BREAST CANCERby: D. Katsaros M.D.

HISTORY*Eight references to breast DZ are made in the Smith papyrus (3000 BC), which may have been written by Imhotep, and included descriptions of breast abscess, CA and trauma. Depending on the Dx, 3 forms of Tx were re: i)Fire drill (a type of cauterization) used for I+D ii)Observation iii) The lesion was considered uncurable (CA).*In the preantiseptic era, Tx varied from no Tx to application of ointments + caustics to amputation of smaller lesions c application of pressure or cautery. *In the 16th century, the suture ligature was used for hemostasis.*Louis Petit (1700) described en block resex c Ax dissex.*However it is Hallstead who is credited c describing the radical mastex at John's Hopkins (Baltimore). With the RM, Hallstead reduced the local recurrence rate from 50% to 6%.Haagensen modified the RM to what it is today.1) The Halstedian view of breast CA: The v local recurrence achieved c RM led to the Halstedian concept that breast CA is a local DZ that progresses in an orderly manner (see table). Since the Halstedian view sees nds as bariers to systemic DZ, pts c + nds are potentially curable with en blocc resection. It is now clear however, that the Halstedian view does not apply to all cancers. However, there is data that supports the Hallstedian view in some pts. For example:

i)Mammographic screening of asymptomatic pts v 5 y mortality by 30%. This suggests that breast CA is not metastatic from the outset; that a certain tumor "burden" is needed to overcome the peripheral immune system. On the other hand, the fact that there is improvement in survival from mammographic screening suggests that mets can occur early in the DZ i.e. between mammographic detection but before clinical detection.

ii)*The Alabama Breast Cancer Study showed improved survival for RM over MRM for stage IIb and IIIa DZ. *Meir (U of C) showed improved survival c XRM over RM for medial-central DZ. *Peterson (U of Oregon) showed improved survival c URM over RM for stage I-II DZ that was sustained even p a 25 yr F/U.*Ferguson reviewed 8 studies that compared extensive surgery vs conservative Tx and found significant improvement in two, favorable trend in 5-all favoring the larger operation. iii)A more theoretical reason favoring the Hallstedian view, at least in some pts,is that as tumors ^ in size, the likelelihood of mets ^ in a sigmoidal distribution. For breast CA the tumor diameter @ c a 50% probability of mets=3.6 cm (fig. 9-1). iv)Fields has shown improved survival c MRM but not chemoTx in Inflammatory Breast CA.v)If breast CA is systemic from the outset, why is survival a fxn of tumor size and nodal status.2) Fisher's hypothesis of breast CA suggests that breast CA metastisizes early (before the clinical recognition of DZ); that breast CA is a systemic-not a local DZ; that positive nds are a predictor of mets but are not barriers to mets. Thus, the presence of + nds implies the need for AdjuventTx-not en bloc resex. As a corrolary, variations in local Tx (RT vs lumpex vs MRM) are unlikely to affect survival. The arguments for Fisher's view are: i)Studies, like the Milan and NASB B-06 trials have shown lumpex + RT to be as effective as MRM.

ii)About 20-30% of node neg. pts develop mets. Thus, these pts had micromets at the time of RM and RM offers no survival advantage here. iii)Furthermore, 90% of our Tx failures will be 2o to systemic or visceral recurrence NOT to local recurrence. This is esp. true for

node + pts...systemic adjuvant Tx is needed in node pos. pts. As a corolary, the trend has been that less extensive local control is needed for cure. iv)Halstead was seeing much more advanced DZ than we are now. About 66% of Halstead's pts had Stage III DZ and 60% had + ax. nodes. In contrast, 85% of today's pts have stage I or II DZ; 10% present c stage III DZ and only 5% present with stage IV DZ. Thus, it would have been tough for Halstead to consider more limited resections in this time.3)The intermediate view of breast CA is that in at least some pts c breast CA (5-10%), the DZ is orderly and spreads distally only some time after clinical detectability. What Model of Breast CA is correct?*The ideal trial to evaluate these models would be to randomize pts c early breast CA into effective local Tx vs no local Tx or systemic Tx s the possibility of "salvage". Such trial has never been done and would be viewed as unethical. However, some trials have given us some valuable information re: breast CA behavior.

EPIDEMIOLOGY*#1 CA of Women but # 2 killer of Fs p Lung CA.*135K out of 435K new CA cases are breast CA vs only 52K new lung CAs. However, more Fs die from lung CA than breast CA.

RISK FACTORS*About 70%-90% of Fs have no identifiable risk factors.*Those who do have risk factors should be F/U more closely.

Major Risk Factors*Age: Mean age=60 y/o. It is the #1 breast mass p 50 y/o.*For Fs < 35 y/o:Fibrocystic Cgs, FibroAdenoma, Mastitis, CA*For Fs 35-50: Fibrocystic Cgs, CA, FibroAdenoma, Mastitis*For Fs > 50: CA, Fibrocystic Cgs, Traumatic Fat Necrosis, Mastitis.*Race: Whites > Blacks*Sex: Fs (99%) >> Ms (1%).*PMHx: A Hx of Breast CA on one side ^ risk x 4x to c/l breast. A Hx/o Endometrial (major risk), Ovarian, Colon + Thyroid CA also ^ risk for Breast CA (minor risk)*FHx: A FHx of 1st degree relatives ^ risk by 4x. If the 1st degree relative had b/l premenopausal breast CA, the risk to the pt=50% i.e. like an autosomal dominant pattern...consider b/l Mastex.*Some Fibrocystic Changes:*Not all fibrocystic Cgs are significant. Significant Cgs are:*Epithelial hyperplasia that is > 4 cells thick.*Pappilomatosis/papilloma c fibrovascular core ^ risk to 4x.*Atypical ductal/lobular hyperplasia

Minor Risk Factors*Early Menarche (< 12 y/o) - Late Menopause (> 50 y/o). *Nulliparity/Late First pregnancy (>30 y/o). However it is not clear if Fs who defer pregnancy until p 30 y/o are at ^ risk vs those Fs

who have difficulty in becoming pregnant. In contrast, an early 1st pregnancy or BSO are protective. *OCs: esp pure Eol OCs. OCs which contain Pone (like premarin) show no ^ risk. OCs also ^ risk/o endometrial CA + PE.*Obesity.*Diet.^ animal fat may play a role. Excessive EOH consumption is probably a risk factor.*Geography: Highest risk in N Europe/America. Lowest in developing countries.*Low - Dose Radiation (100 - 1000 rads before 35 y/o)

SYMPTOMS & SIGNS*See Table 18-3*Early Findings: *Mammographic abnormality. Mammograms will miss 15% of all CAs.*Palpable mass. In 90% of cases, the pt discovers the mass herself.*Later Findings:Skin or nipple retraction, fixed mass, palpable Ax nodes, inflammatory appearance.Peau d'orange=edema+/-erythema of the skin. *Nipple retraction can also be caused by duct ectasia->fibrosis. It is usually present for many yrs + is frequently b/l.*Paget's DZ=Intraductal CA of the large sinuses under the nipple. CA cells cross the epidermal -epithelial jxn + enter the epidermal layer of the nipple. Clinically, this lesion looks like a dry psoriatic nipple lesion.*The inflammatory changes are 2o to tumor obstruction of the dermal lymphatics.*Late Findings: Ulceration, Supraclavicular nodes, bone pain, arm edema, mets(->wt. loss).

EMBRYOLOGY*Breasts develop from thickened ectodermal tissue that lies on the milk streak-which courses from the pubis to the axillae->nipple bud (8 wks). The ductal system sprouts from the nipple bud down into the SQ fat.

HISTOLOGY*The breast is composed mainly of:Epithelium, stroma + fat. In pts < 30 y/o, epithelium + stroma predominates. In older pts, fat

replaces these tissues.*Cooper's Ligaments coalesce at the superficial layer of the superficial fascia. Because these ligs are anchored to the skin, a CA may cause dimpling from a distance.*The correct plane for MRM is the retromammary space-as first described by Gross.*The major ducts (cuboidal ep.)->lactiferous sinuses->15-20 orifices on the areola (squamous ep). Paget's DZ=Intraductal CA of the large sinuses under the nipple. CA cells cross the squamo-cuboidal (epidermal-epithelial) jxn + enter the epidermal layer of the nipple. Clinically, this lesion looks like a dry psoriatic nipple lesion. *The entire ductal system is surrounded by by specialized myoepithelial cells (which sit on the BM)->contract + propel milk to surface.

PHYSIOLOGY*In the late luteal phase, there is accumulation of fluid + intralobular edema ->breast engorgement +/- pain. On PE or mammogram you may have the development of a transient dominant mass. F/U this mass over a few cycles.*Menopause=cessation of menses x 6+m.

ANATOMY*The apex of the axilla=costoclavicular (Halstead's) ligament=clavipectoral fascia.Arteries(3)1) Axillary a.->lateral thoracic a.->lateral +central breast. See Fig.2) Internal thoracic a.->perforating branches->supply medial + central breast.3) Intercostal as (spaces 3-5)->supply the posterior breast.

Veins(3)1)The Axillary vein drains the lateral + central breast, chest wall + pecs.2)The internal mammary vs drain the central + medial breast->innominate v.3)Intercostal vs drain the posterior breast + drain into the vertebral vs posteriorly + azygous v centrally

Nerves(5)

1) Long Thoracic n:Innervates the serratus ant. m.->winged scapula.2) Thoracodorsal n:Is under the thoracodorsal v. Inervates the latissimus dorsi. May be sacrificed to remove tumor containing nds.3) Lateral pectoral n:Originates in the brachial plexus, crosses over the axillary v and then i)penetrates the belly of the pec minor (62%) or ii) travels under-then around the lateral borer then over the pec minor (38%) to supply the lower 1/3 + costabdominal insertions of the pec minor. It also sends some fibers into the axillary fat pad which are sectioned during axillary dissection into the clavipectoral fascia. Its main significance though is that it usually is dissected in a Patey MRM.4) Medial Pectoral n:Originates in the brachial plexus, crosses over the axillary v and branches into the pec major.Part of it penetrates the interpectoral space + supplies the clavicular + pectoral insertions of the pec major. This point is often damaged when the interpectoral fat is entered + excised while looking for Rotter's nds. Preservation of this nerve is mandatory in the Patey MRM because if it is dissected, then both of the nerves to the pec major will be lost.5) Intercostal brachial (brachial cutaneous) n:Is routinely lost c level I Ax dissex or higher. Its dissection causes cutaneous anesthesia of the medial arm + axillae and the postmastex pain syndrome (5%). A low lwvel I dissex avoids dissex near the Ax vein...avoiding ligation of this n. Let pts know of this ahead of time.

Lymph Nodes (4):*The pec minor is enclosed in the clavipectoral fascia-which fuses laterally c the axillary fascia. When one disects the Ax fascia, one finds the level I nds. In radical mastex, 50-100 nds may be retrieved. Fewer nds are received c MRM. The number of nds retrieved varies from pt to pt.

1) Axillary Nodal Group of Nodes:*Level I Nodes=Lateral to pec minor:

i)Ext. mammary (Pectoral) nds course laterally to the long thoracic n. ii) Axillary vein group of nds are anterior to the vein. iii) Scapular (subscapular)ns. travel c the thoracodorsal vessels.*Skip mets=mets to Rotter's nds or level II-III nds without involvement of level I nds. Skip mets occur in 13% of pts. In the Schwartz study, 13/17 pts had skip nds to level 2+3 nds, 2/17 had skip mets to level 3 nds only (1.1%), 2/17 had skip mets to Rotter's nds only (1.1%). Rosen found that the presence of skip mets is not related to size, location of breast mass, or histology of tumor.*Level II Nodes=Central Ax group.Are under the Pec minor and are the earliest major site of lymph drainage...this is the nodal group most often palpated, and the group in which clinical estimation of DZ is based.*Level III Nodes=Apical (Subclavicular) nds. Are medial + under the pec minor-between the pec minor + Halstead's lig. Virtually the entire breast lymphatic drainage rains into the apical nds including: i)External mammary nds (Level I) ii) Internal mammary nds iii)Rotter's nds iv)direct drainage of the lateral breast via the retropectoral pathway.

*The DBCG (Danish Breast Cancer Co-op Group) estimated the false negative rate 3128 node negative pts c MRM and a low Ax. dissex. The study showed that the risk of i/l recurrence is less likely with higher numbers of negative Ax nds taken initially (fig. 2). The differences in the life-table curves are all statisticallly significant (p=.0001). However, since the median number of Ax nds removed in this study was 4, it can be seen why a substantial number of pts willl be underdiagnosed as having -Ax. nds. Thus, it would be nice to have at least 5 Ax nds so as to say that the risk/o i/l reccurence is < 5%.

2) Rotter's Nodes=Interpectoral nds=Between pec minor + major. In pts c + Ax nds about 7 -19% will have + Rotter's nds (Cody study vs Durkin study). In pts c - Ax nds, only .3-7% will have + Rotter's nds (Cody study vs Durkin study). See Table 8. The questions re: Rotter's nds are:a) What does + Rotter's nds mean?

*If you believe in the Hallstead model, then + Rotter's nds, in the abscence of distant mets, means potentially curable DZ...RM is needed.

*If you believe in the Fischer model, + Rotter's nds is asign of systemic DZ...adjuvant Tx is TxOC.

b) Are pts c + Rotter's nds but - Ax nds at risk for systemic DZ? Nobody realy knows. Limited data c small numbers of pts show that pts c isolated Rotter's nds are not at ^ risk of systemic DZ. More specifically: *Haagensen has reported 3 pts who were Ax Node -/Rotter's nds + who were DZ free p 10 yrs vs 14% mortality if Ax nds were +. *Kay reported that all 4 of his Rotter's +/Ax - pts are alive p 5 yrs.

c) Is a meticulous search for Rotter's nds justified? This is controversial. i)Cody, despite his own study results, re: routine dissex of Rotter's nds during MRM. This is esp. true for Ax nd + pts. He says that dissex for Rotter's nds is easy and takes little time. Furthermore, with MRM being used over RM for stage 2 -3 DZ, Rotter's nd dissex is especially important. The potential benefits of this dissection in pts are: *Prevention of local recurrence if Rotter's nds are + in Ax + pts (7-20% of pts). *Pathologic upgrading of the CA if Rotter's nds are + but Ax nds are - (in .3-7% of pts) *In both these cases, these pts you would be converted from a MRM to a RM (7-30%). ii)My idea is to sample Rotter's nds if they seem grossly involved, but not go out of your way to meticulous dissect for them. If Rotter's nds are grossly palpable during a MRM, it would be advised to convert it to a RM. Data from the Haagensen and Rosen studies may be used to support this approach:*Haagensen reported that 66% of his Rotter's nds were < 1mm in diameter. Furthermore, Rosen showed that the prognosis of pts with micromets (CA < 2mm in diameter) is comparable to that of pts with negative nds. 3)Internal Mammary nds. Are N3 nds...stage 3b DZ. Mammary nds are positive in 20%-50% (Urban study) of pts c operable breast CA. Urban states that 5% of his pts had +mammary nds and -Ax nds. The Meir and Lacour studies showed improved survival with XRM in pts c central-medial breast CAs but a v survival when XRM was done for lateral CAs. Interestingly, in the Meir series, 23% of central-medial lesions had + mammary nds vs 19% for lateral nds (no statistical difference). Perhaps the longer distance and a different route (intercostal lymphatics) of lateral CA drainage explains wh there is no benefit of XRT in lateral lesions.

4) Supraclavicular nds. Are M1 nds...stage 4 DZ.

*Lymphatic Drainage:a)The medial + central breast lymphatics follow the drainage of the internal thoracic (mammary) bvs + empty into the internal mammary nds->Apical nds (Level III nds)->Supraclavicular nds. The supraclavicular nds are the terminal ends of the internal mammary/apical nds. The presence of supraclavicular nds (Stage IV DZ) is a sign of lymphatic permeation + obstruxn of the inferior deep cervical nds (near the IJ-SCV junxn).b)Lateral drainage of the lateral breast is via 2 routes: i)transpectoral route: Rotter's nds->follow the thoracoacromial a->subclavicular (apical) nds=Levl III nds ii)retropectoral route:lateral breast drains directly to the subclavicular nds.c)Central + subareolar tissue drains both i)medially to the internal mammary nds-> subclavicular nds and ii)laterally to the apical nds. directly. *However, its not as simple as this.In the Meir series, 23% of central -medial lesions had + mammary nds vs 19% for lateral nds (no statistical difference). This implies that all parts of the breast can drain everywhere.

Types of Axillary Dissection*Sampling=Removal of an axillary node(s) from the lower axilla without taking precise anatomic boundaries.*Low Axillary Dissex=en bloc excision of level I nds, including clearing of the axillary v.*Low Level I Dissex=As above, but the superior dissection does not include the axillary v. Insted, it stops below the intercostal brachial n.Thus there is no risk of postmastex pain syndrome (6%) from dividing this n. and no risk of lymphedema since the axillary v was not dissected. This is usually done in pts c DCIS c microinvasion or with "can not r/o" invasion.*Level I and II Dissex=Done by i) relaxation of the i/l arm to relax the pec major and ii) excision of level II nds.*Full axillary Dissex (Levels 1-3)=Removal of the entire axillary contents, from latissimus dorsi to Hallstead's lig.The pec minor may be taken or preserved.a)What type of Axillary disection should be performed?*The re: from the Sloan-Kettering concensus conference is that: *A level I+II Ax dissex is needed for pts c clinically - Ax. nds. *A full (level I-III) Ax dissex is needed for pts c suspicious or clinically + Ax. nds.

b) What is the rationalle for performing an Ax Dissex?i)Ax Dissection gives us information about recurrence. The DBCG study also showed how the number of Ax nds removed is predictive of local recurrence. Thus the Ax nds are going to be either negative or positive. If you have recovered at least 5 nds, and they're all -, then you may tell the pt. that her risk/o local recurrence is <5%. If some of these Ax nds are +, then you may estimate her risk of i/l recurrence (fig. 2) as well as her survival (table 9 -9). In contrast, if the nodal status is not known, up t o 20% of these pts will have i/l recurrence. ii)Prognostic information: The number of nds positive is the most important prognosticator of survival. iii)It may be more curative. Recall the studies that support the Hallstedian view of breast CA.iv)Adjuvant Tx:In the Fisher view, all node + pts need systemic ChemoTx.v)RT:It would better guide RT for 2 reasons: i)A clip is placed on the medial margin of the ax. dissex. The radiologist uses this clip as a guide to give RT medial to the clip. RT lateral to the clip is given c extensive ax DZ (8+ positive Ax nds, gross ax. involvement, extention of the CA past the capsule of the nds). ii)The pt may not need RT if the nds are negative?

c)Why perform a level I - II Ax dissex or higher? *Skip mets occur in 13% of pts. Level 2 Ax nds are the site of skip mets in 10 -13% of cases; 1% of skip mets occur to level 3 nds; another .3-7% skip to Rotter's nds and 5% skip to mammary nds. However, taking only level 1-2 nds has been criticized by some as being too conservative because: *The Schwartz study did not address the issue of micromets. Ordinarily, a pathologist will section a nd in 1 -2 places. Step-sectioning of nds, to determine micromets, is usually not done. However, about 20% of pts c micromets to level 1 nds will have micromets to level 3 nds. A level 1-2 dissection would leave this DZ behind. *There is no evience that dissecting out 2-3 more cm to get to level 3 nds is @ c more risk of arm edema.

OFFICE W/U OF COMON BREAST PATHOLOGY

*Obtain H&P1) FOR MAMMOGRAPHIC ABNORMALITIES: A Kopans' spring hookwire is used for needle LOC->then the pt goes to the OR. If no firm mass is present, the specimen is sent to radiology for confirmation. If a mass is felt, it is sent to pathology. For ER-PR Rs you need 1 cm (100 mg) of tissue. If there is only 1 cm of tissue, then the entire specimen is sent for permanent section because making a tissue Dx is more important than getting ER Rs. Also, while fresh tissue is more accurate than permanent section for obtaining ER-PR status, permanent sections may also be used.

MAMMOGRAM*Currently, 2 types of mammography are being used: *Film/screen mammography=On standard X-ray film *Xeromammography-On paper c blue background.*Studies show that both techniques have similar sensetivity, specificity + radiation exposure.*The Duke Study shows which mammographic lesions are most likely to be CAs (see table 2): i)Stellate masses > ii)Architectural deformities iii)Calcifications (scattered>number=10+)Who should get a mammogram? *Any pt c a palpable mass >/= 30 y/o should get one. In a pt < 30 y/o a mammogram is rarely used -even in the presence of a palpable mass. In these pts, do a needle LOC. *Get a baseline screening mammogram between 35-40 y/o then PE+mammo Q 1-2 yrs, then PE+mammo Q 1 yr for pts>50 y/o.These recommendations only apply to asymptomatic pts. Pts c active DZ are individualized.*How effective is screening mammography in improving survival?*Overall there is a 23% reduction in 5 yr mortality in the screened population + a 50% reduction in pts > 50 y/o.The above results are in part based on:*The Health Insurance Plan (HIP) study of NY which randomized 62K Fs (1963-1982) to mammogram + PE x 4 yrs. *The Breast Cancer Detection Demonstration Project (BCDDP) f/u 280K Fs x 5 yrs. It detected 4,240 CAs. Those c early detection (i.e. mammographic abnormality s a palpable mass) had fewer + nds (16% vs 37%) and a better 5 yr survival (85% vs 61%) than pts who presented c a palpable mass.

2) FOR A PALPABLE MASS: *Get a mammogram for all pts>/= 30 y/o before FNA. This is so that potential hemorhage into an aspirated cyst does not obscure tha mammogram. Then follow the algorithm here.

FINE NEEDLE ASPIRATION (FNA):*Because FNA may give occasional rare false cytologic findings, most authorities in the USA would NOT re: definitive Tx based solely on FNA. On the other hand, Fisher says that if tumor is detected by either cytology or core Bx, definitive Tx (lumpex vs MRM) can be planned s the need foropen Bx. In either case, at very least a FNA is used to triage a breast lump. Thus a pt c a nonbloody FNA c complete resolution of the mass is f/u p 8 wks. In contrast a +FNA allows you to explore all the surgical options c the pt. *Use a #21 needle to aspirate the mass. The specimen is submitted in either buffered saline (Normosol) or fixed on a slide c 95% EOH. The posibilities are:

1) A clear or green - tinge fluid is w/drawn c complete disappearance of the mass. This probably represents a simple cyst. Discard the fluid + see the pt p 2 m to make sure the mass does not recurr.2) Bloody fluid suggests a pappilloma. Send off to cytology.Plan for excisional Bx regardless.3) Solid mass. Plan for OR regardless. Possibilities are: *The mass feels scirrhous:CA, Radial scar, Fat necrosis, sclerosing adenosis can all produce a hard mass, skin dimpling and microcalcifications. *The mass feels rubbery...fibroadenoma is likely.Aspirate in several places, smear on slide & send off to cytology.*TRU - CUT (CORE) BX may be done on larger (>2 cm) superficial masses that may be fixed between the fingers. The specimen is sent for ER -PR Rs. INDICATIONS FOR EXCISIONAL Bx/Lumpex:1)*FNA fails to resolve the mass completely. *The mass reappears in the same area p 3 FNAs. *The mass accumulates fluid rapidly (w/in 2 wks) of the 1st FNA.2) FNA produces thick, clear or blood tinged fluid.3) All solid masses of the breast c - or equivocal FNAs should get a Tru-Cut or excisional Bx. 4) All nipple D/Cs from a single duct.*The timing of this Bx/lumpex may be in 1-2 wks in an elderly pt c a suspicious mass to 3-6 m in a college student c a non-suspicious mass.*Fischer believes that a 2 step procedure, c an open Bx as the first step, often results in a disturbed tumor edge (by hematoma + inflammation) thus making lumpex technically more difficult-esp. when LA is used over GA. This is why Fischer re: the 1 step approach whenever possible. Thus if the FNA or core Bx are + then the pt is instructed on MRM vs lumpex. If the FNA is inconclusive, then Fisher discusses lumpex vs MRM prior to surgery. If the potential for CA is high, Fisher then places the pt under GA + performs a lumpex. If the frozen is + for CA, he completes the Ax dissex in one step. This avoids the risks and costs of 2 anesthesias and avoids the higher risk/o wound infection + seromas @ c 2 -step procedures.

3)FOR NIPPLE D/C*Nipple D/C is the second most common breast symptom that requires surgery. It occurs in 4-8% of surgical breast pts. D/C

Typically occurs in younger (35 y/o) pts and is usually a sign of benign breast DZ. See Table 1. *However, some forms of nipple D/C are @ c CA. To properly workup a D/C you must know:A) IS THE D/C TRUE + SIGNIFICANT? True D/Cs come from one or more duct/s) and are spontaneous. False D/Cs can occur in pts c inverted nipples, eczemoid lesions, traumatic erosions (jogger's nipples), HSV infections, mammmary duct fistulas, etc. Also, grey,cloudy or milky D/Cs that are elicited p firm pressure on the nipple are not significant esp. in pts taking OCs/tranquilizers, who are perimenopausal or s/p BSO. However, Pagets' DZ may mimick nipple psoriasis...do a punch Bx at the squamo -cuboidal jxn. in suspicious cases.

B) IS THE D/C SURGICALLY SIGNIFICANT?*Significant D/Cs that usually DO NOT require surgery include:1) Purulent D/C, usually from multiple ducts of a single nipple. Is @ c pain, tenderness, erythema. Is usually caused by SA complicating a mastitis or abscess. TxOC=GmStain, c/s + PO ABs. If an abscess occurs, TxOC=I+D c aerobic/anaerobic c/s, AFB, fungall c/s + Bx of the abscess wall to r/o an underlying CA.

2) Milky D/C is usually b/l + comes from multiple ducts(Galactorrhea) but may be unilateral in galactocele (a post -partum, milk filled cyst).*In equivocal cases, verify that the D/C is milk by sending it for TLC to test for lactose. i) For Galactorrhea, get a serum [Prolactin]. Normoprolactinemic galactorhea is usually benign i.e. usually @ c meds (see table). Hyperprolactinemic galactorrhea +/or amenorhea needs further w/u because it is the most common presentation of prolactinoma in females. See my algorhytm. If [Prolactin] is ^ do a CT of head to check the status of the sella turcica.Pituitary adenomas need OR, pituitary hyperplasia->^[Prolactin] may be Tx c Bromocriptine (Parlodel).See my algorhytm.ii) For a Galactocele (=a well circumscribed, easily movable milk filled cyst which usually occurs post-partum or up to 6-10 m p stopping breast feeding). DxOC=Gm stain, c/s are - but Lactose TLC is +. Surgery is needed if it becomes superinfected. TxOC=Aspiration of the creamy fluid

3) Multicolored (green>yellow,white,grey,brown,red) or sticky D/C is usually b/l + from multiple ducts. It is seen c fibrocystic Cgs and no further w/u is usually needed. However, in equivocal cases you may send the fluid for:*Cultures are - for pathologic bacteria. Green D/C may be mistaken for pus.*Guiac/Wright stain are - for blood. Red D/C may be mistaken for blood.*TLC is - for lactose.Milk may appear as gray,cloudy or white D/C.*Cytology shows an acellular materilal c some desquamated cells.It is caused by duct ectasia or comedomastitis + is usually seen in younger pts (40 y/o). TxOC=nipple hygiene c hexaclorophene (pHisoHex) or Betadine and abstinance from ANY nipple manipulation. Eol may help postmenopausal pts.

4)D/C from multiple ducts: If the D/C is from multiple ducts, is not milky + is not @ c a mass, it can be confidently Dx as breast nodularity or duct ectasia. The D/C may be grey,brown,black or bloody. Different ducts may D/C a different color. TxOC=reassurance that nothing need be done. Bacteriologic, cytologic or mammographic investigations are unnecessary and may ^ the anxiety from BFP results.The D/C will subside spontaneously, however in 50% of pts it may persist or recurr over many years.

*Breast Nodularity (Fibrocystic Cgs).In 187/249 pts (75%) the condition most often @ c nipple D/C was benign breast nodularity seen with ovarian cycles. This condition may be @ c pain, edema, segmental, diffuse or b/l lumpiness. Most pts c breast nodularity + D/C have D/C from multiple ducts of one or both nipples (112/187=60%).In 60/187 of these pts (32%) the D/C was from a single duct of one nipple. In 8% no D/C could be elicited by the examiner. The median age for this group is 35 y/o. About 80% of pts were younger than 50 y/o, 20% of pts were 50 y/o+.

*Duct Ectasia. In the post-menopausal pts, the most frequent benign breast condition @ c nipple D/C is duct ectasia=multiple dilated ducts filled c grey fluid.*Comedomastitis:Called duct ectasia by some investigators,it is @ c a transverse nipple cleft.The D/C comes from the cleft or fistula rather than the ducts + is often sticky + foul smelling.

*Significant D/Cs that DO require surgery include:1) All D/Cs @ with a lump . *CAs: Only 2% of breast CAs produce D/C and only 4%-9% of breast D/Cs are malignant. In this series CA was seen in 10/249 pts c nipple D/C (4%). Thus CAs rarely present as D/Cs and nipple D/Cs are rarely malignant. Malignant breast CAs are usually @ c a palpable mass (80%) in older (50+ y/o) pts. In the rare instance that nipple D/C is @ c non-palpable CA, the CA will be of a low grade (DCIS,LCIS,papillary CA). In summary, the likelihood of a D/C being cancerous increases with: *Age> 50 y/o (mean age=56) *Presence of a lump (in 80% of nipple D/Cs @ c CA) *U/L or single duct D/C *+ Cytology, + mammogram or + galactogram *Type of D/C:serous(yellow)-serosanguinous (pink)-sanguinous(bloody) ->clear (watery). *Leis reports a high incidence of CA c serosanguinous/sanguinous + clear D/Cs (see graph). However 78% of pts c CA in the Leis study had palpable mass-only 12% (8/67) had no palpable mass. What is the NL Hx of single duct D/Cs s a palpable mass? A low incidence of low grade CAs (see below).

2) D/Cs coming from a single duct.If the D/C is from a single duct, it is most likely an intraductal papilloma. Papillomas are a benign codition. Nevertheless single duct D/Cs (i.e. probable papillomas) should be explored. Why? 1) Chaudry explored 292 pts c single duct D/C who had no palpable mass and found 8 infiltrating CAs (3%) + 8 in situ lesions (3%)...there is a small @ between single duct D/Cs and CA.2)Multiple (peripheral) papillomas are seen in 14% of pts and are @ c ^ risk/o CA. However, they are usually @ c a mass and only rarely have a D/C (See below).3)Mammography yields BFNs(10%) and BFPs (1.4%). Galactography (contrast mammography) was "better".4)Cytology yields BFPs (16%) and BFNs (2%)

*(Intra)ductal papilloma: Mean age=57 y/o (32-97 y/o). Papillomas are virtually never palpable. All pts (19/19) in Leis series had D/C from a single duct. The D/C was serous (9/19), blody-black (6/19) or serosanguinous (4/19). See below for more details.

3) Pts c significant or persistent D/C (not @ c a mass or bloody or watery D/C) may be explored-NOT because CA is a significant possibility, but to try to rid the pt of the D/C. The options for exploration are:i)Insert a (lacrimal) probe/blunt needle into the duct + incise it to locate the papilloma. Leis (MUSC) does not recommend this because this technique can create false passages. Also, at least 14% of papillomas are multiple and involve different ducts. Complete duct excision insures the removal of all potential pathology.

ii)Complete duct excision. If the pt is <30 y/o, or in those pts anxious to breast feed their kids, only the involved duct + surrounding tissue is excised. Otherwise, complete excision of the central ducts is done (see fig).

Technique of Central Duct Excision:*Collodion is applied on the nipple surface x 1 wk before surgery so that the involved duct(s) become more distended. The pt is advised to not squeeze the nipple pre-op.*A circumareolar incision is made (A). This incision is never carried more than 50% around the areola so that the blood suply is not compromised. The central portion of the incision is located above the mass or mammographic abnormality-if one is present.*After the ducts are dissected out, they are tied proximally to prevent fluid from being expressed -which would make duct isolation more difficult (c).*The proximal ducts are transected flush c the skin to insure their complete removal (d).*The incision is carried deep into the parenchyma to include distal dilated ducts, masses or other suspicious tissue.*Unless CA is obvious, it is better to rely on permanent paraffin sections rather than frozen section. This is because it may be hard to differentiate a premalignant lesion like intraductal papillary hyperplasia c atypia from an in situ CA like intraductal papillary lesion.*Avoid deep closures to get a better cosmetic result.*Avoid dressing the nipple itself by using a dressing c a hole in its center.

BRIEF WHO CLASSIFICATION OF BREAST NEOPLASMS (% OF ALL CAs)*Notice how 90% of Breast CAs are Infiltrative Ductal CAs (or variants of infiltrative intraductal). The other 10% of CAs are lobular (either LCIS or Invasive Lobular CA).Benign Breast Masses Include:*Fibrocystic Changes*Fibroadenoma*Mastitis*Scar*Fat Necrosis*Abscess*Galact0ocele*Duct ectasia/Comedomastitis*Papilloma*Lactating/Tubular AdenomasI. EPITHELIAL TUMORSA. Benign *Intraductal Pappilloma*Tubular + Lactating Adenomas*Adenoma of the Nipple

B. Malignant1.In Situ (Noninvasive) CAs Have a 25%(DCIS)-40% (LCIS) rate of bilaterality!a) DCIS (Intraductal Carcinoma in situ)...........................................2% b) LCIS (Lobular Carcinoma in situ)................................................2%

2. Invasive CAsa) Invasive (infiltrative) Ductal CA .................................................75%*In generall, the below variants, reflecting their more differentiated phenotype, have a better prognosis than ductal CA NTS. Medullary CA is an exception to this rule. The variants *Medullary CA ..................................................................7%*Mucinous(Colloid) CA ....................................................3%*Tubular CA ......................................................................1%*Pappilary CA....................................................................1%*Juvenile (Secretory)........................................................<1%*Adenoid Cstic CA...........................................................<1%*CA c metaplasia (Squamous, spindle cell, osseous, cartilagenous)

*Inflammatory Carcinoma

b) Paget's DZ=Infiltrating intraductal CA of the Nipple...................1%

c) Invasive Lobular CA......................................................................7%

II. MIXED CT + EPITHELIAL TUMORS*FibraAdenoma*Phyllodes Tumor (Cystosarcoma Phyllodes)*Carcinosarcoma

III. MISCELLANEOUS TUMORS*Soft Tissue Tumors*Skin Tumors*Hematopoeitic Tumors

IV. UNCLASSIFIED TUMORS

V FIBROCYSTIC DZ/MAMMARY DISPLASIA

VI. TUMOR LIKE LESIONS

*Gynecomastia*Galactocele*Inflamatory Pseudotumor*Duct Ectasia.*Hamartoma*Others:Abscent Breast Tissue,Accessory Breast Tissue.

VII BILATERAL BREAST CANCER

VIII NATURAL HISTORY OF BREST CANCER

EXPANDED WHO CLASSIFICATION OF BREAST NEOPLASMS*Notice how 90% of Breast CAs are Infiltrative Ductal CAs (or variants of infiltrative intraductal). The other 10% of CAs are lobular (either LCIS or Invasive Lobular CA).

I. EPITHELIAL TUMORSA. Benign *Intraductal Pappilloma.Mean age=57 y/o (32-97 y/o).*Solitary Intraductal papillomas are benign true polyps of ducts. They are macroscopic .3-.5cm cm masses under the areola that frequently present as a bloody D/C (80% of cases) from a single duct. Rarely they may be palpable and be as large as 4 cm. All pts (19/19) in Leis series had D/C from a single duct. The D/C was serous (9/19), blody-black (6/19) or serosanguinous (4/19). If the D/C is yellow, serous, black or bloody it makes papilloma most likely.If the D/C is gray, green or thick, it is likely to be breast nodularity and some MDs would not even explore these. Explore suspicious D/Cs because:1) Single duct D/Cs have a low @ c low grade CAs. Chaudry explored 292 pts c single duct D/C who had no palpable mass and found 8 infiltrating CAs (3%) + 8 in situ lesions (3%)...there is a small @ between single duct D/Cs and CA.2)Multiple (peripheral) papillomas are seen in 14% of pts and are @ c ^ risk/o CA. However, they are usually @ c a mass and only rarely have a D/C (See below).3)Mammography yields BFNs(10%) and BFPs (1.4%). Galactography (contrast mammography) was "better".4)Cytology yields BFPs (16%) and BFNs (2%)

Multiple (peripheral) Intraductal Papillomas. Account for 14% of all papillomas.*Unlike the solitary papillomas, multiple papillomas usually present as a mass, rarely as a nipple D/C. They are usually NOT subareolar but peripheral and often b/l. They are @ c multiple recurrences (23% p 20 yrs) and a slight ^ risk/o CA (12%/20 yrs).

TxOC=total>>limited duct excision:Tx1)Complete duct excision is TxOC.Tx2)Single Duct Excision:If the pt is <30 y/o, or in those pts anxious to breast feed their kids, only the involved duct + surrounding tissue is excised. Some authors re: that you insert a (lacrimal) probe/blunt needle into the duct + incise it to locate the papilloma. Leis (MUSC) does not recommend this because this technique can create false passages. Also, at least 14% of papillomas are multiple and involve different ducts. Complete duct excision insures the removal of all potential pathology.

*Papillomatosis vs Papillomas vs Papillary (Cribiform) DCIS. Papillomatosis (epitheliosis) is an epithelial hyperplasia which is @ with a mild ^ in CA esp in pts c atypia. Central pappilomas are benign neoplasms, peripheral papillomas are @ c some ^ risk/o breast CA. Papillary DCIS is a pre-malignant condition.*Juvenile Papillomatosis. Mean age=23. Present c a mass. Atypia is seen in 74%. These pta are at higher risk (4%) of breast CA. They have a strong FHx of breast CA (4%) which presents early (mean=-27 y/o)

*Lactating + Tubular Adenomas*Lactating Adenomas=Mobile breast masses during pregnancy/lactation which look like fibroadenomas. Unlike fibroadenomas, the have minimal stromal tisue.*Tubular Adenomas=are just like lactating adenomas only they occur in young nonpregnant pts.

*Adenoma of the Nipple

B. Malignant1.In Situ (Noninvasive) CAs Have a 25%(DCIS)-40% (LCIS) rate of bilaterality!a) DCIS (Intraductal Carcinoma in situ)...................................2%*Is a heterogeneous group of DZs with a broad spectrum of i)histologies, ii)presentations, iii)Tx.

DCIS Histology*In DCIS the ducts become filled c malignant epithelium. In the solid (comedo) form, the ducts expand to palpable size. The central detritus may undergo dystrophic calcification that may be seen on mammogram. Thus DCIS, like invasive ductal CA, classically presents as a palpable mass +/- suspicious (i.e. clustered) calcifications but has a much more favorable prognosis than invasive CA. While LCIS may represent a marker to CA rather than an in situ lesion (which is why some authoriries re: calling LCIS "lobular neoplasia" instead), DCIS is still seen as an in situ CA. However, there is evidence that even in the case of DCIS, it may not be the in situ form of invasive CA. The evidence for this includes: i)Preservation of the basement membrane, the sine

qua non of DCIS, is only confirmed in 10-20% of specimens that are called DCIS. Even lesions that ma be designated as DCID by LM, often turn out to have microinvasion by EM. ii)DCIS, as contrasted c invasive CA,is more often @ c proliferative fibrocystic changes (64% vs 35%); and a germinal-center-predominance pattern (30% vs 12%) but less @ c stromal elastosis (50% vs 90%). These differences suggest two different DZs.*Classically DCIS is sub-classified under various histologies:*Comedo type of DCIS. The most common, and most virulent DCIS.*Papillary (cribiform) type of DCIS. Less likely to form palpable masses or mammographic calcifications.*Micropapillary*Solid*However, DCIS has various heterogeneous histologies:*At one end of the spectrum it may be hard to distinguish DCIS c highly atypical hyperplasia. At the other extreme it may be hard to distinguish DCIS c invasive CA. Because of the latter difficulty, about 2% of pts Dx c DCIS have + Ax nodes. *DCIS may extend into lobules and LCIS may extend into ducts. This sometimes makes the differentiation between these two CAs difficult.*Thus DCIS is best described by its extent(i.e. size), invasiveness, multicentricity, multifocality + involvement of margins. Get a complete description from the pathologist.Presentation of DCIS*Historically, i.e. before the widespread use of mammography, DCIS presented as palpable tumors or as nipple D/C +/ - a palpable mass. Here, DCIS occured in only 1-5% of all CAs. These pts were Tx c mastex c near 100% cure. Due to the universal application of mastex, the natural Hx of DCIS was never fully known. With the advent of mammographic screening, DCIS is now seen in up to 20% of screened pts, usually presenting as a microcalcifications on screening mammograms or incidently p Bx for another mamographic abnormality (e.g. fibroadenoma). TxOC For DCISTx1) Mastex c Level 1 or higher Ax Dissex (MRM) has been the standard Tx for DCIS in the past and is @ with a cure rate of nearly 100%. At the moment, it is still the TxOC. MRM is best indicated for pts c large lesions (>4cm), incomplete margins, multifocal DZ, multicentric DZ.

Q1) What constitutes extensive DZ - i.e DZ requiring MRM? Nobody knows for sure, but I am sayin DCIS>5cm is extensive because, as can be seen by the study of Lagios (Table 8), the incidence of multicentricity + invasivenes=Fxn of the size of the main tumor. Thus in pts c lesions > 4 cm 100% had multicentric DZ + 70% had occult invasion.

*Q2) Do pts c DCIS need an Ax dissex?Yes for 2 reasons: i)Because local excision may be inadequate to fully exclude occult invasive CA. In those who do have occult invasive CA, some will be picked up c + nds. In either case, the presence of + nds (seen in 2% of pts c DCIS) indicates the need for chemoTx. ii) The absolute Dx of DCIS can not be assured c frozen section.

Because of the controversy surounding Q1 and Q2, less aggressive alternatives to MRM may be appropriate:Tx2) Mastex c low level I Ax dissex (to avoid ligating the intercostal brachial n).Tx3) Total mastex alone s Ax Dissex. Probably not a good option.Tx4) Lumpex + RT. Q3) Can we ID a subset of pts c DCIS who might benefit from lesser surgery i.e. lumpex + RT? There are no solid answers here. However as can be seen by the study of Lagios (Table 8), the incidence of multicentricity + invasivenes=Fxn of the size of the main tumor. Thus in pts c lesions < 2 cm, none had invasive DZ or multicentricity. Thes pts may benefit from conservative Tx. Furthermore, although DCIS may be a different DZ than invasive CA, there is no evidence that it is more malignant...if lumpex + RT is effective for invasive DZ, it is probably OK for DCIS.

Q4) Is there any data that supports conservative data. There are no conclusive studies out on this yet. However, in the NSABP B06 trial 78 of their 2072 pts had DCIS.Of these 71 pts, 5/22 (23%) of those Tx c lumpex alone had recurrence vs only 2/29 (7%) recurrence in the lumpex + RT group. Tx failure was=4% in the RT+lumpex group vs 2% in the MRM group (no statistical difference). However, this study had a short f/u (39 m). For this reason, an NASBP (B -17) trial currently underway is designed to answer this question. In the meantime, the Joint Center for Radiation Therapy (JCRT) has published guidelines for conservative Tx for DCIS (see Table 11-4).

Tx5) Lumpex alone is reserved for small lesions (<2 cm).*Although precise data is lacking, it is likely that the risk/o local recurrence will be higher c lumpex than c mastex. The NASBP B-06 trial showed 23% recurrence p 39 m in their lumpex arm + 7% recurrence in their lumpex + RT arm. Furthermore, 40% of recurrences (i.e. 10%) were early invasive CAs. Page + Rosen showed that 30% of pts c DCIS develop imvasive CA p 6-10 yrs. In nearly all these pts, the invasive CA occured at or near the original Bx site.

Q4)What is the risk of bilaterality c DCIS? Not known.*Risk/o bilaterality=4-25%?? Data on simultaneous +/or sequential bilateral DCIS are not in. Alpers found DCIS in 48% of breasts c/l to the site of CA, yet the cumulative risk/o breast CA in the c/l breast=12% p 20 yrs. Webber reported a 4% risk of

c/l invasive CA in pts c DCIS p 9 yrs. The bottom line is that most recurrent DCIS will develop near the original Bx site, but the pt is an ^ risk/o 4% for invasive CA in the c/l breast...f/u both breasts in these pts c annual PEs + mammograms.

Definition of Terms:*Multicentricity=Multiple quadrants of the same breast.About 33% of DCIS are multicentric.*Multifocality=multiple local areas of involvement. Lesions that are multifocal, are much more likely to be multicentric.

*LCIS (Lobular Carcinoma in situ).........................................2%Epidemiology:*Age:43 yo W=B/F. *About 80-90% of pts are premenopausal. This suggests that LCIS regresses p menopause. However the risk of invasive CA does NOT regress p menopause.

Symptoms/Signs*Unlike DCIS, LCIS never forms a palpable mass + does NOT have a typical mammographic abnormality. Thus, LCIS is typically found p Bx of some other lesion. For these reasond the true incidence of LCIS is not known -varying from 2-4% in autopsy studies to 10-66% in mastex series.

Risk/o CA*Pts c LCIS have 7-12x higher risk of developing CA than controls. About 20-40% of pts c LCIS will develop invasive CA p 24 yrs. About 50% of these CAs will be in the c/l breast. The risk/o bilaterality is 30%. *About 75% of the invasive CAs are ductal and 25% are lobular. The high incidence of ductal CA in pts c LCIS suggests that LCIS is a marker for subsequent CA rather than a premalignant lesion perse. On the other hand, pts c LCIS have a higher incidence of lobular CA, thus the LCIS in this subgroup may represent in situ CA.

TxOC for LCIS*Pts c LCIS have a 7-12x higher incidence of invasive CA. Different authors have different views re: how this higher incidence should be managed:Tx1)Close f/u: PE Q 4 m + mammogram Q yr). This is the TxOC in most centers. The rationalle for this Tx is: *In the Haagensen series, conservative Tx for LCIS was @ c a death in 4% mortality and mets in 28%. These figures were similar to their results for stage I DZ in the general population. Thus, they conclude that conservative Tx is indicated.*Similar risk ratios exist in pts whose mothers had b/l breast CA-and mastectomy is not usually re: for these pts either.

Tx2) Close F/U + Tamoxifen 10 mg PO BID as part of a protocol.

Tx3) B/L mastex may be reasonable option for selected pts. Rosen et. al. re: b/l mastex in pts c a prominent FHx; breasts that are unsuitable for long f/u; extreme pt anxiety. The rationalle for this Tx is that b/l mastex is the only way of diminishing subsequent risk.

*If b/l mastex is chosen, remember that: *Ax. nodal dissex or removal of pecs is unnecessary *RT has no proven benefit. *B/L breast reconstruction may be offered concurrently.

Tx4) Total mastex + mirror Bx is still re: by Newman. The rationalle for this Tx is that: *About 24% of c/l mirror Bxs will be + for LCIS. These pts will need c/l mastex. *In the experience of Rosen et. al., pts c negative mirror Bx had no c/l breast CA develop p 15 yrs of f/u. A reason for why this may work is not clear. However, some authors' "mirror Bx" is really an UOQ quadrantex...the lack of c/l breast CA in the Rosen study may represent bias from a subtotal mastex.

2. INVASIVE CASHISTOLOGIC TYPES OF INTRADUCTAL INVASIVE CAs*Invasive (infiltrative) Ductal CA ......................................75%*Some autors add the term NOS (Not Otherwise Specified) or NST (No Special Type) to denote the fact that this does not have one of the more distinctive intraductal histologies noted below. *In generall, the below variants, reflecting their more differentiated phenotype, have a better prognosis than ductal CA NTS. Medullary CA is an exception to this rule. The variants *Medullary CA ...........................................................7%*Mucinous(Colloid) CA ..................................................3%*Tubular CA .............................................................1%*Pappilary CA............................................................1%*Juvenile (Secretory)*Adenoid Cstic CA*CA c metaplasia (Squamous, spindle cell, osseous, cartilagenous)

*Paget's DZ=Infiltrating intraductal CA of the Nipple.....................1%

*Invasive Lobular CA......................................................7%*Small round cells that infiltrate the stroma in "indian File fashion.*The risk/o B/L DZ=*TxOC is the same as Invasive intraductal CA.

MANAGEMENT OF BREAST CA:*W/U a mammographic abnormality, suspicious mass or nipple D/C as indicated previously.*TxOC is Based on the Stage (see below).*Ploidy,tumor factors affecting prognosis, ER-PR Rs, Oncogenes, Cathepsin-D, enzymes are all recorded when available. See the Future Trends section below.

TXOC FOR EARLY BREAST CA (STAGE I - II DZ) SURGERY *Currently, there is no place for segmental mastex or lumpex alone for the Tx of Breast CA. You need Ax dissex + RT too. *At a consensus conference at MD Anderson in 1985, there was an attempt made to define the various surgical procedures as follows:

Tx1) Lumpex (Tumorex)=removal of the gross tumor without attention to margins *Lumpex is not adequate Tx and is @ c a high local recurrence rate. However the NASBP B -06 trial showed no change in survival p 8 yrs.

Tx2) Wide Local Excision (limited resex, partial/segmental mastex) + Ax Dissex+RT is adequate Tx for local control. *Wide excision=excision of tumor c grossly NL margins. *Tylectomy, described in the Guy's Hospital trials=a wide excision c 3 cm margins.

Tx3)Quadrantex + Ax Dissection+RT. *Quadrantex=en block removal of tumor + pectoralis fascia. Most clinicians view a quadrentex to be too deforming.Technique:*If an excisional Bx c adequate margins has been obtained, only an Ax Dissex is needed.If an incomplete excisional Bx is obtained or a Core or Incisional Bx are + then the tumor needs to be completely excised and an Ax Dissex performed. What is adequate? Fisher defines adequate as "grossly clear of tumor". Herman says adequate =2-3 cm. ReMine says adequate =.5-1 cm.*A transverse eliptical incision is made around the mass and adequate margins are taken if possible. Fischer says that no special effort is made in removing pec. fascia. This Hallstedian concept does not apply here. However, if the CA is close to the fascia, you mmay take fascia too. Herman takes fascia routinely. In any case, the aim is to obtain grossly clear margins. Underlying skin is removed, not for better Tx, but to orient the pathologist. All borders are then labeled c ties.*A seperate, 4-6 cm transverse axillary incision is made 2-3 cm below the apex of the axilla at the border of the axillary hair line. Medially, the incision is carried to the edge of the pec major. Laterally it is taken to the latissimus dorsi. Flaps are made and the incision is taken down until the Ax v. + its branched are IDd. The nerves are IDd + the nds are removed as in a MRM.*An ellipticalmincision is made as shown. If the mass is in the UOQ, then it is extended into the axilla for disex. If the mass is anywhere else, then the axilary incision is seperate.*A JP drain is placed on the Ax dissex. No drain is needed for the lumpex.*A nurse instructs the pt on arm + shoulder excercises + drain management.*The radiation therapist visits the pt on POD#1. RT can be started p 7-10d.

*The pt goes home on POD #1-2.

Q1)What are the indications of conservative Tx? Idealy:*The tumor is small (< 4 cm)*Is in a favorable location (i.e. not subareolar)*Breast is large.

Q2)What are the contraindications against conservative Tx?*See Table 3

Q3)What are the results of conservative Tx?*The NASBP B-06 study randomized 1843 pts c tumors </= 4 cm to lumpex vs lumpex +RT vs MRM. All pts c +Ax Nds got 5FU+melphalan. All pts c lumpex but incomplete margins got MRM but were kept in their original group. Those c RT got 5000 rads over 5 wks. From table 2 one can see that:i) Lumpex alone showed greater regional recurrent DZ (Table 2) but no difference in overall survival, DFS or distant DFS (Table 4). ii)RT gave fewer local failures. iii)The rate of tumor recurrence in the i/l breast c lumpex p 5/8 yrs was 28%/40% vs lumpex +RT p 5/8 yrs=7.7%/10.4%. Table 2 does NOT consider recurrence of CA in the i/l p lumpex a Tx failure. It lumps these pts under "alive s evidence of DZ".

Note:Local recurrence=Recurrence in the chest wall or scar. Regional recurrence = Recurrence to the i/l Ax, internal mammary, or supraclavicular nds.Distant Recurrences=Mets.

Tx4) Total (Simple) Mastex. *The term total mastex is preferred to "simple" mastex because the latter implies a lesser procedure to the pt.*Indications for a total mastex are: *In pts c DCIS or LCIS who have no clinical evidence of Axillary mets. In these pts, the incidence of ax. mets=1-2%.*In selected pts undergoing prophylactic mastex of the c/l breast. *In pts requiring a salvage mastex p wide excision+Ax dissex were done who had either + margins on the specimen or recurrent CA. *As a palliative procedure in pts c bulky breast DZ and distant mets.

*An NSABP trial comparing RM vs TM+RT vs TMshowed no difference in 10 yr survival in node negative or node positive pts (se fig. 5)Tx5) Modified Radical Mastexctomy (MRM)=Excision of breast+Ax Nds+/-Pec minor.Is of 3 types:Q1) What are the indications for MRM?*Any pt with operable breast CA (stages 1-3) when the CA is not fixed to the pec major. Often, the surgeon can not be sure if the underlying pec major/fascia were entered during Bx. Other times, a small portion of the muscle/fascia may be involved. Although some would re: a RM in these cases, there is little to gain in sacrificing the pec major in these cases. In these cases, a MRM c saucerization of the involved pec major is probably OK.*Lumpex/Quadrantex is contraindicated in some pts c early breast CA (see Table 3)

Q2) What types of MRMs are there? There are 3 basic Types:*Auchincloss MRM. Does not remove the pec minor...Level III nds are NOT removed. Removal of level 3 nds will potentially benefit only 2% of pts. *Patey MRM. Removes the pec minor but preserves the overlying pec major. The idea is to remove the level 3 nds while preserving the pec major for a better cosmetic result. Preservation of the medial pec. n is "mandatory" c the Patey MRM. The problem is that the lateral pec. n is divided c this procedure->atrophy, fibrosis, v ROM of the pec major. Thus, this procedure is not recoommended. Technique of Patey MRM:*The forearm, arm + breast are prepped and draped. The forearm gets a stockinet for future forearm mobilization.*As in the Auchincloss MRM, the breast + the pec major fascia are dissected in the medial to lateral direction -leaving the breast attached to the axilla.*The clavipectoral fascia is entered. But instead of doing the Ax dissex, the pec major is retracted out of the way and the pec minor is divided near the coracoid process. Retraction of the pec major may the medial pec. n so be careful.*The pec minor is also dissected from its chest wall and dissected in a medial to lateral direction. Rotter's nds are taken c care not to damage the neurovascular bundle.*Although preserving the lateral pectoral n during a Patey MRM is desirale, it is usually not possible to do this.*The forearm is then flexed so as to better expose Halstead's ligament and level III nds. Branches to the axillary v. are tied c silk sutures.*The forearm is returned to the extended position to allow removal of level I nds.

*Scanlon MRM. This is a modification of the Patey MRM. Here, the pec minor is divided (so as to remove the level 3 nds) but not removed. *Adjuvant ChemoTx is given p 2-5 d if the nodes are positive. Q3) What are the complications of MRM? (5)*Skin necrosis (8%) is 2o to: i)Thin skin flaps ii)tight pressure dressings. TxOC=i)routine post-op wound care,The skin will heal c 2o intent ii)Occasionaly a skin graft may be necessary.

*Seromas occur most often in:i) obese pts ii)pts whose nds are pathologically involved iii)two-step>one step procedures iv)Pts who beggin shoulder excercises to early (w/in 1 wk). However, this last point is debatable.Seromas are at ^ risk/o infection. TxOC=Prevention.Pressure dressings are NOT effective and may cause skin necrosis. Aitken re: tacking the skin flaps c 25-30 sutures to the chest wall so as to v the dead space. Shoulder mobilization is delayed to avoid tearing the sutures. If the amount of seroma formation >150 cc despite twice weekly aspiration, consider placing a percutaneous drain under local.

*Wound Infections (5 - 23%) occur in pts c i)DIDNT HEEL ii)prolonged drainage iii)Skin necrosis iv)seroma formation v)second procedure w/in 1 wk of first procedure (23%)>2-step procedure(12%) p 1 wk > one-step procedures(5%).Bugs=SA and Strep. TxOC=IVABs pre-op.

*Lymphedema(6 - 60%) =A lifetime risk, almost always @ c a low level infections of the extremity. The incidence ^ c radical surgery and RT. TxOC=i)Prevention. Avoid BP cuffs, blood draws to i/l side. Avoid heavy lifting, cuts/burns to i/l side (wear gloves). ii)At the first sign of edema give ABs, warm soaks, hand elevation. Once the edema is established, it is difficult to correct.

*Postmastex Pain Synd.(5%)=Debilitating pain may occurs afetr dissex of the interocostalbrachial n. Often a trigger point is IDd, indicating a neuroma. TxOC= i)Injection of EOH ii)reoperation to excise neuroma-but neither Tx is very effective.

Tx6) Radical Mastex=MRM+Pec major/minor but internal mammary nds are left intact. *Today's RM was originally described by Halstead and perfected by Haagensen.Q1)Is RM of proven benefit?*The Alabama Breast Cancer Project randomized 100 pts to RM vs MRM and found that RM had a 71% 10 yr survival vs a 64% 10 yr survival for MRM. L22222ike other studies, there was a trend favoring RM but statistical significance was not achieved. However, when pts c T2 DZ c palpable ax nodes(N1 + possibly N2) and pts c T3 DZ an palpable nds (N1+ possibly N2) were looked as a subgroup, RM has improved survival over MRM (p=.05)...In this randomized prospective study, RM showed improved survival over MRM for stage 2b-3a DZ.

Q2) What are the Indications of RM?*Stage IIb and IIIa DZ*Large bulky tumors involving the pec major/fascia. Wilson does not re: RM in all thes cases. He advocates MRM c local excision of the muscle + RT + ChemoTx.

*Grossly involved Rotter's nds *Large bulky axillary nodal DZ

Technique of Radical Mastectomy:*The original Hallstead technique involved a vertical incision c skin graft closure. However, in today's RMs the incision is as for an MRM.*In the RM, the breast is not removed from the pec major fascia. Instead, the pec major is dissected from its humeral attachement. The pec major is then dissected laterally to medially + devided at its sternal attachment.*After the pec major is divided at its sternal attachment, the pec minor is IDd. It is divided from the coracoid + rib attachments and removed from the medial to lateral direction. The interpectoral area is removedd en blocc.*After the pec major + minor muscles are removed, the Ax dissex is as in MRM.

Tx7) Extended radical(XRM)=RM+Internal mammary nds.Q1)Does XRM offer survival advantage over RM?Yes, for cental-medial lesions. No for lateral lesions.*Meir (U. of Chicago) randomized 123 pts c stage 1-2 DZ to XRM (EXT) vs RM. The overall 10y survival rates were: XRM=74% vs RM=60% (p=.13). However, if one looks at pts c medial-central lesions (66% of all pts), then the 10 yr survival are: XRM=85.7% vs RM=60% (p=.025). No adjuvant Tx was used here.

*Lacour randomized 243 pts to either RM or XRM (EM) and found XRM had ^ survival in pts c central -medial lesions (p=.05) but was @ c v survival in pts c lateral lesions (p=.07). See table 3.

Q2)What is the rationalle for the XRM?*Mammary nds are positive in 20% of pts c operable breast CA. However 23% of central-medial lesions have + mammary nds vs 19% for lateral nds (no statistical difference). Thus, the positivity of the mammary nds alone does not explain the improved survival of XRM. Perhaps the longer distance and a different route (intercostal lymphatics) of lateral CA drainage explains why there is no benefit of XRT in lateral lesions.*Previous studies that compared XRM to Total Mastex + RT (Kaae) and XRM to RM (Lacour) did not use the, more rigorous, complete en bloc mammary node excision described by Urban. Hence the Meir study was initiated.

Q3)Who should be offered an XRM? At the U of C, Meir re: XRM to: *All pts c operable central-medial lesions *All pts c stage 2-3 DZ.

Tx8) Ultraradical Mastex (URM)=RM+Supracalvicular ndsQ1) What is the rationalle for the URM?*In the RM, the axillary v. is seldom completely cleared by the dissection. The long thoracic and thoracodorsal neurovascular lymphatic bundles are invariably protected and preserved. For this reason, the URM as refined by Haagensen was tried. In the URM:*The widest possible en bloc resection of the dermal lymphatics is done (400 -500 cm^2). The defect created requires skin grafting and/or sliding deltoid flaps.*The en block dissex starts c the supraclavicular nds, one or both neurovascular bundles (i.e. long thoracin n and thoracodorsal n).The retrospective Oregon study (Peterson) showed significantly improved 25 yr survival for pts c T2-3/N0 breast CA who had URM vs RM (see table).

Q2) In today's world of conservative Tx is there a place for the URM? *Conservative Tx (lumpex+RT) may give equivallent 10 yr survival as MRM, but it does not improve survival. The URM improved survival in this study.*The long-term results of RT (used in lumpex+RT) are not known. Will RT ^ the risk of cardiac death p 15-20 yrs?

*Bottom Line:In today's era, it is unlikely to win many converts to the URM. However, pts may be given this option in randomized studies that compare the URM to the conservative Tx of the day.

ADJUVANT THERAPY FOR EARLY BREAST CANCER*In pts c early breast CA, 50% are node-/50% are node+. About 30% of node- pts+50% of node + pts will relapse p 10 yrs. Although adjuvent Tx is well established for node + pts, in node- pts adjuvent Tx is controversial. *About 70% of pts are ER+-esp. postmenopausal pts. See table 10. These pts are the most responsive to hormonal Tx (see table 11).

ADJUVENT TX IN NODE - /ER+ PATIENTS *The NSABP B - 14 trial randomized 2644 ER+ pts (ER>10 fmol) to tamoxifen vs placebo.After 4 yrs DFS was 83% vs 77% but there was no improvement in overall survival (93% vs 92%).The advantage in DFS was significant in both pre and postmenopausal pts-esp. in the former...TxOC=lifelong Tamoxifen Tx.

ADJUVENT TX IN NODE - /ER - PATIENTS 1) The Ludwig Trial V randomized 1275 node - pts to receive one round of Perioperative Chemo (PC) within 36 hrs of MRM vs. No PC*The regimen given is shown in Table 1. The results are shown in Table 3 show a slight, but statistically significant, improvement in Disease-Free Survival (DFS) after 4 yrs (77% vs 73%) in both pre and postmenopausal pts who were ER-. However, there was no improvement in overall mortality.*Complications to ChemoTx were:Alopecia (7%), Death(.2%), life-threatening infection (.7%), dehiscence (.7%), PE (.5%).

2) The National Surgical Adjuvant Breast and Bowel Project (NSABP) B-13 trial (Fisher) randomized 679 node-/ER- pts to 12 courses of sequential chemoTx (methothrexate+5fu+leukovirin).Like the Ludwig trial, all pts, both pre and post menopausal, showed improvement in DFS (80% vs 71%) but no improvement in mortality p 4 yrs f/u (87% vs 86%). The improved DFS was especially seen in postmenopausal pts. See Fig. 2Knowing that about 30% of node - pts will develop mets, do the above studies justify adjuvant Tx in all node- pts? What is a clinician to do?i)All pts should be offered entry into a clinical trial, if available.ii)In 1988 the National Cancer Institute issued a Clinical Alert that has widely been interpreted as saying that all pts c node- CA receive CT. Whether this cost effective is debatable. Its been estimated that the life expectancy of a premenopausal pt would ^ by 11m ($15K) and by 8 m in the post menopausal pt ($19k)iii) An alternative is to try to stratify pts into high risk groups. High risk pts are those < 49 y/o c ER - aneuploid tumors > 2cm (and esp. > 3cm), S-phase >10%, ^ tumor markers. However, the stratification of risk groups is evolving.

ADJUVENT TX IN NODE+ PTS*Postmenopausal pts c ER+ Rs get Tamoxifen. All other pts get Chemo. See Table 1.*Largely based on the Ludwig +NASABP B-13/B14 trials, the NIH issued a clinical alert on 5/18/88 which made the below recommendations.

TXOC FOR LOCALLY ADVANCED BREAST CA (STAGE III DZ + INFLAMATORY BREAST CA)*Stage 3 DZ=10% of all breast Cas. Chemotherapy*TxOC=Doxorubricin-containing multi-drug ChemoTx x4 cycles+->Mastex and/or RT (see the Swain study)->CTx6-12m. *Median survival=39 m (3 y).*Note: The Alab.Breast CA Project showed ^ survival c RM (over MRM) in pts c stage IIIa DZ.

Studies on Advanced CA:*An NCI study by Swain gave CT+HT->Open Bx. If Bx was + for CA then a mastex + RT was given. If Bx was - only RT was given*The DeLena study (Milan) showed higher r remission p Mastex (100%) vs RT (60%) but the total response rate was the same (75%)*In a nonrandomized study, Field reported improved survival c CT->RT+Mastex vs CT->RT only.*High-Dose CT + marrow transplantation are investigational in stage 3b DZ.Surgery*As noted above, doxorubricin containing multirug CT is the primary form of Tx->+/or Mastex/RT.

INFLAMATORY BREAST CA (IBC)Epidemiology*Is 1-4% of all breast CAs.*57 yo W=B pts.Symptoms - Signs/DxOC *The criteria for Dx are controversial. Originally, Lee + Tannenbaum defined IBC as redness in more than 33% of the breast s the presence of a mass or ulceration (Surg. Gyn.Onc. 1924; 39: 580-595).Usually the breast is warm, tender + edematous (peau d'orange) but these are not sufficient clinical criteria for Dx. The erythema + edema is due to involvement of the dermal lymphatics c tumor emboli*A histopathologic Dx of IBC requires the presence tumor emboli in the dermal lymphatics. Parenchymal lymphatic invasion is common, but not sufficient for Dx.Prognostic Factors*Univariate analysis (Fields et. al. Cancer 1989; 63:1225) analyzed 15 variables (table 2). Features @ c statistically ^ survival1) Mastex showed marked improvement in RFS+ survival in both uni+multivariate analysis. Mastex provides 2 advantages over RT for local control: i)It provides immediate reduction in tumor burden s significant interruption of the ChemoTx. ii)It provides tissue for analysis-e.g. to measur response to chemoTx.Features c a trend to ^ survival but not attaining statistical significance:2) ChemoTx had marginal improvement of survival in multivariate analysis.3) Race:Although Black pts fared worse than white pts on univariate analysis, this was not statistically significant. But, blacks were more likely to get a mastex. Thus they would be expected to have a better (not worse) relapse free survival (RFS) -but they don't. Thus, when multivariate analysis is applied (table 3), blacks nearly attained significantly more RFS than whites.4a) Diffuse vs Discrete Mass: While size of the mass was not significant, the presence of a diffuse mass retained significance in the multivariate analysis for RFS but not for survival.4b) Tumor Size:Pts c tumors < 8cm have significantly lower RFS and higher survival on univariate analysis. However, this advantage is lost on multivariate analysis because pts c a discrete mass were more likely to receive mastex (+ have better survival) than those who had larger masses.

Features c NO effect on survival which have been sited in other studies5) Diagnostic Group:Pts c IBD were sorted by clinical criteria (C+) and/or histologic criteria-i.e. involvement of dermal lymphatics (DL). No differences were found. Thes findings are in contrast to many studies, esp. in Europe, in which the degree of clinical DZ is @ c prognosis. However, most of these studies: i)Use looser criteria for defining IBD i.e. they include localized DZ (which have a better prognosis) + extensive DZ together ii)They usuallyDx by clinical criteria only + do not use histopath Dx. In these series, when one looks at the extent of the inflammation, localized DZ has a better prognosis than diffuse DZ-but localized DZ is not true IBD. Data frm the Surveillance, Epidem+EndResults (SEER) program and other studies show that the presence of DL is worse for prognosis. This study, and others, find no relationship. Thus this is controversial.6) Nodal Stage/Number were not significant. Other studies, c less stringent diagnostic criteria, do find significance.

Features not A c ^ survival in any study.7) Age + menopausal status-see table 2.8) ER/PR Status: About 51%/55% of pts are ER+/PR+.No effect on survival.9) Tx Era:No effect on survival p multivariate analysis because more recent groups were treated by tripple modality Tx.

*Multivariate Analysis*In multivariate analysis, the independent prognostic factors for improved survival,inorder of significance, were mastex, chemoTx, race, and diffuse vs discrete tumors-see Table 3.

TxOC for IBD*TxOC= a multidisciplinary approach like in stage III DZ except that the demographics, response rates + median survival are worse in inflammatory CA.*Duke Study:i) Preop ChemoTx c Cyclophosphamide (400 mg/m^2), 5FU (400 mg/m^2), vincristine (1 mg/m^2), doxorubricin (10 mg/m^2) Q wk x 6 wksii) After being off of chemoTx x 7-10 d, the pt gets a mastex if the tumor is resectable. iii)If the tumor is not resectable, the pt gets 3K-5K rads of RT->ChemoTx p 7-10 d on PRN basis->Retry mastex.*Survival=40%(37-72%) p 30m (18-56 m).

Surgery

26

Q1) What type of breast surgery is needed in IBD?*The mastex that removes the CA c the most minimal morbidity:

Tx1) Simple MastexTx2) Radical Mastex(RM) =MRM+Pec major/minor but internal mammary nds are left intact. Indications for RM are:*CA that has penetrated into the pec major/fascia-Stage 3b(T4/Nx)*Grossly involved Rotter's nds*Large, bulky axillary nodal DZ*Stage IIb (T3/N0) and stage IIIa DZ (T3/N1-2)-as per the ABCP trial.

Tx3) Extended radical (XRM) =RM+Internal mammary nds. Indications are:*All pts c operable central-medial lesions-As per study by Meir of U of C.*All pts c stage 2-3 DZ. This is a re: by Meir but it is not proved by his study.

Tx4)Ultraradical Mastex (URM).*Had proven benefit over RM in a retrospective study in pts c T2-3/N0 DZ but is not studied in IBC.

Radiation TxQ1)What are the indications of RT? *RT is only indicated in pts c positive Ax nds, esp. if 4+ nds are involved. In these cases, RT will v the local recurrence rate even if adjuvant Tx is used.Q2) When is RT preferred over surgery? A: In pts c positive Ax nds who:*Are poor surgical risks*Have residual CA p surgery*Hhave inoperable CA p CT.

Q2)What are the contraindications of RT? RT is not indicated in:*Pts c - Ax. nds, except if the local DZ is extending locally.*The use of postmastex RT remains highly controversial. There is evidence that such Tx may ^ the chance of survival, esp when adjuvant Tx is also used. However, the long term effects of RT (e.g. cardiac DZ) ay outweigh its short-term benefits.

Q3)What is the evidence for/against RT? See Table 16-10.*In study by Perloff 113 pts received ChemoTx for stage 3 DZ. Of these, 91 pts (81) were deemed operable. These 81 pts were then randomized to either RT or surgery for local control.Median survival c surgery=29m vs 24m c RT-no significant difference.

27

PAGET'S DISEASE OF THE BREASTEpidemiology*Paget DZ=.7-2.3% of all CAs*61 YOW=B F

Symptoms and Signs:*Nipple changes (60%):D/C (bloody->yellow), eczemoid changes.*Mass (54%). Pts c mass present younger (49 y/o).*+ Ax nds (40%). Notice how + Ax nds occcur mainly in pts c a mass (66%) and only in few pts c isolated nipple D/C (8%). See Fig. 24-17.

*DxOC*B/L mammograms (esp. in pts > 30 y/o) c magnification views of the i/l subareolar area.*The DxOC=Punch or incisional Bx. Also you should Bx suspicious areas/masses on mammogram. *You should send any D/C for cytology. However, a negative cytology should not be considered definitive. Only a Bx is definitive.

Histology:*The Paget cell= a large, ovoid cell c a clear cytoplasm and large nucleus. Typically it is located on the malpighian layer of the skin.

Q1)Is the Paget Cell a malignant cell or a reactive cell? This is controversial. Nobody knows for sure.A1:Behavior that implies that Paget's cells are benign are: i)Paget cells do not invade deeper tissues ii)Dendritic melanocytes and Paget cells both stain c DOPA. This suggests that Paget cells are melanocytes. iii)Paget cells form desmosomes-just like epidermal cells. On the other hand Paget cells, but not melanocytes or epidermal cells, stain c PAS stains and CEA Ag.These latter features suggest Paget cells have a glandular origin.

A2:Behavior that implies that Paget's cells are malignant includes: i)The resemblance of Paget cells to the subjacent invasive CA cells. ii)Paget cells have a cytoplasmic-staining pattern siilar to to malignant ductal cells.

TxOC *Tx1=Total mastex +/ - Ax dissex. Mastex c/s Ax dissex (MRM) is indicated for most pts c Paget DZ. This includes pts c Paget DZ with: i) Multicentric (diffuse) DCIS ii) Multicentric invasive CA iii) DCIS or CA at the resection margins iv) Palpable mass/nds (54%/40%) or mammographic mass.

Q1) What is the rationalle for Total mastex in these pts? *For i-iii) The rationalle is obvious.*For iv) While survival rates for pts c Paget DZ who have DCIS only is close to 100%, it is vv in pts with +nds>palpable mass (see table 24-17)...agressive Tx is indicated in these pts.

Q2)What kind of Ax nd dissex should be performed? This is controversial.*In the past, a RM was standard Tx and MRM was performed when there were no palpable mass(es) or nds.*Currently, many authors re: MRM in pts c a mass and total mastex in pts s a mass.However, the incience of + nds in pts c nipple only DZ is 8%. For many authors, this is too high and they re:MRM for these pts too.

Tx2)Wide excision of the nipple - areola complex and underlying tissue +/- RT c close F/U in highly selected pts. Q1)When is conservative Tx for Paget DZ indicated:*For Paget DZ confined to the nipple +/- lactiferous duct involvement but s a clinical mass/nds.

Q2)What's the rationalle for conservative Tx? *A review of the world literature (79 pts) who were Tx conservatively (local excision +/ - RT) for Paget DZ c DCIS only have shown near 100% survival c recurrence in 11%. The selection criteria in these studies, except for the fact that all pts were nd-,is often poorly defined.*Lagios likes to view Paget DZ like DCIS of the nipple. Thus, Paget DZ predicts for multicentricity, for extensive local DZ

(i.e.intraductal CA involving the terminal lactiferous ducts) and for invasive CA. Hence pts c areolar involvement, no mass, NL mammogram and NL PE can be viewed the same way limited DCISis viewed-i.e. ameable to conservative Tx only.

Q3) What is the role of RT in pts c Paget DZ c DCIS? Unknown-i.e. the data c RT for Paget DZ is limited. This is why RT is not being re: for Paget DZ c diffuse or multifocal DCIS.*Fourget Tx 17 pts c Paget DZ of nipple only-i.e. no masses/nds. Recurrence occured in 3/17 p a 90 m F/U.*Stockdale had similar pts but 16/19 of his pts relapsed p 63 m. Moreover, of pts c Paget DZ and a mass Tx c RT only he had 6/7 relapses.

INVASIVE (INFILTRATING) LOBULAR CA Epidemiology*Pure lobular CAs account for 3% of all CAs. With less restrictive histologic criteria and the inclusion of "variant forms", it is seen in 10-14% of invasive CAs.*45-56 y/o W=B F.*The risk/o b/l DZ is high: 6-28%.*50% are ER+

Symptoms/Signs*Mass c ill-defined margins. UOQ is most common site.*We do NOT see: Calcifications, Nipple involvement or D/C in pure lobular CA. These symptoms may be seen when there is a concurrent ductal CA. *Mets occur in unusual locations e.g.: Carcinomatous meningitis; retroperitoneal mets-> +/- urethral obstruxn; serosal mets->GI obstruxn. Mets to stomach, ovaries, uterus are common. Mets often have no apparent mass but are often diffuse infiltrations or thickened serosa/adventitia.*Rarely, ectopic hormone production occurs:ACTH, PTH, calcitonin, Epi.

Gross Tissue/Histology*Grossly they range in size from microscopic to large tumors that infiltrate the entire breast. The margins tend to be indistinct.Minute granules may feel sand-like.*The tumor cells have small round nuclei, limited cytosol c variable amounts of intracytoplasmic mucinous lumina. When cells contain a large cytoplasmic mucin vacuole they are singet rings cells. Singet ring cells may also be seen c ductal CAs too.**The classic (Indian-file) histology is seen in 30% of specimens and and includes: Indian filing (=linear arrangement of tumor cells), targetoid growth (=a tendency to grow circumferentially around ducts/loboles) and a desmoplastic stromal reaction.*Other Histologic variants are: Mixed (29%), solid (22%), alveolar (19%), tublar (1%), trabecular (1%). Antigenic Markers:*About 50% are ER+, the same as ductal CAs. *CEA is seen-esp. when there is mucin present. *a-Lactalbumin in 20-100%. This is sometimes helpful in identification. For example, lobular CA c mets to the stomach mimck primary linitis plastica gastric CA. Both have singet cells, mucin, CEA. But the lobular CA may have ER+ Rs.*[Fibronectin] is v in invasive lobular CAs but ^ in ductal CAs. Fibronectin contributes to cell adhesiveness. Low [fibronectin] may account for the diffuse growth pattern of lobular CAs. Fibronectin is a noncollagenous glycoP that is found on basement PM and collagen. *Some tumors have been found to contain:bHCG, calcitonin, Epi, argentaffin granules (3-25%). Sometimes, the microscopic appearance resembles the tissue that makes these Hs. The most notable example is lobular CA c choriocarcinomatous differentiation->aggressive course->death.

DxOC*Mammogram:The lack of a definite mass and abscence of calcifications makes mammographic Dx difficult.Prognosis*When corrected for stage, survival is similar to ductal CAs i.e. the most important determinants of survival are node status and tumor size.*Prognosis is also worse c choriocarcinomatous metaplasia. *Pts c classic (indian-file) histology are younger, more likely to be premenopausal and may have a more favorable prognosis than the variant histologies. The last point is controversial. TxOCTx1) MRM for stage 1 - 2 lobular CA is TxOC. Tx2) Lumpex + RT is another option but should be viewed as investigational. The Beth Israel study compared the efficacy of lumpex + RT between 49 pts c invasive lobular CA vs 561 pts c invasive ductal CA. After a f/u of 75 m (6.25 yrs), the recurrence rate was 12% (7/49) for lobular CA (presumably a more multicentric CA) vs 11% for ductal CA (see fig.1). Other important findings in this study were:i)All seven of the lobular recurrences were near the resection site-not at multicentric sites. This suggests that local recurrences represent a failure to excise the primary site...it is re: that microscopically clean margins are obtained before RT is given. This is esp. important c lobular CA since a discreet area of involvement is difficult to fin.ii)No clinical or morphologic features were predictive of recurrence. Of particular importance was the fact that the presence or the extent of lobular CA in situ did NOT predict recurrences in the way DCIS predicts for invasive ductal CA.iii)Careful lifetime f/u is re: for these pts. In this study, most of the recurrences were p 4 yrs and the clinical presentation of these recurrent CAs was often very subtle: mammary parenchymal thickening, retraction.

II. MIXED CT + EPITHELIAL TUMORS*FibroAdenoma*FibroAdenomas are common in any menstruating pt. They vv p menopause.*No malignant potential.*Mammography can not distiguish cysts from fibroadenomas but US can.

*Giant FibroAdenoma (GF):GF is a descriptive term for any fibroadenoma > 5 cm.*Juvenile FifroAdenoma (JF):A fibroadenoma of adolescents. It is more fibrous + often a GF. Benign Cystosarcoma Phyllodes is a tumor that may be confused c JF. Excision of either tumor is curative. In contrast, malignant cystosarcoma phyllodes has a poor prognosis.

*Phyllodes Tumor (Cystosarcoma Phyllodes=CF)Epidemiology:*45 y/o B>W F. In malignant DZ age=48 y/o. *#1 Sarcoma of breast but rare (18 cases at CCF p 18 yrs).*At CCF 10/15 were benign (66%); 3/15 malignant (20%); 2/15 were borderline (30%).

Pathophysiology: *May arise de novo or from previous fibroadenoma? *Grossly has a "leaflike" appearance c multiple cystic + gellatinous areas.*Microscopically it looks like a fibroadenoma c more stroma. The malignant types have more pleomorphysm, atypia, necrosis -like a sarcoma.*The gross + microscopic appearance do not accurately forecast the malignant potential of these tumors. *Mets can occur c/s reccurence. Mets are mainly to: lungs +bone> L-S, pancreas, GI. Although lymph node enlargement is seen in 17%, nodal mets are rare.

Sympotoms/Signs:*u/l > b/l mass that may/may not be present as a stable lump present for many yrs-> grows progressively + rapidly over 12-18m.*Niple involvement is rare (1/15)*Nodal involvement is by direct extention. Mets to nds is rare (1/15).*Co-existent DZ may be found:fibroadenoma, lipoma, adenoCA, fibrocystic DZ

TxOC:Surgery:Tx1) Total mastex (10/18) s Ax nodal disex->recurrence in 4/10. Mets in 3/10. Mastex may be preffered in recurrent DZ, large tumors, rapidly growing tumors.

*Note: i)Nodal dissex is not necessary because nodal mets are rare.ii)Local reccurence is one of the characteristic features of this tumor, usually w/in 2 yrs p OR. Progression to mets is a late but variable complication, occuring 6w-8m p OR.

Tx2) Wide Local excision in 8/18 - >recurrence in 6/8 . Mets in 2/8. Thus, excission is @ c a higher recurrence. It may be preferrred in small tumors.

ChemoTx: CF is often ER or PR positive but it has no fxnal Rs...Hormonal manipulation is NOT effective.

RTx:Is generally considdered ineffective.

*Carcinosarcoma

III. MISCELLANEOUS TUMORS*Soft Tissue Tumors*Skin Tumors*Hematopoeitic Tumors

IV. UNCLASSIFIED TUMORS

V FIBROCYSTIC DZ/MAMMARY DISPLASIA*Peak age for Benign cysts=45 y/o. Incidence v before + after this.*Due to fibrosis-> stricture at ductules c continued secretion->cysts. The scarring takes a while to form, most pts are > 35 y/o. Also, the incidence vv p menopause.*Atyppical Changes are @ c CA.

VI.(Benign) TUMOR LIKE LESIONS*Gynecomastia*In young boys it is called puberal hypertrophy. It is very common, usually b/l > u/l. TxOC=nothing since it usually regresses.Cosmetic surgery if requested.*In men>50 y/o it is called senescent hypertrophy. Gynecomastia is symetrical, is frequently tender + u/l, is @ c ESLF, ESRF, malnutrition, meds (dig, thiazides,theophylline,estrogen Tx). TxOC=nothing, unless cosmetic surgery is required. In contrast, CA is usually an asymetrical periareolar mass fixed to tissues that is usually not tender. Bx any suspicious mass.

DEVELOPMENTAL STAGES*Classification of Sex Maturity in Girls*StagePubic HairBreasts . 1 (<11)NoneNo Buds2(11)Sparse,Straight HairBreast Bud Stage3(12)More hair,beginning to curl^ Size but no contour4(13)Coarse,curly,abundant-but less than adultSecondary mound of areola above the breast5 (15)Adult feminine triangle spread to medial surface of thighsAreola recedes + only nipple is raised. *Classification of Sex Maturity in Boys*StagePubic HairPenis/Testes 1(<12)NonePreadolescent2(12)Sparse,Straight Hair at base of penisSlight enlargement/Pink scrotum3(13)Hair is curly, dark, more denseLonger/larger4(14)NL density, limited distributionGlans develops/Larger, dark scrotum5(16)Adult distribution to thighsAdult size

*Galactocele*Duct Ectasia.*Inflamatory Pseudotumor

*Hamartoma.*A discrete nodule that contains closely packed lobules. Clinically, it is indistinguishable from a fibroadenoma. It is benign.*Tubular adenoma/Mammary adenoma=Ductules packed closely together s supporting stroma. During pregnancy these tumors may ^ in size.

*Abscent Breast Tissue:*Amastia=Abscent Breast Tissue*Athelia=Abscent nipple

*Accessory Breast Tissue:Occurs often. Usually a cosmetic problem only.*Polymastisa=Accessory Breast Tissue*Supernumirary Nipples

BILATERAL BREAST CAs Epidemiology*Synchronous (simultaneous) CA is seen n .1-2% of pts. *Metachronous (sequential) CA is seen in 3% (1-12%) of pts depending on the length of f/u. Fisher detected 66 metachronous CAs in 1578 pts c breast CA p 10 yrs of f/u (4.2%). Of these, 59/1578 (3.7%) were invasive and 7/1578 (.5%) were in situ.The anual risk/o metachronous CA was constant and <1%/yr for all 10 yrs except for yr #2-whose rate was 1.7%/yr (see fig. 1).*The percentage of sequential b/l CAs is .4%/yr ... the cumulative % of a sequential primary CA is dependant on the length of F/U.*The wide range of b/l DZ reported in the literature may be related to the fact that i)bilaterality is a function of time of f/u ii) multicentricity ^ c tumor size + histologic tumor type iii) the definition of a second primary tumor is not well defined iv)The use of mammography. Risk Factors for b/l DZ Are:*Age:The cumulative risk of c/l breast CA=6x for F<44; 4x for F<60; 2x for F=60+. The relative risk of c/l CA=1%/yr. With routine mammography the rate of detection ^ by 5x more. Adami's study (Sweden) f/u the cumulative b/l breast CA risk in 1423 pts in Sweden. This study showed a relatively constant cumulative risk of 5.1% per decade (similar to the NASBP trial above). This rate was4x higher in pts<50 y/o.*Family Hx:If the pt's first degree relative had b/l breast CA before/after menopause, her risk/o CA=9x/4x higher. Fisher found that women c b/l DZ were twice as likely to report breast CAs in their relatives as Fs c u/l CA, however, this difference was not statistically significant in 1578 pts.*Multicentricity:Is found in 30% of MRM specimens (50% are DCIS, 50% are invasive). Pts c multicentric invasive CA on one breast (i.e. those c 2 or more primary tumors one one breast) have 4x higher risk/o B/L DZ.*Histology: In pts c LCIS, c/l CA is found in 25-40%, however only 50% of these CAs are invasive. Also, this range is dependant on coexistant histology. Thus, pts c LCIS+infiltrating duct CA have a 60% risk/o B/l CA. Pts c LCIS alone or infiltrating duct CA alone have a 28%/23% risk/o B/L DZ. Pts c DCIS have a 1% risk/o c/l CA. Pts c invasive lobular CA are also at ^ risk of c/l CA but the risk has not been quantified. Anaplastic and tubular CAs are more often b/l. Proliferative fibrocystic DZ near the dominant mass and absent sinus histiocytes are @ c B/L DZ.*Size:T>2 cm is @ c b/l DZ.*Nipple involvement is @ c b/l DZ.*ERPR+ tumors are more often b/l than ERPR- CAs.*Time:Actuarial risk/o b/l CA v the longer the pt survives from the primary operation (see Table 24-23). *Mammography:In the Guy's Hospital series, the introduction of mammography ^ their detection of simultaneous breast CA by 2.4%. On the other hand, Senofsky did not find ^ detection c mammo but earlier stage detection of c/l CA from a median of 39m to 19m.*Contralateral Bx:When generous portions of c/l breast are removed (such as mirror image Bx or outer quadrant excision) the incidence of synchronous lesions is 4-12%. Urban found CA in 13% of pts who had c/l random Bx. Interestingly, this latter number approaches the 16% detection rate sited for c/l mastex. He also screened pts c -mammo/PE c random Bx and detected CA (mainly DCIS) in 8%. Of these, aout 50% are in situ.*Despite the statistical significance of most of the above features, these features have a low predictive value for b/l DZ.

DxOC*It is important to distinguish between b/l CA vs CA c c/l mets as follows:*The presence of 2 different histologies (e.g. medullary vs mucinous) is strong evidence for two de novo primary CAs. In the Fisher study, 50% of the primary CAs were distinguishable by this feature alone.*In situ DZ is seen c 1o DZ,never c mets.Absent in situ DZ is seen c mets or 1o DZ. The presence of in situ DZ is probably the most reliable marker of a second primary. However, it must be kept in mind that some Cas (esp. medullary CAs) may not have an in situ component. Fisher was able to Dx 75% of his second primary Cas with the presence of the situ component alone.*If the second CA is of a lower (more differentiated) histology than the first, this suggests a second primary.*Fisher says that "scar" CAs are primary CAs. He defined "scar" CAs as:lobular invasive Cas c targetoid epithelium and multicentric proliferation.*On mammogram mets tend to be multiple, are well circumscribed and are unlikely to have calcifications. Primaries are single, stellate and are @ c calcifications in 50%.*Mets occur in the SQ fat, 1o DZ occurs in ducts/lobules.*Isolated mets to the c/l breast, s mets to other organs is rare. Do a thorough search for mets elswhere.*Leis accepted the Dx of new 1o DZ if it occured 5 yrs p the 1st CA or if the nuclear differentiation was greater in the 2nd CA. However, placing a specific time limit on mets makes no sense for 2 reasons: i)In the case of the >5yr time limit, this time limit may be too restrictive because it disregards the concept of "dormancy". Thus, many CAs (e.g. breast, colon, ovary, melanomas) may be dormant for many yrs before mets appear. ii)Other authors re: CAs that recurr w/in 2 yrs to be mets. However, about 50% of synchronous breast CAs occur w/n 2 yrs of the 1st CA, 80% recur wi/ 5 yrs of each other and 90% recurr w/in 7 yrs of each other (see fig. 1). Thus time limits, are too arbitraty.

*Mets from extramammary sites are rare. Only 250 reported cases. They occured in 1.5% of Urban's 4K operable breast CAs.*Fisher used the 1st 4 differential criteria in his study.

TxOC:*Pts c b/l synchronous CA should get a metastatic w/u. If the w/u is negative, TxOC=b/l MRM +/ - reconstruction or b/l wide excision + RT.

*If u/l DZ is found, the approach to the c/l breast is controversial. Two general approaches have been adopted for Tx, depending on how one interprets the data.

*Tx1=Close F/U of c/l breast. The rationalle for this approach is that:i)Pts c b/l DZ have the same prognosis as pts c u/l DZ. The NASBP B-04 trial, probably the most definitive study to address this question, showed no difference in survival in pts c b/l DZ p a f/u of 10 yrs. Other studies show a worse prognosis c b/l DZ. Much of the controversy in the literature stems from the differences in defining what constitutes a second primary CA and the lack of controls for stage in the c/l CA.ii)Random c/l breast Bx is unlikely to detect c/l DZ.iii)Finding and treating c/l DZ. esp. if it is in situ DZ, is unlikely to improve outcome.iv)Prophylactic mastex would subject a lot of women to unnecessary surgery i.e. only 1 in 20 mastectomies would be lifesaving. On the other hand, Chaudry et. al. estimated that c/l CA would develop in 15% of pts p 20 yrs. Thus, prophylactic mastex would benefit 15% and be unnecessary in 85%.

*Tx2=Simultaneous B/l mastex. Rationalle for this Tx includes:i)Pts c b/l DZ have a poorer prognosis than pts c u/l DZii)Random c/l breast Bx detects significant DZ (13%) even in the presence of NL mammogram and PE.iii)Finding and treating c/l DZ, even LCIS, improves the chances for cure.On the basis of this data, Leis re:c/l mastex in high risk pts i.e. young pts c significant FHx or c multifocal or lobular CA. In the Leis series, 17% of the c/l breasts were + for CA and 50% of these were invasive.Chaudry et. al. estimated that c/l CA would develop in 15% of pts p 20 yrs. Thus, prophylactic mastex would benefit 15% and be unnecessary in 85%.

*Tx3: The best approach is somewhere in between these two.

*Q1) What type of Tx is NOT recommended?*SQ mastex of the c/l breast is not re: for either Tx or prevention because it does not remove all of the breast. *Sequential b/l mastex is an older practice that is not indicated because the latter has ^ morbidity/cost + requires unnecessary delay (2-3 wks or longer if wound complications occur).

Prognosis:*Survival is as good as the worse of the two primary CAs. Fracchia and others have reported poorer survival c b/l CA. Frachia reported 30% recurrence c b/l CA vs 16% recurrence c u/l DZ. NATURAL HX OF BREAST CA*Bloom collected 250 pts c unTx Breast CA in England from 1805-1933. The median survival in these pts was 2.7 yrs (Fig. 15.)

FUTURE TRENDSI BIOLOGIC INDICATORS*Historically , predictions of outcome of breast CA were based on: i)Size of the tumor. Tumors < 2cm have only a 5% of causing death in 5 yrs. In contrast, tumors > 3cm have a 4% recuurence/death rate (from mets) per yr. ii)Number of Ax nodes involved. 50% of pts are node-/50% are node+. About 30% of node- pts+50% of node + pts will relapse p 10 yrs. iii)Menopausal status of pt. iv)ER-PR Rs:ER-PR+ pts have a 5-10% better survival.

*Now several other pronostic factors have been IDd:1) Cell Ploidy2) %S-Phase3) Proto-Oncogenes4) Growth Factors5) Cathepsin D6) Screening Antigens

1) Cell Ploidy. NL cells are euploid, and become tetraploid just before mitosis. Aneuploidy is when a cell contains other than a haploid multiple of DNA. Aggressive Cas are usually aneuploid rather than diploid. However, several studies have now shown that the % of Diploid cells that are in S phase is more predictive of malignancy + survival than aneuploidy.2) %S - Phase/DNA Flow Cytometry: *Technique of DNA Flow Cytometryi) The DNA of a cell suspension from rehydrated paraffinn (wax) tissue sections is stained c a fluorescent (phenilindole) stain. The suspension is run through a laser beam + the fluorescence is measured.ii)The cellular fluorescence generated is proportional to DNA contentiii)Typically the flow cytometer measures the fluorescent signals from 10-50K cells + displays the result in a DNA frequency distribution histogram (see below).iv)Diploid tumors show a single peak (A) which, by convention, is calibrated to channel 50-which corresponds to Go-G1 of the cell cycle. Lying to the R of this peak is a population of cells c double DNA content i.e. cells in G2 or mitosis. In between these peaks, are a group of cells in S phase c intermediate DNA. The graphs give the area under each curve.v)The DNA Index=the relative DNA content of the abnormal population/DNA content of the NL population. Thus, if the DNA index=1, you have an apparently diploid specimen (more than 1 peak). If the DNA content>1 then you have aneuploidy. In table 1, note how only 25% (120/473)of the submited breast CA specimens were diploid-the rest were either aneuploid.vi)Coefficient of Variance (CV). Most (75%) of breast CAs are aneuploid-i.e contain more than one peaks on the histogram. However, as can be seen in Fig. 2, even apparently diploid DNA histograms (i.e. histograms c only one peak) may have a wide coefficient of Varience (CV). This suggests additional DNA peaks (i.e more aneuploidy) lynig close to Go-G1 that can not be resolved by current methods. Such histograms are not fully assessible + are called "diploid with a wide CV' or "wide CV diploid". In studies, such histograms are followed seperately (see table 1).*Limitations of Flow Cytometry:i)The resolving power is not sensitive enough to pick up gains or losses of single chromosomes.ii)Not sensitive enough to detect gene amplification regions or translocations. Thus a NL histogram does NOT mean a NL karyotype.iii)The sample represents tumor cells + a variable number of NL cells. Thus sampling error may change all of the measured parameters. Thus, a low S-phase may mean either a low grade tumor or a high grade tumor mixed c NL cells.iv) Significant variation of S phase etc. will occur w/in each tumor.v) Cells rehydrated from paraffin blocks show poorer resolution than fresh tissue.*The study by Clark et. al. (NEJM 1989; 320:627-633) showed that that pts c diploid tumors with low S values have significantly lower DFS (but no improved survival was demonstrated) when compared to pts c aneuploid tumors or pts c diploid tumors c high S values (see fig.2). They also found that the S phase status of the tumor only added prognostic information to diploid tumors -not in aneuploid tumors. In contrast, the PR status of the tumor stratified aneuploid tumors better (see fig. 3). Patients c diploid tumors and low S-phase would probably not benefit from adjuvant Tx. Unfortunately, only 28% of pts had diploid tumors with low S values. That leaves 72% of pts in a gray zone. Obviously other risk factors (e.g. translocation, rearrangement, oncogene expresssion, etc.) must play a role.

*Fixed/Static Cytometry*In static cytometry, the tissue is fixed in a slide + is dyed c fluorescent dye. The slide is then put under a microscope that projects the image on a computer screen. The operator can then shine the laser to individual cells + obtain individual histograms.*This method is especially useful fore small tumors. It can also be used to study other cellular antigens, receptors, etc.3) Proto - Oncogenes

*Oncogenes are genes carried in CA cells which seem to be responsible for their malignant behavior. These genes are derived by somatic mutation from closely related proto-oncogenes.*Proto-oncogenes are NORMAL cellular genes which control growth + regulation. They may be genes that control anything from growth factor Rs to kinases to secretory effector Ps to intranuclear regulatory Ps.*In breast CA, some oncogenes that have been IDd are: *her-2 (neu)->codes for a growth factor receptor. In breast CA pts c + nodes, gene amplification of her -2 has been studied + overexpression of her-2 has been @ c shorter relapses in node+ (but not node -) pts. *int-2, ras and myc oncogenes are being studied;int-2 holds promise.*Thus, traditionally, node- pts were not given CTx but node + pts were. With the newer biologic markers,it may be possible to further stratify pts s.t.:*High risk node- pts are IDd (i.e. who have an ^^ risk/o recurrence) who may benefit from CTx. Several prospective studies are being run that give stage I pts (<2cm, - nodes) who are deemed to be high risk for recurrence (S-phase % > 10%) CTx vs no CTx for those c low S-phase. *Higher risk node+ pts may be IDd who may benefit from more intensive CTx 4) Epidermal Growth Factor (EGF). EGF is involved in NL cell growth. EGF receptors (EGFRs) have also been IDd in breast CAs. In fact, CAs that are ER- are usually EGFR+. In these tumors, EGF fills the role that Estrogen plays in stimulating the growth of ER+ tumors. Tyne has found that:*ER+/EGFR+ pts are less responsive to HormoneTx. Should these pts get chemo?*ER-/EGFR+ pts had a lower survival than ER-/EGFR- pts. Shoul these pts receive more intensive chemoTx?*Node - pts who are EGFR+ are more likely to recurr. Chemo?

5) Cathepsin D *Cathespin D is lysosomal protease (common to most tissues) that has 2 actions:i)It has lysosomal protease activity (activated at low pH) that degrades the extracellular matrix-> important for stromal invasion. ii)It has mitogenic activity (when stimulated c ER or PR?) that is found in breast CAs.*It is an independent predictor of poor prognosis in node - (but not node +) pts.

6) Tumor Markers*CA 15 - 3 *CA 15-3 is an Ag of breast CA cells whose role is unknown.*CA 15-3 > CEA in predicting the presence of breast CA + of measuring Tx*CA 15-3 is elevated (>25 u/cc) in most pts c breast CA:Stage I=16%, Stage II=54%; stage 3-4=91%. However, in the Kerin study, CA15-3 was elevated in pts c stage 3+4 DZ but NOT ^ in stage 1-2 DZ or in NL pts. In either case, CA 15-3 would make a poor screening test, but may be useful as a screen of occult mets.*CA 15-3 accurately reflects response to Tx in most (75%) of pts. Thus, 25% of pts c objective responses will have ^ CA 15-3 levels.*CEA is ^ in only 20% of pts c breast CA. ^ CEA levels are @ c a much worse prognosis.

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