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Endocrine mucin-producing sweat gland carcinoma with GATA3 expression: report of two cases

2017; Elsevier BV; Volume: 49; Issue: 7 Linguagem: Inglês

10.1016/j.pathol.2017.08.018

1465-3931

Yueh‐Hung Chou, Yu‐Chen Chang, Yen-Lin Huang, Chen‐Tu Wu,

Ear and Head Tumors

Endocrine mucin-producing sweat gland carcinoma (EMPSGC) is a rare, low-grade cutaneous adnexal carcinoma with neuroendocrine differentiation and may be a precursor lesion of mucinous carcinoma of the skin (MCS). The tumour typically affects the eyelids of elderly women and is morphologically analogous to endocrine ductal carcinoma in situ (eDCIS)/solid papillary carcinoma (SPC) of the breast.1Zembowicz A. Garcia C.F. Tannous Z.S. et al.Endocrine mucin-producing sweat gland carcinoma. Twelve new cases suggest that it is a precursor of some invasive mucinous carcinomas.Am J Surg Pathol. 2005; 29: 1330-1339Crossref PubMed Scopus (96) Google Scholar, 2Shon W. Salomão D.R. WT1 expression in endocrine mucin-producing sweat gland carcinoma: a study of 13 cases.Int J Dermatol. 2014; 53: 1228-1234Crossref PubMed Scopus (24) Google Scholar Given the overlapping histological and immunohistochemical features, differentiating EMPSGC from cutaneous metastasis of a breast cancer is important but often difficult. GATA binding protein 3 (GATA3) is a transcription factor that has recently been identified as a useful immunohistochemical marker highly expressed in urothelial and breast carcinomas. However, GATA3 expression in EMPSGC is rarely discussed and not well understood.3Abdulkader M. Kuhar M. Hattab E. et al.GATA3 positivity in endocrine mucin-producing sweat gland carcinoma and invasive mucinous carcinoma of the eyelid: report of 2 cases.Am J Dermatopathol. 2016; 38: 789-791Crossref PubMed Scopus (16) Google Scholar Here, we present two cases of GATA3 positive EMPSGC (including the first documented male case) and review the relevant literature. The first case was an 87-year-old man presenting with a 7 mm painless solitary nodule on his left cheek (Fig. 1A), slowly growing over the course of 1 year. The patient did not have clinical evidence of a breast carcinoma or other visceral malignancy. Excisional biopsy was performed under the impression of hidradenoma. Histopathological examination showed a multinodular dermal tumour with solid and cribriform patterns (Fig. 1B). Under high power, the lesion was composed of polygonal cells with monomorphic nuclei, finely stippled chromatin and abundant eosinophilic cytoplasm (Fig. 1C). The tumour border was focally infiltrative with extravasated mucin pools (Fig. 1D). Immunohistochemically, the tumour was positive for oestrogen receptor (ER) (Fig. 1E), progesterone receptor (PR), GATA3 (Fig. 1F), Wilms tumour 1 (WT1) and synaptophysin (Fig. 1G). p63 immunostain demonstrated a preserved myoepithelial layer around non-invasive dermal nodules and was lost in infiltrative areas (Fig. 1H). Mucicarmine stain highlighted intracellular and extracellular mucin (Fig. 1I). An EMPSGC with associated mucinous carcinoma was diagnosed. Subsequent panendoscopy, colonoscopy and ultrasound examination of the breast and abdomen were normal. Since the surgical margin from the first excision was positive, a re-excision was performed to achieve clear margins (greater than 5 mm). No recurrence was noted after 10 months. The second case was a 55-year-old woman without underlying diseases, who presented with a 2 mm papule on the left upper eyelid for 3 months. A surgical procedure was performed for cosmetic reasons. Histopathological examination revealed a well-circumscribed dermal tumour composed of uniform cells with abundant cytoplasm. Solid and cribriform arrangements were noted and mucin production was evident (Fig. 2A). A frank invasive component was not identified. Immunohistochemically, the tumour was positive for ER (Fig. 2B), PR, GATA3 (Fig. 2C) and synaptophysin (Fig. 2D). However, the lesion disappeared in deeper sections used for p63 and WT1 immunostains. The diagnosis of EMPSGC was confirmed after bilateral mammography and computed tomography of the chest and abdomen showed negative findings. Although the surgical margin was close (0.5 mm to the excision margin), the patient refused to have a second operation due to cosmetic concerns. Close follow-up was recommended and no recurrence was noted 4 months after excision. EMPSGC is a rare, low-grade cutaneous adnexal carcinoma initially described by Flieder et al. in 1997. To date, approximately 49 cases have been reported in the English literature, including 13 cases identified in a retrospective study.2Shon W. Salomão D.R. WT1 expression in endocrine mucin-producing sweat gland carcinoma: a study of 13 cases.Int J Dermatol. 2014; 53: 1228-1234Crossref PubMed Scopus (24) Google Scholar The tumour typically affects elderly Caucasian women (female:male = 33:16), with a mean age at diagnosis of 65.6 years (range 29–88 years). The eyelid is the most common location (44 cases), followed by cheek (4 cases) and chest (1 case). Combining the present two cases, EMPSGC has only been reported in five Asian patients.4Inozume T. Kawasaki T. Harada K. et al.A case of endocrine mucin-producing sweat gland carcinoma.Pathol Int. 2012; 62: 344-346Crossref PubMed Scopus (17) Google Scholar, 5Koike T. Mikami T. Maegawa J. et al.Recurrent endocrine mucin-producing sweat gland carcinoma in the eyelid.Australas J Dermatol. 2013; 54: e46-e49Crossref PubMed Scopus (24) Google Scholar, 6Tsai J.H. Hsiao T.L. Chen Y.Y. et al.Endocrine mucin-producing sweat gland carcinoma occurring on extra-facial site: a case report.J Cutan Pathol. 2014; 41: 544-547Crossref PubMed Scopus (21) Google Scholar Unlike the general epidemiological profile, a marked male predominance is observed in the Asian ethnic group, with a male-to-female ratio of 4:1. In fact, the second case in the current report documents the first EMPSGC in an Asian female. EMPSGC also has a higher rate of extra-eyelid location in Asian patients (eyelid:cheek:chest = 2:2:1). The clinical presentation of EMPSGC is a slowly growing nodule without distinctive characteristics, suggesting its malignant nature. The diagnosis is based on histological and immunohistochemical features that are analogous to eDCIS/SPC of the breast. eDCIS/SPC is an in situ mammary lesion with neuroendocrine differentiation, associated with high ER/PR expression, and represents the precursor of type B invasive mucinous carcinoma. Similar to eDCIS/SPC, EMPSGC is a multinodular tumour composed of uniform cells with finely stippled chromatin, inconspicuous nucleoli and abundant eosinophilic cytoplasm. Variable architectural patterns can be found, including solid, cystic, papillary and cribriform. Cytological atypia and mitotic activity are usually low. Intracellular and extracellular mucin is present and can be highlighted with a mucin stain. Like its mammary counterpart, EMPSGC demonstrates positive staining for ER/PR and at least one neuroendocrine marker, such as synaptophysin, chromogranin and neuron-specific enolase.1Zembowicz A. Garcia C.F. Tannous Z.S. et al.Endocrine mucin-producing sweat gland carcinoma. Twelve new cases suggest that it is a precursor of some invasive mucinous carcinomas.Am J Surg Pathol. 2005; 29: 1330-1339Crossref PubMed Scopus (96) Google Scholar, 2Shon W. Salomão D.R. WT1 expression in endocrine mucin-producing sweat gland carcinoma: a study of 13 cases.Int J Dermatol. 2014; 53: 1228-1234Crossref PubMed Scopus (24) Google Scholar Positivity for cytokeratins 8 and 18 (CK8 and CK18) and negativity for CK5/6 in EMPSGC also overlaps with the immunoprofile of SPC.7Fernandez-Flores A. Cassarino D.S. Endocrine mucin-producing sweat gland carcinoma: a study of three cases and CK8, CK18 and CD5/6 immunoexpression.J Cutan Pathol. 2015; 42: 578-586Crossref PubMed Scopus (19) Google Scholar Some reported cases observed a morphological continuum of multistage tumour progression, ranging from benign eccrine cysts, atypical intracystic proliferation, EMPSGC, to MCS. WT1 protein, a transcription factor, was overexpressed in areas of atypical epithelial proliferation but not in the benign eccrine component. These findings suggest EMPSGC may be a precursor of MCS. WT1 up-regulation plays a role in oncogenesis of such a tumour spectrum.1Zembowicz A. Garcia C.F. Tannous Z.S. et al.Endocrine mucin-producing sweat gland carcinoma. Twelve new cases suggest that it is a precursor of some invasive mucinous carcinomas.Am J Surg Pathol. 2005; 29: 1330-1339Crossref PubMed Scopus (96) Google Scholar, 2Shon W. Salomão D.R. WT1 expression in endocrine mucin-producing sweat gland carcinoma: a study of 13 cases.Int J Dermatol. 2014; 53: 1228-1234Crossref PubMed Scopus (24) Google Scholar, 6Tsai J.H. Hsiao T.L. Chen Y.Y. et al.Endocrine mucin-producing sweat gland carcinoma occurring on extra-facial site: a case report.J Cutan Pathol. 2014; 41: 544-547Crossref PubMed Scopus (21) Google Scholar EMPSGC is associated with MCS in 50% of cases.1Zembowicz A. Garcia C.F. Tannous Z.S. et al.Endocrine mucin-producing sweat gland carcinoma. Twelve new cases suggest that it is a precursor of some invasive mucinous carcinomas.Am J Surg Pathol. 2005; 29: 1330-1339Crossref PubMed Scopus (96) Google Scholar The initial step of the transition is the breakdown of expansile tumour nodules and subsequent formation of mucin pools. The process of 'inverse cell polarity' facilitates the progression. Being proposed in mucinous carcinoma of breast and pancreas, 'inverse cell polarity' indicates the tumour cells with altered polarity gain apical secretory properties and secrete the mucin toward the stromal direction rather than the luminal side.1Zembowicz A. Garcia C.F. Tannous Z.S. et al.Endocrine mucin-producing sweat gland carcinoma. Twelve new cases suggest that it is a precursor of some invasive mucinous carcinomas.Am J Surg Pathol. 2005; 29: 1330-1339Crossref PubMed Scopus (96) Google Scholar, 8Adsay N.V. Merati K. Nassar H. et al.Pathogenesis of colloid (pure mucinous) carcinoma of exocrine organs: coupling of gel-forming mucin (MUC2) production with altered cell polarity and abnormal cell-stroma interaction may be the key factor in the morphogenesis and indolent behavior of colloid carcinoma in the breast and pancreas.Am J Surg Pathol. 2003; 27: 571-578Crossref PubMed Scopus (144) Google Scholar Despite the well-documented association between EMPSGC and MCS, it is worth noting that unlike EMPSGC, MCS shows a male predominance and does not always exhibit neuroendocrine differentiation. Extra-facial involvement is not rare.1Zembowicz A. Garcia C.F. Tannous Z.S. et al.Endocrine mucin-producing sweat gland carcinoma. Twelve new cases suggest that it is a precursor of some invasive mucinous carcinomas.Am J Surg Pathol. 2005; 29: 1330-1339Crossref PubMed Scopus (96) Google Scholar, 9LeBoit P.E. Burg G. Weedon D. et al.World Health Organization Classification of Tumours. Pathology and Genetics of Skin Tumours. IARC, Lyon2006Google Scholar, 10Kim J.B. Choi J.H. Kim J.H. et al.A case of primary cutaneous mucinous carcinoma with neuroendocrine differentiation.Ann Dermatol. 2010; 22: 472-477Crossref PubMed Scopus (14) Google Scholar It is well established that mucinous carcinoma of the breast can be divided into two major groups: type A is paucicellular and without neuroendocrine differentiation while type B is hypercellular and with neuroendocrine differentiation. Corresponding subsets can be observed in MCS. MCS with type A pattern lacks neuroendocrine differentiation and resembles type A mucinous carcinoma of the breast. On the other hand, MCS with type B pattern resembles type B mucinous carcinoma of the breast and shows neuroendocrine differentiation.1Zembowicz A. Garcia C.F. Tannous Z.S. et al.Endocrine mucin-producing sweat gland carcinoma. Twelve new cases suggest that it is a precursor of some invasive mucinous carcinomas.Am J Surg Pathol. 2005; 29: 1330-1339Crossref PubMed Scopus (96) Google Scholar, 10Kim J.B. Choi J.H. Kim J.H. et al.A case of primary cutaneous mucinous carcinoma with neuroendocrine differentiation.Ann Dermatol. 2010; 22: 472-477Crossref PubMed Scopus (14) Google Scholar, 11Lakhani S.R. Ellis I.O. Schnitt S.J. et al.WHO Classification of Tumours of the Breast.4th ed. IARC, Lyon2012Google Scholar It is logical to assume EMPSGC may be the precursor of MCS with type B pattern but is probably unrelated to MCS with type A pattern. Additional studies are needed to support the hypothesis. Several tumours arising from sweat gland, breast, and salivary gland show comparable morphological and immunohistochemical features, reflecting the common embryological origin of these organs. Well-known examples include pleomorphic adenoma, adenoid cystic carcinoma, and mucinous carcinoma. EMPSGC of the sweat gland is analogous to eDCIS/SPC of the breast and should be added to the list.3Abdulkader M. Kuhar M. Hattab E. et al.GATA3 positivity in endocrine mucin-producing sweat gland carcinoma and invasive mucinous carcinoma of the eyelid: report of 2 cases.Am J Dermatopathol. 2016; 38: 789-791Crossref PubMed Scopus (16) Google Scholar, 6Tsai J.H. Hsiao T.L. Chen Y.Y. et al.Endocrine mucin-producing sweat gland carcinoma occurring on extra-facial site: a case report.J Cutan Pathol. 2014; 41: 544-547Crossref PubMed Scopus (21) Google Scholar Analogous tumours with identical genetic change have been documented. For instance, ETV6-NTRK3 fusion gene is observed in both secretory carcinoma of the breast and mammary analogue secretory carcinoma of the salivary gland.12Skálová A. Vanecek T. Sima R. et al.Mammary analogue secretory carcinoma of salivary glands, containing the ETV6-NTRK3 fusion gene: a hitherto undescribed salivary gland tumor entity.Am J Surg Pathol. 2010; 34: 599-608Crossref PubMed Scopus (684) Google Scholar Papillary carcinoma of the breast has been reported to have mutations in the PIK3CA and AKT1 genes. However, identical genetic alterations were not identified in EMPSGC, suggesting the molecular profile of EMPSGC may differ from its mammary counterpart.13Cornejo K.M. Hutchinson L. Meng X. et al.Endocrine mucin-producing sweat gland carcinoma of the eyelid: a report of a case with molecular analysis.Am J Dermatopathol. 2016; 38: 636-638Crossref PubMed Scopus (16) Google Scholar Due to similar histological and immunohistochemical features, cutaneous metastasis from a mammary carcinoma is one of the most important differential diagnoses of EMPSGC. The presence of non-invasive component with a preserved myoepithelial layer is vital evidence to support a primary cutaneous lesion of EMPSGC.3Abdulkader M. Kuhar M. Hattab E. et al.GATA3 positivity in endocrine mucin-producing sweat gland carcinoma and invasive mucinous carcinoma of the eyelid: report of 2 cases.Am J Dermatopathol. 2016; 38: 789-791Crossref PubMed Scopus (16) Google Scholar, 7Fernandez-Flores A. Cassarino D.S. Endocrine mucin-producing sweat gland carcinoma: a study of three cases and CK8, CK18 and CD5/6 immunoexpression.J Cutan Pathol. 2015; 42: 578-586Crossref PubMed Scopus (19) Google Scholar Myoepithelial markers such as calponin, actin, p63 and S100 can be of help in the detection of myoepithelial cells. In cases where myoepithelial cell is unable to be detected immunohistochemically, the diagnosis of EMPSGC is made in conjunction with the lack of a primary visceral malignancy.1Zembowicz A. Garcia C.F. Tannous Z.S. et al.Endocrine mucin-producing sweat gland carcinoma. Twelve new cases suggest that it is a precursor of some invasive mucinous carcinomas.Am J Surg Pathol. 2005; 29: 1330-1339Crossref PubMed Scopus (96) Google Scholar, 4Inozume T. Kawasaki T. Harada K. et al.A case of endocrine mucin-producing sweat gland carcinoma.Pathol Int. 2012; 62: 344-346Crossref PubMed Scopus (17) Google Scholar, 6Tsai J.H. Hsiao T.L. Chen Y.Y. et al.Endocrine mucin-producing sweat gland carcinoma occurring on extra-facial site: a case report.J Cutan Pathol. 2014; 41: 544-547Crossref PubMed Scopus (21) Google Scholar, 7Fernandez-Flores A. Cassarino D.S. Endocrine mucin-producing sweat gland carcinoma: a study of three cases and CK8, CK18 and CD5/6 immunoexpression.J Cutan Pathol. 2015; 42: 578-586Crossref PubMed Scopus (19) Google Scholar EMPSGC should also be differentiated from other cutaneous adnexal tumours, hidradenoma in particular. Among the 13 EMPSGCs identified by Shon et al. in a retrospective study, eight were initially diagnosed as hidradenomas.2Shon W. Salomão D.R. WT1 expression in endocrine mucin-producing sweat gland carcinoma: a study of 13 cases.Int J Dermatol. 2014; 53: 1228-1234Crossref PubMed Scopus (24) Google Scholar Both tumours show nodular and cystic architectures. Unlike the uniform cytology of EMPSGC, hidradenoma reveals a mixture of polygonal cells with clear cell areas and squamoid differentiation. Concomitant expression of hormonal and neuroendocrine markers, a unique immunoprofile of EMPSGC, is not observed in hidradenoma.1Zembowicz A. Garcia C.F. Tannous Z.S. et al.Endocrine mucin-producing sweat gland carcinoma. Twelve new cases suggest that it is a precursor of some invasive mucinous carcinomas.Am J Surg Pathol. 2005; 29: 1330-1339Crossref PubMed Scopus (96) Google Scholar, 6Tsai J.H. Hsiao T.L. Chen Y.Y. et al.Endocrine mucin-producing sweat gland carcinoma occurring on extra-facial site: a case report.J Cutan Pathol. 2014; 41: 544-547Crossref PubMed Scopus (21) Google Scholar GATA3 is a zinc finger transcription factor crucial to the differentiation of breast ductal epithelium, urothelium, hair follicles, and T-lymphocytes. GATA3 immunohistochemistry is a sensitive marker to confirm the mammary or urothelial origin of carcinomas, either in primary or metastatic sites.3Abdulkader M. Kuhar M. Hattab E. et al.GATA3 positivity in endocrine mucin-producing sweat gland carcinoma and invasive mucinous carcinoma of the eyelid: report of 2 cases.Am J Dermatopathol. 2016; 38: 789-791Crossref PubMed Scopus (16) Google Scholar In female breast cancers, a striking correlation between ER and GATA3 expression is well-established by immunohistochemical techniques and cDNA arrays. GATA3 is almost exclusively present in ER positive patients and is associated with lower tumour grade.14Gonzalez R.S. Wang J. Kraus T. et al.GATA-3 expression in male and female breast cancers: comparison of clinicopathologic parameters and prognostic relevance.Hum Pathol. 2013; 44: 1065-1070Abstract Full Text Full Text PDF PubMed Scopus (39) Google Scholar However, in male breast cancers the result is inconsistent among different studies. Gonzalez et al. reported GATA3 positivity was recognised in only one-third of male patients and was unrelated to ER expression and prognosis.14Gonzalez R.S. Wang J. Kraus T. et al.GATA-3 expression in male and female breast cancers: comparison of clinicopathologic parameters and prognostic relevance.Hum Pathol. 2013; 44: 1065-1070Abstract Full Text Full Text PDF PubMed Scopus (39) Google Scholar On the contrary, Serdy et al. observed that 98% of male breast cancers showed GATA3 positivity and correlated with high ER expression rate.15Serdy K.M. Leone J.P. Dabbs D.J. et al.Male breast cancer: a single-institution clinicopathologic and immunohistochemical study.Am J Clin Pathol. 2017; 147: 110-119PubMed Google Scholar EMPSGC is invariably positive for ER regardless of gender. On the other hand, GATA3 positivity in EMPSGC is rarely discussed and has only been reported in two female patients.3Abdulkader M. Kuhar M. Hattab E. et al.GATA3 positivity in endocrine mucin-producing sweat gland carcinoma and invasive mucinous carcinoma of the eyelid: report of 2 cases.Am J Dermatopathol. 2016; 38: 789-791Crossref PubMed Scopus (16) Google Scholar Due to the rarity of the entity and the tendency to affect women, GATA3 expression has never been studied in male patients to the best of our knowledge. Two additional cases of GATA3 positive EMPSGC are described in the current report, including the first male case in the literature. In all four cases (3 women and 1 man), GATA3 exhibits diffuse and intense nuclear staining in both in situ and invasive mucinous (if present) components. These findings, although limited, suggest GATA3 correlates with ER status and is highly expressed in EMPSGC in both sexes. GATA3 positivity further reinforces the immunohistochemical similarity between EMPSGC and cutaneous metastasis of breast cancers, and as a result, is of limited value in the differential diagnosis. Hormonal markers also have no role in making the distinction. As shown in the current report, the definite diagnosis of EMPSGC relies either on the detection of non-invasive component with myoepithelial rimming (Case 1), or the absence of underlying mammary malignancy (Case 2). The authors state that there are no conflicts of interest to disclose.