Syringoid eccrine carcinoma (SEC) is an extremely rare malignant adnexal tumor with eccrine differentiation first described by Freeman and Wilkemann in 1969 as eccrine epithelioma [1]. Its name originates from histological pattern which resembles that one of a syringoma by showing ductal, cystic, and comma-like epithelial components in a fibrocollagenous matrix. Primary eccrine carcinoma, syringomatous carcinoma, eccrine syringomatous carcinoma, eccrine epithelioma, malignant syringoma, and sweat gland carcinoma with syringomatous features are considered to be synonyms of SEC [2].

Sweat gland carcinomas had been classified on the basis of the corresponding classification of benign sweat gland adenomas, as proposed by Berg and McDivitt in 1968 [3]. Recent studies have more simply classified sweat gland carcinomas into eccrine and apocrine tumors, with reference to the type of secretion: eccrine sweat glands open directly onto the surface of the skin and are widely distributed almost everywhere; apocrine sweat glands secrete sweat into the pilary canal of the hair follicle rather than opening directly onto the surface of the skin, and can be found in the armpit, areola, perineum, ear, and eyelid [4].

Carcinomas of the vulva are a relatively common gynecologic malignancy of the female genital tract and represent 3-5% of all diagnosed female genital malignancies; squamous cell carcinoma comprises 90% of these tumors. On the other hand, primary vulvar glandular neoplasms are rare, accounting for 1% of all malignant neoplasms of the vulva. Adnexal adenocarcinomas of the vulva are exceedingly rare, accounting for less than 0.1% of all vulvar carcinomas [5]. They make up less than 0.001% of all skin cancers [6]. Their incidence is less than 0.005% of all tumor specimens resected surgically [4]. SEC usually affects subjects in the fourth to seventh decades of life [3].

Most of the lesions described in literature were solitary and firm nodules or infiltrating rose plaques occurring on scalp, eyelid, nose, chin, external auditory canal, chest wall, nipple, abdominal skin, perineal-scrotal skin, and vulva [2-12]. SEC shows a slow growth pattern and has often been present for many years, sometimes decades, before diagnosis [13]. It sometimes runs an indolent course which may be complicated by local recurrence [2]. It sometimes has a propensity for destructive local infiltrations and can recur after excision [9], as well as spread to regional lymph nodes or give distant metastases [2,4,5].

Fewer than 50 cases have been reported under the name of SEC and its synonyms [11]. Due to limited availability of literature, there is a lack of a universally accepted staging system [9] and the diagnosis and management of these tumors are quite difficult [4].

SEC is a dermal lesion without epidermal connection. Epithelial cells are usually organized in strands with lumen formation, which is called syringoma-like tadpole morphology. Basaloid cells have uniform hyperchromatic nuclei. There usually is an infiltrative growth pattern with deep invasion and extension into the subcutaneous tissue or skeletal muscle, and a common perineural and lymphovascular invasion. Mitotic activity is variable.

The differential diagnosis of SEC includes primary cutaneous adenoid cystic carcinoma (PCACC), microcystic adnexal carcinoma, infundibular carcinoma, adenocarcinoma with skin metastases, sclerosing basal cell carcinoma (BCC), desmoplastic trichoepithelioma, and syringoma.

PCACC is a rare, slow-growing tumor that consists of cords of basaloid cells, characteristic sieve-like cribriform growth, and mucin production not usually present in SEC. The tumor cells are typically small, cuboidal, and monomorphic.

Microcystic adnexal carcinomas show both eccrine and follicular differentiation with basaloid cells forming keratin-filled cysts, absent in SEC.

Common features of infundibular carcinoma are hair follicular infundibulum attachment, sheets of basaloid cells organized superficially in small nests, and pseudoglandular pattern in deep and squamous differentiation; desmoplastic stroma is the only similarity with SEC.

Metastatic adenocarcinoma of the skin usually presents in patients with a clinical history of preexisting disease. Carcinoma of the breast, lung, kidney, colon, stomach, and ovaries can be differentiated from SEC usually through morphology and immunohistochemistry. Compared to primary eccrine carcinomas, metastatic adenocarcimonas are generally high-grade lesions with remarkable atypia.

Sclerosing BCC shows infiltrative basaloid cells organized in palisading arrangement. SEC never demonstrates the palisading arrangement seen in BCC and other hair follicular-derived carcinomas. It is an epidermal tumor with prominent sclerosing stroma that does not have lumen formation. There can be tadpole-shaped ductal structures, but they are uncommon. Other variants of BCC assist in diagnosis since they often coexist with the sclerosing variant, such as nodular, micronodular or superficial multicentric tumors. Cellular atypia is common.

Desmoplastic tricoepithelioma is typically a cutaneous lesion with a central dell. Microscopic features are tadpoleshaped ductal structures in a sclerotic stroma, clefts between collagen fibres, calcifications, and keratinous cysts.

Syringomas are the benign counterparts of SEC [11]. They most commonly present as multiple small flesh-colored papules. On histology, they are superficial dermal lesions made of small ducts lined by benign cuboidal cells forming tadpole-like structures within a fibrocollagenous matrix without perineural and lymphovascular involvement. Cellularity, anaplasia, and deep invasiveness are pivotal element in differential diagnosis between syringoma and SEC [10].

The immunophenotype of SEC is not specific and often not diriment nor essential or useful in diagnosing primary eccrine carcinomas. Nevertheless, the expression of high and low-molecular weight cytokeratin (CK5/6, CK7, CK14) and epithelial membrane antigen (EMA) or carcinoembryonic antigen (CEA) on lumina is common. Other antigens, such as estrogen receptor (ER), progesterone receptor (PR), and p63 have also been reported to be sometimes positive in SEC. In literature, variations in the expression of all markers are described, with the exception of monoclonal CEA. SEC are certainly of sweat gland differentiation, expressing features of both the dermal duct and secretory portion of normal sweat glands. This histological and immunoistochemical variability makes SEC able to differentiate along multiple routes, thus creating the wide range of the tumor’s clinical expressions [6]. Some authors report a negative immunostaining for G-81, a monoclonal antibody against dermcidin (DCD). Since DCD is normally expressed in eccrine sweat glands, the lack of DCD immunoreactivity may depend on insufficient degree of differentiation towards secretory cells, postulating a prognostic value for G-81. However it is not a useful marker to differentiate eccrine from apocrine cells in other sweat glands tumors, because DCD is only expressed in cutaneous mixed tumors [14].

On January 2017, a 33-year-old woman referred to Cannizzaro Hospital Gynecology and Obstetrics Unit for a 3×1.5-cm rightsided normal skin-colored tender nodular lesion on her major labrum (Figure 1). She stated that this nodule appeared two years before, becoming increasingly larger in the last six months. A previous biopsy performed at an outside hospital on November 2016 suggested a diagnosis of SEC with wide extension of the tumor over resection margins. An inside expert pathologist reviewed the case finding monomorphic poroid cells with deep invasive pattern, pseudoglandular behavior with cuticular-like differentiation spaces, fat tissue, and perineural extension with positive margins, thus confirming the previous diagnosis (Figures 2A, 2B). Accepted criteria on Haematoxylin and Eosin (H&E) were used to make the diagnosis on formalin-fixed paraffin-embedded tissue sections.

Figure 1.

— A normal skin-colored tender nodular lesion on right major labrum.

Figure 2.

— A: SEC: monomorphic hypercromatic poroid cells with deep invasive pattern extending from junction of the reticular dermis to subcutaneous fat (H&E, original magnification ×2). B: High-power view shows a dermal infiltrate with tadpole morphology characteristic of SEC (H&E, original magnification ×10).

She did not suffer from any disease, never underwent radiation therapy, never had trauma or surgery, nor used local or systemic medical treatments. Family history was negative for neoplasms.

Positron emission Tomography (PET) performed in December 2016 documented tracer buildup on right vulva, with neither high metabolic activity in other locations, nor lymphadenopathy.

During hospitalization, a general check up consisting of blood tests, electrocardiography, pelvic ultrasound examination, and chest radiography demonstrated the patient’s well-being. Tumor markers CEA, Ca125, Ca15-3, and Ca 19-9 were also negative.

The woman underwent a right anterior hemivulvectomy with minor labrum preservation, without complications and was discharged on the next day. On histology, another expert pathologist confirmed it was a SEC with a 1.2-cm subcutaneous tissue infiltration in depth. Remarkable scarring fibrosis was noticed. Tumoral cells were organized in small nests with perineural and perivascular invasion (Figures 3A, 3B). Resection margins were tumor-free, obtaining oncologic radicality (FIGO Stage IB, Nx). Results were also esthetically acceptable, gaining the patient’s compliance (Figure 4).

Figure 3.

— A: Pseudoglandular behavior with cuticular-like differentiation spaces, fat tissue, and perineural extension with positive margins (H&E, original magnification ×4). B: Perineural infiltration by basaloid nests of syringoid carcinoma (H&E, original magnification ×10).

Figure 4.

— Final appearance after the right anterior hemivulvectomy with minor labrum preservation.

Taking into account the SEC rareness, a review of last 16 years literature was performed. In addition, the present team asked the Rare Tumor Institute based in Milan for advice, in order to formulate the best follow up protocol patient-tailored. Since SEC has commonly a local recurrence disposition and a potential for distant metastasis, the patient underwent a clinical gynecological evaluation and ultrasonographic bilateral inguinal lymph nodes examination in June 2017, which were found to be negative. The following control planned in three months was also negative.

Despite the low number of cases described in literature, it is unanimously acknowledged that the recommended treatment of all subtypes of sweat gland carcinomas is wide surgical excision associated with regional lymph node dissection in case of clinically positive nodes, because of SEC potential for destructive local tissue and regional infiltration, as well as distant metastasis. Some authors advocate prophylactic regional lymph node dissection in patients with recurrent lesions after wide excision or with highly undifferentiated tumors [4].

A striking case is described by Goglia et al., who performed a demolitive and reconstructive surgery of the perineal region in a 46-year-old man affected by persistent Müllerian duct syndrome with SEC originated from scrotal skin, probably due to previous reconstructive surgeries for hypospadia during the prepubertal age. The tumor spread in the perineal region and lower abdomen three months after surgery; a colostomy became necessary to bypass the neoplastic invasion of the rectal and anal tracts six months after [12].

Shah et al. treated a 41-year-old woman with SEC determining cicatricial entropion of the eyelid and persistent foreign body sensation with a full thickness excision of half lower lid and a Hughes tarsoconjunctival pedicle flap to reconstruct the posterior lamella, despite two previous biopsies negative for malignancy. In this case, an aggressive surgical behavior has found to be successful for malignancy diagnosis and treatment, and the 12 months follow up was disease-free [7].

Kshirsagar et al. described the case of a 60-year-old patient with left anterolateral chest wall SEC with cortical break and erosion of the sixth and seventh ribs, who was treated with wide excision of the swelling with segmental excision of the involved segments of the ribs with pleura, followed by a delto-pectoral fasciocutaneous flap. No follow up data are reported because the patient missed subsequent checks [4].

Ahmed et al. reported the case of SEC of the external auditory canal (EAC) in a 57-year-old female, treated with wide surgical excision through external auditory canal and covering of the raw area by split thickness skin graft from post auricular area. The authors questioned to whether to consider a lateral temporal bone resection instead of a wide local excision, as a EAC tumor would have required, but concluded a wide excision with Mohs micrographic surgery may be safely performed in absence of multifocality or distant metastases. To the present authors’ knowledge, they provided the longest disease-free interval, with no recurrence after a four-year close follow up [9].

On one hand local recurrences of these tumors may be massive; on the other, metastases rarely occur, yet they are not impossible. In literature, there are reports indicating both single-agent and combination chemotherapy have been used infrequently and, at best, have shown only a temporary benefit. Nishizawa et al. described the case of a SEC infiltrating the rectus abdominis muscle, with multiple metastases in the lungs, right bronchus, para-aortic lymph nodes, T11, right S1, and bilateral ilium. The patient was treated with seven cycles of 5-fluorouracil, epirubucin, mitomycin C, vincristine sulfate, and carboplatin, with no changes in size and number of metastatic lesions, thus revealing at least a tumor progression suppression, even if chemotherapy alone was not effective at reducing the tumor size [2].

Sweat gland carcinomas are commonly considered radio resistant; nevertheless Ballardini et al. reported the case of a SEC of the nipple with axillary metastases in a 72-year-old man. The patient underwent a radical mastectomy and ipsilateral axillary lymph node dissection. Metastases were found in four of the 16 lymph nodes removed. Adjuvant radiotherapy at 50 Gray was performed in the axillary and sovraclavear homolateral areas. No relapses were described after 26 months follow up (Table 1) [2-12].

The search for suggestions for treatment in the medical literature revealed very few reports on the SEC of the vulva have been published. Stueben et al. treated a 72-year-old woman affected by a primary adnexal adenocarcinoma of the vulva with a radical hemivulvectomy. Two of the ipsilateral inguinal lymph nodes were positive for metastatic apocrine adenocarcinoma. The distinction between apocrine and eccrine adenocarcinomas makes no clinical difference because the primary treatment for both types is surgical excision of the vulva with margins of 1 cm or greater [5].

Piovano et al. described the case of a 58-year-old woman previously treated with radical hysterectomy Piver III for a squamous cell carcinoma of the cervix (FIGO Stage IIB) and subsequent radiotherapy to the pelvis. She underwent a wide local excision of the lesion followed by a radicalization with left radical vulvectomy and left inguinal lymphadenectomy because of a locally aggressive behavior cited in literature, despite free resection margins. No mention about a preoperative staging is provided. Since inguinal lymph nodes were negative, no adjuvant therapy was administered. The patient experienced inguinal lymphocele and partial vulvar surgical wound dehiscence 12 days after discharge, with significant impairment of quality of life [3].

Prognostic factors are difficult to identify because of the small number of reported cases. Size, histological type, lymph node involvement above all, and distant metastases are those considered more relevant. Several features are associated with a poor prognosis: tumor depth > 7 mm, more than 14 mitotic figures on high-powered magnification, infiltrative margins; an acute change to a rapid growing lesion could be suggestive of a transition to malignancy [8].

Survival rates are substantially unknown due to the lack of data. For what concerns apocrine adenocarcinomas, patients without lymph nodes involvement have a 56% ten-year disease-free survival rate, which decreases to 9% if nodes are involved [5]

No consensus has been reached on follow up periodicity. Some authors generically state ‘frequent’ follow up is essential to detect early recurrence or distant metastases [4]; some others specify every three months [3,12]. The present authors chose to align their conduct to the latter.

To the present authors’ knowledge, the patient in this report is the youngest who ever received a diagnosis of SEC. A single patient age-specific risk has never been supposed. Further studies are needed to better analyze SEC clinical behavior, treatment responsiveness, and survival rates.