LETTER TO THE EDITOR

Minimally invasive mammary Paget’s diseasewithout an underlying breast carcinoma

Matthew Hanna & Shabnam Jaffer & Ira J. Bleiweiss &

Anupma Nayak

Received: 16 May 2013 /Revised: 24 June 2013 /Accepted: 2 July 2013# Springer-Verlag Berlin Heidelberg 2013

Dear Editor,Invasion of mammary intraepidermal Paget’s cells into thesuperficial dermis is extremely rare, and the presence ofinvasive mammary Paget’s disease (MPD) without an under-lying intraductal (DCIS) or invasive breast carcinoma is evenmore infrequent. To date, only three cases of invasive MPDwithout an underlying breast carcinoma have been reportedin the literature [1, 2]. We report here another case of inva-sive MPD unassociated with DCIS or invasive carcinoma ofthe underlying breast. Our case suggests that there is morethan one mechanism by which MPD can arise: a majorityrepresenting contiguous epidermotropic transport of pre-existing in situ or invasive carcinoma of the breast via thelarge lactiferous ducts, and smaller subset of cases without anunderlying DCIS or invasive breast carcinoma probablyarising from a pluripotent cell within the epidermis. Webelieve that invasion of mammary intraepidermal Paget’scells into the dermis is an underreported phenomenon. Werecommend careful scrutiny of skin epidermis sections in allmastectomy cases to recognize incidental MPD and addi-tional deeper levels be performed in all cases of MPD toexclude the possibility of invasion.

A 47-year-old premenopausal patient presented with bi-lateral palpable breast masses detected during self-breastexamination. There was no history of skin changes or nippledischarge. Her family history was notable for breast cancer intwo first-degree and one second-degree relatives. Core biop-sies performed on both breasts yielded the diagnoses ofradial sclerosing papillary lesions. Testing for BRCA muta-tion was performed but was negative for germline or sporad-ic mutations. In view of the patient’s strong family history of

breast cancer and the presence of high-risk lesions bilaterally,she decided to undergo bilateral prophylactic mastectomywith subsequent flap reconstruction.

Gross examination of both breasts revealed prior core bi-opsy sites in the breast parenchyma. Small fibroadenomaswere noted bilaterally. The overlying skin and nipple wereunremarkable. No additional suspicious masses or lesionswere identified. Microscopic examination demonstrated simi-lar histopathological findings in both breasts, with the presenceof radial sclerosing papillary lesions, small fibroadenomata,and background fibrocystic changes. A section from the leftnipple showed intraepidermal cells with vacuolated cytoplasmand atypical nuclei dispersed singly and in small clusterssuggesting the diagnosis of MPD. Additional deeper levelsdemonstrated superficial invasion into the dermis up to thedepth of 0.35 mm from the dermal–epidermal junction. Theinvasive component comprised two well-formed glands and asolid nest (Fig. 1(1A–1C). Since more than 95 % of cases ofMPD are associated with underlying DCIS or invasive ductcarcinoma, extensive sampling of the left breast was subse-quently performed; however, no focus of DCIS or invasivecarcinomawas identified in the underlying breast parenchyma.A small focus of incidental lobular carcinoma in situ (LCIS)was noted (Fig. 1(1D)) separate from the area of invasiveMPD. Immunohistochemical stains revealed that tumor cellswere positive for cytokeratin 7, HER-2 NEU protein (com-plete, membranous, moderate intensity), estrogen receptor,and progesterone receptor, and negative for S-100 protein(Fig. 2). This immunoprofile excluded the possibility of mel-anoma and confirmed the diagnosis of Paget’s disease. Rarecase reports [3] of MPD associated with underlying LCISprompted us to perform an E-cadherin stain. E-cadherin pos-itivity in Paget’s cells and negativity in the LCIS cells con-firmed that these cells are not derived from the underlyingLCIS found incidentally in our case. Fluoresecent in situhybridization (FISH) study to confirm Her-2 NEU amplifica-tion was attempted; however, results were non-contributory

M. Hanna : S. Jaffer : I. J. Bleiweiss :A. Nayak (*)Dubin Breast Center, The Mount Sinai Hospital, Department ofPathology, Icahn School of Medicine at Mount Sinai, One GustaveL. Levy Place, Box-1194, New York, NY 10029, USAe-mail: anupma.nayak@mountsinai.org

Virchows ArchDOI 10.1007/s00428-013-1446-9

due to loss of area of interest in deeper sections utilized forFISH study. Based on the aforementioned morphologic andimmunohistochemical features, we categorized this lesionas minimally invasive mammary Paget’s disease withoutan underlying breast ductal carcinoma.

Invasive MPD is a rare clinicopathologic entity and theoverall low incidence of invasive MPD may be explained, inpart, to an increase in breast conserving surgeries. Duan et al.[2] recently published the clinicopathologic features of sixcases of invasive MPD. One of their six cases was similar to

Fig. 1 Section of the left nipple showing single and small group ofintraepidermal Paget’s cells with atypical nuclei and abundant vacuo-lated cytoplasm (arrows) along with superficially invading well-formed

glands (arrowheads) in the dermis; 1A and 1B higher magnification ofthe same (H & E stain, ×400); 1C solid nest of invasive tumor cells inthe superficial dermis; 1D incidental focus of LCIS

Fig. 2 Immunohistochemistry for CK7, S100 protein, E-cadherin, HER2/NEU, estrogen receptor (ER), and progesterone receptor (PR)

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our case for not being associated with underlying DCIS orinvasive carcinoma. The authors highlighted that invasion inMPD is underrecognized as opposed to extramammary Paget’sdisease where superficial invasion into the dermis has beenreported in up to 16 % of patients [4]. They recommended thatinvasiveMPD should be defined as minimally invasiveMPD ifthe depth of invasion is <1 mm from the dermal–epidermaljunction or basement membrane.

Historically, Paget’s cells are thought to migrate from theunderlying in situ or invasive carcinoma establishing contig-uous spread via the lactiferous ducts into the nipple epidermis[5]. The absence of an in situ and invasive carcinoma in breastparenchyma in our case suggests an alternative etiology insmall subset of MPD cases. The possibility of these cellsarising from either a pluripotent cell or epidermal keratinocyteundergoing metaplasia and malignant transformation withinthe epidermis and subsequently invading through the base-ment membrane into the superficial dermis is plausible.

The clinical implication of superficial invasion in MPD inthe absence of underlying breast carcinoma is uncertain. Therole of sentinel lymph node biopsy (SLNB) is questionablein such cases. SLNB was not attempted in our case due todifficulties in injecting the dye for lymphoscintigraphy ina post-mastectomy patient. However, the case reported by

Duan et al. [2] exhibited isolated tumor clusters in theSLN. Therefore, it would be pragmatic to perform SLNBwith invasion until more cases with long-term follow-upare reported.

To conclude, minimally invasive MPD unassociated withan underlying breast carcinoma is an underrecognized entity.We recommend that additional deeper levels be performed inall cases of MPD to exclude the possibility of invasion.

References

1. Rosen PP (2001) Paget disease of the nipple. In: Rosen's breastpathology, 2nd edn. Philadelphia, Lippincott Williams & Wilkins,pp 571–574

2. Duan X, Sneige N, Gullett AE et al (2012) Invasive Paget disease ofthe breast. Am J Surg Pathol 36:1353–1358

3. Sahoo S, Green I, Rosen PP (2002) Bilateral Paget disease of thenipple associated with lobular carcinoma in situ. Arch Pathol LabMed 126:90–92

4. Parker LP, Parker JR, Bodurka-Bevers D et al (2000) Paget’s diseaseof the vulva: pathology, pattern of involvement, and prognosis.Gynecol Oncol 77:183–189

5. Ashikari R, Park K, Huvos AG et al (1970) Paget’s disease of thebreast. Cancer 26:680–685

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