Syringoma

Etiology

Various genetic aberrations have been documented in cutaneous adnexal neoplasms; explicit mutations or genetic predispositions implicated in syringoma formation remain unidentified beyond experimental models. Despite many documented syringoma cases, the etiology of syringomas remains elusive, with conjecture surrounding hormonal imbalances as a principal etiological factor, given the age of onset in young adulthood. At the same time, alternative perspectives suggest an inflammatory initiation linked to trauma, autoimmune disorders, and sensitivity to thermal stimuli.[4] There is an established association with diabetes mellitus and distinct histopathologic subtypes of syringoma, indicating a potential link to glucose metabolism aberrations. A strong genetic component is also suspected, as rare familial cases have demonstrated an autosomal dominant pattern of syringoma development. Despite these associations, the overarching tumorigenic pathways leading to syringoma development remain elusive.[5]

Epidemiology

Syringomas typically manifest during early adulthood, exhibiting a predilection for females and those of Asian heritage. Additionally, the clear cell variant of syringomas has a well-established association with diabetes mellitus.[6] While syringomas commonly occur sporadically, familial occurrences have been documented, following an autosomal dominant inheritance pattern.[7] Hundreds of cases of syringomas have been documented, as this condition is generally an isolated finding; however, there does appear to be an increased incidence amongst patients with several different underlying genetic syndromes. The most apparent correlation has been established in patients with a known history of trisomy 21, or Down syndrome, and an increased occurrence has also been noted in patients with Ehlers-Danlos and Marfan syndromes as well.[5]

Histopathology

Upon histological examination, syringomas exhibit sweat gland proliferation organized in nests, featuring a distinctive morphology reminiscent of tadpoles or commas. A thin bilayer of cuboidal cells characterizes these formations and often exhibits an eosinophilic cuticle lining the sweat duct, with amorphous sweat observed within the ductal lumen. However, the morphology may vary slightly depending on the specific section plane.[8] The proliferation is typically restricted to the superficial dermis and is enveloped by a sclerotic stromal component.[9] The epithelial portion comprises cells with a pink cytoplasm, which organize to develop tubular structures of relatively homogenous size; however, the clear cell syringoma subtype may exhibit cellular clearing with glycogen, a phenomenon more frequently observed in individuals with diabetes mellitus.[10]

The malignant form, referred to as syringomatous carcinoma, is an uncommon sweat gland malignancy characterized by infiltrative growth and minimal cytologic atypia. This form of carcinoma can be derived from either apocrine or eccrine origins, and microscopic examination typically does not allow for precise lineage identification. This presentation may manifest with an invasive pattern of basaloid or squamous cells, accompanied by a desmoplastic stromal response and cystic structures replete with keratin. There is generally minimal pleomorphism and cellular atypia; a superficial biopsy can potentially lead to an incorrect diagnosis of syringoma.[11]

History and Physical

Syringomas exhibit a notable preference for the periorbital region, with a heightened prevalence on the lower lids, but may also manifest on the forehead, cheeks, genitalia, or axilla.[12] The classic presentation and morphology consist of multiple, discrete, firm papules measuring 2 to 4 mm.[6][13] Infrequently, syringomas may manifest on the palms and soles, classifying them as acral syringomas. Notably, the presumption can be confidently made that these acral syringomas originate from eccrine structures, as this anatomical region exclusively harbors eccrine glands and is devoid of apocrine glands.[14]

Syringomas often develop during adolescence with an eruptive pattern, which is suggestive of hormonal influence. Eruptive syringomas display a more widespread distribution across various anatomical sites, predominantly affecting the trunk, manifesting as multiple, asymptomatic, 1 to 2 mm papules, which can be skin-colored, yellow, or pink. Numerous cases in the medical literature have demonstrated the potential for syringomas arising in an eruptive pattern to regress over multiple years spontaneously; the majority of these lesions will persist without treatment.[12]

Evaluation

The evaluation of syringoma should begin with a comprehensive medical history and physical examination, as the diagnosis is often clinical. Syringomas typically manifest as numerous, painless, well-defined, skin-colored papules measuring several millimeters in diameter. A skin biopsy is valuable when diagnostic uncertainty arises, revealing characteristic histopathological features. Beyond histopathological analysis, routine diagnostic assessments, such as laboratory tests or radiographic studies, are not typically ordered for individuals with syringoma.[5] In cases where the clear cell subtype is detected, referral for an assessment of underlying diabetes mellitus is prudent. While numerous genetic anomalies have been recognized in a wide variety of adnexal tumors, mutations intricately linked to syringoma development remain elusive.[15]

Dermoscopic examination of suspected syringomas may offer valuable insights, although the lack of reported cases hampers its utility since the widespread adoption of dermoscopy as a diagnostic tool. A review of the limited dermoscopic descriptions in the literature reveals several prominent findings associated with syringomas, often featuring multiple yellow to white-colored, oval-shaped globules overlying a diffuse background of orange or pink.[16] Furthermore, pinpoint and small linear vessel aggregates have also been commonly observed.[17]

The conclusive diagnosis of syringoma is ascertained through histopathological analysis. The microscopic features may exhibit similarities to basal cell carcinoma and other adnexal neoplasms, often necessitating the utilization of immunohistochemical staining to achieve heightened diagnostic precision.[18]

Treatment / Management

Syringomas are characterized by a benign adnexal proliferation with minimal proliferative capacity; consequently, post-diagnosis intervention is not warranted unless the patient expresses a desire for removal due to cosmetic-related concerns or histopathological evaluation yields concern for syringomatous carcinoma.[19] The surgical removal of syringomatous carcinoma is often via Mohs micrographic surgery, emphasizing the importance of accurate microscopic classification for optimal care.[11](B3)

Observation of lesion regression in adulthood has been documented; however, the regression rate remains unclear. Various treatment modalities exist for syringomas, including electrosurgical destruction, cryotherapy, snip excision, topical trichloroacetic acid, and punch excision, all of which have been attempted with variable success.[6] One of the more commonly established and reliable methods for eliminating syringomas documented in the medical literature is intralesional electrodesiccation, with several studies demonstrating no long-term adverse events and low recurrence rates.[20](B3)

There is no universally agreed-upon first-line treatment for eruptive syringomas.[6] In patients with eruptive syringomas or those with a multitude of lesions present on the eyelids, laser ablation may be a preferable choice, as several studies have demonstrated satisfactory cosmetic results when treating with CO₂ laser techniques.[21](B3)

For any therapeutic intervention, the patient should be informed of the potential risks, including scarring or recurrence. Additionally, due to its prominence, frequency, and prolonged duration, hypopigmentation following cryotherapy should be discussed with patients with darker skin colors.[22] Overall, therapeutic considerations for syringomas involve a nuanced approach tailored to each case's specific characteristics and challenges.

Differential Diagnosis

The diagnosis of syringoma can often be made using clinical evaluation alone; however, cases with atypical features can overlap with many other cutaneous neoplasms. The differential diagnoses for syringoma include milia, angiofibroma, xanthoma, hidrocystoma, fibrofolliculoma, trichoepithelioma, and xanthelasma, particularly in the context of eyelid lesions.[5] Moreover, in patients presenting with eruptive syringomas, the differential can broaden to a variety of other papular conditions, such as papular sarcoidosis, plane warts, acne vulgaris, Darier disease, lichen planus, pseudoxanthoma elasticum, and sebaceous hyperplasia, can be considered as well.[8]

On histological evaluation, syringomas typically present with a distinctive absence of keratinization, the absence of multiple horn cysts, and a lack of follicular differentiation. Recognition of these features prompts consideration of alternative diagnostic possibilities within the histological differential diagnosis for syringoma. In such instances, the diagnostic likelihood leans toward desmoplastic trichoepithelioma or microcystic adnexal carcinoma.[23]

Desmoplastic trichoepithelioma is a common neoplasm in clinical practice that should be included in the histological differential diagnosis for syringoma. On histopathologic evaluation, this entity demonstrates several characteristic features, including follicular differentiation, horn cysts, and dystrophic calcification, with the notable absence of sweat ducts.[24]

Microcystic adnexal carcinoma shares histological similarities with syringoma, as it involves the presence of sweat ducts; however, this neoplasm diverges with additional follicular differentiation and horn cysts. Microcystic adnexal carcinoma also demonstrates deeper tissue infiltration into the deep dermis and subcutaneous tissue, along with perineural invasion, features conspicuously absent in syringoma.[7]

Another prevalent differential, morpheaform basal cell carcinoma, showcases features such as follicular differentiation, horn cysts, apoptotic cells, the absence of sweat ducts, and atypical cells with heightened mitotic activity, which are not routinely observed in syringomas.[25]

This meticulous histological analysis facilitates a precise differentiation of syringoma from potential alternative diagnoses within a clinical context.

Prognosis

Syringomas are benign adnexal neoplasms distinguished by ductal differentiation in sweat glands. This may pose cosmetic concerns, especially in the context of multifocal facial lesions; however, despite rare reports of malignant syringomas, there have been no documented cases of malignant transformation. Malignant syringomas exhibit a de novo origin rather than arising from preexisting lesions. Consequently, no treatment is required, and the prognosis for syringomas is outstanding.[26]

The eruptive syringoma variant has demonstrated potential for spontaneous regression over several years.[27] This is in contrast with the more typical presentation involving multiple asymptomatic facial lesions, which tend to persist unless procedural intervention is pursued.[19]

Complications

As previously emphasized, syringomas are benign, without inherent risks of invasive behavior or malignant transformation. Despite this, patients may develop cosmetic concerns and request treatment when numerous lesions are present.[3] Complications stemming from destructive interventions can include scarring, infection, hyper or hypopigmentation, and recurrence. Determining exact recurrence rates across treatment modalities is hindered by the scarcity of histopathologic confirmation before treatment. Several systemic reviews have been performed and have revealed a broad spectrum of success rates among various treatment methods. Regardless, the recurrence of syringomas following treatment has no association with heightened morbidity or mortality.[5]