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Diagnosis and Discussion: Case 1150

Final Diagnosis

Microcystic adnexal carcinoma, infiltrating into skeletal muscle. Perineural invasion is present, but no lymphovascular invasion is identified.

Discussion

Goldstein et al. (1982) initially described microcytic adnexal carcinoma (MAC) through six cases as a distinct entity separate from other benign adnexal neoplasms.1 Additional terminology referencing this neoplasm include sclerosing sweat duct carcinoma, syringomatoid carcinoma, eccrine epithelioma and malignant syringoma, but are currently not recommended, per WHO BlueBooks.2

A greater depth of information on MACs have been added to the current literature with reviews describing 1968 cases by Worley et al. (2019), 223 cases from the National Cancer Institute Surveillance, Epidemiology, and End Results (SEER) database by Yu et al (2010), 51 cases in Japanese patients by Ohtsuka et al (2002), and in 48 cases by Chiller et al (2000).3-6

The reported average age in these reviews vary from 60 to 68 years with documented overall age range from 11 to 90 years. Across the four large studies, there maintained a slight female predominance with three of the four series ranging from 54.1% to 65% female population in the study cohorts. MACs are generally located in the head and neck region (~75%), but other locations such as trunk, upper limbs and shoulders, lower limbs and hips, vulva, buttock and toes, have been recognized.4-6

MAC is an infiltrative neoplasm that involves the dermis and often extends to underlying tissues composing of cornifying cysts with compact or keratinous material, solid nests, strands and columns of small monomorphous epithelial cells and ducts of two layers of small cuboidal cells. Perineural invasion is a common feature, but pleomorphism, necrosis and mitotic figures are infrequent. The stroma can be sclerotic, hyalinized and paucicellular and granulomatous foreign body reaction to ruptured cysts can be seen. Focal clear cell change is frequent. A solid variant of this neoplasm on the scalp has been described in 14 cases and generally has an abundance of pink cytoplasm or clear cell change.7 High-grade features including marked cytological atypia, nuclear pleomorphism, brisk and atypical mitotic activity and necrosis have been described in two cases.8

Immunohistochemical analysis is non-specific. MAC stains for various cytokeratins and p63; expression of PHLDA1 is variable. Ductal differentiation can be highlighted by staining for EMA or CEA.9-10 The proliferation is low.

Differential diagnosis includes morpheaform basal cell carcinoma, desmoplastic squamous cell carcinoma, desmoplastic trichoepithelioma, trichoadenoma and syringoma.11

The staging of MAC correlates with the staging system for cutaneous squamous cell carcinoma outlined by the American Joint Committee on Cancer (AJCC) staging.12

Chan et al (2020) described 18 microcystic adnexal carcinomas by targeted, multiplexed PCR-based DNA next-generation sequencing.13 The most recurrent mutation was TP53 inactivation in four tumors. In addition, frame-preserving insertions affecting the kinase domain of the JAK1 gene was detected in 3 cases, and were nonoverlapping with TP53 mutations.13 Chen et al (2017) published a case report of a microcystic adnexal carcinoma with TP53 mutation and chromosomal losses in cyclin dependent kinase inhibitor 2A (CDKN2A) and cyclin dependent kinase inhibitor 2B (CDKN2B) with response to systemic antineoplastic chemotherapy.14 Yu et al (2022) demonstrated that four genes in the calcium signaling pathway including calcium voltage-gated channel subunit alpha 1 S (CACNA1S), ATPase sarcoplasmic/endoplasmic reticulum Ca2+ transporting 1 (ATP2A1), ryanodine receptor 1 (RYR1), and myosin light chain kinase 3 (MYLK3), were upregulated and then been verified by immunohistochemistry.15

MACs are locally aggressive and capable of involving deep underlying tissue, including bone. When incompletely excised, MAC is associated with frequent recurrence, but regional lymph node and distant metastases are rare.2 

Worley et al. published treatment guidelines in JAMA Dermatology for microcystic adnexal carcinoma informed by systemic review including 5 key findings: (1) A deep skin biopsy that includes subcutis is required for diagnosis. (2) MAC confined to the skin is best treated by surgery that examines the surrounding and deep edges of tissue removed (Mohs micrographic surgery or complete circumferential peripheral and deep margin assessment).  (3) For MACs with high risk for recurrence, surgically unresectable tumors, or patients who cannot have surgery for medical reasons, radiotherapy can be considered for adjuvant treatment. (4) For follow up, the patient should be seen by a physician familiar with MAC every 6 to 12 months for the first 5 years after treatment. Patient education on photoprotection, periodic skin self-examination, postoperative healing, and the possible normal changes in local sensation (eg, initial hyperalgesia) should be considered. (5) There is limited evidence to guide the treatment of metastasis in MAC due to its rarity. The study was limited due to the fact that the current medical literature on MAC comprises only retrospective reviews and descriptions of individual patients and there are no controlled studies to guide management.3

References

  1. Goldstein DJ, Barr RJ, Santa Cruz DJ. Microcystic adnexal carcinoma: a distinct clinicopathologic entity. Cancer. 1982 Aug 1;50(3):566-72. doi: 10.1002/1097-0142(19820801)50:3<566::aid-cncr2820500330>3.0.co;2-q. PMID: 7093897.
  2. Kazakov DV, Requena L, Harms P, et al. Microcytic adnexal carcinoma. In: WHO Classification of Tumours Editorial Board. Skin tumours. Lyon (France): International Agency for Research on Cancer; forthcoming. (WHO classification of tumours series, 5th ed.; vol. 12). https://publications.iarc.fr.
  3. Worley B, Owen JL, Barker CA, Behshad R, Bichakjian CK, Bolotin D, Bordeaux JS, Bradshaw S, Cartee TV, Chandra S, Cho N, Choi J, Council ML, Eisen DB, Golda N, Huang CC, Ibrahim SF, Jiang SIB, Kim J, Lacutoure M, Lawrence N, Lee EH, Leitenberger JJ, Maher IA, Mann M, Minkis K, Mittal B, Nehal KS, Neuhaus I, Ozog DM, Petersen B, Samie F, Shin TM, Sobanko JF, Somani AK, Stebbins WG, Thomas JR, Thomas V, Tse D, Waldman A, Xu YG, Yu SS, Zeitouni NC, Ramsay T, Poon E, Alam M. Evidence-Based Clinical Practice Guidelines for Microcystic Adnexal Carcinoma: Informed by a Systematic Review. JAMA Dermatol. 2019 Sep 1;155(9):1059-1068. doi: 10.1001/jamadermatol.2019.1251. PMID: 31268498.
  4. Yu JB, Blitzblau RC, Patel SC, Decker RH, Wilson LD. Surveillance, Epidemiology, and End Results (SEER) database analysis of microcystic adnexal carcinoma (sclerosing sweat duct carcinoma) of the skin. Am J Clin Oncol. 2010 Apr;33(2):125-7. doi: 10.1097/COC.0b013e31819791eb. PMID: 19675445.
  5. Ohtsuka H, Nagamatsu S. Microcystic adnexal carcinoma: review of 51 Japanese patients. Dermatology. 2002;204(3):190-3. doi: 10.1159/000057880. PMID: 12037446.
  6. Chiller K, Passaro D, Scheuller M, Singer M, McCalmont T, Grekin RC. Microcystic adnexal carcinoma: forty-eight cases, their treatment, and their outcome. Arch Dermatol. 2000 Nov;136(11):1355-9. doi: 10.1001/archderm.136.11.1355. PMID: 11074698.
  7. Llamas-Velasco M, Pérez-Gónzalez YC, Bosch-Príncep R, Fernández-Figueras MT, Rütten A. Solid carcinoma is a variant of microcystic adnexal carcinoma: A 14-case series. J Cutan Pathol. 2018 Dec;45(12):897-904. doi: 10.1111/cup.13351. Epub 2018 Oct 9. PMID: 30187501.
  8. Brenn T, Wiedemeyer K, Calonje E. Morphologically high-grade microcystic adnexal carcinoma: a report of two cases. Histopathology. 2020 Sep;77(3):449-452. doi: 10.1111/his.14130. Epub 2020 Jul 2. PMID: 32359178.
  9. Frouin E, Vignon-Pennamen MD, Balme B, Cavelier-Balloy B, Zimmermann U, Ortonne N, Carlotti A, Pinquier L, André J, Cribier B. Anatomoclinical study of 30 cases of sclerosing sweat duct carcinomas (microcystic adnexal carcinoma, syringomatous carcinoma and squamoid eccrine ductal carcinoma). J Eur Acad Dermatol Venereol. 2015 Oct;29(10):1978-94. doi: 10.1111/jdv.13127. Epub 2015 Apr 15. PMID: 25873411.
  10. Wick MR, Cooper PH, Swanson PE, Kaye VN, Sun TT. Microcystic adnexal carcinoma. An immunohistochemical comparison with other cutaneous appendage tumors. Arch Dermatol. 1990 Feb;126(2):189-94. doi: 10.1001/archderm.126.2.189. PMID: 1689137.
  11. Zito PM, Mazzoni T. Microcystic Adnexal Carcinoma. 2023 Apr 24. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2025 Jan–. PMID: 32491780.
  12. Amin MB, Edge SB, Greene FL, et al, eds. AJCC Cancer Staging Manual. 8th ed. New York: Springer; 2017.
  13. Chan MP, Plouffe KR, Liu CJ, Palanisamy N, Carskadon S, Zhao L, Nazarian RM, Durham AB, Johnson TM, Andea AA, Patel RM, Lowe L, Fullen DR, Brown NA, Tomlins SA, Udager AM, Harms PW. Next-generation sequencing implicates oncogenic roles for p53 and JAK/STAT signaling in microcystic adnexal carcinomas. Mod Pathol. 2020 Jun;33(6):1092-1103. doi: 10.1038/s41379-019-0424-4. Epub 2019 Dec 19. PMID: 31857679.
  14. Chen MB, Laber DA. Metastatic Microcystic Adnexal Carcinoma with DNA Sequencing Results and Response to Systemic Antineoplastic Chemotherapy. Anticancer Res. 2017 Sep;37(9):5109-5111. doi: 10.21873/anticanres.11929. PMID: 28870941.
  15. Yu S, Wang Y, Tang B, Liu X, Song L, Xu G, Zhu H, Sun H. Four calcium signaling pathway-related genes were upregulated in microcystic adnexal carcinoma: transcriptome analysis and immunohistochemical validation. World J Surg Oncol. 2022 May 4;20(1):142. doi: 10.1186/s12957-022-02601-6. PMID: 35509066; PMCID: PMC9066904.