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Disease Entity

Eccrine sweat gland carcinoma (ESGC): ICD-10-CM L74.9

Disease

Humans have the highest density of eccrine sweat glands of any mammal. Eccrine sweat glands (ESG) arise from ectodermal appendages and can be found in differential densities throughout the human body. The highest concentrations in humans are found in the axillary region and the eyelids/orbits, and the primary function being thermoregulation (“efficient evaporative eccrine cooling”). Dysfunction or loss through disease/injury leads to significant clinical morbidity.

ESGC is an extremely rare malignancy (accounting for < 0.01% of diagnosed cutaneous malignancies), most frequently found on the eyelids, of the elderly.

ESGC classification schemes (*indicates relatively common types):
- Benign ESGC:
  - Poroma
  - Hidradenoma
  - Spiradenoma
  - Cylindroma
  - Syringometaplasia
  - Syringoma
  - Syringofibroadenoma
  - Chondroid syringoma
- Malignant ESGC (locally aggressive with high recurrence rate):
  - *Porocarcinoma
    - Stains positive for cytokeratins (CKs) and PAS
  - *Syringoid eccrine carcinoma
    - Stains positive for CKs, PAS, and D-PAS
  - *Adenoid cystic carcinoma
  - *Mucinous carcinoma
    - Stains positive for PAS
    - Most commonly arise on the eyelids and head/neck regions
    - Male predilection (average age of diagnosis: 62 years)
  - Hidradenocarcinoma
  - Malignant spiradenoma carcinoma
  - Malignant cylindroma
  - Microcystic adnexal carcinoma
  - Ductal papillary adenocarcinoma
- Unclassifiable sweat gland tumors:
  - *Ductal ESGC
    - Well-differentiated "signet-ring" ductal carcinoma
    - Poorly-differentiated "histiocytoid-variant" ductal carcinoma
  - Basaloid eccrine carcinoma
  - Clear cell eccrine carcinoma

Epidemiology

Incidence/Prevalence: Extremely rare

Risk Factors

Age (most commonly diagnosed in 6th-8th decades of life)
Family history
Immunosuppression
Ultraviolet radiation

Diagnosis

Clinical Presentation

(not mutually exclusive and capable of having various combinations of the below)

Progressive painless infiltration (redness, swelling) or growth (periorbital mass) of one or both eyelids
Ocular or facial pain
Associated pain with metastases (lymph nodes, parotid gland, bone, skin, lung, and/or liver)
"Monocle-like" appearance to the affected eyelid(s)
Brown, blue, and/or red nodule, papule, or ulcerative lesion anywhere on the body but most commonly:
- Lower extremities
- Head and neck
- Upper extremities

Differential Diagnosis

Adult orbital tumors:
- Metastatic tumors
- Lymphoid tumors
- Cavernous hemangiomas
- Mesenchymal tumors
- Neurilemmoma
- Neurofibroma
Adult extraconal orbital lesions
- Mucocele
- Localized neurofibroma
- Optic nerve sheath meningioma
Based on histology:
- Cutaneous neoplasms containing signet-ring cells:
  - Basal cell carcinoma
  - Squamous cell carcinoma
  - Melanocytic tumors
    - Cylindroma
    - Lymphoma

Diagnostic Procedures

PET/CT Orbit, MRI Orbit, bone scintigraphy
- Initial imaging for evaluation of a structural abnormalities
Exenteration with subsequent histological evaluation
Early diagnosis is paramount but sometimes challenging due to morphological similarity to other common tumors and lack of consistent immunohistochemical markers

Pathology

Histologically, ESGC closely resembles a general inflammatory process and is nearly identical to that of breast ductal adenocarcinoma, lacrimal gland adenocarcinoma, and salivary gland adenocarcinoma. ESGC is centered on the dermis and composed of tubular structures lined by atypical basaloid cells, with perineural invasion being common. Specific morphology depends on the distinct ESGC subtype entity.
Associated tumor markers:
- Simple epithelial CKs commonly expressed:
  - CKs 7, 8, 18, 19
  - Epithelial membrane antigen (EMA)
- Stratified epithelial cytokeratins less commonly expressed:
  - CKs 5, 14
- Focally expressed:
  - Carcinoembryonic antigen (CEA)
  - S100

Genetics and Molecular Pathways

In mouse models, ESG and hair follicle densities have been shown to be inversely regulated by the transcription factor Engrailed1 (En1), which is encoded on a region of mouse chromosome 1.
In both mouse models and humans, ESG and hair follicle formation share critical, common molecular pathways: canonical Wnt, bone morphogenetic protein, ectodysplasin, sonic hedgehog. The precise differential formation (and underlying molecular mechanisms) of ESG versus hair follicles is poorly understood.

Management

General treatment approaches

First-line intervention: surgical excision with wide margins (skin biopsy)
- Pathological staging using pTNM criteria
- If necessary, orbital exenteration
- If necessary, adjuvant radiotherapy and/or chemotherapy (e.g. 5-FU)
- Progression of the tumor after surgical resection or failed adjuvant therapies is possible
PET/CT Orbit, MRI Orbit, bone scintigraphy
- Repeat imaging for evaluating therapeutic effectiveness and tumor recurrences
Multidisciplinary management team including medical oncologist, surgeon, dermatologist, dermatopathologist, pharmacist, and/or ophthalmologist depending upon location and extent of disease process.
Due to the rarity of ESGC, no randomized control trials exist examining management options

Prognosis

Protracted course over several years with an overall favorable prognosis with timely intervention in a treatment-responsive tumor. However, an unfavorable prognosis is associated with delayed interventions, metastatic lesions (reaching lymph nodes, parotid gland, bone, skin, lung, and/or liver), and recurrent disease despite conventional surgical excision. Close long-term follow-up recommended. Relative mortality rate is 80%, while the 10-year disease survival rate is 9%.

References

Zhang L, Ge S, Fan X. A brief review of different types of sweat-gland carcinomas in the eyelid and orbit. Onco Targets Ther. 2013;6:331–340. Published 2013 Apr 9. doi:10.2147/OTT.S41287
Kim YM, Kim JW, Oh, DE. A case of Histiocytoid Variant Eccrine Sweat Gland Carcinoma of the Orbit. Korean J Ophthalmol. 2011 Feb; 25(1):54-56. Published 2011 Jan 7.
Kramer TR, Grossniklaus HE, McLean IW, et al. Histiocytoid variant of eccrine sweat gland carcinoma of the eyelid and orbit: report of five cases. Ophthalmology. 2002;109:553–559.
Seredyka-Burduk M, Burduk PK, Bodnar M, Malukiewicz G, Kopczynski A. Bilateral primary histiocytoid eccrine sweat gland carcinoma of eyelids. Braz J Otorhinolaryngol. 2018;94:665---68
The Wills Eye Manual: Office and Emergency Room Diagnosis and Treatment of Eye Disease. Philadelphia: Lippincott, 2017.
Kamberov YG, Karlsson EK, Kamberova GL, et al. A genetic basis of variation in eccrine sweat gland and hair follicle density. Proc Natl Acad Sci U S A. 2015;112(32):9932–9937. doi:10.1073/pnas.1511680112
Kaseb H, Babiker HM. Cancer, An Overview of Eccrine Carcinoma. [Updated 2019 May 15]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2019 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK541042/
Sidiropoulos M, Sade S, Al-Habeeb A, Ghazarian D. Syringoid eccrine carcinoma: a clinicopathological and immunohistochemical study of four cases. J. Clin. Pathol. 2011 Sep;64(9):788-92.
Larson K, Babiker HM, Kovoor A, Liau J, Eldersveld J, Elquza E. Oral Capecitabine Achieves Response in Metastatic Eccrine Carcinoma. Case Rep Oncol Med. 2018;2018:7127048.
Urso C, Bondi R, Paglierani M, Salvadori A, Anichini C, Giannini A. Carcinomas of sweat glands: report of 60 cases. Arch. Pathol. Lab. Med. 2001 Apr;125(4):498-505.
Swanson PE, Cherwitz DL, Neumann MP, Wick MR. Eccrine sweat gland carcinoma: an histologic and immunohistochemical study of 32 cases. J. Cutan. Pathol. 1987 Apr;14(2):65-86.
Ohnishi T, Kaneko S, Egi M, Takizawa H, Watanabe S. Syringoid eccrine carcinoma: report of a case with immunohistochemical analysis of cytokeratin expression. Am J Dermatopathol. 2002 Oct;24(5):409-13.
Abedi SM, Yu R, Salama S, Alowami S. Syringoid eccrine carcinoma. Cutis. 2015 Sep;96(3):162,191-2.
Hemalatha, AL, Kausalya, SK,, Amita, K, Sanjay, M, Lavanya, MS. Primary mucinous eccrine adenocarcinoma - a rare malignant cutaneous adnexal neoplasm at an unconventional site. J Clin Diagn Res. 2014;8(8):FD14–FD15. doi:10.7860/JCDR/2014/9797.4754

Eccrine Sweat Gland Carcinoma