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Original Study

Endocrine Mucin-Producing Sweat Gland Carcinoma: Emerging Evidence of Multicentric Cutaneous Origin and Occasional Concurrence With Analogous Breast Tumors

Ravi, Priyanka Y. MD*; Walsh, Noreen M. MD*,†,‡; Archibald, Curtis MD§; Pasternak, Sylvia MD*,†,‡,§

Author Information
The American Journal of Dermatopathology: May 2022 - Volume 44 - Issue 5 - p 321-326
doi: 10.1097/DAD.0000000000002132
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Endocrine mucin-producing sweat gland carcinoma (EMPSGC), first described in 1997 by Flieder et al, is a low-grade primary cutaneous adnexal neoplasm with a predilection for the periorbital skin.1,2 Clinically, the tumor is characterized by a slowly enlarging flesh-colored papule, nodule, or plaque, often featuring cystic elements.3 EMPSGC is observed most commonly in women in the seventh decade of life, the overall age range being 48–84 years.4 The tumor, albeit rare, has been a topic of interest in the medical literature in recent years, and an increased awareness of the entity has prompted publication of more than 80 cases to date.

Much of the interest in EMPSGC has been focused on its role as a putative precursor of mucinous carcinoma (MC) of the skin, and this association is now generally accepted. Studies have shown that these tumors exist on a morphologic spectrum ranging from a predominant cyst with an intermediate solid/cystic in situ carcinoma (EMPSGC) to a locally invasive MC.5 Morphologically and immunohistochemically, EMPSGC is analogous to solid papillary carcinoma of the breast.6,7 Both tumors are low-grade solid/cystic adenocarcinomas with mucin production and immunohistochemical coexpression of neuroendocrine and breast-type markers [eg, CK7, estrogen receptors (ERs), progesterone receptors (PRs), GCDFP-15, and GATA-3].4,8,9 Similarly, both lesions are considered precursors of invasive mucinous carcinoma at their respective sites.4 From a biological perspective, EMPSGC and cutaneous MC can recur locally, but metastatic disease has not been reported.10,11

Recent reports of multicentric EMPSGC in the literature have drawn attention to a novel aspect of these tumors. These data and our experience with similar local cases prompted us to conduct a retrospective study of EMPSGC and cutaneous MC at our institution. In addition to exploring a potential multicentric cutaneous origin for these tumors, we also sought a history of previous or concurrent extracutaneous neoplasms of potential interest in these patients. Our objectives were to validate the emerging concept of multicentricity of EMPSGC and to examine its potential relationship to other hormonally sensitive tumors.


Study Group

Institutional research ethics board approval to pursue this retrospective study was obtained (REB file # 1026949). We performed a computerized search of the laboratory information system in the Division of Anatomical Pathology to identify cases of EMPSGC and invasive mucinous carcinoma of the eyelid in the period from January 2000 to February 2021. The patients' electronic medical records were reviewed in search of demographic (age and sex) and clinical data [site(s), description, and diagnosis] pertaining to the skin tumors. Evidence of previous or concurrent tumors in other organs was also sought. All cases were reviewed by 2 of the authors (S.P. and P.Y.R.) to validate the diagnoses and to document morphological and immunohistochemical features of the lesions. One or more of immunohistochemical markers [ER, PR, chromogranin, synaptophysin, CD56, epithelial membrane antigen (EMA), carcinogenic embryonic antigen (CEA), EpCAM/BerEp4, cytokeratin 7 (CK7), cytokeratin 20 (CK20), GATA-3, GCDFCP-15, and mammaglobin] were performed in these cases; methodology is presented in Table 1.

TABLE 1. - Summary of Immunohistochemistry Methodology
Antibody Clone Dilution Concentration
ER ER SP1 (rabbit monoclonal) Predilute 1 μg/mL
PR PR clone 16 1/80 6.8 g/L
Chromogranin LK2H10 1/2000 22.4 μg/mL
Synaptophysin 27g12 1/25 42 mg/L
CD56 MRQ42 Predilute 0.22 μg/mL
EMA E29 (mouse monoclonal) Predilute 0.54 μg/mL
CEA CEA31 (mouse monoclonal) Predilute 0.47 μg/mL
EpCAM VV-1D9 1/500 1 mg/mL
CK7 OV-TL12/30 1/200 168 mg/L
CK20 KS20.8 1/100 95 mg/L
GATA-3 L50-823 (mouse monoclonal) Predilute 3.45 μg/mL
GCDFP-15 EP1582Y (rabbit monoclonal) 1/1000 67.8 μg/mL
Mammaglobin 31A5 (rabbit monoclonal) Predilute 0.05 μg/mL


Demographic and Clinical Details

The study group included 9 patients. The lesions occurred in both sexes but were slightly more common in men (55%) than women (45%). The overall mean age at presentation was 76 years (range 59–98 years). On average, men tended to present at a slightly younger age than women (72 vs. 81 years). Eight patients had 1 or more EMPSGC, with or without coexisting invasive mucinous carcinoma. One patient had an invasive mucinous carcinoma of the eyelid without an identifiable EMPSGC. In 7 of 8 cases (7/8) of EMPSGC, an associated invasive mucinous carcinoma was present. Three patients had multicentric skin lesions (2 cases with 2 lesions each and 1 case with 3 lesions) (Figs. 1 and 2).

Clinical appearance of EMPSGC and associated mucinous carcinoma involving the cheek (A) and left upper eyelid (B) (case no. 2).
Clinical appearance of EMPSGC involving the medial aspect of the lower eyelid (A) and adjoining separate EMPSGC with associated mucinous carcinoma at the lateral aspect of the lower eyelid (B) (case no. 4).

Except for 1 lesion located on the cheek (Fig. 1), all occurred on the eyelids. The left side (58%) was slightly more commonly involved than the right. The lesions tended to develop in a slowly progressive manner (months to years). The clinical impressions, when documented, included a cyst (3 cases), basal cell carcinoma (3 cases), and a mole (1 case). The lesions ranged in size from 2.5 to 12 mm. In 1 case, a recurrent lesion developed 2 years after the primary lesion was excised, previously deemed clear after histopathological examination. Relevant demographic and clinical data are summarized in Table 2.

TABLE 2. - Summary of Clinical and Demographical Data With Associated Noncutaneous Tumors
Case Age Sex Clinical Impression Location Diagnosis Size Recurrence Associated Noncutaneous Lesions
1 75 F Cyst LL eyelid EMPSGC 7 mm No Mucinous carcinoma, right breast
LU eyelid EMPSGC 6 mm No Endometrioid endometrial adenocarcinoma
2 59 F Cyst RL eyelid MC 4 mm No
LU eyelid EMPSGC and MC 4 mm No None
Left cheek EMPSGC and MC 6 mm No
3 73 M BCC LU eyelid EMPSGC and MC 5 mm No Intraductal papilloma breast
4 79 M BCC RL medial eyelid EMPSGC 5 mm No None
RL lateral eyelid EMPSGC and MC 2.5 mm No None
5 98 F BCC RL eyelid EMPSGC and MC 8 mm No None
6 76 M Chalazion RU lateral eyelid MC 6 mm Yes None
RU medial eyelid MC 4 mm Yes
7 92 F Cyst LU eyelid EMPSGC 10 mm Persistent None
8 71 M BCC LL eyelid EMPSGC and MC 12 mm No None
9 65 M Mole Forehead EMPSGC and MC N/A No None
BCC, basal cell carcinoma; LL, left lower; LU, left upper; RL, right lower; RU, right upper.

Histopathological Features

Histologically, the EMPSGCs consisted of 1 or more circumscribed tumor nodules in the dermis, sparing the epidermis. The lesions demonstrated a continuum of features, ranging from simple cysts lined by a single layer of cuboidal epithelium surrounded by myoepithelial cells to more complex cystic elements with multilayering of the epithelium and variable formation of micropapillary structures, cribriform patterns, and occasionally papillae with fibrovascular cores. Some solid tumor nodules with occasional lumina and evidence of intra/extra cytoplasmic mucin production (highlighted by alcian blue stain) were also observed. The tumor cells were small, relatively bland, with round to oval nuclei, stippled chromatin, and moderate eosinophilic cytoplasm. Occasional mitotic figures were present. All tumors lacked cytological atypia, lymphovascular invasion, perineural invasion, or necrosis. In 7 of 8 cases, the EMPSGC was seen to be intimately associated with invasive mucinous carcinoma. One case was an invasive mucinous carcinoma with bilateral eyelid involvement. The latter was characterized by small nests and clusters of epithelial cells within pools of extracellular mucin. Examples of EMPSGC and invasive mucinous carcinoma cases are presented in Figures 2 and 3, respectively.

EMPSGC with associated invasive mucinous carcinoma, H&E (A). On immunohistochemistry, the tumor cells are positive for CK7 (B), ER receptor (C), and chromogranin (D) (case no. 2).


Immunohistochemistry was performed on all cases, except for case no. 6 (recurrent multicentric mucinous carcinoma of the eyelid diagnosed solely by morphology). There were no clinical or radiological features suggestive of mucinous carcinoma elsewhere in the body. On the remaining 8 cases, at least 1 neuroendocrine marker (synaptophysin, chromogranin, or CD56) along with 1 or more of CK7, GCDFP, mammaglobin, or GATA-3 was performed. By immunohistochemistry, tumor cells were at least focally positive for 1 or more neuroendocrine markers, including chromogranin (5/7 cases), synaptophysin (6/7 cases), CD56 (4/5 cases), EMA (6/6 cases), CEA (3/3 cases), EpCAM (3/3 cases), ER (7/7 cases), PR (7/7 cases), GATA-3 (5/5 cases), GCDFP-15 (6/6 cases), and mammaglobin (1/1 case). All cases were negative for CK20 (8/8 cases).

EMPSGC and Associated Noncutaneous Tumors

In this series, we identified 3 cases with multicentric lesions. Case no. 2 had lesions involving both the eyelids and the left cheek, and case no. 4 demonstrated separate lesions involving medial and lateral aspects of the lower right eyelid. Case no. 1 initially presented with an EMPSGC involving the left upper eyelid. This was excised and no recurrences developed. Three years later, another EMPSGC developed on the lower left eyelid. A concurrent invasive mucinous carcinoma of the right breast, stage I, ER/PR positive, and HER-2 negative, was diagnosed the same year as the lower eyelid lesion. There was no evidence of lymphovascular invasion. One sampled right axillary sentinel lymph node was negative. This patient also had a remote history of stage 1 endometrioid carcinoma of the endometrium, diagnosed 20 years previously.

Case no. 3, a 73-year-old male patient, was diagnosed with EMPSGC of the left upper eyelid and a systemic investigation at the time uncovered a synchronous intraductal papilloma of the left breast. Case no. 7 was a persistent EMPSGC that continue to harbor similar morphology of the initial lesion, without evidence of an invasive mucinous component, after 5 years. Of note, in most cases where an invasive carcinoma was identified, a precursor EMPSGC was present (7/8). The findings of multicentricity are summarized in Table 2.


Our knowledge of EMPSGC is limited by the fact that it was described less than 30 years ago, and it is a rare tumor. Nonetheless, it has generated interest and controversy in the medical literature for several reasons. Until recently, its potential role as a precursor of mucinous carcinoma of the skin has been the main focus of attention, but that link has now been established. Some authors considered the existence of a nonneuroendocrine primary cutaneous mucinous carcinoma based on literature reports that predate the description of EMPSGC. Additional studies are necessary to determine whether indeed a distinct second type of primary cutaneous mucinous carcinoma exists.12

The debate in relation to the requisite criteria for invasive versus noninvasive disease in EMPSGC seems resolved. It is now accepted that similar to what occurs in solid papillary carcinoma of the breast, an expansile pattern of growth (even with loss of the myoepithelial rim reflecting a carcinoma with pushing invasion) should still be regarded as in situ disease because of the indolent behavior. Extracellular pools of mucin and/or infiltrating of tumor glands indicate progression to mucinous adenocarcinoma.13,14

A new feature of interest, namely, a multicentric cutaneous origin of the tumor, has emerged in the form of isolated reports of this phenomenon.15–19 In addition, the occasional concurrence of EMPSGC with an analogous tumor in the breast or with other extracutaneous hormonally sensitive neoplasms has raised the possibility of a biological susceptibility to the development of such neoplasms in some individuals.

Although endocrine mucin-producing sweat gland carcinoma is more common among elderly women, these neoplasms were interestingly more common among men in our cohort. A recent case series by Nakamura et al reported 4 cases of EMPSGC in men in an East Asian population, and rare individual case reports in men have been published.20,21

Multicentric tumors are rare. Reports of multicentric cutaneous EMPSGC and MC are summarized in Table 3. Furst et al15 described 2 distinct mucinous adenocarcinomas of the right lower eyelid and cheek. Bertagnoli et al16 and more recently Burris et al17 described bilateral mucinous carcinoma of the eyelid. Stiegler et al18 described multicentric primary mucinous carcinoma involving the left upper and lower eyelids as 3 distinct lesions. Jedrych et al22 reported a case of EMPSGC of the left lower eyelid and an invasive mucinous ductal carcinoma of the breast associated with a focal in situ component.22 More recently, Nishimoto et al reported a 71-year-old woman with 3 lesions on the face (right cheek, left cheek, and left upper eyelid)—2 EPMSGC and 1 invasive mucinous carcinoma. In addition, invasive ductal carcinoma of the breast was diagnosed simultaneously.19

TABLE 3. - Reports of Multicentric Cutaneous EMPSGC and Primary Mucinous Carcinoma
Studies Published EMPSGC/Mucinous Carcinoma Gender Age Location Associated Noncutaneous Tumors
Furst et al15 Multicentric primary MC Female 70 Right eyelid and cheek None
Bertagnoli et al16 Bilateral primary MC Female 55 Right and left lower eyelids None
Burris et al17 Bilateral primary MC Female 71 Right and left upper eyelids None
Stiegler et al18 Primary multicentric MC Female 68 Left upper and lower eyelids None
Jedrych et al22 EMPSGC Female 75 Left lower eyelid Mucinous carcinoma breast
Nishimoto et al19 Multicentric EMPSGC and MC Female 71 Left cheek, right cheek, and left upper eyelid Invasive ductal carcinoma of the breast uterine cancer; details unavailable
EMPSGC, endocrine mucin-producing sweat gland carcinoma; MC, mucinous carcinoma.

Concurrence between EMPSGC and potentially related tumors in other organs has been recorded less frequently, and it is unclear whether this is coincidental or biologically meaningful. It is tempting to suspect a relationship between the EMPSGC and mucinous carcinoma of the breast in the case reported by Jedrych et al.22 Alternatively, given the prevalence of mammary carcinoma in general, the observation of a ductal carcinoma of the breast (and a history of uterine cancer) in the patient with EMPSGC described by Nishimoto et al19 may be a chance occurrence.

The observation of MC in association with EMPSGC in 7 patients in this series is in keeping with the currently acknowledged relationship between these entities. Of novel interest is the documentation of multicentric EMPSGC in 3 individuals in the cohort. This observation, added to isolated reports of the same phenomenon in the literature, suggests that it is a feature of these neoplasms. Moreover, the occurrence of the tumors on the eyelids bilaterally, and on the upper and lower lids of individual patients, is worthy of note. Hypothetically, the development of 2 tumor nodules in close proximity to one another could raise the possibility of a “field effect” (eg, carcinogenesis superimposed on preneoplastic change at an affected site). However, the more widely dispersed distribution of the lesions argues in favor of a broad-based propensity to the development of EMPSGC, for unknown reasons.

Recent studies have highlighted the positivity of insulinoma-mediated protein -1(INSM1) and MUC-2 in EMPSGC.23,24 Mathew et al postulated that a multipotent conjunctival progenitor cell could be the cell of origin in EMPSGC. Conjunctival goblet cells are MUC-2 positive. In addition, multipotent precursors of MUC-2 secretory cells in salivary ducts may explain the occasional case of EMPSCG around the ear or cheek. Next generation sequencing analysis has suggested a multistep mutational pathogenesis for EMPSGC.24 Further studies along these lines are likely to reveal the specific pathogenesis of these tumors in time.

Documentation of a synchronous mucinous carcinoma of the breast in 1 of the 3 patients with multicentric EMPSGC in this study is intriguing. It is the second reported example of concurrence of EMPSGC and MC of the breast, and it raises the possibility of a link between the 2. Of practical importance in this setting is the need to exclude a metastasis from the breast to the skin. The presence of in situ lesions represents good evidence to assume independent primary tumors at both sites supporting the concept of a predisposition to apocrine neoplasia in the skin and the breast. Whether the history of endometrial carcinoma in the same patient invokes a susceptibility to the development of hormonally sensitive tumors of different kinds in 1 individual is as yet unclear.

One male patient with EMPSGC in our series was found to have a ductal papilloma of the breast. This case deserves special mention. After the diagnosis of EMPSGC in the patient's left upper eyelid, the pathologist suggested that, by convention, a metastasis from the breast be excluded. This was pertinent because the patient had reported a nipple discharge on the left side. After mammography and discovery of a mass in the affected breast, the lesion was excised, ultimately leading to a diagnosis of ductal papilloma in that breast. Given the rarity of breast tumors of any kind in men, this observation of an apocrine neoplasm, albeit benign, in a patient with an EMPSGC of the eyelid serves to reinforce the concept of an underlying susceptibility to the development of apocrine tumors in certain individuals.

The value of our observational study lies in its support for previous isolated observations of multicentricity of EMPSGC and its rare concurrence with analogous tumors in the breast. The series is small, and the data at present are insufficient to yield meaningful conclusions. It does, however, stimulate interest in the biology of these tumors and serves as a catalyst for further study. Ideally, a larger series of cases need to be examined, and strategies undertaken to detect an underlying biological susceptibility to the development of such neoplasms in affected individuals.

Given the common embryologic origin of cutaneous apocrine glands and mammary glands, it is not surprising that they should give rise to similar neoplasms. To explain the multicentricity of EMPSGC and its occasional association with analogous breast tumors, a genetic condition and/or an abnormal sensitivity to hormonally driven neoplasia has been proposed. Several precedents for a multiplicity of cutaneous adnexal neoplasms serving as a marker of a genetic syndrome exist. These include sebaceous neoplasms in Muir–Torre syndrome, tumors of the folliculosebaceous–apocrine apparatus in Brooke–Spiegler syndrome, and many others. It remains to be seen whether EMPSGC is a member of this group.


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endocrine mucin-producing sweat gland carcinoma; endocrine ductal carcinoma in situ; eccrine carcinoma; adnexal neoplasm; eyelid; mucinous carcinoma eyelid

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