Primary Cutaneous Secretory Carcinoma: A Case Report and Literature Review

Cutaneous secretory carcinomas (CSCs) are primary neoplasms of the skin that have been just recently described in the literature through case reports and series. In this case, a cutaneous lesion was found on the left temporal region of an 83-year-old male. He was referred to plastic surgery for complete excision, with negative margins confirmed by pathology. Histology, immunostaining, and genetic testing showed characteristics confirming the diagnosis of CSC and were supported by the information present in the current literature. Our patient showed no evidence of nodal disease or recurrence during regular follow-ups. Given the rarity of CSCs, we aim to present our experience regarding the diagnosis, pathological analysis, and management of our patient as well as summarize the present literature to further open avenues of research.


Introduction
Cutaneous secretory carcinomas (CSCs) are primary neoplasms of the skin that share similar pathological characteristics to mammary-analog secretory carcinomas (MASCs) and secretory breast carcinomas (SBCs). This novel tumor has only recently been identified in case reports and case series, first appearing in the literature in 2009 [1]. Although the axilla is the most common location for CSC, its presence throughout the body has been reported [2]. A key genetic identifier in the literature is the (12;15)(p13;q25) translocation which results in the ETS variation transcription factor 6-neurotrophic tyrosine receptor kinase 3 (ETV6-NTRK3) gene fusion, a genetic property present in CSC, MASC, and SBC tumors [3].
In this report, we describe a unique CSC with microcystic morphology, positive immunostainings, such as S100, SOX10, and PanTRK, and the presence of an NTRK3 gene recombination, similar to previous MASC and CSC reports, found on the left temporal region of an 83-year-old male without any radiographic evidence of nearby primary salivary gland tumor or nodal disease.

Case Presentation
An 83-year-old Hispanic male with a past medical history of temporal arteritis and numerous tan, flat lentigines on his face and arms presented with a one-year history of a gradually growing, non-pruritic, and non-painful left temporal skin lesion. The lesion initially presented as a small red bump that became larger and darker over time. On presentation, the lesion was a round, raised, firm, and fixed papule measuring approximately 7 mm × 7 mm with an irregular but smooth surface ( Figure 1). The papule had a reddish hue with a small area of dark blue/purple coloration. DermLite DL4W Dermoscopy (DermLite LLC, San Juan Capistrano, CA, USA) in both polarized and non-polarized modes showed mixed features, predominantly milky red with yellow globules, a somewhat rhomboid configuration, and occasional white lines. The dark blue/purple area of the lesion contained multiple adjacent blue globules.

FIGURE 1: Gross appearance of the cutaneous secretory carcinoma lesion.
On histology, the tumor was fully circumscribed in the dermis and contained a multi-cystic and patchy micropapillary architecture ( Figure 2). There was variable mono-to multi-layered lining and bland-tomildly enlarged cytology, with central prominent eosinophilic secretions, a common characteristic of secretory carcinoma [4] (Figure 3).  Immunostaining demonstrated strongly positive S100 staining ( Figure 4A), a common characteristic of CSCs, MASCs, and SBCs [3]. Tumor cells were positive for cytokeratin 7 (CK7), epithelial membrane antigen (EMA), SOX10 ( Figure 4B), gross cystic disease fluid protein (GCDFP), and estrogen receptor (ER) (about 20% of cells with variable intensity). Strong expression of PanTRK protein was also noted ( Figure 4C). Myoepithelial cells were not visualized on smooth muscle actin, p40 ( Figure 4D), and p63 stains. Synaptophysin, chromogranin, mucin, CK20, and thyroid transcription factor-1 (TTF-1) were negative. Break apart fluorescence signal pattern for NTRK3 was observed in 40% of nuclei, with a normal reference range of 11.6%, and an abnormal signal pattern in 16% of nuclei, with a normal cut-off of 9%, indicating NTRK3 rearrangement and deletion of the 5' region of NTRK3. The patient was referred to a plastic and reconstructive surgeon for definitive management with complete excision. The lesion was excised with 5 mm margins and closed primarily. Negative margins were later confirmed. The patient had an uncomplicated postoperative course and was referred to surgical oncology for follow-up. No evidence of salivary tumor or nodal disease was identified on radiographic imaging. The patient is alive and disease-free after five months of follow-up.

Discussion
This case further highlights the presence of secretory carcinomas, although typically reported in the breast and salivary gland, in the skin. Literature on this rare tumor is scarce, and the identification of key pathology is an area for future research. Through a review of the present literature on CSC, we found the mean age of patients was 50.3 years, and the median was 44 years (range: 13-98 years), with 29.2% of patients being male. The most common area of the presentation is the axilla, but other locations include the neck, groin, thigh, nipple, cheek, and eyelid [2] (Table 1). Our patient's lesion was located on the left temporal region, a relatively rare location when compared to other reports ( Table 1).   The reviewing pathologist described the tumor specimen in our case as 7 mm × 7 mm and completely circumscribed in the dermis with a depth of 1 cm. The tumor had a multi-cystic architecture, multi-layered lining, bland-to-mildly enlarged cytology, and central eosinophilic secretions. This histology closely resembles similar tumors described in the breast, parotid gland, and thyroid gland. Primary breast and parotid gland origin were excluded through proper clinical examinations and history. Immunohistochemistry staining was positive for CK7, EMA, S100, GCDFP, ER, and SOX10. The staining was negative for synaptophysin, chromogranin, mucin, TTF-1, and CK20. The negative TTF-1 excluded thyroid carcinoma. The staining was also negative for p40, p63, and smooth muscle actin, which are indicative of myoepithelial cells. The tumor expressed PanTRK through the detection of wild-type TRK protein and NTRK fusion gene. NTRK3 rearrangement was detected as well; however, NTRK3 fusion with the specific ETV6 partner gene has not been confirmed yet. Abnormality found on the break-apart probe together with the diffuse expression of NTRK protein via immunohistochemistry supports the role of NTRK3 in oncogenesis in this case as well [15]. ETV6 fusion with NTRK3 is the most common fusion cited in the literature on CSCs and is present in most of these tumors ( Table 1).
Surgical excision is the primary treatment for CSC [12]. In patients where initial biopsy or excision showed positive margins, re-excision was performed. Management for our patient was the excision of the nodule with negative margins which was closed primarily. Wound management was followed up with plastic surgery and continued by the patient. Although not necessary for our patient due to negative margins and lack of sentinel lymph node involvement, entrectinib, a tyrosine-receptor kinase (TRK) inhibitor, can help patients with recurrent and metastatic disease and has been therapeutic in a case of MASC [16]. TRK inhibitors may be beneficial for our patient in the event of recurrence or metastasis, given the NTRK3 gene fusion that leads to oncogenic properties of the impacted cells.
CSCs are generally indolent [15], with only one definitive incidence of metastasis reported previously [14].
Our patient was followed up on postoperative day 15 with plastic surgery and at one month and two months post-excision with surgical oncology for further workup. The current plan is annual CT scanning with surgical oncology follow-up for monitoring. Close follow-up is recommended given the unknown nature of this tumor type, and precautionary imaging is recommended to identify a possible primary salivary gland source or spread to adjacent lymph nodes. The prognosis is favorable, with only one report of metastasis for MASC [17] and one definitive reported metastasis for CSC [14].
Currently, cases of CSCs are rare in the literature, so we aim to add to the current body of literature through our experience in the diagnosis, pathological analysis, and management of our patient. Accumulation of this research can open avenues for standardization in the identification of this tumor type, and, ultimately, allow for earlier diagnosis and personalized treatment.
A large single or multi-institutional study is necessary to confirm reported pathology markers and conduct genetic studies that identify CSCs. Given the rarity of this tumor type in the literature, the lack of long-term