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Histopathology of endocrine mucin-producing sweat gland carcinoma of the eyelid

      A 74-year-old male presented to the oculoplastic surgery service with a left lower eyelid margin lesion that had enlarged over the previous 8 months. Results from an incisional biopsy performed by his plastic surgeon suggested dermal carcinoma. A second opinion on the histopathology of the lesion resulted in a diagnosis of eccrine adenocarcinoma. The patient had a history of a similar left lower eyelid lesion that had been resected 20 years previously with no signs of recurrence for 15 years. Histopathology from this past surgery was not available.
      The patient reported noticing subtle changes in the affected eyelid margin over the past 5 years. Over the 8 months before his presentation, the area began to enlarge more rapidly. The patient was an ex-smoker of 40 pack-years with a history of colon cancer and benign prostatic hyperplasia. Findings of ophthalmic and orbital examinations, including visual acuity, intraocular pressure, pupil reactivity, and eye motility, were all within normal limits. The result of periocular examination was significant for a well-defined left lower eyelid margin lesion that measured 3.4 mm in greatest diameter and was associated with madarosis, telangiectasia, and distortion of the eyelid margin architecture (Fig. 1). Trigeminal sensation was intact bilaterally, and there was no palpable lymphadenopathy of the head and neck region.
      Figure thumbnail gr1
      Fig. 1Left eyelid papule (3.4 mm) with associated madarosis, telangiectasia, and distortion of the eyelid margin architecture.
      The patient consented to proceed with excisional biopsy and en face frozen section control of the medial and lateral margins. Although the frozen sections were reported to be free of malignancy, the permanent histopathology revealed low-grade endocrine mucin-producing sweat gland carcinoma (EMPSGC). There was a well- circumscribed multinodular tumour composed of lobules of mildly atypical epithelial cells containing mucin deep within the dermis (Fig. 2).
      Figure thumbnail gr2
      Fig. 2(A) Eyelid endocrine mucin-producing sweat gland carcinoma (EMPSGC) that appears multinodular (haematoxylin and eosin, 2×). (B) CK-7 (10×). (C) Neuron-specific enolase (NSE) (10×). (D) CD57 (20×).
      The immunohistochemical profile was CK7 (+), NSE (+), multifocal CD57 (+), multifocal synaptophysin (+), multifocal chromogranin (+), estrogen receptor (+), CK20 (−), and GCDFP15 (−). The smooth muscle actin calponin stain highlighted a prominent basal layer and, in conjunction with the silhouette seen in sections stained with hematoxylin and eosin, confirmed that there was no evidence of invasive mucinous carcinoma. One focus of the tumour remained present in the medial margin of the permanent section. The patient consented to proceed with a second block resection using 3-mm clinical margins and reconstruction using a temporal rotational flap. The second specimen revealed no evidence of residual malignancy.
      Regional and systemic workup included computed tomography scan of the head and neck and liver function serological tests, the findings of which were all normal. At 1-year follow-up, there were no signs of tumour recurrence, and twice-yearly follow-ups were recommended.
      EMPSGC is a rare, low-grade cutaneous neoplasm seen in the periocular region of individuals between the fifth and seventh decade of life and affects females more than males.
      • Shimizu I.
      • Dufresne R.
      • Robinson-Bostom L.
      Endocrine mucin-producing sweat gland carcinoma.
      • Hoguet A.
      • Warrow D.
      • Milite J.
      • et al.
      Mucin-producing sweat gland carcinoma of the eyelid: diagnostic and prognostic considerations.
      • Zhang L.
      • Ge S.
      • Fan X.
      A brief review of different types of sweat-gland carcinomas in the eyelid and orbit.
      • Cardoso J.C.
      • Calonje E.
      Malignant sweat gland tumours: an update.
      Although EMPSGC is a rare entity, it is likely under-reported.
      • Turnbull L.I.
      • Puchalsky D.R.
      • Xu Y.G.
      • Bennett D.D.
      A cystic growth on the lower eyelid: a presentation of two cases.
      There have been 2 recent reports of EMPSGC: 3 cases by Fernandez-Flores and Cassarino,
      • Turnbull L.I.
      • Puchalsky D.R.
      • Xu Y.G.
      • Bennett D.D.
      A cystic growth on the lower eyelid: a presentation of two cases.
      and 2 cases by Turnbull et al.
      • Fernandez-Flores A.
      • Cassarino D.S.
      Endocrine mucin-producing sweat gland carcinoma: a study of three cases and CK8, CK18 and CD5/6 immunoexpression.
      Moreover, a retrospective study by Shon et al.
      • Shon W.
      • Salomao D.R.
      WT1 expression in endocrine mucin-producing sweat gland carcinoma: a study of 13 cases.
      discovered 13 cases of EMPSGC, only 4 of which were correctly diagnosed initially. Combining the current case with the cases referenced in these previous reports, approximately 46 cases of EMPSGC are reported in the literature (41 involved the eyelid, 4 involved the cheek, and 1 involved an extrafacial site).
      • Turnbull L.I.
      • Puchalsky D.R.
      • Xu Y.G.
      • Bennett D.D.
      A cystic growth on the lower eyelid: a presentation of two cases.
      • Fernandez-Flores A.
      • Cassarino D.S.
      Endocrine mucin-producing sweat gland carcinoma: a study of three cases and CK8, CK18 and CD5/6 immunoexpression.
      EMPSGC is considered to be associated with primary mucinous carcinoma and can exist as in situ disease only, in situ plus invasive carcinoma, or invasive mucinous carcinoma only.
      • Zembowicz A.
      • Garcia C.F.
      • Tannous Z.S.
      • Mihm M.C.
      • Koerner F.
      • Pilch B.Z.
      Endocrine mucin-producing sweat gland carcinoma: twelve new cases suggest that it is a precursor of some invasive mucinous carcinomas.
      There have been approximately 150 cases of mucinous carcinoma reported in the literature, ranging from noninvasive to invasive forms.
      • Homma E.
      • Hata H.
      • Aoyagi S.
      • Shimizu H.
      Primary mucinous carcinoma of the skin with in-transit metastasis.
      • Koike T.
      • Mikami T.
      • Maegawa J.
      • Iwai T.
      • Wada H.
      • Yamanaka S.
      Recurrent endocrine mucin-producing sweat gland carcinoma in the eyelid.
      Flieder et al.
      • Flieder A.
      • Koerner F.C.
      • Pilch B.Z.
      • Maluf H.M.
      Endocrine mucin-producing sweat gland carcinoma: a cutaneous neoplasm analogous to solid papillary carcinoma of breast.
      described 2 cases of eyelid EMPSGC, 1 of which progressed to an invasive mucinous carcinoma. Mucinous tumours of extraorbital sites were first described in 1971 by Mendoza and Helwig.
      • Mendoza S.
      • Helwig E.
      Mucinous (adenocystic) carcinoma of the skin.
      In 1979, Wright and Font reported a case series of 21 eyelid mucinous carcinomas in which 40% had local recurrences and 1 patient died from extensive local invasion.
      • Wright J.D.
      • Font R.L.
      Mucinous sweat gland adenocarcinoma of eyelid: a clinicopathologic study of 21 cases with histochemical and electron microscopic observations.
      Recently, Tsai et al.
      • Tsai J.-H.
      • Hsiao T.-L.
      • Chen Y.-Y.
      • Hsiao C.-H.
      • Liau J.-Y.
      Endocrine mucin-producing sweat gland carcinoma occurring on extra-facial site: a case report.
      reported the first case of EMPSGC to present extrafacially, but there is a lack of consensus regarding whether this lesion was truly EMPSGC or ductal carcinoma in situ of the breast.
      • Fernandez-Flores A.
      • Cassarino D.S.
      Endocrine mucin-producing sweat gland carcinoma: a study of three cases and CK8, CK18 and CD5/6 immunoexpression.
      • Tsai J.-H.
      • Hsiao T.-L.
      • Chen Y.-Y.
      • Hsiao C.-H.
      • Liau J.-Y.
      Endocrine mucin-producing sweat gland carcinoma occurring on extra-facial site: a case report.
      EMPSGC typically presents as a poorly demarcated plaque or a nondistinctive swelling on the eyelid or face.
      • Cardoso J.C.
      • Calonje E.
      Malignant sweat gland tumours: an update.
      Similarly, mucinous carcinoma typically presents as a nonspecific, fleshy nodule or papule in the ocular region that can also involve the head (eyelid [38%], face [20%], scalp [12%]), limbs, or abdominal region.
      • Mendoza S.
      • Helwig E.
      Mucinous (adenocystic) carcinoma of the skin.
      Although the local recurrence rate after surgical resection for mucinous carcinomas is 26%–40% and the regional lymph node metastasis rate is 4%–11%, no metastases of EMPSGC have been reported.
      • Hoguet A.
      • Warrow D.
      • Milite J.
      • et al.
      Mucin-producing sweat gland carcinoma of the eyelid: diagnostic and prognostic considerations.
      • Zhang L.
      • Ge S.
      • Fan X.
      A brief review of different types of sweat-gland carcinomas in the eyelid and orbit.
      Histopathology reveals that the tumour consists of round to oval, small- to medium-sized epithelial cells; low cytological atypia; and mucin production, which is largely intracellular.
      • Hoguet A.
      • Warrow D.
      • Milite J.
      • et al.
      Mucin-producing sweat gland carcinoma of the eyelid: diagnostic and prognostic considerations.
      Positive but variable staining with neuroendocrine markers NSE, synaptophysin, chromogranin, and CD57—and a preserved myoepithelial layer—helps differentiate EMPSGC from primary invasive mucinous and metastatic carcinoma.
      • Cardoso J.C.
      • Calonje E.
      Malignant sweat gland tumours: an update.
      Immunohistochemical analysis typically demonstrates positive staining for CK7, CAM 5.2, epithelial membrane antigen, estrogen receptor, progesterone receptor, and variable staining with NSE, synaptophysin, chromogranin, and CD57.
      • Zembowicz A.
      • Garcia C.F.
      • Tannous Z.S.
      • Mihm M.C.
      • Koerner F.
      • Pilch B.Z.
      Endocrine mucin-producing sweat gland carcinoma: twelve new cases suggest that it is a precursor of some invasive mucinous carcinomas.
      • Dorokhova O.
      • Amin B.
      • Jacobson M.
      XXXIV Symposium of the International Society of Dermatopathology, Florence, September 26–28, 2013.
      The diagnosis of EMPSGC can be challenging for both the clinician and the pathologist. The differential diagnosis includes chalazion, pyogenic granuloma, benign follicular cysts, hemangioma, myxoma, lipoma, papilloma, keratoacanthoma, sebaceous carcinoma, squamous cell carcinoma, basal cell carcinoma, adenoid cystic carcinoma, malignant melanoma, Kaposi sarcoma, and metastatic adenocarcinoma.
      • Zhang L.
      • Ge S.
      • Fan X.
      A brief review of different types of sweat-gland carcinomas in the eyelid and orbit.
      Awareness of this rare clinical entity and a combination of clinical, histopathological, and immunohistochemical testing are necessary to establish the correct diagnosis.
      • Tsai J.-H.
      • Hsiao T.-L.
      • Chen Y.-Y.
      • Hsiao C.-H.
      • Liau J.-Y.
      Endocrine mucin-producing sweat gland carcinoma occurring on extra-facial site: a case report.
      We report a case of eyelid margin EMPSGC—often a histopathologic diagnostic challenge. This is a rare, low-grade malignant tumour with a predilection for the eyelid. More importantly, invasive mucinous carcinoma that can have regional and systemic metastases may develop from EMPSGCs. Our case represents a localized recurrence of an EMPSGC despite the low recurrence rates reported in the literature, prompting the consideration of wide-margin excisions and closer follow-up until more cases of the entity have been studied.
      • Cardoso J.C.
      • Calonje E.
      Malignant sweat gland tumours: an update.

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