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Sponsored by American Blight Society Grant IRG 70-002-29.
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Jessica Wang-Rodriguez M.D.1,2, Keith Cross1, Scott Gallagher M.D.3, Marcia Djahanban2, Janet M Armstrong2, Noel Wiedner M.D.1 and David H Shapiro M.D.3,4
Male breast blight is rare, and acquaintance of it in any audible academy is limited. Our accepted compassionate apropos its biology, accustomed history, and assay strategies has been extrapolated from its changeable counterpart. The aim of this abstraction is to appraise the announcement patterns of estrogen receptor (ER), progesterone receptor (PR), MiB1 (Ki67), Her-2/neu (c-erbB2), and p53 and to accessory them with the prognosis, presentation, staging, management, and survival/outcome in macho breast blight articular through the Veterans Administration civic blight registry. Sixty-five cases of macho breast blight were advised for classification. Bump blocks were requested from anniversary academy for immunohistochemical staining and appraisal of ER, PR, p53, Her2-neu, and MiB1. Seventeen age- and disease-matched macho adept patients with breast gynecomastia were acclimated as controls. Acceptable anxiety abstracts were calm for allegory with changeable breast cancers (i.e., age, lymph bulge status, analytic staging, bump size, histological grade, and advantageous and all-embracing survival). Macho breast blight had worse advantageous adaptation than controls (P = .03). The analytic date behindhand of bump admeasurement or lymph bulge alteration was the audible best cogent anxiety agency (P < .0001). ER-positive patients appeared to accept a bigger adaptation than did ER-negative patients (P = .03, univariate; P not cogent in multivariate) and did not account from assay with tamoxifen (P = .0027, univariate; P = .42, multivariate). MiB1 and PR expressions did not accessory with assay or survival, and p53 was associated with beneath ache chargeless adaptation (P = .07, univariate; P = .047, multivariate). Date for stage, Her2-neu was associated with beneath advantageous adaptation (P < .0001) and activated with absolute lymph nodes (P = .08). Anaplasty abandoned adjoin anaplasty with accessory treatments (chemotherapy, radiotherapy, tamoxifen, or combination) did not appearance any adaptation difference. Accessory assay seemed to be associated with worse outcome. In the Veterans Administration hospital setting, the analytic date and the expressions of p53 and Her2-neu in macho breast blight may be prognostically advantageous markers in allegorical approaching assay in -to-be studies, admitting ER, PR, and MiB1 expressions are of bound value.
Estrogen receptor, Her2-neu, Hormone receptors, Immunohistochemistry, Ki-67, Macho breast carcinoma, Mib-1, p53, Progesterone receptor
Male breast blight is rare, with an estimated 1,000 to 1,400 new cases per year (1). The bump phenotypic alterations are not able-bodied studied, and acquaintance is mainly accepted from that of changeable breast cancer. Although both diseases accept similarities, there are notable differences in accident factors, prognosis, and survival. Arise differences amid macho and changeable breast blight accept been noted, and macho breast blight has a addiction to present at college analytic stages and with added lymph bulge metastases (2, 3, 4). Abounding atomic markers are attainable for the bigger compassionate of changeable breast blight tumorigenesis and ache progression and possibly to adviser treatment. However, few studies accept been performed on the macho breast counterpart. The analytic and dissection compassionate of breast blight in macho patients is bound because the accident of this ache is absolutely low in any audible academy (2, 3, 5, 6, 7).
The aim of this abstraction is to appraise the anxiety role of MiB1 (Ki-67, admeasurement antigen), Her-2/neu oncogene, and p53 protein mutation, as able-bodied as acceptable anxiety markers of estrogen receptor (ER) and progesterone receptor (PR) announcement in macho breast carcinomas from archived bump blocks acquired from assorted Veterans Administration (VA) hospitals application immunohistochemical methods. The after-effects will be activated with the patient's analytic date and advantageous and all-embracing survival.
The Veterans Affairs database provides a altered antecedent of a ample cardinal of macho patients attainable for analysis. The patient's annal are attainable in a connected architecture through a audible attainable computer system. Advice was acquired from the Department of Veteran's Affairs (DVA) Blight Registry, and Accommodating Assay File (PTF), application the ICD-CM analytic codes 611.1 (hypertrophy of the macho breast), 611.72 (breast agglomeration or mass), 217 (benign bump macho breast), 175.9 (malignant bump macho breast). Individual VA bump registrars and medical almanac departments that listed patients advised with these diagnoses were contacted and the annal requested. The Beneficiary Identification and Almanac Area Arrangement were acclimated to access abstracts on bloodshed afterwards discharge. These databases absolute from 80–90% of the recorded veterans' deaths. If an added assay of the abstracts compared with the abstracts in the U.S. Social Security Administration bootless to announce death, again the accommodating was recorded as animate at their aftermost accepted aftereffect date.
Charts of cases of macho breast blight articular over a decade were acquired from the annal departments of the VA hospitals. Assay included demographic data, history of the onset, and presentation in the breast including a mass, breadth of tenderness, or nipple change or addition of the breast. Concrete allegation were categorized for the area and admeasurement of the bane and the nipple areolar circuitous and the attendance of bounded adenopathy. Comorbidities as able-bodied as added systemic concrete allegation of acceptation were noted. An added breast tissue ascendancy of 17 noncancerous macho adept patients akin for age and basal medical diseases with assay of gynecomastia was acclimated for allegory of the stains.
Original anatomy letters were adjourned to accommodate histology, grade, nuclear analysis, and receptor status. Acceptable anxiety abstracts were calm to analyze with that of changeable breast cancers (i.e., age, lymph bulge status, analytic and dissection staging, bump size, and histological grade). Accessory assay (chemotherapy, radiation, or tamoxifen) was noted. Bump blocks were requested from anniversary academy for immunohistochemical staining for ERs and PRs (DAKO, Carpinteria, CA) as able-bodied as afresh declared breast blight anxiety markers such as p53 (Novocastra Laboratory Ltd., Newcastle, UK), Her2-Neu (DAKO), and Ki-67 (MiB1-Innovex, Inc., Parsippany, NJ), application accustomed antigen retrieval method. Anatomy slides were advised apart and accordingly by two pathologists (JWR and NW) for nuclear allocation according to the adapted Bloom and Richardson arrangement (8), allocation of tumors, and appraisal of the immunohistochemical stains. Discrepancies were bound afterwards circumstantial assay of the cases in question. Back there were discrepancies of the nuclear grade, histologic type, or ER and PR receptor cachet from the aboriginal dissection report, the new histological brand or staining after-effects were recorded for our abstracts analysis. The accommodating medical annal and tissue blocks absolute aboriginal identification numbers and accordingly acceptable the action of institutional assay for use of beastly annal and tissue; the abstraction was accustomed by the institutional assay lath at University of California, San Diego.
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ER and PR nuclear stains were categorized as absolute or negative. The absolute staining was accustomed as >50% of the corpuscle nuclei stained. p53 nuclear stains were denticulate as absolute for strong, compatible staining of the bump nuclei, as accepted for anemic or focal nuclear staining, and as abrogating for no staining. Her2-Neu announcement was graded as absolute back strong, bleary stains amidst the absolute cytoplasmic ambit of the bump corpuscle (equivalent to the FDA-approved DAKO HercepTest 2 and 3 ), accepted for fractional bleary staining (1 ), and abrogating for ambiguous or no staining of the bump beef (0 ; 9). The announcement characteristics were adapted to three variables to advance statistical ability because Her2-Neu-positive cases were too few in our cohort. MiB1 was bidding as a allotment per 1000 bump cells. Appropriate absolute controls from changeable breast tumors were acclimated for anniversary antibody.
Statistical assay was activated to abstracts fatigued from abstraction of the database itself, as able-bodied as allegory to letters in the abstract of macho breast blight in the accepted population, and of changeable breast cancer. All statistical analyses acclimated StatView Version 5.0.1 (SAS Institute, Inc., Cary, NC). Allegory of absolute abstracts was done with either 2 or Fisher's exact assay depending on the sample size. Allegory of afterwards abstracts was done with the t test. Adaptation assay was performed with the Kaplan-Meier curves and acceptation bent by log-rank assay (KM-LR) for called groups of patients. The ambit cogent in the log-rank univariate assay were activated in the stepwise corruption procedures. The multivariate assay was performed application the Cox's proportional hazard models. Afterlife due to bump and bump ceremony was advised failures. Those patients who died of added causes or were animate afterwards ache were censored at the time of afterlife or were absent to follow-up.
A absolute of 241 patients were articular in the VA bump anthology database, but abandoned 65 patients had complete aftereffect history and anatomy blocks attainable in the athenaeum for review. The patients were diagnosed amid 1990–2000, with a boilerplate aftereffect of 36.7 months (range = 1–134 mo). Seventeen cases of age-matched macho patients with amiable gynecomastia were advised as control. The boilerplate age for the macho breast blight patients was 68.2 12 years (range, 35 to 89 y) and for ascendancy patients, 66 8 years (range, 52 to 81 y; P = ns). The after-effects of the dissection assay by the authors (JWR and/or NW) as able-bodied as added accommodating demographic abstracts were abbreviated in Table 1. The all-embracing adaptation for macho breast blight patients was decidedly worse than that for the ascendancy macho patients (36 27 mo for MBC adjoin 51 36 mo for control, P = .03, Kaplan-Meier and log rank; Fig. 1 and Table 2). There was no aberration in patients' smoker cachet (30% MBC adjoin 45% control) and added accomplishments medical histories amid the MBC and ascendancy patients. Abandoned two MBC patients had accurate ancestors history of breast blight (one mother and one sister). Tumors that absolute ductal blight in situ (DCIS) did not advise adaptation advantage (30.3 23.4 mo afterwards DCIS adjoin 32.5 8.4 mo with DCIS, P = .8, Table 2). The boilerplate bump admeasurement was 2.9 1.9 cm (range, 0.3 to 10 cm). There was no adaptation aberration in bump size, histological grade, or lymph bulge alteration at the time of assay in this accomplice (Table 2). There was a trend of added bump brand that was associated with a college cardinal of absolute lymph nodes (P = .09). However, avant-garde bump date (American Joint Committee on Cancer) was acerb associated with beneath advantageous adaptation (Kaplan-Meier and log rank P < .0001; Fig. 2), implying that bump alteration was decidedly associated with adverse survival.
The all-embracing adaptation for patients with macho breast blight (MBC) adjoin ascendancy patients with amiable gynecomastia. The adaptation is decidedly worse in patients with breast blight (P = .03).
The advantageous adaptation of MBC patients in four analytic stages. There is a statistically cogent aberration in adaptation with attention to stages (P < .0001).
The after-effects of the immunohistochemical assay of the antibodies, ER, PR, MiB1, Her2-neu, and p53 were abbreviated in Table 3. Stains for ER, PR, MiB1, and p53 showed audible nuclear staining in bump cells, admitting Her2-neu stains were artlessly bleary (Fig. 3). The cardinal of ER- and PR-positive tumors was not decidedly altered from control. The beggarly allotment of MiB1 in tumors was 10.6% and 3.5% in ascendancy cases, and no ascendancy cases had a MiB1 account of >10.6% (P = .0088). p53 was bidding added in tumors than in controls (P = .0087). The Her2-neu absolute amount was 9%, and all of the ascendancy cases were Her2-neu abrogating (P = .10).
Patients with ER-positive tumors appeared to accept a bigger adaptation (n = 62, P = .03, KM-LR) than did patients who were ER abrogating (n = 3) in the univariate assay but not in multivariate analysis. In Table 4, ER did not accessory with bump grade, lymph bulge positivity, or analytic stages at diagnosis. PR-positive tumors activated with high-grade tumors (P = .04; Table 4). However, PR did not action any differences in advantageous survival. College MiB1 allotment (>10.6%) did not arise to accessory with absolute lymph nodes, bump grades, stage, or adaptation (Table 4). There was no alternation amid p53 and bump grade, lymph bulge metastasis, or date in MBC patients (Table 4), but there was a advancement that p53 tumors had beneath advantageous adaptation (P = .07; Fig. 4), and this alternation became acknowledging back stratified by date in multivariate assay (P = .047).
Disease-free adaptation in patients with p53-positive tumors was worse than patients with p53-negative or accepted tumors (P = .07). Back stratified by stage, the aberration became statistically cogent (P = .047).
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Her2-neu-positive patients tended to accept absolute lymph nodes (P = .08; Table 4) and a college cardinal of absolute lymph nodes (P = .04). Worse advantageous adaptation in Her2-neu-positive tumors was empiric in both aboriginal Date I/II and backward Date III/IV patients (P < .0001; Fig. 5). Multivariate assay performed on stage, p53, and Her2-neu connected to appearance that avant-garde date (P = .0001) and absolute Her2-neu in Date III/IV patients (P = .04, Fig. 6) were absolute adverse anxiety factors, but p53 was not (P = .4).
Her2 adjoin date in advantageous survival. Her2-neu-positive and -negative tumors were stratified by patient's analytic stage, aboriginal (I/II) adjoin backward (III/IV). In both aboriginal and backward stages, patients with Her2 tumors had a worse advantageous adaptation (P < .0001).
Ninety-seven percent of the patients underwent anaplasty (n = 62). The types of anaplasty included simple mastectomy (n = 9), excisional biopsy abandoned (n = 2), adapted abolitionist mastectomy (n = 41), and abolitionist mastectomy (n = 10). Twenty-nine percent of the patients chose to accept anaplasty as the abandoned therapy, admitting 71% of the patients had anaplasty and accessory therapies. Accessory therapies included chemotherapy (n = 15), hormonal assay (tamoxifen, n = 27), radiotherapy (n = 17), or a aggregate of the aloft (n = 15). There was no bendability or specific belief in accessory assay in this cohort, and the options were absitively on either by the patients' physicians or patients themselves. There was no aberration in adaptation in patients accepting accessory assay adjoin patients who had abandoned anaplasty (mean adaptation = 39 30 mo for anaplasty abandoned adjoin 30 24 mo in anaplasty added accessory therapy, P = .29). This award was accepted by the log rank test.
When comparing the adaptation of assorted antigen-positive tumors and their treatment, we begin that the ER-positive patients who were on hormonal (tamoxifen) assay had a beneath favorable adaptation (P = .0027, univariate analysis), but this acceptation was beneath in multivariate assay (P = .42). Back comparing the patients' stages with attention to accessory therapy, a worse advantageous adaptation was apparent in patients who accustomed radiotherapy or chemotherapy than in patients who did not accept either assay (P = .0002 and 0.0003, respectively). However, the statistical ability was clearly beneath because of baby sample size. Added markers were not cogent in alms adaptation account in patients who accustomed accessory therapy.
Male breast blight usually presents as a painless, close subareolar accumulation or a accumulation in the aerial alien division of the breast. Some of the accident factors active accommodate diet (10), booze intake, blubber (11), tobacco abuse, and altitude associated with added estrogen or decreased androgen, medications, or radiation acknowledgment (12). Agnate to the case of breast blight in females, a ancestors history of breast blight in men or women increases the accident for breast blight (13). One abstraction arise that low-stage patients had college brand tumors and beneath adaptation (14). However, in general, the ache behaves like changeable breast cancer, afterward agnate patterns of bounded aggression and metastasis.
The called accommodating citizenry was somewhat altered than the accepted citizenry in their aggressive service, anatomic history, and added exposures. However, patients' similarities to the accepted citizenry did abide in their age, bounded location, ache at presentation, and histological types. Therefore, abounding of the allegation and abstracts administer not abandoned to the adept population, but to some degree, to the accepted macho population.
The absolute histological blazon was entering ductal carcinoma, although about one third of the carcinomas additionally had a basic of DCIS. Bump size, absolute lymph nodes, bump grade, attendance of DCIS, or histological types did not accord to cast in this cohort.
Many attempts accept been fabricated to abstraction macho breast blight at the atomic and abiogenetic levels. However, these studies accept been bound to a baby cardinal of patients and accept abridged aftereffect data. Hormone receptors in changeable breast blight are able-bodied characterized. Absolute expressions of ERs and PRs accessory with bigger adaptation and acknowledgment to estrogen antagonists such as tamoxifen (15), behindhand of bump size, stage, and age. Added biomarkers advantageous in free the cast of changeable breast blight accommodate bump microvessel density, p53 expression, bump size, and peritumoral aqueous aggression (16) in node-negative tumors. Added prognostically important markers are added Ki-67 action associated with aerial mitotic basis and aerial bump brand (17), epidermal advance agency receptor, and bump angiogenesis (18, 19).
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In macho breast carcinoma, several alternation arise a college allotment of hormonal receptor positivity than changeable breast cancers. The ER-positive amount in our alternation (95%) was college than that apparent in the changeable breast blight or gynecomastia. However, abounding studies appropriate that the announcement of ER or PR in macho breast blight had no affiliation with acknowledgment to endocrine assay or cast (20, 21, 22), admitting one alternation approved a worse aftereffect (23). One beforehand attendant abstraction appropriate that accessory assay in accession to anaplasty was associated with favorable adaptation (24). In our study, ER-positive tumors activated with bigger adaptation than did ER-negative tumors in univariate analysis, but our ER-negative patients were few (n = 3), and all died anon afterwards the antecedent diagnosis. We begin that hormonal assay did not arise to account ER-positive patients. Neither chemotherapy nor radiation seemed to account adaptation in early- or late-stage patients. These arguable after-effects may be due to the facts that (1) there was a alternative bent because there was no constant ameliorative dieting in hormone-positive or -negative patients and abounding accustomed accessory assay as a atrocious attack to advance survival; and (2) ER and PR may comedy altered roles in their endocrine adjustment of macho breast adjoin changeable breast carcinoma.
In changeable breast cancer, p53 gene mutations and deletions are the best frequently empiric single-gene alterations (25). p53 alteration inhibits corpuscle afterlife through apoptosis. The aberrant p53 protein has a decidedly best half-life than the wild-type p53 protein and is apparent by immunohistochemical methods. Amid 18 and 58% of macho breast cancers were absolute for p53 by immunohistochemistry (21, 22, 26) in three abstraction alternation of 17–41 patients, suggesting that macho breast blight absolute abnormally expressed, aberrant p53 protein. These studies showed a statistical trend (but one not statistically significant, because of baby sample size) adjoin poorer aftereffect and beyond bump size. Absolute p53 alteration (15.4%) in our alternation had a statistically cogent beneath advantageous adaptation back stratified by date only, which accepted the antecedent trend.
The monoclonal antibiotic MiB1 (Ki-67), a altitude of corpuscle proliferative activity, was articular as a abeyant anxiety brand in breast blight in which a college allotment activated with added bump mitotic basis and bump brand (17). Antecedent studies showed that 20–40% of macho breast carcinomas were absolute for MiB1 (20, 21). These carcinomas had anemic to able associations amid aerial MiB1 array and androgen receptor negativity and worse cast (20). Our beggarly MiB1 allotment was 10.6%, college than that of gynecomastia (3.5%). However, college MiB1 did not accessory with lymph bulge metastasis, bump grade, stage, or advantageous survival.
The proto-oncogene Her2-neu (c-erbB-2), localized to chromosome 17q21, encodes a transmembrane tyrosine kinase advance agency receptor. Her-2/neu shares ample affinity with the epidermal advance agency receptor. Her2-neu gene addition has been associated with the development of breast blight in beastly models and is apparent in 10–34% of breast carcinomas (27). One activated adjustment in assessing Her2-neu cachet in accepted analytic ambience is by immunohistochemistry, although fluorescence in situ admixture (FISH) for Her2-neu gene addition may action added advice on ache cast and admiration assay acknowledgment (28, 29). On immunohistochemistry, a distinct, bleary staining arrangement is apparent back the receptor is present. Numerous studies of Her2-neu gene and protein announcement accessory with poor cast in changeable breast cancers, abnormally in node-positive patients (30), but few abstracts are attainable in the macho counterpart. A few studies with bound numbers of patients appearance that Her2-neu protein overexpression as abstinent by immunohistochemistry is present in 1.7–45% of macho breast blight patients, but adaptation assay is bound by baby sample admeasurement (21, 22, 31, 32, 33) and by no bright affiliation with survival. A contempo breast blight assay directed adjoin the Her2-neu (anti-Her2 antibodies—Herceptin, all-encompassing name trastuzamab) is ability analytic balloon and shows abeyant account in the assay of metastatic disease, either as a audible abettor or in aggregate with added chemotherapy (34). No analytic trials to date accept activated anti-Her2 antibodies for the assay of macho breast carcinoma.
Her2-neu overexpression was low in our alternation (9%) compared with added studies, and this may be due to a added acrimonious belief for free a absolute expression, but absolute Her2-neu was associated with worse adaptation in multivariate assay on Her2-neu and date (P = .0001), and Her2-neu positivity was apparent added generally in tumors with metastatic lymph nodes (P = .08). Analytic trials for anti-Her2-neu may be amiable in lymph bulge positive, late-stage, and Her2-neu-positive patients.
In conclusion, macho breast blight in the adept citizenry is a ache of earlier men and presents about 10 years after than does changeable breast cancer. Although the ache occurs after in activity of men who frequently accept abounding added medical illnesses, these patients do accept a worse advantageous adaptation than do commensurable men of agnate age and medical accomplishments but with amiable breast accumulation such as gynecomastia.
We evaluated bristles abeyant anxiety markers in the abstraction of macho breast blight in this VA cohort. We begin that avant-garde American Joint Committee on Blight date and absolute Her2-Neu associated with Date III/IV tumors were the abandoned absolute anxiety factors affecting adverse survival. The attendance of ER, PR, or college MiB1 allotment did not arise to be of cogent anxiety amount or accessible in allegorical treatment. p53-positive tumors may be associated with worse advantageous survival. Absolute Her2-neu announcement was associated with college cardinal of absolute lymph nodes and worse advantageous survival. Anti-Her2-neu assay may be of account in these patients. Anaplasty abandoned seemed to be acceptable assay for the majority of the patients. Chemotherapy or radiation did not arise to add adaptation account in these patients. However, prospectively randomized, multicenter analytic trials application these markers to coat macho breast blight patients are bare to affirm these findings.
The authors accede Steven Claunch for his abstruse ability in immunohistochemistry. The authors are beholden to the accidental VA medical centers (VAMCs) for their cases: Alexandria VAMC, Alexandria, LA; Alvin C. York VAMC, Murfreesboro, TN; Ann Arbor VAMC, Ann Arbor, MI; Augusta VAMC, Augusta, GA; Biloxi VAMC, Biloxi, MS; Boise VAMC, Boise, ID; Boston VAMC, Boston, MA; Brooklyn VAMC, Brooklyn, NY; VA Medical Center, Fayetteville, Arkansas; Hunter Homes McGuire VAMC, Richmond, VA; G. V. Sonny Montgomery VAMC, Jackson, MS; Lexington VAMC, Lexington, KY; Clement J. Zablocki VAMC, Milwaukee, WI; New Orleans VAMC, New Orleans, LA; Portland VAMC, Portland, OR; VA Roseburg Health Care System, Roseburg, OR; Salem VAMC, Salem, VA; VA San Diego Health Care System, San Diego, CA; San Juan VAMC, San Juan, PR; Overton Brooks VA Medical Center, Shreveport, Louisiana; St. Louis VAMC, St. Louis, MO
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