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Current management of breast cancer
ELSEVIER
Current Management of Breast Cancer R. Anthony Perez-Tamayo, MD, PhD, and Douglas S. Tyler, aid
Surgeru Update
DEPARTMENT OF GENERAL AND THORACIC SURGERY, DUKE U N I V E R S I T Y M E D I C A L C E N T E R , DURHAM, NORTH CAROLINA 27710, U.S.A.
Ahstract
Epidemiolonn
Breast cancer is the second leading cause of cancer deaths in women, and is responsible f o r 44,300 deaths in 1996. Its incidence is rising, in part owing to improvements in mammographic screening. Current guidelines for mammography and their support are reviewed. Presenting symptoms of breast cancer and the conduct of a history and physical exam geared toward the evaluation of breast malignancy are briefly described. An algorithm for the workup of palpable masses and nonpalpable abnormalities is presented, including a discussion of the role of stereotactic biopsy. A summary of the pathology, natural history and treatment options for ductal and lobular in situ malignancies is given, with particular attention to the role of breast conservation, its risks and benefits. The controversies surrounding breast conservation versus modified
Based on data from 1983 to 1987 and on mortality rates from 1987 for the United States, 12% of all women develop breast cancer and 3.5% die of this disease (1). According to statistics from the American Cancer Society, in 1996 there were an estimated 184,300 new eases of breast cancer diagnosed in women and 44,300 deaths in women from breast cancer (2). The incidence of breast cancer has increased especially dramatically since 1982. Mthougb there is disagreement as to the reasons for this increase in ageadjusted incidence, there is e\~dence to support that it may- be the result of increased detection of breast cancers at an earlier stage found by, screening man> mography (3).
radical mastectomy and the role of adjuvant and radiation therapy in the management of invasive breast cancer are summarized. Currently available figures for the success of high-dose
chemotherapy/hematopoietic stem cell transplantation in the setting of metastatic breast cancer are quoted. © R. A. Perez-Tamayo and D. S. Tyler. MEDICAL UPDATE FOR PSYCHIATRISTS 1:5; 165-172, 1996.
groups: The sensitMty of mammography in the woman younger than age 50 is reduced by tissue density, and is focused on a population with a lower incidence of the disease. Without conclusive evidence of altered mortality rates with screening mammography between ages 40 and 49, the National Cancer Institute announced that it would not continue to recommend routine screening mammograms for women in this age group. Other organizations such as the American Cancer Society and the American College of Radiology continue to recommend mammograms every 1-2 years in this age group. All organizations agree that clinical breast examination as well as mammography are both essential for optimal screening, and that annual mammography should be done for women aged 50 and over.
Screening Mammographn The benefit from screening mammography has been a subject of substantial controversy. Although screening mammography increases detection of smaller tumors, with uninvolved axillary nodes and noninvasive histologies, statistics may not show improvement in mortality rates because of a number of inherent biases. Screening may be detecting eventually lethal cancer at an earlier stage (lead-time bias); less aggressive, slow-growing cancers that will not lead to death (length-time bias); tumors in the gray zone between atypia and tree malignancy ( overdiagnosis bias ) ; and tumors in a specific group with different risks from the overall population (selection bias). Hams et al. analyzed the resuits of seven trials of maminograpby whose randomization removes these biases, and concluded that screening mammography rednced breast cancer mortality by a conservative estimate of 25% ( 1 ). The benefits of screening mamlnography have not been shown to extend to all age
Presentation Patients with breast cancer will principall), present with a palpable breast mass. Before the advent of screening malnmography, 65% of breast cancer cases presented as breast masses. Other breast-related symptoms such as skin changes, changes in shape and size of a breast, breast pain, and nipple discharge only infrequently lead to a diagnosis of breast cancer. Features that distinguish potentially malignant nipple discharge are spontaneous (rather than induced) discharge; unilaterality, association with a mass; and a bloody, serosanguineous, or watery character. Even so, up to 80% of surgical specimens for nipple discharge will show benign causes, such as papilloma or duct eetasia (4). With the advent of mammography, presentation with a nonpalpable abnormality is increasingly common.
Historn and Phnsical Exam © 199G R. A. Perez-Tamauo and D. S. Tuler ISSN 1082-7579/gG/SlS.DO PII SIO82-7579(gG)OQQ78-7
Address reprint requests to: Douglas S. Tyler, M.D., Assistant Professor, Department of General and Thoracic Surgery,, Duke University, C5026 Veterans Administration Medical Center, Durham, NC 27710.
The key features in the medical history of a patient with a breast complaint are the patient's age, her age at menarehe, the number of pregnancies, number of
MEDICALUPDATEFOB PSYCHIATRISTS
R. A. Perez-Tamayo and D. S. Tyler
live births, and age at first birth. Inquiries should be made as to a family histou of breast cancer, including age of the affected relative, age of onset, and presence of bilateral disease. A previous surgical history of breast biopsies and their histologie diagnosis should be obtained. For premenopausal women, the date of the last menstrual period, length and regularity of cycles, and use of oral contraceptives should be determined. For the postmenopausal woman, date of menopause and whether the patient uses hormone replacement therapy are important details to record. The technique of breast examination is well known. The inspection of both breasts in supine and upright positions while noting asymmetry, palpation of axillary and other nodal fields, and examination of the nipple should be emphasized. The breast should be palpated with the flat part of the fingers. A pinching technique should not be used, as it will spuriously create the impression of a mass. The suspicions dominant mass gathers in tissue around it, with poorly described margins, and its texture is dissimilar from other areas of the breast. A rubbery, well-marginated, motile mass in a young woman is most likely to be a fibroadenoma. All abnormalities in the postmenopausal woman should be treated with greater suspicion.
Diagnostic Work-up
The initial step in the work-up of the palpable breast mass is mainmography. The purpose of the mammogram is to rule out not malignancy in the mass, but occult abnormalities in the remaining breast tissue. It is rarely advisable to employ mammography in the woman under 30 years of age, as the densi~ of the breast tissue obscures visualization of abnormalities. The next issue is to determine whether the mass is solid of cystic. Although some have used ultrasonography for this purpose, aspiration with a fine needle (22-gauge) serves the same purpose more expediently and at less expense. The incidence of breast cancer in breast cysts is only around 1%, and of these the vast majority are distinguished by blood?, fluid or by a residual mass revealed after aspiration. If the fluid is bloody it can be sent for cytologic analysis. Fine-needle aspiration
can also be used to biopsy the solid mass (FNAB). The 22-gauge needle is passed several times through the mass under constant suction and the aspirated material fixed in 95% ethanol. In the hands of an experienced cytopathologist, this technique approaches 90% accuracy. FNAB should be deferred until after a mammogram is obtained, as the sequelae (e.g., hematoma) of the biopsy can distort anatomy and lead to a false positive. It can be used to increase confidence in the clinical and/or mammographic diagnosis of a benign mass, which can then be followed xvithout surgical biopsy. A positive e~ologic diagnosis of malignancy cannot distinguish between invasive and in situ histologies, but indicates the need for open biopsy. A lesion suspicious for malignancy by physical exam and/or mamlnography but with a negative FNAB should still be excised, and many x~611forego FNAB in this situation; but taken together, when all three tests suggest a benign mass the false-negative rate was 0.7%. When all three suggest lnalignancy, the false-positive rate has been reported as 0.4% (5). The evaluation of the nonpalpable mass is most commonly prompted by an abnormal mammogram demonstrating either suspicious densities or microcaleifications suggestive of malignancy. Areas of lnicrocaleification usually require open biopsy if more than five spots are present in a cluster. As the lesions are not palpable, the technique of biopsy in these patients requires malnmographie localization with passage of a needle into the abnormality. A wire hook is then deployed into the lesion to mark it and images obtained to assist the surgeon in excision of the abnormal area. The wire is used to guide the excision. At the end of the procedure, the specimen is X-rayed to ensure that the microcaleifieations have been included in the specimen. A nonpalpable mass lesion can be approached initially bv stereotactic or ultrasound-guided needle biopsy, either FNAB or a core-biopsy capable of yielding histologic diagnosis. If a diagnosis is not obtained in this fashion, needle-localization biopsy isthen utilized. Lesions of low ( 1 % - 2 % ) risk can be followed at 6 months with a repeat naamlnogram, and lesions of negligible risk can re166
ceive the follow-up normal for that age group (6). Stereotactic core biopsy is receiving increasing attention as a low-cost, reliable alternative to needle-localized breast biopsy, which can have an operator-dependent failure rate in producing an interpretable speeilnen in the setting of nonpalpable breast cancer (7). A significant criticism of this technique is that as it has low cosmetic impact and is relatively inexpensive, it may be overused to biopsy patients who would have otherwise been followed with the even less expensive clinical breast exam/ lnammography combination (8). Information derived from the biopsy, clinical exam, and mammography w411 determine the surgical procedure of choice, which can be undertaken immediately after biopsy in many cases. Figure 1 demonstrates a commonly used clinical algorithm. Classification of Breast Cancer
Breast cancer can be divided into noninvasive and invasive categories. The noninvasive foruas are confined behind basement membranes and therefore have virtually negligible incidence of systemic spread. Noninvasive--sometimes known as lninimal--breast cancer arises from the two major cellular populations of the breast, duetular and lobular cells. Whatever the form of breast cancer, the goals of treatment are to cure, obtain local or regional control, stage the disease appropriately so the prognosis and treatment options are well understood, and achieve the best cosmetic result possible given the other goals. Ductal Carcinoma In $ilu
Pathology Ductal carcinoma in situ ( DCIS ) is made up of several snbt)qpes: solid, micropapillary, cribrifonn, and comedo. However, there is sufficient disparity between the aggressiveness of comedo and noncomedo forms that the subb,pes are usefully grouped in this way. Comedo DCIS is characterized by pleomorphic nuclei, fiequent mitotic figures, and necrotic cellular debris in the center of ducts. Comedo DCIS has a higher proliferative rate as measured by th)lnidine-labeling studies, overexpression of the e-erbB-2 oncogene in ahnost all cases, and high degree of
Current Management of Breast Cancer
MEDICAL UPDATE FOIl PSYCHIATRISTS
1 Clinical Breast Exam and Mammography
Palpable
Non-Palpable Lesion
Lesion
J Cystic Fluid
Fine-Needle Aspiration Cytology
.j
Breast Ultrasound
---...
or Suspicious Mammographic Localization
Non-BloodyI
Needle ~ LocaUsation vs. Biopsy and Specimen Radiography
Discard
Fluid
Open Biopsy
R!peat
ClinicalBreast Exam and Mammography Ultrasound
Stereotactic Biopsy
~ ~o-~
~
/ Benign
LocalResection AxillaryDisection Radiation Therapy
vs ModifiedRadicalMastectomy
Surveillance of Remaining and Contralateral Breast FinurB 1. Algorithm for diagnostic work-up and therapy of abnormalities detected on physical exam or by mammography.
aneuploidy by flow cytometry, and is associated with mieroinvasion more frequently than the other subtypes (9,10). Comedo DCIS is therefore thought to have a shorter intraduetal growth phase. In addition, eomedo DCIS tumors more frequently lack estrogen receptors than do noncomedo forms.
Natural History The obvious concern with in situ malignancies is that they will progress to invasive malignancies capable of metastasis.
Before the advent of inan~mography, DCIS presented as a palpable mass, nipple discharge, in the setting of Paget's disease of the nipple, or as an incidental finding on breast biopsy. The DCIS of this time period might be more likely to exhibit the beginnings of invasive behavior, microinvasion. Mieroinvasion is rarely seen in lesions < 25 mm in diameter. Meanwhile, the vast majority of microinvasion is seen in lesions > 45 mm in diameter. Currently, over 80% of DCIS lesions present as nonpalpable mammographic abnormalities. The natural histou of DCIS is confused by this difference 167
in the biological behavior of tile earlier described DClS, probably related to the fact that DCIS is detected at a much earlier stage today than "20 years ago. The best insight into the behavior of untreated DCIS is given by the series by Page et al. ( 11 ) and Rosen and Kinne (12) of patients whose specimens were interpreted as benign at the time of biopsy but who, retrospectively reviewed, ultimately turned out to be noncomedo DCIS. The ipsilateral recurrence ofinvasive breast cancer was 30%, occurring 5 - 1 0 years after the initial biopsy.
R. A. Perez-Tamayo and D. S. Tyler
Treatment Options Total mastectomy. Given the potential for DCIS to progress to an invasive and metastatic malignancy, total mastectomy remains the gold standard therapeutic choice. Balch et al. combined data from seven series to quote a local recurrence rate of 3.1% and a mortality of 2.3% after total masteetomy, which involves the removal of all breast tissue with no resection of axillary contents or muscle (13). Axillary dissection is hardly ever indicated, as DCIS is associated with nodal metastasis < 2% of the time (14). Its use is limited to the rare situations when DCIS presents as a palpable tumor of very large size (e.g., > 3 era), or with proven extensive microinvasion. Although local or regional control and cure goals are satisfied with this approach, and staging generally only needs involve the breast tissue itself, the cosmetic result is poor unless reconstruction is employed. Breast reconstruction, which can take place immediately after total mastectomy, has developed into a highly effective adjunct. A variety of techniques including silicone- or salinefilled implants or autologous flaps are available xvith excellent results.
Segmental resection with and without radiation. Holland et al. demonstrated that nearly all DCIS lesions detected with current techniques are unicentric, albeit occasionally extensive in a fashion that is difficult to evaluate with mammography (15). DCIS tends to track in a segmental distribution toward the nipple. These features, coupled with the low potential for systemic spread of DCIS and the desire to cure wlfile achieving a breast-sparing cosmetic result, have driven the interest in segmental resection as a means of treating DCIS. Segmental resection 'alone has been associated with local recurrence rates as high as 63% and as low as 10%. As most recurrence occurs at the site of the original excision, it is not surprising that this highly variable local failure rate should be associated with inadequately cleared margins mad with larger lesions. These results compare poorly with the gold standam of total masteetomy. The addition of radiation therapy to segmental resection reliably lowers local recurrence to 9.4%, with a mortality of only 1.7% (13). The results m~, even be better with appropriately selected pa-
MEDICAL UPDATE FOR PSYCHIATRISTS
tients. NSABP trial B-17 is currently examining the use of segmental resection with negative margins together with irradiation, and 80% of the patients have asylnptomatic DCIS. Initial results were reported in 1993 and showed a reduction in the incidence of second ipsilateral breast cancers from 10.4% to 7.5% in patients receiving radiation 'after lumpectomy for noninvasive forms, and fi'om 10.5% to 2.9% for invasive fornas of intraductal breast cancer. Mthough the local recurrence can often be addressed with masteetomy, 50% of the recurrence exhibits invasion, impl~ng that a nraJignaancy that wotdd have been essentially curable with masteetomy has been allowed to progress to a potentially lethal form. Patients who desire the breast-sparing cosmetic result of this treatment mod'aJib, shotdd be counseled of the higher risk of local recmTenee compared with lnastectomy. Segmental resection with radiotherapy should not be used with patients with extensive microealeifications on mammogram, patients for whom clear margins are difficult to obtain, and patients who are pregnant or have selerodenna.
Adjuvant Therapy. NSABP Protocol B-24 is currently examining whether tamoxifen antihormonal therapy can decrease recurrence of breast cancer in patients with DCIS who are treated with breast conser,~ing surgery (lumpeetomy and radiation therapy), hoping to demonstrate an advantage similar to that seen with tamoxifen in im;asive breast cancer. There is no established role at this time for cytotoxic or hormonal therapy in the treatment of DCIS.
nant lesion that progress to full-blown malignancy. Invasive breast cancer develops in 37% of patients with LCIS, with a mortality of up to 16% (16). Greater than 50% of these malignancies are ductal in origin. Presenting most frequently as an incidental finding on biopsy, the risk of developing a subseqnent invasive cancer is the same in each breast regardless of the site of the original biopsy or whether the biopsy margins are positive. LCIS is highly nmlticentric in nature, and is associated with axillary nodal metastases in <1% of patients. LCIS tends to occur in prelnenopausal women.
Treatment Options Bilateral Mastectomy. Bilateral masteetolny by removing all breast tissue is
the surest way to decrease risk of invasire malignancy to negligible levels in patients with LCIS. This option may be particularly worthy of consideration in the younger patient who has more years of increased risk ahead of her, especially given the effectiveness of modern reconstructive procedures. As the rate of axillary nodal metastases is so low, axillary dissection is unnecessary.
Observation. Patients may elect to have close follow-up with mammography and clinical exam rather than undergo bilateral mastectolny. The patient must understand that her risk is 12-fold greater than the general population. Mirror-image biopsy of the contralateral breast is no longer adx~isedwhen a suspicious lesion is noted in the LCIS patient and evaluated with excision, as the risk of malignancy is equal in "allbreast tissue.
Adjuvant therapy. No chemotherapy Lobular Carcinoma In $ i t u
Pathology Lobular carcinoma in situ ( LCIS ) is distinguished by malignant proliferation of the terminal lobular-ductal unit, contained by its basement membrane. The malignant cells are slightly larger than the normal aeinar cells and are characterized by a normal cytoplasm to nucleus ration and rare mitotic figures.
or hormonal therapy is currently advocated for LCIS. As the premenopausal hormonal state may be related to the pathogenesis of LCIS and LCIS-related breast cancer, NSABP Protocol P-1 will evaluate the use of tamoxifen to decrease the rate of breast cancer in this high-risk population.
Invasive Breast Cancer
Pathology Natural History Lobular carcinoma in situ is best understood as a marker of increased risk for breast cancer rather than as a premalig168
Invasive breast cancer demonstrates five common histologic patterns that often are seen in combination with each other in excised breast tissue. These patterns
Current Management of Breast Cancer
MEDICAL UPDATE FOR PSYCHIATRISTS
Table !. TNM Staging of Breast Cancer.
Primary tumor (T) TX TO Tis T1 Tla Tlb Tle T2 T3 T4 T4a T4b T4c T4d Regional
Primary tumor cannot be assessed No evidence of primary tumor Carcinoma in situ. Intraduetal carcinoma, lobular carcinoma in situ, or Paget's disease of the nipple with no tumor Tumor --<2.0 cm in greater dimension Tumor -<0.5 cm in greatest dimension Tumor >0.5 tin but not >1.0 cm in greatest diiuension Tumor > I 0 cm but not >2.0 cm in greatest dimension Tumor >2.0 em but not >5.0 cm in greatest dimension Tmnor >5.0 cm in greatest dimension Tumor of any size with direct extension to chest wall or skin Extension to chest wall Edema (including peau d'orange) or ulceration of the skin of the breast or satellite skin nodules confined to the same breast Both T4a and T4b above Inflammatory carcinoma lymph node involvement (N) (clinical)
NX NO N1
Regional lymph nodes cannot be assessed (e.g., previously removed) No regional lymph node metastasis Metastasis to movable ipsilateral axillary b~mph node(s) Metastasis to ipsilateral axillary lymph node(s) fixed to one another or the N2 other structures N3 Metastasis to ipsilateral mammary lymph node(s) Distant metastasis (M)
Natural Historff
mx MO
Presence of distant metastasis cannot be assessed No distant metastasis Distant metastasis (includes metastasis to ipsilateral supraclavicular lymph ml node[s J) Stage grouping Stage 0 Stage 1 Stage Ila Stage lib Stage I l i a
Stage l l l b Stage IV
Tis T1 TO T1 T2 T2 T3 TO T1 T2 T3 T4 Any T Ally T
can be associated with behavior of the malignancy. Infiltrating ductal carcinoma accounts for 75% of all breast cancers, and is classically described as a seirrhous, gritty, hard mass. There can be varying a m o u n t s of DCIS in the specimen, along with the invasive ductal portions that can spread to the axillary nodes via the lymphatics and hematogenously to bones, lung, liver, and brain. When combined with infiltrating duetal carcinoma, the other histologies will tend to
NO NO N1 N1 NO N1 NO N2 N2 N2 N1, N2 Any N N3" Any N
MO MO MO MO MO MO MO MO MO MO MO MO MO ml
have similar prognoses to purely infiltrating ductal lesions. Infiltrating lobular carcinoma is the subtype encountered in 5 % - 1 0 % of cases. Like L C I S , it is of}en multicentric, and although it carries the same smwival rates as invasive ductal carcinoma, it has a predilection for metastasis to serosa of bowel and lneninges. Tubular carcinoma is a more unusual subtype that comprises 2% of cases. Its epon}qnous tubular histoloD~ is only rarely associated with axillary metasta169
sis, and therefore carries a much better prognosis than other forms of breast cancer. Medullape carcinoma of the breast, 5 % - 7 % of all breast cancer, has a favorable prognosis as long as all of its component histologic features are present: poorly differentiated nuclei, syncytial gro\~ech pattern, well-eiremnsei-ibed borders, intense infiltration with lymphocytes and plasma cells, and a paucity of coincident DCIS. Mutinous carcinoma accounts for 3% of 'all breast cancers and is typified by slow-growing, bulb, tumors, with copious amounts of extracellular mucin surrounding clustered tumor cells. The greater the mutinous character of a breast carcinoma, the better its prognosis.
Some mention should be made of predisposing factors for invasive breast cancer, especially in light of media attention on the subject. Well-known risk factors include sex, age, prior breast cancer, endogenous endocrine factors (earl): menarche, age at menopause, parity, age at first full-term pregnancy), and exogenous hormone use. Any family histolT of breast cancer increases the patient's risk, but only cancer in a firstdegree relative raises it significantly. This increased ~isk is substantially larger if the relative had breast cancer before menopause. Recent discovmies in the field of genetics have located the gent responsible for earlv-onset familial breast cancer. Women'x~4th the BtlCA1 gent, which is located on chromosome 17% or the BRCA2 gent. located on 13q, have a 70%-90% cumulative chance of developing breast caucer. Since the media reports of this diseove u , patients will frequently present with the fear that they suffer from these abnormalities despite the lack of the usual strong family histol T and the fact that genetic breast cancer represents only 3% of breast malignancies. The most important determinants of the prognosis of a case of breast cancer are tmnor size and axillaQ~node status. They are the basis of the TNM staging system of breast cancer (Table 1). The size of the tumor, or of the largest mass when several ipsilateral tumors are present, is judged by physical exam or by mammogram. Bilateral cancers are staged separately. Dimpling and nipple
R. A. Perez-Tauuzyo and D. S. Tyler Table 2. Toxicity From Adjuvant Therapy.
I. Chemotherapy (CMF or FAC regimens) A. Common (>50% of patients) Weight gain Alopecia Nausea/vomiting Leukopenia Thromboeytopenia Amenorrhea B. Oeeasional (>10%-15%) Hemorrhagic cystitis C. Uncommon (<1%) Sepsis Cardiac toxicity Secondary malignancies Thrombophlebitis II. Tamoxifen hormonal therapy A. Common (>50% of patients) Hot flashes B. Occasional (>10%-15%) Weight gain Thrombophlebitis Nausea Vaginitis C. Uncommon (<1%) Pulmonary embolus Endometrial carcinoma (disputed)
retraction have no effect on staging. Inflammatory carcinoma has its own staging classification and is so called for the appearance caused by edema secondary to malignant cells plugging lymphatics. Axillary node status is difficult to reliably assess clinically. In one series, 17% of clinically TIN0 patients and "27% of clinically T2N0 patients had histologically positive nodes. Staging is therefore determined by histologic evaluation of axillary nodes. The number of histologically positive nodes has definite prognostic value, so the N classification reflects this by subdividing patients according to these data. Earlu-Stage Invasive Breast Cancer Stage I and II invasive breast cancers are termed early stage and comprise three-quarters of all breast cancer. Treatment Options Masteetomy with or without Reconstruction. The modified radical mastectomy (MRM) in its most widely accepted form involves the removal of all breast tissue off the pectoralis major muscle and chest wall, including the an-
MEDICALUPDATEFOIl PSYCHIATRISTS
terior pectoralis major fascia in the resection. Implied in the procedure is an axillary dissection of the level I and II nodes, lateral to and behind the pectoralis minor muscle. The borders of this dissection are the axillary vein superiorly and the latissiluus dorsi laterally. The long thoracic and thoraeodorsal nerves are identified and preserved, although the intercostal braehial nerve is often sacrificed, leaving an anesthetic patch in the posteromedial aspect of the upper arm. Drains are left to prevent the accumulation of lymph and serum under the skin flaps (if no reconstruction is performed immediately), and in the axilla. These are removed when daily volume decreases to 30 ml/day, which usually occurs in the first postoperative week. Modified radical lnasteetomy achieves local control through extirpation of the breast tissue. Recurrence-free survival at 5 years approaches 85% in node-negative patients and 60% in patients with one to three positive nodes (17). The majority of recurrence is local or regional and is associated with systemic disease. The mental health care professional will be well aware of the cosmetic disadvantages of unreconstructed M RM and the sense of perceived disfigurement and loss of body image that patients can suffer. Historically, reconstruction was delayed 2 years as it was feared that reconstruction might obscure the 80% of locally recurrent disease that would be manifest at that time. As these suspicions were not borne out, the current standard of care is for immediate reconstruction. Reconstructive techniques most commonly involve the subpectoral placement of implants (with or without the use of tissue expanders), or the use of autologous muscle faps, the most common being the transverse rectus abdoIninis muscle (TRAM) flap. These options should be entertained with all patients except those unable to withstand the prolonged anesthetic for the combined MRM and reconstruction, or those patients who do not feel reconstruction would improve their quality of life.
Local Resection with and without Radiation. Breast conservation represents an attempt to remove the primau tumor with a 1-era margin, and to obtain local or regional control with radiation therapy, as opposed to the extirpation 170
of all ipsilateral breast tissue. Local recurrence after breast conservation approaches is usually treated with mastectomy. A comparison of survival rates between breast conservation, breast conservation with radiation therapy, and MRM reveals no significant difference. Local recurrence is, however, a failure of therapy that negates the goal of breast conservation and is distressing to the patient. The addition of radiation therapy to local resection reduces the local recurrence rate by at least twothirds, from 35% to 10% (18). Axillary dissection is performed in all these patients principally for its importance in staging, but also because of its measurable contribution to regional control. More recently, the role of axillary dissection for patients with tumors > 2 em in size has been discussed. Many" of these patients will receive adjuvant therapy based on the size of the primary. In this group of patients in whom axillary dissection might not add to the overall treatment plan, radiation therapy can provide good local control. Not all patients are suitable candidates for conservative approaches: the tumor must be <4 em, though there are trials examining whether preoperative neoadjuvant chemotherapy and radiation ean allow more advanced patients to participate. Multifoeality or multicentricity by careful exam or detailed mammography should also exclude a patient from breast conservation therapy. Tumors with an extensive intraduetal component have a tendency to exhibit tongues of tumor extension or additional tumor loci beyond a 2em zone surrounding the tumor and require special care (19). The importance of clear intraoperative labeling of margins is obvious. If a clear 1-cm margin cannot be obtained on two attempts at reexeision, the patient should receive MRM ('20).
Adjuvant Therapy. The control of systemic disease is undertaken by eytotoxic agents aimed at highly replicative cells or by exploitation of the hormonal axis of breast tissue. Agencies aimed at the hormonal control of breast caneer include ovarian ablation and tamoxifen therapy, of which tamoxifen therapy is by far the more widely used. Cytotoxic combinations commonly employed against breast cancer are CMF (cyclophosphamide, methotrexate, 5-fluorouracil) and the doxorubicin-based FAC (5-fluorouraeil, adriamycin, cyelophos-
Current Management of Breast Cancer
MEDICAL UPDATE FOR PSYCHIATRISTS
ESR ~ " Positive
Premenopausal
f
~
ESR __~. Negative
Multiagent Chemotherapy Possible Tamoxifen
Multiagent Chemotherapy I
ESR ----~I Tamoxifen, Possible -/~'Positive Multiagent Chemotherapy Postmenopausal -
"~
ESR Negative
Multiagent Chemotherapy Possible Tamoxifen
<1 cm
f
ESR Negative
f v4_xi... Nod
"•
~" I
N°ne
I
_>1 cm, "- < 2 cm - - ~
Possible Multiagent Chemotherapy Consider prognostic factors
>2 cm...
Multiagent Chemotherapy ] 1
<1 c m
None [
v
ESR Positive >lcm
Tamoxifen Possible Multiagent Chemotherapy
Figure 2. Algorithm for adjuvant therapy in early-Stage invasive breast cancer.
phamide). It is important to consider the toxicity of these adjuvants to temper enthusiasm at applying their impressive benefits (Table 2) (13). To best understand the use of adjuvant therapy, one should review some insights from the Early Breast Cancer Triallists Collaborative Group (EBCTCG) meta-analyses of prospective series. Adjuvant therapy, tamoxifen or chemotherapy, has a potential 20% benefit regardless of nodal status, improving 5-year survival from 55% in patients treated with surgery alone to 64% in node-positive patients, and from 92% to 94% in node-negative patients. EBCTCG strongly suggested
that chemotherapy is far more effective in patients younger than 50 ).,ears, while talnoxifen achieves its greatest effect in women 50 and older. The relevant benefits of adjuvant therapy do not significantly vary with number of nodes positive, and instead depend far more on age and estrogen receptor status. Women with estrogen receptor-rich tumors have a far greater benefit from tamoxifen than their receptor-negative counterparts. The efficacy of tamoxifen in women > age 50 is the same when given alone or in conjunction with chemotherapy (21). An area of controversv occurs in node-negative patients as to whether 171
the risks of chemohonnonal therapy outweigh the benefits in treating disease with no clinically or pathologically evident systemic spread. McGuire et al. (21) ana1)~ed a number of tumor characteristics (size, receptor status, ploidy, nuclear grade, s-phase fraction, cathepsin D level) known to indicate more aggressive behavior in terms of the risk of recurrence at 5 years from node-negative breast em~cer. These factors, of which size is the most reliable, can be used to help determine the indication for adjuvant therapy
(22). A sample algorithm to guide decision making for adjuvant therapy is summarized in Figure 2.
B. A. Perez-Tamayo and D. S. Tyler
Locallu Advanced and M e t a s t a t i c Breast Cancer Space limits a substantive discussion of late-stage invasive breast eaneer. Breast conservation is usually no longer an issue, and breast surgery is dedicated to local or regional control. Radiation therapy is used in the operative field for local or regional control and in the management of specific metastases. A total of 66% of patients with metastatic breast cancer respond to standard-dose chemotherapy, but only 20% or fewer approach complete response (23). Disease-free survival at 10 years is < 5 % for patients who had a complete response to chemotherapy. The median survival for patients with metastatic breast caneer is 2 years (24). High-dose chemotherapy and bone m a r r o w / h e m a t o p o i eric stem cell transplantation have been employed to combat late-stage breast cancer with 5-year disease-free survival in Stage IV patients quoted as 1 0 % 20% (25). The c o s t - b e n e f i t ratio of this therapy has been controversial in the managed care environment and has gained a great deal of media attention.
Conclusions The m a n a g e m e n t of breast cancer at any stage is a multidisciplinary effort, as primary care providers interact with surgeons and radiologists in earlier stages and with radiation oncologists and medical oncologists in later stages. This article has sought to review recent developments in m a n a g e m e n t of this disease and present information usefill to those involved with the care of these patients. Many of the decisions involved do not trade in altered survival statistics, but ultimately revolve around the patient's peace of mind and her satisfae-
MEDICAL UPDATE FOR PSYCHIATRISTS
tion with her body image, issues that fall squarely in the sphere of the mental health care professional.
Referenees 1. Harris JR, LM, Veronesi U, Willett W. Breast cancer (first of three parts). N Engl J Med 1992;327:319-328. 2. Parker SL, TI', Bolden S, Wingo PA. Cancer statistics, 1996. CA Cancer J Clin 1996;46:5-27. 3. Miller BA, FE, Hankey BF. Recent incident trends for breast cancer in women and the relevance of early detection: An update. CA Cancer J clin 1993;43:2741. 4. Murad T, CG, Mouriesse H. Nipple discharge from the breast. Annals Surg 1982; 195. 5. Layfield LJ, GB, Cramer H. Fine needle aspiration in the management of breast masses. Pathol Annu 1989;24:23. 6. Morrow M, SR, Cregger B, et al. Preoperative evaluation of abnormal mammographic findings to avoid unnecessary breast biopsies. Arch Surg 1994;129: 1091. 7. Schmidt RA. Stereotactic breast biopsy. CA Cancer J Clin 1994;44:172-191. 8. Hernandez LE, CP, Striclder SA, Akers MM, Dunn MM. Are stereotactic biopsies adequate? Surgery 1994; 116:610615. 9. Lodato RF, MH, Greene MI, et al. hnmunohistochemical evaluation of CerbB-2 oncogene expression in duetal carcinoma in situ and a~,pical ductal hyperplasia of the breast. Mod Pathol 1990; 3:449-454. 10. Meyer JS. Cell kinetics of histologic variants of in situ breast carcinoma. Breast Cancer Res Treat 1986;7:171180. 11. Page DL, DW, Rogers LW, Landenberger M. Intraductal carcinoma of the breast: Follow-up after biopsy only. Cancer 1964; 17:1501-1527. 12. Rosen PP, BD, Kinne DE. The clinical significance of preinvasive breast carcinoma. Cancer 1980;46:919-925. 13. Balch DM, SS, Bland KI. Clinical deci-
sion-making in early' breast cancer. Anhal Surgery 1993;217:207-225. 14. Frazier TG, CE, Gallaher HS, et al. Prognosis and treatment in minimal breast cancer. AmJ Surg 1977; 133:697701. 15. Holland R, HJ, Verbeek ALM, et al. Extent, distribution, and mammographic/ histological correlations of breast ductal carcinoma in situ. Lancet 1990;315: 519-522. 16. Rosen PP, LP, Braun DW, et al. Lobular carcinoma in situ of the breast: Detailed analysis of 99 patients with average follow-up of 24 ),ears. Am J Surg Pathol 1978;3:225-251. 17. Rosemond GP, MW. Modified radical mastectomy, in B. R. Nyhus LM, Ed., MasCeryof Surgery. IJttle, Brown, 1992, pp. 310-318. 18. Fisher B, AS. Conservative surge~- for the management of invasive and nonhlvasive carcinoma of tile breast: NSABP Trials. World j Surg 1994; 18:63-69. 19. Holland R, CJ, Gelman R, et al. The presence of an extensive intraductal component follox~4nga limited excision correlates with prominent residiral disease in the remainder of the breast. J Clin Oncol 1991; 8:113-118. 20. Eberlein TJ. Current management of carcinoma of the breast. Annal Surg 1994; 220:121-136. 21. Hortoba~4 GN, BA. Current status of adjuvant ustemic therapy for primary breast cancer: Progress and cvntroversy. CA Cancer J Clin 1995;45:199-226. '2:2. MeGuire WL. How to use prognostic tZac,tots in axillar),-node-negative breast cancer patients. J Natl CA Inst 1990;82:1006. 23. Hortobag~i GN. Salvage chemotherapy for metastatic breast cancer. Semin Hematol 1987;'24 ( Suppl 1 ):,56-61. "24. Hortobagyi GN, FD, Buzdar AU, et al. Complete remissions in metastatic breast cancer: A thirteen-year follow-up report. Proc ASCO 1988;7:37a. 25. Appelbaum FR. The use of bone marrow and periphend blood stem cell transplantation in the treatment of cancer. CA Cancer J Clin 1996;46:142-164.
Current Management of Breast Cancer R. Anthony Perez-Tamayo, MD, PhD, and Douglas S. Tyler, aid
Surgeru Update
DEPARTMENT OF GENERAL AND THORACIC SURGERY, DUKE U N I V E R S I T Y M E D I C A L C E N T E R , DURHAM, NORTH CAROLINA 27710, U.S.A.
Ahstract
Epidemiolonn
Breast cancer is the second leading cause of cancer deaths in women, and is responsible f o r 44,300 deaths in 1996. Its incidence is rising, in part owing to improvements in mammographic screening. Current guidelines for mammography and their support are reviewed. Presenting symptoms of breast cancer and the conduct of a history and physical exam geared toward the evaluation of breast malignancy are briefly described. An algorithm for the workup of palpable masses and nonpalpable abnormalities is presented, including a discussion of the role of stereotactic biopsy. A summary of the pathology, natural history and treatment options for ductal and lobular in situ malignancies is given, with particular attention to the role of breast conservation, its risks and benefits. The controversies surrounding breast conservation versus modified
Based on data from 1983 to 1987 and on mortality rates from 1987 for the United States, 12% of all women develop breast cancer and 3.5% die of this disease (1). According to statistics from the American Cancer Society, in 1996 there were an estimated 184,300 new eases of breast cancer diagnosed in women and 44,300 deaths in women from breast cancer (2). The incidence of breast cancer has increased especially dramatically since 1982. Mthougb there is disagreement as to the reasons for this increase in ageadjusted incidence, there is e\~dence to support that it may- be the result of increased detection of breast cancers at an earlier stage found by, screening man> mography (3).
radical mastectomy and the role of adjuvant and radiation therapy in the management of invasive breast cancer are summarized. Currently available figures for the success of high-dose
chemotherapy/hematopoietic stem cell transplantation in the setting of metastatic breast cancer are quoted. © R. A. Perez-Tamayo and D. S. Tyler. MEDICAL UPDATE FOR PSYCHIATRISTS 1:5; 165-172, 1996.
groups: The sensitMty of mammography in the woman younger than age 50 is reduced by tissue density, and is focused on a population with a lower incidence of the disease. Without conclusive evidence of altered mortality rates with screening mammography between ages 40 and 49, the National Cancer Institute announced that it would not continue to recommend routine screening mammograms for women in this age group. Other organizations such as the American Cancer Society and the American College of Radiology continue to recommend mammograms every 1-2 years in this age group. All organizations agree that clinical breast examination as well as mammography are both essential for optimal screening, and that annual mammography should be done for women aged 50 and over.
Screening Mammographn The benefit from screening mammography has been a subject of substantial controversy. Although screening mammography increases detection of smaller tumors, with uninvolved axillary nodes and noninvasive histologies, statistics may not show improvement in mortality rates because of a number of inherent biases. Screening may be detecting eventually lethal cancer at an earlier stage (lead-time bias); less aggressive, slow-growing cancers that will not lead to death (length-time bias); tumors in the gray zone between atypia and tree malignancy ( overdiagnosis bias ) ; and tumors in a specific group with different risks from the overall population (selection bias). Hams et al. analyzed the resuits of seven trials of maminograpby whose randomization removes these biases, and concluded that screening mammography rednced breast cancer mortality by a conservative estimate of 25% ( 1 ). The benefits of screening mamlnography have not been shown to extend to all age
Presentation Patients with breast cancer will principall), present with a palpable breast mass. Before the advent of screening malnmography, 65% of breast cancer cases presented as breast masses. Other breast-related symptoms such as skin changes, changes in shape and size of a breast, breast pain, and nipple discharge only infrequently lead to a diagnosis of breast cancer. Features that distinguish potentially malignant nipple discharge are spontaneous (rather than induced) discharge; unilaterality, association with a mass; and a bloody, serosanguineous, or watery character. Even so, up to 80% of surgical specimens for nipple discharge will show benign causes, such as papilloma or duct eetasia (4). With the advent of mammography, presentation with a nonpalpable abnormality is increasingly common.
Historn and Phnsical Exam © 199G R. A. Perez-Tamauo and D. S. Tuler ISSN 1082-7579/gG/SlS.DO PII SIO82-7579(gG)OQQ78-7
Address reprint requests to: Douglas S. Tyler, M.D., Assistant Professor, Department of General and Thoracic Surgery,, Duke University, C5026 Veterans Administration Medical Center, Durham, NC 27710.
The key features in the medical history of a patient with a breast complaint are the patient's age, her age at menarehe, the number of pregnancies, number of
MEDICALUPDATEFOB PSYCHIATRISTS
R. A. Perez-Tamayo and D. S. Tyler
live births, and age at first birth. Inquiries should be made as to a family histou of breast cancer, including age of the affected relative, age of onset, and presence of bilateral disease. A previous surgical history of breast biopsies and their histologie diagnosis should be obtained. For premenopausal women, the date of the last menstrual period, length and regularity of cycles, and use of oral contraceptives should be determined. For the postmenopausal woman, date of menopause and whether the patient uses hormone replacement therapy are important details to record. The technique of breast examination is well known. The inspection of both breasts in supine and upright positions while noting asymmetry, palpation of axillary and other nodal fields, and examination of the nipple should be emphasized. The breast should be palpated with the flat part of the fingers. A pinching technique should not be used, as it will spuriously create the impression of a mass. The suspicions dominant mass gathers in tissue around it, with poorly described margins, and its texture is dissimilar from other areas of the breast. A rubbery, well-marginated, motile mass in a young woman is most likely to be a fibroadenoma. All abnormalities in the postmenopausal woman should be treated with greater suspicion.
Diagnostic Work-up
The initial step in the work-up of the palpable breast mass is mainmography. The purpose of the mammogram is to rule out not malignancy in the mass, but occult abnormalities in the remaining breast tissue. It is rarely advisable to employ mammography in the woman under 30 years of age, as the densi~ of the breast tissue obscures visualization of abnormalities. The next issue is to determine whether the mass is solid of cystic. Although some have used ultrasonography for this purpose, aspiration with a fine needle (22-gauge) serves the same purpose more expediently and at less expense. The incidence of breast cancer in breast cysts is only around 1%, and of these the vast majority are distinguished by blood?, fluid or by a residual mass revealed after aspiration. If the fluid is bloody it can be sent for cytologic analysis. Fine-needle aspiration
can also be used to biopsy the solid mass (FNAB). The 22-gauge needle is passed several times through the mass under constant suction and the aspirated material fixed in 95% ethanol. In the hands of an experienced cytopathologist, this technique approaches 90% accuracy. FNAB should be deferred until after a mammogram is obtained, as the sequelae (e.g., hematoma) of the biopsy can distort anatomy and lead to a false positive. It can be used to increase confidence in the clinical and/or mammographic diagnosis of a benign mass, which can then be followed xvithout surgical biopsy. A positive e~ologic diagnosis of malignancy cannot distinguish between invasive and in situ histologies, but indicates the need for open biopsy. A lesion suspicious for malignancy by physical exam and/or mamlnography but with a negative FNAB should still be excised, and many x~611forego FNAB in this situation; but taken together, when all three tests suggest a benign mass the false-negative rate was 0.7%. When all three suggest lnalignancy, the false-positive rate has been reported as 0.4% (5). The evaluation of the nonpalpable mass is most commonly prompted by an abnormal mammogram demonstrating either suspicious densities or microcaleifications suggestive of malignancy. Areas of lnicrocaleification usually require open biopsy if more than five spots are present in a cluster. As the lesions are not palpable, the technique of biopsy in these patients requires malnmographie localization with passage of a needle into the abnormality. A wire hook is then deployed into the lesion to mark it and images obtained to assist the surgeon in excision of the abnormal area. The wire is used to guide the excision. At the end of the procedure, the specimen is X-rayed to ensure that the microcaleifieations have been included in the specimen. A nonpalpable mass lesion can be approached initially bv stereotactic or ultrasound-guided needle biopsy, either FNAB or a core-biopsy capable of yielding histologic diagnosis. If a diagnosis is not obtained in this fashion, needle-localization biopsy isthen utilized. Lesions of low ( 1 % - 2 % ) risk can be followed at 6 months with a repeat naamlnogram, and lesions of negligible risk can re166
ceive the follow-up normal for that age group (6). Stereotactic core biopsy is receiving increasing attention as a low-cost, reliable alternative to needle-localized breast biopsy, which can have an operator-dependent failure rate in producing an interpretable speeilnen in the setting of nonpalpable breast cancer (7). A significant criticism of this technique is that as it has low cosmetic impact and is relatively inexpensive, it may be overused to biopsy patients who would have otherwise been followed with the even less expensive clinical breast exam/ lnammography combination (8). Information derived from the biopsy, clinical exam, and mammography w411 determine the surgical procedure of choice, which can be undertaken immediately after biopsy in many cases. Figure 1 demonstrates a commonly used clinical algorithm. Classification of Breast Cancer
Breast cancer can be divided into noninvasive and invasive categories. The noninvasive foruas are confined behind basement membranes and therefore have virtually negligible incidence of systemic spread. Noninvasive--sometimes known as lninimal--breast cancer arises from the two major cellular populations of the breast, duetular and lobular cells. Whatever the form of breast cancer, the goals of treatment are to cure, obtain local or regional control, stage the disease appropriately so the prognosis and treatment options are well understood, and achieve the best cosmetic result possible given the other goals. Ductal Carcinoma In $ilu
Pathology Ductal carcinoma in situ ( DCIS ) is made up of several snbt)qpes: solid, micropapillary, cribrifonn, and comedo. However, there is sufficient disparity between the aggressiveness of comedo and noncomedo forms that the subb,pes are usefully grouped in this way. Comedo DCIS is characterized by pleomorphic nuclei, fiequent mitotic figures, and necrotic cellular debris in the center of ducts. Comedo DCIS has a higher proliferative rate as measured by th)lnidine-labeling studies, overexpression of the e-erbB-2 oncogene in ahnost all cases, and high degree of
Current Management of Breast Cancer
MEDICAL UPDATE FOIl PSYCHIATRISTS
1 Clinical Breast Exam and Mammography
Palpable
Non-Palpable Lesion
Lesion
J Cystic Fluid
Fine-Needle Aspiration Cytology
.j
Breast Ultrasound
---...
or Suspicious Mammographic Localization
Non-BloodyI
Needle ~ LocaUsation vs. Biopsy and Specimen Radiography
Discard
Fluid
Open Biopsy
R!peat
ClinicalBreast Exam and Mammography Ultrasound
Stereotactic Biopsy
~ ~o-~
~
/ Benign
LocalResection AxillaryDisection Radiation Therapy
vs ModifiedRadicalMastectomy
Surveillance of Remaining and Contralateral Breast FinurB 1. Algorithm for diagnostic work-up and therapy of abnormalities detected on physical exam or by mammography.
aneuploidy by flow cytometry, and is associated with mieroinvasion more frequently than the other subtypes (9,10). Comedo DCIS is therefore thought to have a shorter intraduetal growth phase. In addition, eomedo DCIS tumors more frequently lack estrogen receptors than do noncomedo forms.
Natural History The obvious concern with in situ malignancies is that they will progress to invasive malignancies capable of metastasis.
Before the advent of inan~mography, DCIS presented as a palpable mass, nipple discharge, in the setting of Paget's disease of the nipple, or as an incidental finding on breast biopsy. The DCIS of this time period might be more likely to exhibit the beginnings of invasive behavior, microinvasion. Mieroinvasion is rarely seen in lesions < 25 mm in diameter. Meanwhile, the vast majority of microinvasion is seen in lesions > 45 mm in diameter. Currently, over 80% of DCIS lesions present as nonpalpable mammographic abnormalities. The natural histou of DCIS is confused by this difference 167
in the biological behavior of tile earlier described DClS, probably related to the fact that DCIS is detected at a much earlier stage today than "20 years ago. The best insight into the behavior of untreated DCIS is given by the series by Page et al. ( 11 ) and Rosen and Kinne (12) of patients whose specimens were interpreted as benign at the time of biopsy but who, retrospectively reviewed, ultimately turned out to be noncomedo DCIS. The ipsilateral recurrence ofinvasive breast cancer was 30%, occurring 5 - 1 0 years after the initial biopsy.
R. A. Perez-Tamayo and D. S. Tyler
Treatment Options Total mastectomy. Given the potential for DCIS to progress to an invasive and metastatic malignancy, total mastectomy remains the gold standard therapeutic choice. Balch et al. combined data from seven series to quote a local recurrence rate of 3.1% and a mortality of 2.3% after total masteetomy, which involves the removal of all breast tissue with no resection of axillary contents or muscle (13). Axillary dissection is hardly ever indicated, as DCIS is associated with nodal metastasis < 2% of the time (14). Its use is limited to the rare situations when DCIS presents as a palpable tumor of very large size (e.g., > 3 era), or with proven extensive microinvasion. Although local or regional control and cure goals are satisfied with this approach, and staging generally only needs involve the breast tissue itself, the cosmetic result is poor unless reconstruction is employed. Breast reconstruction, which can take place immediately after total mastectomy, has developed into a highly effective adjunct. A variety of techniques including silicone- or salinefilled implants or autologous flaps are available xvith excellent results.
Segmental resection with and without radiation. Holland et al. demonstrated that nearly all DCIS lesions detected with current techniques are unicentric, albeit occasionally extensive in a fashion that is difficult to evaluate with mammography (15). DCIS tends to track in a segmental distribution toward the nipple. These features, coupled with the low potential for systemic spread of DCIS and the desire to cure wlfile achieving a breast-sparing cosmetic result, have driven the interest in segmental resection as a means of treating DCIS. Segmental resection 'alone has been associated with local recurrence rates as high as 63% and as low as 10%. As most recurrence occurs at the site of the original excision, it is not surprising that this highly variable local failure rate should be associated with inadequately cleared margins mad with larger lesions. These results compare poorly with the gold standam of total masteetomy. The addition of radiation therapy to segmental resection reliably lowers local recurrence to 9.4%, with a mortality of only 1.7% (13). The results m~, even be better with appropriately selected pa-
MEDICAL UPDATE FOR PSYCHIATRISTS
tients. NSABP trial B-17 is currently examining the use of segmental resection with negative margins together with irradiation, and 80% of the patients have asylnptomatic DCIS. Initial results were reported in 1993 and showed a reduction in the incidence of second ipsilateral breast cancers from 10.4% to 7.5% in patients receiving radiation 'after lumpectomy for noninvasive forms, and fi'om 10.5% to 2.9% for invasive fornas of intraductal breast cancer. Mthough the local recurrence can often be addressed with masteetomy, 50% of the recurrence exhibits invasion, impl~ng that a nraJignaancy that wotdd have been essentially curable with masteetomy has been allowed to progress to a potentially lethal form. Patients who desire the breast-sparing cosmetic result of this treatment mod'aJib, shotdd be counseled of the higher risk of local recmTenee compared with lnastectomy. Segmental resection with radiotherapy should not be used with patients with extensive microealeifications on mammogram, patients for whom clear margins are difficult to obtain, and patients who are pregnant or have selerodenna.
Adjuvant Therapy. NSABP Protocol B-24 is currently examining whether tamoxifen antihormonal therapy can decrease recurrence of breast cancer in patients with DCIS who are treated with breast conser,~ing surgery (lumpeetomy and radiation therapy), hoping to demonstrate an advantage similar to that seen with tamoxifen in im;asive breast cancer. There is no established role at this time for cytotoxic or hormonal therapy in the treatment of DCIS.
nant lesion that progress to full-blown malignancy. Invasive breast cancer develops in 37% of patients with LCIS, with a mortality of up to 16% (16). Greater than 50% of these malignancies are ductal in origin. Presenting most frequently as an incidental finding on biopsy, the risk of developing a subseqnent invasive cancer is the same in each breast regardless of the site of the original biopsy or whether the biopsy margins are positive. LCIS is highly nmlticentric in nature, and is associated with axillary nodal metastases in <1% of patients. LCIS tends to occur in prelnenopausal women.
Treatment Options Bilateral Mastectomy. Bilateral masteetolny by removing all breast tissue is
the surest way to decrease risk of invasire malignancy to negligible levels in patients with LCIS. This option may be particularly worthy of consideration in the younger patient who has more years of increased risk ahead of her, especially given the effectiveness of modern reconstructive procedures. As the rate of axillary nodal metastases is so low, axillary dissection is unnecessary.
Observation. Patients may elect to have close follow-up with mammography and clinical exam rather than undergo bilateral mastectolny. The patient must understand that her risk is 12-fold greater than the general population. Mirror-image biopsy of the contralateral breast is no longer adx~isedwhen a suspicious lesion is noted in the LCIS patient and evaluated with excision, as the risk of malignancy is equal in "allbreast tissue.
Adjuvant therapy. No chemotherapy Lobular Carcinoma In $ i t u
Pathology Lobular carcinoma in situ ( LCIS ) is distinguished by malignant proliferation of the terminal lobular-ductal unit, contained by its basement membrane. The malignant cells are slightly larger than the normal aeinar cells and are characterized by a normal cytoplasm to nucleus ration and rare mitotic figures.
or hormonal therapy is currently advocated for LCIS. As the premenopausal hormonal state may be related to the pathogenesis of LCIS and LCIS-related breast cancer, NSABP Protocol P-1 will evaluate the use of tamoxifen to decrease the rate of breast cancer in this high-risk population.
Invasive Breast Cancer
Pathology Natural History Lobular carcinoma in situ is best understood as a marker of increased risk for breast cancer rather than as a premalig168
Invasive breast cancer demonstrates five common histologic patterns that often are seen in combination with each other in excised breast tissue. These patterns
Current Management of Breast Cancer
MEDICAL UPDATE FOR PSYCHIATRISTS
Table !. TNM Staging of Breast Cancer.
Primary tumor (T) TX TO Tis T1 Tla Tlb Tle T2 T3 T4 T4a T4b T4c T4d Regional
Primary tumor cannot be assessed No evidence of primary tumor Carcinoma in situ. Intraduetal carcinoma, lobular carcinoma in situ, or Paget's disease of the nipple with no tumor Tumor --<2.0 cm in greater dimension Tumor -<0.5 cm in greatest dimension Tumor >0.5 tin but not >1.0 cm in greatest diiuension Tumor > I 0 cm but not >2.0 cm in greatest dimension Tumor >2.0 em but not >5.0 cm in greatest dimension Tmnor >5.0 cm in greatest dimension Tumor of any size with direct extension to chest wall or skin Extension to chest wall Edema (including peau d'orange) or ulceration of the skin of the breast or satellite skin nodules confined to the same breast Both T4a and T4b above Inflammatory carcinoma lymph node involvement (N) (clinical)
NX NO N1
Regional lymph nodes cannot be assessed (e.g., previously removed) No regional lymph node metastasis Metastasis to movable ipsilateral axillary b~mph node(s) Metastasis to ipsilateral axillary lymph node(s) fixed to one another or the N2 other structures N3 Metastasis to ipsilateral mammary lymph node(s) Distant metastasis (M)
Natural Historff
mx MO
Presence of distant metastasis cannot be assessed No distant metastasis Distant metastasis (includes metastasis to ipsilateral supraclavicular lymph ml node[s J) Stage grouping Stage 0 Stage 1 Stage Ila Stage lib Stage I l i a
Stage l l l b Stage IV
Tis T1 TO T1 T2 T2 T3 TO T1 T2 T3 T4 Any T Ally T
can be associated with behavior of the malignancy. Infiltrating ductal carcinoma accounts for 75% of all breast cancers, and is classically described as a seirrhous, gritty, hard mass. There can be varying a m o u n t s of DCIS in the specimen, along with the invasive ductal portions that can spread to the axillary nodes via the lymphatics and hematogenously to bones, lung, liver, and brain. When combined with infiltrating duetal carcinoma, the other histologies will tend to
NO NO N1 N1 NO N1 NO N2 N2 N2 N1, N2 Any N N3" Any N
MO MO MO MO MO MO MO MO MO MO MO MO MO ml
have similar prognoses to purely infiltrating ductal lesions. Infiltrating lobular carcinoma is the subtype encountered in 5 % - 1 0 % of cases. Like L C I S , it is of}en multicentric, and although it carries the same smwival rates as invasive ductal carcinoma, it has a predilection for metastasis to serosa of bowel and lneninges. Tubular carcinoma is a more unusual subtype that comprises 2% of cases. Its epon}qnous tubular histoloD~ is only rarely associated with axillary metasta169
sis, and therefore carries a much better prognosis than other forms of breast cancer. Medullape carcinoma of the breast, 5 % - 7 % of all breast cancer, has a favorable prognosis as long as all of its component histologic features are present: poorly differentiated nuclei, syncytial gro\~ech pattern, well-eiremnsei-ibed borders, intense infiltration with lymphocytes and plasma cells, and a paucity of coincident DCIS. Mutinous carcinoma accounts for 3% of 'all breast cancers and is typified by slow-growing, bulb, tumors, with copious amounts of extracellular mucin surrounding clustered tumor cells. The greater the mutinous character of a breast carcinoma, the better its prognosis.
Some mention should be made of predisposing factors for invasive breast cancer, especially in light of media attention on the subject. Well-known risk factors include sex, age, prior breast cancer, endogenous endocrine factors (earl): menarche, age at menopause, parity, age at first full-term pregnancy), and exogenous hormone use. Any family histolT of breast cancer increases the patient's risk, but only cancer in a firstdegree relative raises it significantly. This increased ~isk is substantially larger if the relative had breast cancer before menopause. Recent discovmies in the field of genetics have located the gent responsible for earlv-onset familial breast cancer. Women'x~4th the BtlCA1 gent, which is located on chromosome 17% or the BRCA2 gent. located on 13q, have a 70%-90% cumulative chance of developing breast caucer. Since the media reports of this diseove u , patients will frequently present with the fear that they suffer from these abnormalities despite the lack of the usual strong family histol T and the fact that genetic breast cancer represents only 3% of breast malignancies. The most important determinants of the prognosis of a case of breast cancer are tmnor size and axillaQ~node status. They are the basis of the TNM staging system of breast cancer (Table 1). The size of the tumor, or of the largest mass when several ipsilateral tumors are present, is judged by physical exam or by mammogram. Bilateral cancers are staged separately. Dimpling and nipple
R. A. Perez-Tauuzyo and D. S. Tyler Table 2. Toxicity From Adjuvant Therapy.
I. Chemotherapy (CMF or FAC regimens) A. Common (>50% of patients) Weight gain Alopecia Nausea/vomiting Leukopenia Thromboeytopenia Amenorrhea B. Oeeasional (>10%-15%) Hemorrhagic cystitis C. Uncommon (<1%) Sepsis Cardiac toxicity Secondary malignancies Thrombophlebitis II. Tamoxifen hormonal therapy A. Common (>50% of patients) Hot flashes B. Occasional (>10%-15%) Weight gain Thrombophlebitis Nausea Vaginitis C. Uncommon (<1%) Pulmonary embolus Endometrial carcinoma (disputed)
retraction have no effect on staging. Inflammatory carcinoma has its own staging classification and is so called for the appearance caused by edema secondary to malignant cells plugging lymphatics. Axillary node status is difficult to reliably assess clinically. In one series, 17% of clinically TIN0 patients and "27% of clinically T2N0 patients had histologically positive nodes. Staging is therefore determined by histologic evaluation of axillary nodes. The number of histologically positive nodes has definite prognostic value, so the N classification reflects this by subdividing patients according to these data. Earlu-Stage Invasive Breast Cancer Stage I and II invasive breast cancers are termed early stage and comprise three-quarters of all breast cancer. Treatment Options Masteetomy with or without Reconstruction. The modified radical mastectomy (MRM) in its most widely accepted form involves the removal of all breast tissue off the pectoralis major muscle and chest wall, including the an-
MEDICALUPDATEFOIl PSYCHIATRISTS
terior pectoralis major fascia in the resection. Implied in the procedure is an axillary dissection of the level I and II nodes, lateral to and behind the pectoralis minor muscle. The borders of this dissection are the axillary vein superiorly and the latissiluus dorsi laterally. The long thoracic and thoraeodorsal nerves are identified and preserved, although the intercostal braehial nerve is often sacrificed, leaving an anesthetic patch in the posteromedial aspect of the upper arm. Drains are left to prevent the accumulation of lymph and serum under the skin flaps (if no reconstruction is performed immediately), and in the axilla. These are removed when daily volume decreases to 30 ml/day, which usually occurs in the first postoperative week. Modified radical lnasteetomy achieves local control through extirpation of the breast tissue. Recurrence-free survival at 5 years approaches 85% in node-negative patients and 60% in patients with one to three positive nodes (17). The majority of recurrence is local or regional and is associated with systemic disease. The mental health care professional will be well aware of the cosmetic disadvantages of unreconstructed M RM and the sense of perceived disfigurement and loss of body image that patients can suffer. Historically, reconstruction was delayed 2 years as it was feared that reconstruction might obscure the 80% of locally recurrent disease that would be manifest at that time. As these suspicions were not borne out, the current standard of care is for immediate reconstruction. Reconstructive techniques most commonly involve the subpectoral placement of implants (with or without the use of tissue expanders), or the use of autologous muscle faps, the most common being the transverse rectus abdoIninis muscle (TRAM) flap. These options should be entertained with all patients except those unable to withstand the prolonged anesthetic for the combined MRM and reconstruction, or those patients who do not feel reconstruction would improve their quality of life.
Local Resection with and without Radiation. Breast conservation represents an attempt to remove the primau tumor with a 1-era margin, and to obtain local or regional control with radiation therapy, as opposed to the extirpation 170
of all ipsilateral breast tissue. Local recurrence after breast conservation approaches is usually treated with mastectomy. A comparison of survival rates between breast conservation, breast conservation with radiation therapy, and MRM reveals no significant difference. Local recurrence is, however, a failure of therapy that negates the goal of breast conservation and is distressing to the patient. The addition of radiation therapy to local resection reduces the local recurrence rate by at least twothirds, from 35% to 10% (18). Axillary dissection is performed in all these patients principally for its importance in staging, but also because of its measurable contribution to regional control. More recently, the role of axillary dissection for patients with tumors > 2 em in size has been discussed. Many" of these patients will receive adjuvant therapy based on the size of the primary. In this group of patients in whom axillary dissection might not add to the overall treatment plan, radiation therapy can provide good local control. Not all patients are suitable candidates for conservative approaches: the tumor must be <4 em, though there are trials examining whether preoperative neoadjuvant chemotherapy and radiation ean allow more advanced patients to participate. Multifoeality or multicentricity by careful exam or detailed mammography should also exclude a patient from breast conservation therapy. Tumors with an extensive intraduetal component have a tendency to exhibit tongues of tumor extension or additional tumor loci beyond a 2em zone surrounding the tumor and require special care (19). The importance of clear intraoperative labeling of margins is obvious. If a clear 1-cm margin cannot be obtained on two attempts at reexeision, the patient should receive MRM ('20).
Adjuvant Therapy. The control of systemic disease is undertaken by eytotoxic agents aimed at highly replicative cells or by exploitation of the hormonal axis of breast tissue. Agencies aimed at the hormonal control of breast caneer include ovarian ablation and tamoxifen therapy, of which tamoxifen therapy is by far the more widely used. Cytotoxic combinations commonly employed against breast cancer are CMF (cyclophosphamide, methotrexate, 5-fluorouracil) and the doxorubicin-based FAC (5-fluorouraeil, adriamycin, cyelophos-
Current Management of Breast Cancer
MEDICAL UPDATE FOR PSYCHIATRISTS
ESR ~ " Positive
Premenopausal
f
~
ESR __~. Negative
Multiagent Chemotherapy Possible Tamoxifen
Multiagent Chemotherapy I
ESR ----~I Tamoxifen, Possible -/~'Positive Multiagent Chemotherapy Postmenopausal -
"~
ESR Negative
Multiagent Chemotherapy Possible Tamoxifen
<1 cm
f
ESR Negative
f v4_xi... Nod
"•
~" I
N°ne
I
_>1 cm, "- < 2 cm - - ~
Possible Multiagent Chemotherapy Consider prognostic factors
>2 cm...
Multiagent Chemotherapy ] 1
<1 c m
None [
v
ESR Positive >lcm
Tamoxifen Possible Multiagent Chemotherapy
Figure 2. Algorithm for adjuvant therapy in early-Stage invasive breast cancer.
phamide). It is important to consider the toxicity of these adjuvants to temper enthusiasm at applying their impressive benefits (Table 2) (13). To best understand the use of adjuvant therapy, one should review some insights from the Early Breast Cancer Triallists Collaborative Group (EBCTCG) meta-analyses of prospective series. Adjuvant therapy, tamoxifen or chemotherapy, has a potential 20% benefit regardless of nodal status, improving 5-year survival from 55% in patients treated with surgery alone to 64% in node-positive patients, and from 92% to 94% in node-negative patients. EBCTCG strongly suggested
that chemotherapy is far more effective in patients younger than 50 ).,ears, while talnoxifen achieves its greatest effect in women 50 and older. The relevant benefits of adjuvant therapy do not significantly vary with number of nodes positive, and instead depend far more on age and estrogen receptor status. Women with estrogen receptor-rich tumors have a far greater benefit from tamoxifen than their receptor-negative counterparts. The efficacy of tamoxifen in women > age 50 is the same when given alone or in conjunction with chemotherapy (21). An area of controversv occurs in node-negative patients as to whether 171
the risks of chemohonnonal therapy outweigh the benefits in treating disease with no clinically or pathologically evident systemic spread. McGuire et al. (21) ana1)~ed a number of tumor characteristics (size, receptor status, ploidy, nuclear grade, s-phase fraction, cathepsin D level) known to indicate more aggressive behavior in terms of the risk of recurrence at 5 years from node-negative breast em~cer. These factors, of which size is the most reliable, can be used to help determine the indication for adjuvant therapy
(22). A sample algorithm to guide decision making for adjuvant therapy is summarized in Figure 2.
B. A. Perez-Tamayo and D. S. Tyler
Locallu Advanced and M e t a s t a t i c Breast Cancer Space limits a substantive discussion of late-stage invasive breast eaneer. Breast conservation is usually no longer an issue, and breast surgery is dedicated to local or regional control. Radiation therapy is used in the operative field for local or regional control and in the management of specific metastases. A total of 66% of patients with metastatic breast cancer respond to standard-dose chemotherapy, but only 20% or fewer approach complete response (23). Disease-free survival at 10 years is < 5 % for patients who had a complete response to chemotherapy. The median survival for patients with metastatic breast caneer is 2 years (24). High-dose chemotherapy and bone m a r r o w / h e m a t o p o i eric stem cell transplantation have been employed to combat late-stage breast cancer with 5-year disease-free survival in Stage IV patients quoted as 1 0 % 20% (25). The c o s t - b e n e f i t ratio of this therapy has been controversial in the managed care environment and has gained a great deal of media attention.
Conclusions The m a n a g e m e n t of breast cancer at any stage is a multidisciplinary effort, as primary care providers interact with surgeons and radiologists in earlier stages and with radiation oncologists and medical oncologists in later stages. This article has sought to review recent developments in m a n a g e m e n t of this disease and present information usefill to those involved with the care of these patients. Many of the decisions involved do not trade in altered survival statistics, but ultimately revolve around the patient's peace of mind and her satisfae-
MEDICAL UPDATE FOR PSYCHIATRISTS
tion with her body image, issues that fall squarely in the sphere of the mental health care professional.
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