe thatduct obstruction is required for cyst formation. Gallager and Martin (42)have theorized that hyperplasia represents a nonobligatory, preliminarystep toward neoplasia. Even when atypical changes develop,hyperplasia appears to represent a reversible process, but in asignificant proportion of women atypical ductal epithelial hyperplasialikely progresses to intraductal carcinoma. Some studies suggest thatatypical lobular hyperplasia may also be a step in the progressiontoward breast cancer (43). It is likely that atypical hyperplasia is thephenotypical manifestation of genetic changes among a group of cellsthat place those cells closer to the changes needed for a malignancy.Since these cells likely contain several genetic alterations in theprogression to malignancy and are likely â€śgenetically unstable,â€ťthe probability of one of these cells developing all the necessarychanges to become a true malignancy is greater than for normal cells,and hence the increased risk.

Multiple Peripheral Papillomas

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A second type of proliferation has been described in the distal ducts.Microscopic multiple papillomatous growths can be found in this region(44). Pathologists believe that those represent a different process thanthe solitary papillomas of the large ducts. They may represent part of acontinuum of hyperplastic lesions, and it may be that multiplepapillomas of this type are a premalignant change indicating a higherrisk for future malignancy (45).

Ductal Carcinoma In SituThe significance of ductal carcinoma in situ (DCIS) still elicits muchcontroversy. Teleologically one would anticipate that it is the next stepin a continuum that passes from hyperplasia or atypical hyperplasia tointraductal carcinoma proceeding on to frank invasion (infiltratingductal carcinoma). Some do not believe in this progression, but there ismounting evidence that many if not all invasive cancers arise fromDCIS. It is likely that some invasive cancers develop rapidly with littleif any intraductal phase, while some in situ cancers grow for manyyears within the ducts, perhaps never developing an invasive clone. Itis likely, however, that many breast cancers develop in a continuumthat ultimately results in a clone of invasive cells. The duration of eachstep likely varies from individual to individual. In some women all thechanges needed for invasion and metastasis may occur quickly, while inothers, as suggested by the screening trial results, there is sufficienttime at each step to interrupt the natural history of the disease.Different patterns of DCIS are now recognized. The better-differentiatedcribriform types (Fig. 2A-39A) seem to have a slower progression toinvasion, while the more poorly differentiated comedo pattern (Fig.2A-39B) seems to be more rapidly aggressive.

Invasive Ductal CarcinomaWhether infiltrating cancer (see Fig. 2A-39C) develops from in situcancer or develops directly, invasive ductal carcinoma is the mostcommon form of invasive breast cancer and the primary lethal cancer ofthe breast. The cytologic features of the tumor and its growth patternsuggest an origin in the ductal epithelium. When the lesion cannot besubclassified, it is termed â€śinvasive ductal carcinoma NOSâ€ť (for

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â€śnot otherwise specifiedâ€ť). Other subtypes of cancers that arethought to originate from the ductal epithelium include papillary,mucinous (or colloid), medullary, and adenoid cystic cancers. Manyinvasive cancers likely obliterate any residual in situ component, but asnoted earlier, the in situ clones that are not destroyed by the invasivecells can continue to grow in and down the ducts, presenting invasiveand in situ cancer in the same lesion (see Fig. 2A-39D).

Lesions of the LobuleThe most common benign lesions arise in the lobule.

CystsCysts ranging from microscopic to those containing many cubiccentimeters of fluid are probably the result of idiopathic, apocrinemetaplasia of the lobular acinar epithelium. These cells appear to behypersecretory. The increased secretion is not balanced by increasedresorption, and dilatation of the lobule results (Fig. 2A-40). Thefrequent suggestion of an associated obstructed terminal duct may bepart of the process or a result of the dilating lobule causingcompression of the duct.

FibroadenomaFibroadenomas are the result of an idiopathic overgrowth of thespecialized connective tissues surrounding the acini of the lobule. Theacini are drawn out into slit-like spaces (Fig. 2A-41). Subcategories offibroadenomas have been described (intracanalicular andextracanalicular), but these do not appear to have any practicalsignificance.

Most studies suggest that fibroadenomas carry little if any risk for thesubsequent development of breast cancer. Because these lesionscontain epithelium lining the

P.38P.39stretched acini, cancers can arise in fibroadenomas just as they can inany breast epithelium.

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Figure 2A-39 (A) In this form of DCIS, the ducts are filled with cellsthat are aligned and define cribriform spaces. (B) This duct is filled withso many cells that those in the center have died, probably becausenutrients could not reach them. This type of comedo-intraductal cancerappears to develop invasive cells more rapidly than thebetter-differentiated forms of DCIS. (C) These cancer cells have brokenout of the duct and are forming a mass of invasive or infiltrating ductalcarcinoma. The edge of the lesion is at the top of the figure. (D) Theinvasive component (IN) is on the left, while cancecontinues to growwithin the duct as the in situ, intraductal (ID) component in this mixedlesion.

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Figure 2A-40 Early microcyst formation. In this histologic sectionthere are several normal lobules and one whose acini are cysticallydilated. This is likely the early phase in most cyst formation.

Figure 2A-41 The specialized connective tissue has overgrown, andthe acini are now elongated slit-like spaces in this fibroadenoma.Normal lobules can be seen at the right edge of the picture.

One study has suggested that women with complex fibroadenomas,defined as those containing cysts, sclerosing adenosis, epithelialcalcifications, or papillary apocrine changes, were at three times therisk of developing subsequent cancer than comparison groups (46).Women with adjacent proliferative disease, as well as those withfibroadenomas and a family history of breast cancer, were also at someincreased risk (3.9 and 3.7 times, respectively). If Dupont et al arecorrect, these risks last for many decades.

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AdenosisAdenosis is a benign proliferation of the stromal and epithelial elementsof the lobule producing an increase in the number of acinar structures(Fig. 2A-42). Instead of several to 100 acini, adenosis results ininnumerable acini in a lobule. The individual acini are elongated.Viewed three-dimensionally, the lobule looks like a porcupine. Adenosiscan be associated with a scarring process that can distort thearchitecture (sclerosing adenosis) and can sometimes be confused withmalignant change. Calcifications are often seen in the acini.

Figure 2A-42 The acini of this lobule have proliferated so that theynumber in the hundreds. Adenosis makes the three-dimensional lobulelook like a porcupine.

Phylloides TumorThe phylloides tumor is likely related to the fibroadenoma andoccasionally is mistaken for it (Fig. 2A-43). These are also lesions ofthe specialized connective tissue of the lobule. They are usually rapidlygrowing. Approximately 25% recur locally if not completely excised,and as many as 10% may metastasize. The pathologist looks forcellular pleomorphism and invasive rather than pushing borders tosuggest

P.40malignant potential. These lesions frequently have characteristics thatare similar to fibrosarcomas or liposarcomas.

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Figure 2A-43 The phylloides tumor is related to the fibroadenoma andis primarily an abnormal proliferation of the intralobular connectivetissue. Note the extremely cellular stroma (numerous nuclei). Theepithelium-lined spaces may be quite cystic; this explains the previousterminology of the cystosarcoma.

Lobular Neoplasia (Atypical LobularHyperplasia and Lobular Carcinoma In Situ)The differentiation of these lesions has become one of the mostconfusing aspects of breast histology. Although most breast cancersappear to originate in the extralobular terminal ducts, there are thosethat appear to be derived from the epithelial cells within the lobule andare correspondingly called lobular neoplasias (Fig. 2A-44). Although itis not clear that these represent direct precursor lesions, manypathologists require the presence of LCIS to diagnose an invasivecancer as invasive lobular carcinoma. LCIS appears to be a high-risklesion, like atypical hyperplasia. Although the pathologist finds differentcytologic features and patterns

P.41of invasion that distinguish invasive lobular from invasive ductalcarcinoma, both represent cancers with equal potential for lethality.

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Figure 2A-44 This lobule is filled with and distended by monomorphicround cells. This is the appearance of LCIS. Because this does notappear to be a direct, precursor lesion, some prefer to term thisâ€ślobular neoplasia.â€ť

LCIS is a diffuse process usually involving large portions of breasttissue. Women with LCIS are at a higher risk for invasive breast cancerin either breast. In the original work by Rosen et al (47), it has beenobserved that when LCIS is discovered at breast biopsy, both breastsappear to have a similar risk (15%) for the development of an invasivebreast cancer within 20 to 30 years (the total risk is 30%). Althoughinvasive lobular carcinoma is not found without LCIS, women with LCISmay develop an invasive ductal cancer. This has been corroborated in astudy by Bodian et al (48). They found that there was a 1 in 3 chanceof developing breast cancer in either breast after a biopsy thatcontained LCIS; this estimate was 5.4 times the rate in the generalpopulation. The risk decreased with increasing age at diagnosis. Therisk of developing breast cancer remained elevated for at least 20 yearsafter the biopsy.

More recently, the National Surgical Breast Project reported on a12-year follow-up of women who had their LCIS detected whileparticipating in one of its protocols (49). One hundred eighty patientswho had been diagnosed with LCIS had not had any more treatmentthan local excisions. The investigators followed the women and

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evaluated the risk of ipsilateral breast tumor recurrence (IBTR) andcontralateral breast tumor recurrence (CBTR) as well as the death ratesamong these women. During the 12 years of follow-up there were 26(14.4%) IBTRs and 14 (7.8%) CBTRs. Among these, 9 of the womenwith IBTRs (5.0% of the 180) and 10 of the women with CBTRs (5.6%of the total) developed invasive cancers. Eight of the nine invasivecancers that recurred in the ipsilateral breast (88.9%) and six of theeight invasive cancers developing in the contralateral breast (75%)among women who had histology that the authors could review wereinvasive lobular cancers. The investigators also found that 96% of allIBTRs and 100% of the invasive IBTRs developed in the same site asthe original LCIS was found. Fortunately, only 2 women among the 180(1.1%) died of breast cancer: both had invasive cancers, one IBTR andthe other CBTR. The authors concluded that LCIS represents a moreindolent form of in situ breast carcinoma than DCIS. Although it may bea direct precursor to invasive cancer, the recurrence rates are so lowthat they could find â€śno compelling reason to surgically treat LCISother than conservatively.â€ť These data differ from some of the olderresults, with rates of invasive tumor recurrence that are lower thanpredicted by earlier analyses. This might be due to their shorterfollow-up.

Figure 2A-45 The architecture is distorted by an idiopathic scarringprocess with a prominent elastic component that has been givenvarious names (â€śradial scarâ€ť is the most common). This is abenign lesion whose appearance can mimic cancer.

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Many pathologists are now subdividing these lesions and making adistinction between atypical lobular hyperplasia and LCIS. The atypicalforms appear to be linked to a higher rate of ipsilateral development ofbreast cancer (50), while LCIS represents a more bilateral risk. Page etal (50) found that 50 (20%) of the 252 women who had been treatedby biopsy alone subsequently developed invasive breast cancer. Therelative risk of developing breast cancer in women with atypical lobularhyperplasia was 3.1 (95% CI 2.3â€“4.3, p < 0.0001). Among 34 ofthese 50 women (68%), the invasive cancer developed in the samebreast (ipsilateral) that had been diagnosed with atypical lobularhyperplasia; it developed in the contralateral breast in only 12 (24%).They concluded that an invasive carcinoma that develops after apreceding diagnosis of atypical lobular hyperplasia is about three timesmore likely to arise in the same breast that contained the atypicallobular hyperplasia than it is in the opposite breast: â€śOur findingssuggest a model of premalignancy for atypical lobular hyperplasiaintermediate between a local precursor and a generalised risk for bothbreasts.â€ť

P.42

Lesions of the Extralobular Stroma

SarcomasSignificant lesions of the extralobular connective tissue are extremelyunusual. Sarcomas such as liposarcomas and fibrosarcomas do occur,but they are very rare. Angiosarcomas can also occur and are amongthe most lethal of all breast tumors.

Unclassified LesionsAlthough a very common lesion seen histologically, the radial scar hasbecome a more important lesion because of its visibility onmammograms and because its imaging appearance is indistinguishablefrom breast cancer. Its etiology and origin are idiopathic. The lesionsmay be very small or several centimeters in size. Page prefers to callthe larger lesions â€ścomplex sclerosing lesions.â€ť Thought tooriginate at a branching point in the duct network, the lesions often

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show hyperplastic changes (often papillary in appearance), adenosis,cyst formation, and a prominent fibrotic and elastic component, as wellas causing spiculated distortion of the tissue (Fig. 2A-45). Although thisis a scarring process, these lesions are unrelated to previous surgeryand should not be confused with postsurgical change. There has beenan ongoing debate as to the relationship of these lesions to thesubsequent development of breast cancer, but there is no consensus.Jacobs et al (51) suggested that very large radial scars were a riskfactor, but this has not been corroborated, and the excess risk in thatstudy may have been related to the (coincidentally?) associatedatypical changes rather than the radial scar itself.

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