Endocrine mucin-producing sweat gland carcinoma (EMPSGC) is a low-grade primary cutaneous adnexal neoplasm with a predilection for the periorbital skin of women in the seventh decade of life.1,2 Primary cutaneous adnexal neoplasms frequently parallel morphologic and immunohistochemical features of breast tumors, reflecting the common embryological origins of mammary and sweat glands.3 Histologically, EMPSGC bears striking resemblance to solid papillary carcinoma of the breast.3 The latter displays neuroendocrine morphology, a distinctive immunohistochemistry (IHC) profile, and occasional physical continuity with neuroendocrine invasive mucinous carcinoma of the breast (type B) of which solid papillary carcinoma is a putative precursor.4,5 Likewise, EMPSGC has garnered recent interest because of its proposed role as an in situ precursor of primary mucinous sweat gland adenocarcinoma with neuroendocrine features.1,6–10
In 1995, Rahilly et al11 introduced a neuroendocrine subtype of mucinous sweat gland carcinoma (MSC), also known as primary cutaneous mucinous carcinoma. As pathologists increasingly recognized the classic neuroendocrine appearance, the diagnosis of EMPSGC emerged.1,3,12 Despite proposing that EMPSGC represents a histologic analog of solid papillary carcinoma, a breast carcinoma in situ with malignant potential, Flieder et al3 and Zembowicz et al1 implied that the term “EMPSGC” encompasses an entire spectrum of neuroendocrine tumors including in situ-only lesions, lesions with both in situ and invasive components, and invasive mucinous carcinomas. Using one name for multiple points on the continuum, from pre-cancerous eccrine duct proliferations to invasive carcinoma, combined with a lack of specific studies on the associated neuroendocrine-type MSC resulted in diagnostic variation and debate. Diagnosticians using the label “EMPSGC” usually pointed out associated in situ and/or invasive components in their microscopic comments. Yet, there were no definitive clinical guidelines regarding whether to treat EMPSGC as an invasive carcinoma, regardless of its position on the continuum, or as a more indolent lesion. In 2018, the World Health Organization (WHO) Classification of Skin Tumours, for the first time, included a chapter on EMPSGC and definitively recommended that hybrid lesions containing in situ and invasive mucinous components should be diagnosed as mucinous adenocarcinoma (with neuroendocrine features).9
To date, there have been no reports specifically describing the characteristics of this EMPSGC-associated MSC. Moreover, while EMPSGC is exceedingly rare, EMPSGC-associated MSC is even less common. Since Flieder et al3 first named and described EMPSGC in 1997, we have counted 96 reported cases diagnosed as “EMPSGC,” a third of which were published since 2017. Previous reports insinuated identical behavior of EMPSGC-associated MSC and its non-neuroendocrine MSC (non-NE MSC) counterpart. Because of limited data, authors repeatedly cited the recurrence and metastatic potential of non-NE MSC as proxies for EMPSGC-associated MSC to guide diagnostic and treatment decisions.1,6,13–16 We provide a retrospective series of 63 cases previously diagnosed as “EMPSGC” including clinicopathologic features (summarized in Table 1) and deliver a complete summary of the 96 previously reported cases (eTable 1, Supplemental Digital Content 1, http://links.lww.com/PAS/A909).1–3,6–8,10,13,14,16–41 In addition, we present the first case series of EMPSGC-associated MSC and compare it with the series of previously published invasive cases that would now qualify as EMPSGC-associated MSC (Table 2).1–3,6,10,19,21,22,24,26,29,32,41 We compare the unique attributes of EMPSGC-associated MSC with those of Non-NE MSC and consider the prognostic significance of the neuroendocrine differentiation of EMPSGC-associated MSC and EMPSGC.
MATERIALS AND METHODS
Institutional review board approval was obtained for a multi-center retrospective case series with the University of Wisconsin-Madison as the coordinating center. Collaborators represented 13 institutions and their areas of expertise spanned the fields of ophthalmology and oculoplastic surgery, ophthalmic pathology, dermatopathology, neuropathology, and surgical pathology. Collaborators performed retrospective searches for cases diagnosed as “EMPSGC” encountered in their practices from January 1, 1995 to April 30, 2019. Information collected included patient demographics, clinical presentation, initial clinical impression, type of surgical intervention, histologic description, IHC performed, recurrences, and the presence of an invasive mucinous component (Table 1).
A total of 64 cases were collected, with the largest contributions from the departments of ophthalmic pathology at Tufts Medical Center (23), Houston Methodist Hospital (11), New York Eye and Ear Infirmary (8), Johns Hopkins Hospital (7), University of Wisconsin-Madison (5), and Washington University, St. Louis, MO (4). One case each was contributed by the Oregon Health & Science University, University of Texas Southwestern, NorthShore University Health System, Glenview, IL, University of South Florida, University of Calgary, Alberta, Canada, and Kingston Health Sciences Center, Ontario, Canada. Of note, 10 cases had been previously reported.7,17
The collaborators reviewed all cases using hematoxylin and eosin, occasionally periodic acid-Schiff, and various IHC stains. Collaborators were required to verify the presence of an invasive component in the EMPSGC cases and to provide information on any radiologic studies (magnetic resonance imaging, computed tomography scan, mammogram, positron emission tomography scan, etc.) and/or systemic work-up performed within 12 months of the EMPSGC diagnosis. Available clinical information varied from case to case and by institution.
Immunohistochemistry and Exclusion Criteria
All 64 cases were screened for neuroendocrine differentiation by the presence of at least one positively staining neuroendocrine biomarker, synaptophysin, chromogranin, or neuron-specific enolase (NSE).42 We included 4 cases that were negative for synaptophysin and chromogranin, but positive for NSE because they incorporated other convincing features such as characteristic neuroendocrine morphology and estrogen and progesterone receptor (ER and PR) positivity.1–3,7,8,41 We relied on information provided by collaborators regarding stains performed and their interpretations. Because of the retrospective nature of the study, the same stains were not performed in each case. One case was excluded because it did not have adequate information on morphology or staining.
The de-identified data was evaluated using Microsoft Excel software including subset analysis by sex and recurrences. The cases were separated into 2 groups: “EMPSGC (in situ or pushing invasion9)” and “EMPSGC with an invasive mucinous component” (hereafter referred to as “EMPSGC-associated MSC”). Two sample t-tests were used to assess for significant differences in the age of presentation between women and men with EMPSGC and between the cohort without an invasive mucinous component versus the group with EMPSGC-associated MSC. These analyses were repeated for the aggregate series of previously published “EMPSGC” cases, and the results were compared (eTable 2, Supplemental Digital Content 1, http://links.lww.com/PAS/A909).
Demographics and Clinical Information
A total of 63 cases, originally diagnosed as “EMPSGC,” were included in our series and compared with the aggregate of previously published reports (Table 3).1–3,6–8,10,13,14,16–41 Women comprised 66.7% of our cases while 33.3% were men. The overall mean age of clinical presentation was 64 years, with ages ranging from 47 to 87 years. On average, women tended to present at an older age than men (65.9 vs. 60.9 y, P=0.03). Twenty-one of our 63 cases (33.3%) contained an associated invasive mucinous component. There was a significant difference between the average age of presentation of the EMPSGC cases (in situ or pushing invasion) from our series and those from the aggregated series of previously published cases (63 vs. 67.7 y, P=0.04) (eTable 2, Supplemental Digital Content 1, http://links.lww.com/PAS/A909, Comparative Results, Age Analysis).
Lesions were frequently skin-colored and cystic appearing (Fig. 1). Initial clinical impression before pathologic evaluation was available for 45 cases (Table 1). Most often, some sort of benign cyst was suspected (46.7%), followed by suspected basal cell carcinoma (26.7%), or chalazion (6.7%). Other less common initial clinical impressions included adenoma, hemangioma, mucinous carcinoma, apocrine carcinoma, neoplasm of uncertain behavior, and nonmelanoma carcinoma. Only 2 cases (4.4%) were suspected to be EMPSGC before pathologic evaluation. Tumors were predominantly located at the lower eyelid (55.6%), followed by upper eyelid (36.5%), and canthus (3.2%) (eTable 3, Supplemental Digital Content 1, http://links.lww.com/PAS/A909, Site of Lesion Comparison). Two cases had lesions on both upper and lower eyelids, and in one case, the lesion was at the temple. Information about follow-up was reported for 52 cases, and follow-up intervals ranged from 1 to 67 months, with an average follow-up interval of 13 months. There was available data regarding surgical intervention for 48 patients, and all had some sort of excision: wedge/ellipse excision or excisional biopsy (58.3%) or Mohs microsurgery (41.7%).
The overall recurrence rate of our collected cases previously diagnosed as “EMPSGC,” including the 21 that had an invasive mucinous component, was 14.3%. Of the 9 overall recurrences, two-thirds were women. The most common site for recurrence was the lower eyelid (44.4%) followed by the upper eyelid (33.3%). More than half (5/9) of the recurrences were associated with a lesion that included an invasive carcinoma component. No metastases were reported.
All cases shared elements of characteristic neuroendocrine morphology (Fig. 2). The lesions comprised well-demarcated nodules with partially cystic and partially solid, papillary or cribriform architecture. Commonly, cysts were filled with solid proliferations palisading around fibrovascular cores. Tumor cells were usually medium-sized epithelial cells, resembling bland eccrine ductal cells, with bluish cytoplasm and featured round-to-oval nuclei with stippled, “salt and pepper” chromatin (Fig. 3). Foci of both intracellular and extracellular mucin were present (Figs. 3, 4A). Rare mitoses were present in about half (16/31) of the cases that provided information about mitoses. Additional findings included rosette-like structures, small clefts of mucin, fibrous stroma, pigment incontinence, and reactive changes in the overlying eyelid epidermis. Necrosis was never seen. In some cases, smooth muscle actin or p63 IHC stains were used to highlight myoepithelial cells. When a nodule composed of neoplastic cells had an intact rim of myoepithelial cells, it was considered in situ, whereas progression to neuroendocrine mucinous adenocarcinoma was signified by pools of extracellular stromal mucin and/or infiltrating tumor glands and nests that lacked an intact myoepithelial rim (Figs. 2, 4B).1,8,9 Large expansile nodules that looked in situ but lacked intact myoepithelial rims were characterized as having pushing invasion, concept and terminology borrowed from solid papillary carcinoma of the breast.8,9,46,47
All 63 cases in our series were tested for synaptophysin and 90.5% stained positively. Fifty-two of the cases had data about chromogranin staining, and of these, 71.2% stained positively. Within our collection, 55 cases provided data on ER staining and 53 provided data on PR staining, with 98.2% and 96.1% staining positively for ER and PR, respectively (Fig. 5).
EMPSGC-associated Mucinous Sweat Gland Adenocarcinoma
EMPSGC-associated MSC (denoted by the presence of an invasive mucinous component)9 was present in 21 cases with a female predominance (61.9% women vs. 38.1% men). In this invasive adenocarcinoma subset, the overall mean age of clinical presentation was 66.7 years, ranging from 52 to 84 years (Table 2). The average age of women presenting with EMPSGC-associated MSC was higher than that for men (68.9 vs. 63.3 y), but this difference was not significant, P=0.1. This neuroendocrine-type MSC occurred with highest frequency in the lower eyelid (47.6%) followed by the upper eyelid (33.3%), canthus (9.5%), and temple (4.8%). While all of these EMPSGC-associated MSC patients underwent some type of excision, wedge/ellipse excisions or excisional biopsies were most frequent (90.5%), and there were 2 instances of Mohs microsurgery. There were 5/21 recurrences, and 3 of the 5 recurrences were seen in female patients. In the aggregate of previously published cases, there were 22 cases containing an invasive mucinous component, with 4/22 recurrences (all female).3,6,19 Combining these recurrence figures yields an approximate EMPSGC-associated MSC recurrence rate of 21% (5/21 and 4/22). No cases of metastasis were identified in either group.
EMPSGC is a reputedly uncommon, low-grade lesion that predominantly affects the eyelid skin of older women and has the potential of being misdiagnosed or underdiagnosed.10 Previous authors have considered EMPSGC’s morphologic and immunophenotypic similarities to another neuroendocrine neoplasm, solid papillary carcinoma of the breast.1,3–5 In at least some cases, both EMPSGC and solid papillary carcinoma represent precursor lesions to spatially adjacent neuroendocrine mucinous sweat gland or invasive mucinous breast carcinomas, respectively.1,3–5 Mucinous carcinomas of the breast are divided into type A, with no neuroendocrine expression and small cell clusters, and type B, involving larger nests of neuroendocrine-positive neoplastic cells.4,19 As solid papillary carcinoma shares morphology with type B mucinous breast carcinoma, it was deemed a likely precursor. Zembowicz et al adopted a corresponding framework for EMPSGC: they likened cyst-formation within eccrine ducts to atypical ductal hyperplasia in the mammary ducts; atypical cells undermining the eccrine epithelium in EMPSGC akin to pagetoid spread; formation of cystic, solid, and papillary structures without loss of myoepithelial cells in EMPSGC similar to ductal carcinoma in situ with intact myoepithelium; and loss of myoepithelial layers around ducts teeming with tumor cells representative of EMPSGC-associated invasive mucinous adenocarcinoma.1,10,19 Like type B mucinous carcinoma in the breast, EMPSGC-associated MSC represents the neuroendocrine subtype of MSC.1,3,16,19
Included in the analogy was the concept of pushing invasion, which in the context of solid papillary carcinoma, describes a solid pattern of expansile growth rather than frank invasion.1,8,46 While loss of the myoepithelial rim indicates widely accepted evidence of invasion when observed in carcinomas of the breast, pushing invasion, albeit termed “invasion” by definition (due to the loss of myoepithelial rim) is thought of as an in situ entity because of the indolence associated with it.47,48 Pushing invasion or “pushing borders” in solid papillary carcinoma is staged as carcinoma in situ and not like an invasive lesion.48 Similarly, as explained in the fourth edition, WHO Classification of Skin Tumours, an in situ EMPSGC with a focus of pushing invasion should be diagnosed as “EMPSGC” because it lacks a definitive invasive mucinous component.9 As with solid papillary carcinoma, most foci of EMPSGC that appear noninvasive by morphology, in spite of undetectable myoepithelial cells, probably represent examples of carcinoma in situ with compression and obliteration of surrounding myoepithelium, and the degree of compression is likely a function of the size of the duct involved and the rate of growth of the expansile tumor.8,46,47
Notwithstanding these parallels and the distinctions purported, some breast literature authors contested that type A and type B mucinous breast carcinomas were too similar to merit a sharp distinction, and such labeling had no influence on patient survival.19,49 The significance of neuroendocrine differentiation in the histogenesis of primary cutaneous mucinous carcinoma (MSC) was also debated.1,19 Some questioned the utility of verifying neuroendocrine expression with time-intensive, potentially costly IHC when the neuroendocrine variants might ultimately be treated identically to typical non-NE MSC lesions.7,18,19 Remarkably, our results illustrate the more favorable prognosis of reduced recurrence and absence of metastasis in neuroendocrine-type MSC, potentially reassuring factors for patients with this diagnosis.
Awareness about how neuroendocrine-type MSC differs in morphology and behavior from the non-neuroendocrine subtype is essential for accurate diagnosis and appropriate clinical management. Neuroendocrine MSC features a female predominance versus the male predominance of the non-NE MSC. Non-NE MSCs are composed of abundant mucinous areas that comprise more than 90% of the neoplasm; an in situ component may be present but is rarely seen.50 This is in contrast to EMPSGCs and their invasive counterparts, which predominantly feature focal mucin-filled intracytoplasmic vacuoles or smaller pools of extracellular mucin; mucin is typically not abundant.1,8,19,41 Importantly, non-NE MSCs lack characteristic neuroendocrine appearance (ie, bland, uniform tumor cells with medium-sized, round to oval nuclei with diffusely stippled, “salt and pepper” chromatin)1 and often contain atypical mitoses and significant cellular pleomorphism, not seen in neuroendocrine phenotype. As expected, non-NE MSCs do not express neuroendocrine markers using IHC.
Therefore, the combination of positive neuroendocrine staining, characteristic neuroendocrine morphology, and clinical features are taken together to make the diagnosis of EMPSGC or EMPSGC-associated MSC, and the complete IHC profile including ER/PR positivity is contributory.1,3,4,51 As with other neuroendocrine neoplasms, some neuroendocrine-type MSCs and/or EMPSGCs are only positive for one neuroendocrine marker. As in the cases we summarize, neuroendocrine staining may be weak, focal, or even absent in cases with characteristic neuroendocrine appearance.1,9,11,17 With limited data and published reports on neuroendocrine-type MSC, previous discussions regarding the clinical behavior of EMPSGC deferred to the non-NE MSC reports and advocated for identical clinical management.1,13,14,23 The non-NE MSC literature features a 30% recurrence rate,43–45 and 4.4% to 11% rate of metastasis to regional nodes and distant spread. Consequently, non-NE MSC is frequently described as a locally aggressive tumor, with limited metastatic potential,52 that should be taken seriously and completely excised to avoid metastases.10,26,43
Primary non-NE MSC, first described by Lennox and colleagues in 1952, could itself be considered a rarity based on its low prevalence in the literature.12,43–45,53 Lennox and colleagues proposed that all primary mucin-producing tumors of the skin were of sweat gland origin and, naturally, have commonalities.12,53 Non-NE MSC, EMPSGC, and EMPSGC-associated MSC all have a predilection for the eyelid. A hybrid lesion in which an in situ or pushing borders EMPSGC exists in continuity with an invasive mucinous component should be diagnosed as an “invasive adenocarcinoma” according to the WHO’s clarifying EMPSGC chapter.9 Regarding hybrid non-NE MSC lesions, Kazakov and colleagues illustrated how the existence of an in situ component in association with invasive non-NE MSC helps to characterize that lesion as a primary cutaneous neoplasm rather than a metastatic one.1,51 Cutaneous metastases to the face are exceptionally rare, and breast cancer metastases to the eyelid skin have only rarely been reported (1.2%).54 Even though cutaneous metastatic disease is uncommon, when working up non-NE MSC, it is imperative to rule out metastasis from a different primary.43,50
By default, even in the case of EMPSGC, authors recommended the preliminary step of ruling out secondary metastases via mammogram and other imaging modalities,14,55 supposing that neuroendocrine mucinous carcinoma of the breast would be the most likely culprit due to similar morphology and a shared positivity for both neuroendocrine and ER/PR markers. This was recommended even in the case of in situ EMPSGC lesions without evidence of an associated invasive carcinoma.14 However, only 9.5% of the excised EMPSGCs (in situ or with pushing invasion) in our series recurred. This reinforces that, while deserving complete excision and subsequent surveillance,1,6,13,14 EMPSGCs are likely to behave more indolently than invasive disease and, thus, might warrant a less rigorous follow-up regimen. Not surprisingly, the excellent outcomes we observed in cases of EMPSGC lacking associated invasive carcinoma mirrors the favorable outcomes seen in the analogous solid papillary carcinoma cases without invasive components.51
Comparison of our own series of EMPSGC-associated MSC (n=21) with the aggregate series of previously published reports (n=22) shows that primary EMPSGC-associated MSC follows a more indolent course than described in the previous MSC literature that predates the recognition of EMPSGC-associated MSC. Hence, without taking neuroendocrine differentiation into consideration, previous recurrence rates described for MSCs are not good proxies for EMPSGC-associated MSC. We provide the first estimated recurrence rate of 21.0% (5/21 and 4/22; Tables 2, 3) for EMPSGC-associated (neuroendocrine-type) MSC, which is more favorable than the 30% recurrence rate for non-NE MSC cited by previous authors.43–45 Although 2 of the studies behind the 30% recurrence rate attributed to non-NE MSC precede the description of the neuroendocrine subtype, we are convinced that the cases included in the calculation predominantly describe non-NE MSC based on morphologic and clinical features.44,45
Interestingly, our novel series of EMPSGC-associated MSC replicated the female predominance (71.4%, 15/21) reported by Zembowicz et al1 and others.2 The majority (77.8%, 7/9) of EMPSGC-associated MSC cases that recurred after excision were also in female patients, and in our 63 cases diagnosed as “EMPSGC,” women tended to present 5 years later than men on average, P=0.03. Especially intriguing, however, is the complete lack of any reported metastatic disease in the 96 previously published cases diagnosed as EMPSGC, or in our novel 53 cases. It seems that the neuroendocrine differentiation confers the indolence we observe, and likewise, neuroendocrine differentiation has been associated with indolent behavior in the invasive neuroendocrine mucinous counterpart in the breast.40 The counterpart breast literature suggests that low-grade neuroendocrine mucinous breast carcinomas have a low risk of progression and distant dissemination.27
To our knowledge, no cases of metastasis pertaining to EMPSGC-associated MSC have been reported. The likelihood of EMPSGC representing a metastatic lesion from another primary is exceedingly low. However, even without significant threat of recurrence or metastasis, these tumors can be locally destructive and cosmetically disfiguring.34 Completely excising the lesion with wedge excision or slow Mohs surgery is an appropriate intervention to diminish the risk of progression to invasive carcinoma, if in situ, or recurrence.13,14,19 Extensive oncologic work-up along with regular imaging and follow-up for EMPSGC (in situ/pushing invasion) may be excessively cautious given the indolence we encountered. Improved awareness of both EMPSGC and EMPSGC-associated MSC, along with increased understanding of their distinctive characteristics (sex predilection, morphological features, and age of presentation) would facilitate earlier, accurate diagnosis. Correctly diagnosing EMPSGC and EMPSGC-associated MSC carries important prognostic benefits for patients and may avoid undue psychological stress associated with a carcinoma diagnosis.
Since the first neuroendocrine MSC was reported,11 reports and series have consisted of mostly 1 to 3 cases, with the largest of series comprising 9 to 12 cases.1,2,7,41 We provide a more comprehensive analysis, and we are the first group to review and distinguish non-NE MSC from the neuroendocrine subtype and address the value of including a neuroendocrine variant in the differential diagnosis of mucinous cutaneous adnexal neoplasms. Our updated incidence for EMPSGC-associated MSC (33.3% and 31.4%, Table 3) is probably more reflective of the true incidence than the previously reported 50% based on 12 cases.1 Here, we review 43 cases of neuroendocrine-type MSC, but we suspect the actual incidence may be higher. Additional research will continue to improve our understanding of these curious lesions. Nonetheless, we offer a timely update and the largest series in comparison with an aggregate of previously published cases diagnosed as “EMPSGC.” Our results corroborate that EMPSGC is a likely precursor of the neuroendocrine-type MSC.1–3,6,9 Furthermore, we emphasize the differences between EMPSGC and EMPSGC-associated MSC, entities which were until recently diagnostically lumped together as “EMPSGC.”
The authors acknowledge Bret Evers, MD, PhD, of University of Texas Southwester Medical Center for the contribution.
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