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Approach and management of primary ectopic breast carcinoma in the axilla: Where are we? A comprehensive historical literature review

  • Giuseppe Visconti
    Correspondence
    Corresponding author. via Pietro Adami 22, 00168 Rome, Italy. Tel./fax: +39 06 6456 1525.
    Affiliations
    Resident in-training, Department of Plastic and Reconstructive Surgery, Catholic University of ‘Sacro Cuore’ – University Hospital ‘A. Gemelli’, Largo A. Gemelli 8, 00168 Rome, Italy

    Department of Plastic and Reconstructive Surgery, Catholic University of ‘Sacro Cuore’, University Hospital ‘A. Gemelli’, Rome, Italy
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    h Tel.: +31 50 3613531; fax: +31 50 3613043.
    Yassir Eltahir
    Footnotes
    h Tel.: +31 50 3613531; fax: +31 50 3613043.
    Affiliations
    Department of Plastic Surgery, University Medical Centre Groningen, Groningen, the Netherlands

    Consultant Plastic Surgeon, Department of Plastic and Reconstructive Surgery, University Medical Centre Groningen, PO Box 30001, 9700 RB Groningen, the Netherlands
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    i Tel.: +31 50 3613409; fax: +31 50 3611745.
    Robert J. Van Ginkel
    Footnotes
    i Tel.: +31 50 3613409; fax: +31 50 3611745.
    Affiliations
    Department of Plastic Surgery, University Medical Centre Groningen, Groningen, the Netherlands

    Chief, Division of Surgical Oncology, Department of Surgery, University Medical Centre Groningen, PO Box 30001, 9700 RB Groningen, the Netherlands
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    j Tel.: +31 50 3619524; fax: +31 50 3619107.
    Joost Bart
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    Department of Plastic Surgery, University Medical Centre Groningen, Groningen, the Netherlands

    Pathologist, Department of Pathology, University Medical Centre Groningen, PO Box 30001, 9700 RB Groningen, the Netherlands
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    Paul M.N. Werker
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    Department of Plastic Surgery, University Medical Centre Groningen, Groningen, the Netherlands

    Professor and Chief, Department of Plastic and Reconstructive Surgery, University Medical Centre Groningen, PO Box 30001, 9700 RB Groningen, the Netherlands
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    h Tel.: +31 50 3613531; fax: +31 50 3613043.
    i Tel.: +31 50 3613409; fax: +31 50 3611745.
    j Tel.: +31 50 3619524; fax: +31 50 3619107.
    k Tel.: 0031 50 3613531; fax: 0031 50 3613043.
Published:October 11, 2010DOI:https://doi.org/10.1016/j.bjps.2010.08.015

      Summary

      Primary ectopic breast carcinoma is a rare disease and, at present, no specific guidelines on its diagnosis and treatment are available. The purpose of this article is to review the world literature in English on primary ectopic breast carcinoma located in the armpit and to offer guidelines for diagnosis and treatment.
      Data for this review were identified by searches of MEDLINE, PubMed, The Cochrane Library, ACNP (Italian catalogue of journals) and references from relevant articles using relevant search terms and data published in the previous reviews.
      Primary ectopic breast carcinoma of the axilla mostly affects women of over 40 (range 28–90 yrs) years of age. The most frequent histological diagnosis is invasive ductal carcinoma not otherwise specified (NOS) (72%). Because of its rareness, in most cases, the diagnosis is delayed for on average 40.5 months. This disease is rare, but a high level of suspicion for carcinoma is mandatory when confronted with a tumour in this area.
      Once diagnosed, patients should undergo staging, and prognostic and adjuvant treatment procedures identical to orthotopic breast carcinoma guidelines. There are some limitations for the staging. Loco-regional treatment, on indication, combined with endocrine therapy and/or chemotherapy seems the treatment of choice.

      Keywords

      Recently, we were confronted with a patient with a primary ectopic breast carcinoma (PEBC) in the axilla.
      • Visconti G.
      • Eltahir Y.
      • Van Ginkel R.J.
      • et al.
      Reconstruction of an extended defect in the axilla using a thoracodorsal fasciocutaneous perforator flap.
      This is a rare disease and because of this, diagnosis and treatment are delayed. Breast tissue originates from a differentiation of an ectodermal thickening, the milk line or galactic band, which develops in the first 5 weeks of gestation and runs from the axilla to the groin bilaterally. Its incomplete embryonic regression will result in the formation of ectopic supernumerary and/or aberrant breasts along this line. Besides, ectopic breast tissue (EBT) formation has also been found outside the galactic band, that is, in the face, posterior neck, chest, midback, buttock, vulva, flank, hip, posterior and/or lateral thigh, shoulder and upper extremities.
      • Deaver J.B.
      • McFarland J.
      The breast: its anomalies, its diseases, and their treatment.
      For the purpose of this article, we will use the term ‘ectopic breast tissue’ (EBT) for breast tissue found elsewhere than at the pectoralis site, without specifying whether supernumerary or aberrant breast.
      The incidence of EBT is 0.2–6%, being higher in Asians than in Caucasians.
      • Tjalma W.A.
      • Senten L.L.
      The management of ectopic breast cancer–case report.
      • Routiot T.
      • Marchal C.
      • Verhaeghe J.L.
      • et al.
      Breast carcinoma located in ectopic breast tissue: a case report and review of the literature.
      • Kawahara F.
      • Noguchi M.
      • Yamamichi N.
      • et al.
      Ectopic breast cancer: two case reports and review of the Japanese literature.
      The axilla is most frequently involved (70%) and the glandular tissue is located in the subcutaneous tissue and deep dermis. This condition has also been associated with urological malformations.
      • Deaver J.B.
      • McFarland J.
      The breast: its anomalies, its diseases, and their treatment.
      The amount of EBT can vary from a small dimension to the normal breast size.
      • Tjalma W.A.
      • Senten L.L.
      The management of ectopic breast cancer–case report.
      Its presence may cause pain, restriction of arm movement whenever located in the axilla, cosmetic problems and anxiety. Symptoms such as swelling, tenderness and, sometimes, secretion often appear during puberty, pregnancy or lactation.
      • Gutermuth J.
      • Audring H.
      • Voit C.
      • et al.
      Primary carcinoma of ectopic axillary breast tissue.
      In this tissue, the same physiologic and pathologic changes as seen in eutopic breast tissue may occur, including carcinoma formation.
      • Gutermuth J.
      • Audring H.
      • Voit C.
      • et al.
      Primary carcinoma of ectopic axillary breast tissue.
      • Avilés Izquierdo J.A.
      • Martínez Sánchez D.
      • Suárez Fernandez R.
      • et al.
      Pigmented axillary nodule: carcinoma of an ectopic axillary breast.
      • Shin S.J.
      • Sheikh F.S.
      • Allenby P.A.
      • et al.
      Invasive secretory (juvenile) carcinoma arising in ectopic breast tissue of the axilla.
      • Amsler E.
      • Sigal-Zafrani B.
      • Marinho E.
      • et al.
      Ectopic breast cancer of the axilla.
      The purpose of this article is to comprehensively review the literature to take stock of the knowledge on EBT and PEBC and to offer guidelines for diagnosis and treatment.

      Methods of literature search

      A comprehensive literature review on PEBC of the axilla published in English was performed, from 1861 to 2009. Data for this review were primarily identified by searches using MEDLINE, PubMed and The Cochrane Library. Besides, the ACNP (Italian catalogue of journals) was searched as well as references from relevant articles and data published in the previous reviews (Table 1). The search terms used were ‘ectopic breast tissue’, ‘aberrant breast tissue’, ‘axillary breast tissue’, ‘ectopic breast cancer’, ‘aberrant breast cancer’, ‘accessory breast cancer’, ‘ectopic breast carcinoma’, ‘aberrant breast carcinoma’, ‘axillary breast carcinoma’, ‘axillary breast cancer’, ‘primary ectopic breast carcinoma’, ‘axillary mass’, ‘axillary tumour’ and ‘axillary neoplasm’.
      Table 1In this flow diagram it is showed the methods used in the selection of papers included in the review
      Table thumbnail fx1
      All articles were scrutinised for number of cases, patient’s age at diagnosis, risk factors for breast carcinoma, duration of delay in diagnosis and initial misdiagnosis, histology and site of the neoplasm, lymph node involvement and extra lymphatic metastasis, immune histological features, treatment and follow-up such as local recurrence, metastasis, outcome and end of follow-up (Table 2).
      Table 2We review the world literature on axillary ectopic breast carcinoma from 1861 to 2008. The report of the cases was performed in reference to : patient’s age, risk factors for breast carcinoma, months of delayed diagnosis and the initial mis-diagnosis, histology and site of the neoplasm, lymph node and extra lymphatic metastasis, immunohystologic features, treatment and follow-up. It was not possible to provide all the information for each patient to the lack of clinical information found. To our knowledge we report the 171st case of ectopic breast carcinoma in axilla.
      Authors#cases, age()RFDel.,mis-diagnosis()Hyst., site ()LymphN Inv.Immuno-hystologyTreatmentoutcome
      Foerster 1861
      • Marshall M.B.
      • Moynihan J.J.
      • Frost A.
      • et al.
      Ectopic breast cancer: case report and literature review.
      1,(?)Mast+ax
      Wolkman 1875
      • Marshall M.B.
      • Moynihan J.J.
      • Frost A.
      • et al.
      Ectopic breast cancer: case report and literature review.
      1,(?)
      Williams 1891
      • Marshall M.B.
      • Moynihan J.J.
      • Frost A.
      • et al.
      Ectopic breast cancer: case report and literature review.
      1,(29)PosLocRec
      1,(54)PosLoc+Mast+ax
      1,(51)Loc+Mast+ax
      1,(49)Loc+MastRec
      Gangolph 1891
      • Marshall M.B.
      • Moynihan J.J.
      • Frost A.
      • et al.
      Ectopic breast cancer: case report and literature review.
      1,(45)Loc
      Kelly 1898
      • Marshall M.B.
      • Moynihan J.J.
      • Frost A.
      • et al.
      Ectopic breast cancer: case report and literature review.
      1,(80)
      Rouville 1902
      • Marshall M.B.
      • Moynihan J.J.
      • Frost A.
      • et al.
      Ectopic breast cancer: case report and literature review.
      1,(45)Loc
      Deniker 1913
      • Marshall M.B.
      • Moynihan J.J.
      • Frost A.
      • et al.
      Ectopic breast cancer: case report and literature review.
      1,(33)DC,(-)Mast
      Delanoy 1929
      • Marshall M.B.
      • Moynihan J.J.
      • Frost A.
      • et al.
      Ectopic breast cancer: case report and literature review.
      1,(62)DC,(-)
      Montemartini 1929
      • Marshall M.B.
      • Moynihan J.J.
      • Frost A.
      • et al.
      Ectopic breast cancer: case report and literature review.
      1,(40)Loc
      Mornard 1929
      • Marshall M.B.
      • Moynihan J.J.
      • Frost A.
      • et al.
      Ectopic breast cancer: case report and literature review.
      2,(36,62)2 Neg
      Andrews 1929
      • Marshall M.B.
      • Moynihan J.J.
      • Frost A.
      • et al.
      Ectopic breast cancer: case report and literature review.
      1,(79)NegLoc+ax
      Razeman and Bizard 1929
      • Marshall M.B.
      • Moynihan J.J.
      • Frost A.
      • et al.
      Ectopic breast cancer: case report and literature review.
      • Evans D.M.
      • Guyton D.P.
      Carcinoma of the axillary breast.
      284 radExp (2y f-up)
      3 loc+ax
      10 loc+axRec. (2y f-up)
      11-Lost to f-up
      Giacobbe 1930
      • Evans D.M.
      • Guyton D.P.
      Carcinoma of the axillary breast.
      1RadLost to f-up
      Bianchieri 1932
      • Marshall M.B.
      • Moynihan J.J.
      • Frost A.
      • et al.
      Ectopic breast cancer: case report and literature review.
      • Evans D.M.
      • Guyton D.P.
      Carcinoma of the axillary breast.
      1,(57)DC,(-)Extra n mtx (in f-up)Loc+axExp (2y f-up)
      Patel 1932
      • Marshall M.B.
      • Moynihan J.J.
      • Frost A.
      • et al.
      Ectopic breast cancer: case report and literature review.
      1,(32)NegLoc+mastFoD (8 m f-up)
      Massabau et al. 1933
      • Evans D.M.
      • Guyton D.P.
      Carcinoma of the axillary breast.
      1Loc+ax
      Erdman 1934
      • Evans D.M.
      • Guyton D.P.
      Carcinoma of the axillary breast.
      3Rec. (f-up?)
      Matti 1936
      • Marshall M.B.
      • Moynihan J.J.
      • Frost A.
      • et al.
      Ectopic breast cancer: case report and literature review.
      • Evans D.M.
      • Guyton D.P.
      Carcinoma of the axillary breast.
      1,(52)PosXrt+radRec. (f-up?)
      Picagli 1938
      • Marshall M.B.
      • Moynihan J.J.
      • Frost A.
      • et al.
      Ectopic breast cancer: case report and literature review.
      1,(56)Rec
      Rawls 1942
      • Marshall M.B.
      • Moynihan J.J.
      • Frost A.
      • et al.
      Ectopic breast cancer: case report and literature review.
      1,(36)DC,(-)NegLoc, xrt, rad
      1,(42)DC,(-)PosLoc, xrtRec
      Copeland and Geschickter 1945
      • Marshall M.B.
      • Moynihan J.J.
      • Frost A.
      • et al.
      Ectopic breast cancer: case report and literature review.
      • Evans D.M.
      • Guyton D.P.
      Carcinoma of the axillary breast.
      1,(60)DC,(-)Pos (sc)Rad, xrtExp (f-up?)
      1,(67)DC,(-)PosLoc
      1,(55)MeC,(-)PosRec (f-up?)
      1,(42)DC,(-)PosMast
      1,(42)DC,(-)Loc, xrtRec (f-up?)
      1,(39)MeC,(-)LocRec (f-up?)
      1,(46)Mast+ax
      Andreasen 1958
      • Andreasen A.T.
      Medullary carcinoma in an axillary breast.
      1,(40)0 mMeC,(-)Loc+ax
      DeCholnoky 1951
      • Marshall M.B.
      • Moynihan J.J.
      • Frost A.
      • et al.
      Ectopic breast cancer: case report and literature review.
      • Evans D.M.
      • Guyton D.P.
      Carcinoma of the axillary breast.
      1,(44)NegMast+ax
      Stringa 1951
      • Marshall M.B.
      • Moynihan J.J.
      • Frost A.
      • et al.
      Ectopic breast cancer: case report and literature review.
      1,(56)DC,(-)NegLoc
      1,(58)DC,(-)Loc
      1,(40)DC,(-)
      1,(67)DC,(-)
      1,(63)
      Chiari 1958
      • Chiari H.
      Zur frage des karzinomas in aberraten brustdrusengewebe.
      1,(40)DC,(-)Pos.Loc+rtxRec (f-up?)-
      1,(63)DC,(-)NegLoc+Mast
      Cogswell and Czerny 1961
      • Marshall M.B.
      • Moynihan J.J.
      • Frost A.
      • et al.
      Ectopic breast cancer: case report and literature review.
      • Evans D.M.
      • Guyton D.P.
      Carcinoma of the axillary breast.
      1,(40)PosLoc+ax+xrtExp (2y f-up)
      1Loc+xrtFoD (4y f-up)
      Morganfeld 1964
      • Evans D.M.
      • Guyton D.P.
      Carcinoma of the axillary breast.
      1Loc+ax+xrtExp (1y f-up)
      Smith and Greening 1972
      • Marshall M.B.
      • Moynihan J.J.
      • Frost A.
      • et al.
      Ectopic breast cancer: case report and literature review.
      • Evans D.M.
      • Guyton D.P.
      Carcinoma of the axillary breast.
      1(43)AnC,(-)Neg.Loc+ax+xrtFoD (13y f-up)
      1(54)DC,(-)Pos.Loc+ax+xrtFoD (1y f-up)
      1(49)DC/LC,(-)Neg.Loc+ax+xrtFoD (6 m f-up)
      Mikuriya and Tsutomu 1978
      • Mikuriya S.
      • Tsutomu S.
      Pathologic and immunologic analysis for a case with carcinoma of aberrant breast of the axilla.
      1(51)MeC,(-)Pos.Rad
      Abedi et al. 1979
      • Marshall M.B.
      • Moynihan J.J.
      • Frost A.
      • et al.
      Ectopic breast cancer: case report and literature review.
      • Evans D.M.
      • Guyton D.P.
      Carcinoma of the axillary breast.
      1Loc+ax+ctxFoD (4y f-up)
      Interlandi, Minchio 1979
      • Marshall M.B.
      • Moynihan J.J.
      • Frost A.
      • et al.
      Ectopic breast cancer: case report and literature review.
      • Evans D.M.
      • Guyton D.P.
      Carcinoma of the axillary breast.
      1RadFoD (18 m f-up)
      Walker and Fechner 19821(90)––PC,(-)Loc+ax
      Kahn et al. 19823––1 radFoD (9y f-up)
      2 mod
      Matsuoka et al. 1984
      • Matsuoka H.
      • Ueo H.
      • Kuwano H.
      • et al.
      A case of carcinoma originating from accessory breast tissue of the axilla.
      1(53)DCis,(-)Pos.Loc+ax+xrt+ctxFoD (5 m f-up)
      Badejo 1984
      • Evans D.M.
      • Guyton D.P.
      Carcinoma of the axillary breast.
      2RadFoD (4y f-up)
      RadFoD (18 m f-up)
      Marino and Scarpati 1984
      • Evans D.M.
      • Guyton D.P.
      Carcinoma of the axillary breast.
      2Loc+xrtRec. (f-up-)
      Loc+xrtFoD (3y f-up)
      Routiot et al. 1987
      • Routiot T.
      • Marchal C.
      • Verhaeghe J.L.
      • et al.
      Breast carcinoma located in ectopic breast tissue: a case report and review of the literature.
      1No5y,(-)DC, (R)1 ln Pos.ER+, PR+Loc+ax+ctx(dxr-vind-cycl-5FU)+ TAM+xrtFoD (10y f-up)
      Siegel et al 1990
      • Marshall M.B.
      • Moynihan J.J.
      • Frost A.
      • et al.
      Ectopic breast cancer: case report and literature review.
      1(50)DC/LCPos.Loc+ ax+ ctxFoD (1y f-up)
      Evans and Guyton 1993
      • Evans D.M.
      • Guyton D.P.
      Carcinoma of the axillary breast.
      1LC, (L)Neg.ER+, PR+Loc+axFoD (11y f-up)
      Marshall et al 1994
      • Marshall M.B.
      • Moynihan J.J.
      • Frost A.
      • et al.
      Ectopic breast cancer: case report and literature review.
      1(52)NoLC,(R)NegBilateral Rad+axFoD (5y f-up)
      DC,(slqlb)
      Azuma et al. 19971(74)DC, (L)Extra n. mtxPalliationExp. (10 m f-up)
      Yerra et al. 19971(46)No6 m,(SC)DC,(R)Neg.ER+,PR-Loc + axFoD (3y f-up)
      1(59)2 m,(-)AC,(L)Neg.ER+,PR+ (30% of analyzed sample)Loc + axFoD (9 m f-up)
      Nakao et al 1997
      • Nakao A.
      • Saito S.
      • Inoue F.
      • et al.
      Ectopic breast cancer: a case report and review of the Japanese literature.
      1(68)DC, (R)ER-,PR-,CEA++ GCDF15 +Rad+ax+sub+ctx(CMF)FoD (1y f-up)
      Kawahara et al 1997
      • Kawahara F.
      • Noguchi M.
      • Yamamichi N.
      • et al.
      Ectopic breast cancer: two case reports and review of the Japanese literature.
      1(42)1y,(-)DC, (L)Neg.Loc+axFoD(2y9 m f-up)
      1(62)DC, (R)Neg.Loc+axFoD(1y6 m f-up)
      55
      the total number of patient reported is 57, but two cases have been already analized in detail (Mikuriya et al, Matsuoka et al).
      (31-84) of whom 4 men
      3DCisNeg.26 Mod/Rad+ax,28 FoD of whom
      35DC12Neg5TG+ax,24Loc+ax,5 with axillary lymph nodes involvment f-up(1 m to 13y)
      14Pos, 9-2Loc
      10-
      1MeCis
      3MeC3Pos
      1AnCPos
      2NIis1Neg, 1-
      2MC1Pos,1Ng
      Cheong JH et al. 19991(70)10 m,(-)DC,(L)Neg.Loc+ax +xrt+TAMFoD (6 m f-up)
      1(73)BC2 m,(-)MC,(L)Neg.Loc+QU + axFoD(11,4y f-up)
      1(35)DC, (R)Neg.Loc+ax
      1(47)4y,(-)DC,(L)Neg.Loc+ax+xrt+ctx
      1(75)NoDC, (L)Neg.ER-, PR-Rad+ctx(CMF)+TAMFoD (18 m f-up)
      1(62)NoLC, (R)Neg.ER+,PR+Loc + ax + xrt +FoD (7y f-up)
      1(69)NoDC, (L)10 ln Pos.ER+,PR-TAMLoc + ax + xrt + ctx+TAMFoD (8y f-up)
      Shin et al. 2001
      • Shin S.J.
      • Sheikh F.S.
      • Allenby P.A.
      • et al.
      Invasive secretory (juvenile) carcinoma arising in ectopic breast tissue of the axilla.
      1(46)fam8y,(-)LC, (R)Pos.ER-,PR-. Her2/neu -Loc + ax + ctx(AC)
      Amsler et al. 2002
      • Amsler E.
      • Sigal-Zafrani B.
      • Marinho E.
      • et al.
      Ectopic breast cancer of the axilla.
      1(62)4y,(-)LC, (L)Loc + ax + xrt+TAMFoD (f-up-)
      Giron et al. 20041(65)No2,5y,(-)LC, (L)Neg.ER+, PR+Loc + ax + xrt+TAMFoD (6 m f-up)
      Vignal 2005
      • Vignal P.
      Sonographic appearance of a carcinoma developed in ectopic axillary breast tissue.
      1(47)No?,(H)DC, (L)Neg.ER+,PR+Loc+ax+xrt
      Avilés Izquierdo et al. 2005
      • Avilés Izquierdo J.A.
      • Martínez Sánchez D.
      • Suárez Fernandez R.
      • et al.
      Pigmented axillary nodule: carcinoma of an ectopic axillary breast.
      1(43)No1y,(-)DC, (L)1 ln Pos.ER+, PR+Loc + ax + xrt + ctx (CMF)+TAMFoD (2y f-up)
      Bakker et al. 20051 (53)No?DC, (L)NegER+, Pr+Her2/neu -Loc+ aNSB + xrt+TAMFoD (1y f-up)
      Tjalma and Senten 2006
      • Tjalma W.A.
      • Senten L.L.
      The management of ectopic breast cancer–case report.
      1(51)--, (SC)DC, (L)Neg.ER+, PR+Loc+ax+TAMFoD(4y3 m f-up)
      Gutermuth et al. 2006
      • Gutermuth J.
      • Audring H.
      • Voit C.
      • et al.
      Primary carcinoma of ectopic axillary breast tissue.
      1(54)E2-E3t1y,(Ab)DC, (R)2 In Pos.ER+, PR+ CEA-, Her2/neu-Loc + ax+TAMFoD (3y f-up)
      Welch et al 2007
      • Welch T.
      • Lom J.
      • Narayanan C.N.
      Primary ectopic breast cancer of the axilla.
      1(56)famE2t2y,(H)DC,L14 In PosER+, Her2/neu-,PR(5% of analyzed sample)Loc+QU (slq) +ax + ctx(TAC)+(xrt+AI planned)In treatment
      Teke et al. 20081 (52)No6 m,(?)DC, (R)Neg.ER+, Pr+Her2/neu +Loc + ax + xrt+TAMFoD (5y f-up)
      Visconti et al. 20081(61)fam20y,(M)DC,(L)3 In PosER+, PR+, Her2/neu-, GCDFP/15-Loc + ax + xrt+AIFoD (22 m f-up)
      RF: (Risk Factors): Fam (familiarity for breast carcinoma), BC (previous/concomitant eutopic breast cancer), E2t (estradiol theraphy).
      Del. (Delayed diagnosis), misdiagnosis: SC(sebaceous cyst), Ab (abscess), H(hydradenitis), M (many).
      Hist. (Histology): DC(ductal carcinoma), LC (lobular carcinoma), MC (mucoid carcinoma), AC (adenocarcinoma), AnC (anaplastic carcinoma), PC (papillary carcinoma), MeC (medullary carcinoma), MeCis (medullary carcinoma in situ), NIis (non invasive in situ).
      Site: L (left axilla), R (right axilla), slqlb (superior lateral quadrant of left breast).
      Lymph N. inv. (Lymph nodes involvment): Neg. (Negative), Pos. (Positive), Extra n. Mtx (extra nodal metastasis). #ln (number of lymph node), # without ln (number of cases with positive or negative lymph node involvment), sc (subclavicular lymph nodes).
      Treatment: Rad (radical mastectomy), Mod (modified mastectomy), Loc (wide local excision), Mast (unspecified mastectomy),QU (quadrantectomy), slq (superior lateral quadrant), ax (axillary lymphadenectomy), aNSB (axillary node sentinel biopsy) xrt (radiotheraphy), ctx (chemotherapy), TAM (tamoxifen), CMF (cyclophosphamide, methotrexate, 5FU), vind (vindesine), 5FU (5-fluorouracil), cycl (cyclophosphamide), dxr (doxorubicin), TAC (adriamicin, cyclophosphamide, docetaxel), AI (aromatase inhibitor).
      Follow-up: FoD (free of disease), f-up (follow-up), Exp. (expired), Rec. (recurrence of disease).
      a the total number of patient reported is 57, but two cases have been already analized in detail (Mikuriya et al, Matsuoka et al).
      A total of 89 papers on EBT could be identified. Among these, 24 were included in our review because they reported malignancies in EBT of the axilla. As such, a total of 170 cases of axillary PEBC have been reported in these articles prior to our case (Table 1, Table 2).
      It was not possible to identify each variable for every patient.
      All articles found regarding PEBC were case reports and historical reviews. No systematic reviews or clinical trials were available. This limits the ability to draw strong conclusions on the characteristics of this tumour and its behaviour, and therefore, no specific protocols for the diagnosis and management of PEBC are available.

      Demographic data

      The true incidence of PEBC is not clear. It has always been reported as a rare disease. Some authors estimated the incidence of this malignancy based on their experience in relation to EBT (3.8% according to deCholnocky)
      • DeCholnoky T.
      Supernumerary breast.
      or to breast cancer (BC) (0.3% according to Chiari).
      • Chiari H.
      Zur frage des karzinomas in aberraten brustdrusengewebe.
      The limited number of cases and the different methods of evaluation make these figures of limited value.
      Reviews on PEBC have assumed an increased rate of malignant changes in EBT when compared with eutopic breast tissue.
      • Marshall M.B.
      • Moynihan J.J.
      • Frost A.
      • et al.
      Ectopic breast cancer: case report and literature review.
      At present, this cannot be confirmed.
      PEBC shows a lower female sex prevalence than BC. According to our review, 6 of 171 cases were male (two cases reported by Marshall et al.
      • Marshall M.B.
      • Moynihan J.J.
      • Frost A.
      • et al.
      Ectopic breast cancer: case report and literature review.
      and four cases by Nakao et al.
      • Nakao A.
      • Saito S.
      • Inoue F.
      • et al.
      Ectopic breast cancer: a case report and review of the Japanese literature.
      ). Thus, the male-to-female ratio is 0.035 for PEBC compared with the 0.01 value for BC.

      American Cancer Society. Breast Cancer Facts & Figures 2009-2010. Atlanta: American Cancer Society, Inc. Last access: 24/05/2010.

      PEBC seems to affect people at a younger age compared with BC. We found that this malignancy, as well as BC, mainly affects people over 40 years old. In younger patients PEBC is rarely found. The youngest case reported was at 28 years of age and the oldest was 90 years of age. However, PEBC shows a 50% peak of incidence between 40 and 45 years of age (Figure 1) and a median age at diagnosis of 51 years of age, approximately 10 years less than BC.

      American Cancer Society. Breast Cancer Facts & Figures 2009-2010. Atlanta: American Cancer Society, Inc. Last access: 24/05/2010.

      This difference is even higher if one includes the delay in diagnosis for PEBC.
      Figure thumbnail gr1
      Figure 1The dispersion graph describes the age of the patients when they presented with the neoplasm. The patients under 40 years old are rarely interested. The majority are over 40 years old. The group age between 40 and 45 years old is the most interested. 50% of the patients are between 40 and 55 years old.
      It is not clear if PEBC has a race-prevalence as for BC.

      American Cancer Society. Breast Cancer Facts & Figures 2009-2010. Atlanta: American Cancer Society, Inc. Last access: 24/05/2010.

      Asians have a higher incidence of EBT, but it is unknown if they carry a higher risk of developing PEBC.
      There is a general belief that the risk factors for BC apply also to ectopic tissue. Indeed, in our case, there was a familial predisposition for BC and a history of radiation.

      Clinical presentation and examination

      From our review, it may be deduced that the clinical picture of an axillary PEBC is constant. The patient normally consults the physician for the presence of an axillary mass with the following features: persistent unilateral growing subcutaneous/dermic nodule previously misdiagnosed, irregular, firm and not tender, red and painless, without any local symptoms associated. In most cases, the general condition of the patient is good. Some patients may show clinical signs of supernumerary breast such as partial/complete areola and/or nipple at the site of the axillary mass.
      In the presence of these features, the contralateral axilla and both breasts should be clinically examined as well as the supraclavicular fossae and bilateral laterocervical nodes.

      Diagnosis

      The diagnosis of PEBC is not always thought of and is, therefore, often delayed. We found that the delay until diagnosis was missing in most old articles and clear in only 16 cases, including our case
      • Visconti G.
      • Eltahir Y.
      • Van Ginkel R.J.
      • et al.
      Reconstruction of an extended defect in the axilla using a thoracodorsal fasciocutaneous perforator flap.
      From the available data, the calculated delay was 40.5 months on average (range 0 months–20 years). Andreasen’s report
      • Andreasen A.T.
      Medullary carcinoma in an axillary breast.
      is probably the only case in which the diagnosis was suspected preoperatively.
      Axillary PEBC should be included in the differential diagnosis of any axillary mass. We propose a diagnostic algorithm on the signs and symptoms that may aid in the diagnostic process (Table 3).
      Table 3Diagnostic flow-diagram on signs and symptoms for unilateral axillary mass
      Table thumbnail fx2
      The presence of a subcutaneous mass along the milk line with the clinical features described above should provoke a high suspicion for PEBC, and this disease should be ruled out first.
      • Tjalma W.A.
      • Senten L.L.
      The management of ectopic breast cancer–case report.
      • Amsler E.
      • Sigal-Zafrani B.
      • Marinho E.
      • et al.
      Ectopic breast cancer of the axilla.
      To this end, following history and physical examination, ultrasound is the first additional step.
      • Kim E.Y.
      • Ko E.Y.
      • Han B.K.
      • et al.
      Sonography of axillary masses: what should be considered other than the lymph nodes?.
      The presence of a hypo-echoic, not well-defined heterogeneous mass (differential diagnosis: sebaceous cyst), without signs of inflammation such as in hydradenitis, is suspicious.
      • Vignal P.
      Sonographic appearance of a carcinoma developed in ectopic axillary breast tissue.
      Mammography may add further information, for the evaluation of the axillae (microcalcifications) and for both breasts.
      • Muttarak M.
      • Chaiwun B.
      • Peh W.C.
      Role of mammography in diagnosis of axillary abnormalities in women with normal breast examination.
      In case of a suspicious lesion, fine-needle aspiration biopsy (FNAB)/core biopsy of the axillary lump should be performed to harvest cells/tissue for histologic diagnosis.
      • Velanovich V.
      Fine needle aspiration cytology in the diagnosis and management of ectopic breast tissue.
      If a PEBC in the axilla is diagnosed, the regular work-up guidelines for BC should be followed.
      • NCCN- clinical practice guidelines in oncology
      Breast cancer V.2.
      The contralateral axilla should be examined in detail as should be the eutopic breasts. A contrast-enhanced computed tomography (CT) scan and/or magnetic resonance imaging (MRI) might be useful in defining the dimension and the extension of the tumour before surgery.

      Histopathology

      The most frequent histological diagnosis was invasive ductal carcinoma not otherwise specified (NOS) (72%), which is quite similar to that in eutopic breast, where this type of tumour is found in 40–75% of cases.
      • Elston C.W.
      • Ellis I.O.
      Classification of malignant breast disease.
      Invasive lobular carcinoma and medullary carcinoma represent the next frequent histotypes, with a total of 12% of the cases. Other histotypes form the remaining 16%.
      However, when histopathology indicates an axillary carcinoma, it can be difficult to differentiate between a carcinoma of adnexal origin, a breast-like or apocrine carcinoma, a metastatic BC and a PEBC.
      Several pathologic and immunohistologic features can help clarify this matter: (1) Histologic pattern of a primary breast carcinoma in situ. (2) Presence of normal breast tissue surrounding the tumour, areola and/or nipple. (3) Specific immunohistology for BC such as ER (oestrogen receptor) and PR (progesterone receptor), and common breast markers such as gross cystic disease fluid protein (GCDFP)-15. Although Her 2/Neu, CEA and glandular keratins can be expressed in BC, they do not discriminate between a PEBC and a skin adnexal tumour, because they are not specific for the breast. Their expression in other lesions, especially skin adnexal tumours is either not well known or is not different from breast cancer. (4) No malignant lesions in the eutopic breast tissue.
      • Gutermuth J.
      • Audring H.
      • Voit C.
      • et al.
      Primary carcinoma of ectopic axillary breast tissue.
      • Shin S.J.
      • Sheikh F.S.
      • Allenby P.A.
      • et al.
      Invasive secretory (juvenile) carcinoma arising in ectopic breast tissue of the axilla.
      In the diagnosis of PEBC in the armpit, axillary node metastasis should be excluded. Histopathologically, metastases tend to be multiple and exhibit expansive growth.

      Lymphatic spread

      In BC, homolateral axillary and internal mammary nodes are considered possible sites of lymphatic metastasis. The lymphatic spread of axillary PEBC is most likely only towards the homolateral axillary nodes and from there towards the supraclavicular nodes because this is the normal lymphatic drainage of the subcutaneous and cutaneous tissues of the armpit. In addition, indeed, in the literature, we found that, when present, nodes’ dissemination involved only the homolateral axillary nodes and, in one case, the ipsilateral supraclavicular nodes.
      Therefore, we believe that involvement of the internal mammary lymph nodes should be looked upon as distant metastases (M1) rather than N1 or N2 disease.

      Staging

      After diagnosis of a PEBC has been made, staging is performed, and this depends on tumour size and lymph node status, combined with clinical symptoms. The role of sentinel node biopsy (SNB) for PEBC of the axilla is not clear. The general trend has been to perform axillary clearance in all patients. We found only one case, which underwent R0 local excision and SNB (found negative) plus radiation and endocrine therapy. The Free of Disease (FoD) period reported for this patient is only 1 year.
      • Matsuoka H.
      • Ueo H.
      • Kuwano H.
      • et al.
      A case of carcinoma originating from accessory breast tissue of the axilla.
      Additional staging may include chest X-ray, abdomen and cervical ultrasound, abdomen and thoracic CT scan, breast MRI, brain MRI and bone metastasis detection with 99mTc-disodium oxidronate (HDP) scintigraphy, according to the BC guidelines.

      Prognosis

      The prognosis of PEBC may be considered similar to an equivalent BC, although some authors concurred that it could have a higher rate of lymph node involvement.
      • Routiot T.
      • Marchal C.
      • Verhaeghe J.L.
      • et al.
      Breast carcinoma located in ectopic breast tissue: a case report and review of the literature.
      • Kawahara F.
      • Noguchi M.
      • Yamamichi N.
      • et al.
      Ectopic breast cancer: two case reports and review of the Japanese literature.
      • Gutermuth J.
      • Audring H.
      • Voit C.
      • et al.
      Primary carcinoma of ectopic axillary breast tissue.
      • Shin S.J.
      • Sheikh F.S.
      • Allenby P.A.
      • et al.
      Invasive secretory (juvenile) carcinoma arising in ectopic breast tissue of the axilla.
      • Marshall M.B.
      • Moynihan J.J.
      • Frost A.
      • et al.
      Ectopic breast cancer: case report and literature review.
      • Evans D.M.
      • Guyton D.P.
      Carcinoma of the axillary breast.
      • Welch T.
      • Lom J.
      • Narayanan C.N.
      Primary ectopic breast cancer of the axilla.
      In many reported cases, at diagnosis, there was no lymph node involvement and there was a long-term interval FoD after the treatment. So far, even though the axillary lymph nodes and lymphatic vessels are close to an axillary PEBC, no higher rate of lymph node metastases has been demonstrated than in BC. In our case, no distant metastasis was found, notwithstanding a 20 years’ diagnostic delay.
      Although speculative, this may be explained by the fact that the forming of metastases is related to biologic properties of the tumour rather than to the anatomic properties of the localisation.
      Due to the diagnostic delay, as in our case, tumours might have grown for a longer time, resulting in higher tumour stage and possibly higher lymph node stage, requiring more extensive surgery, potentially leading to worse outcome, or to morbidity due to systemic therapy or to limited survival.
      The diagnostic delay of these malignancies may lead to an apparent poorer prognosis than for BC.
      • Welch T.
      • Lom J.
      • Narayanan C.N.
      Primary ectopic breast cancer of the axilla.

      Treatment

      No specific treatment protocol is available in the literature for axillary PEBC and, furthermore, there is no consensus on whether to excise the EBT prophylactically, to prevent the malignancy.
      • Grossl N.A.
      Supernumerary breast tissue: historical perspectives and clinical features.
      • Emsen I.M.
      Treatment with ultrasound-assisted liposuction of accessory axillary breast tissues.
      Treatment and follow-up details were provided for only 52 cases. In 12 of the reported cases (23%), a local recurrence of the neoplasm occurred following excision, 11 of which dated from the time era between 1891 and 1958. Since 1984, no local recurrence has been reported, apart from our case.
      Six patients died of metastatic disease before publication (12%), five of them within 2 years after the diagnosis. All these cases had had involvement of their axillary nodes. Among these, two presented with extra-nodal growth and one case showed metastasis to the infraclavicular lymph nodes.
      A total of 34 (65%) patients were found FoD at the time of publication. Based on the follow-up period reported, we divided these cases into three groups: shorter than 5 years (25 patients), between 5 and 10 years (five patients) and longer than 10 years (four patients).
      In the 5–10 years FoD group, loco-regional surgery (R0 local excision, axillary lymphadenectomy) plus radiotherapy and endocrine therapy had been successful in three cases, including a patient with 10 positive nodes. Radical mastectomy had been performed on the other two cases, one of which had negative nodes. In the ≥10 years FoD group, all cases underwent loco-regional surgery, two with and two without postoperative radiation treatment. Only one case received endocrine therapy.
      So far, in early days, the surgical approach of this tumour was more aggressive, justified by the limited knowledge of the biological behaviour of BC and by the paucity of adjuvant treatments available: surgeons performed either a local tumourectomy or an ipsilateral prophylactic mastectomy for axillary PEBC. Since 2001, the loco-regional approach only (local excision, axillary clearance and radiation) is preferred (Table 2).
      Adjuvant treatments that had been found to be effective for BC were successfully applied to PEBC as well. In fact, in seven of the nine cases reported with a follow-up of longer than 5 years, two of whom were N+, loco-regional surgery plus radiotherapy, followed by endocrine therapy and/or chemotherapy on indication, was successful until more than 10 years’ follow-up.
      Again, the therapeutic approach used in most of the cases was inspired by the BC treatment guidelines. Hormonal therapy, when appropriate, was an integral part of the treatment, as well.
      From our review, it is conceivable that loco-regional surgery (R0 local excision and axillary lymphadenectomy) plus radiation, followed by hormonal and/or chemotherapy on indication, is effective for patients staged I, II and IIIA–B, according to the American Joint Committee on Cancer (AJCC) stage groupings for BC, when N 1-2 is determined by ipsilateral axillary nodes metastasis.
      A careful follow-up is essential because of the limited knowledge of this tumour.
      Mastectomy, both radical and modified, is no longer performed if the breast is free of any malignant lesion, because it was found that the loco-regional approach, when possible, allows for the same therapeutic result, with a more acceptable aesthetic outcome.
      PEBC is a rare disease. In the presence of any axillary lump, this neoplasm should be the first to be excluded. Once diagnosed, these patients should undergo staging and treatment according to BC guidelines, with some limitations for the staging. As for now, radical excision and axillary lymphadenectomy with or without reconstruction of the defect plus adjuvant radiotherapy combined, on indication, with endocrine therapy and/or chemotherapy, may result in long-term tumour-free survival for patients staged I, II and IIIA–B.

      Conflict of interest

      All the authors disclose any financial and personal relationships with other people or organisations that could inappropriately influence (bias) their work.

      Acknowledgment

      Thanks to Anna Monda for support in statistical analysis.

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