Microcystic Adnexal Carcinoma– like Neoplasm in a Patient With POT1 Mutation

A 72-year-old man with a history of multiple cancers, including melanoma, squamous cell carcinoma (SCC), and basal cell carcinoma (BCC), presented to the dermatology clinic for a regularly scheduled full-body skin examination. His family history was negative for malignancy, but due to his personal history of both primary internal cancers and skin cancers, the patient previously had been referred by dermatology to a medical geneticist for evaluation. He tested positive for a pathogenic POT1 (protection of telomeres 1) variant associated with tumor predisposition, which most often is associated with cutaneous melanoma, chronic lymphocytic leukemia (CLL), angiosarcoma, and gliomas.¹

At the current presentation, physical examination revealed a small, asymmetric, pink papule on the superior thoracic spine. A biopsy of the lesion was performed (Figure 1). Pathology demonstrated cornifying cystic structures with a granulomatous response at the surface of the tumor, ductal differentiation with depth, and infiltrative strands and cords of hyperchromatic cells within a collagenous stroma at the base of the specimen (Figures 2A and 2B). One unusual finding was the presence of prominent clear-cell change within the superficial portion of the neoplasm (Figure 2C). Immunohistochemical stains revealed strong p63 and p40 positivity. Epithelial membrane antigen staining was positive in the hyperchromatic strands and cords with depth but not in the clear-cell superficial portion. Similarly, periodic acid–Schiff–positive material increased within tumor cells in proportion to depth of infiltration. Additional immunohistochemical staining showed carcinoembryonic antigen was largely negative (with rare positivity in a few ductal lumina), with negative results for S100, SOX10, CD117, BerEP4, factor XIIIa, CD34, and cytokeratin 7 (Figures 2D and 2E).

The differential diagnoses included trichilemmal carcinoma (which may manifest with CD34 expression),² clear cell BCC, adenoid cystic carcinoma (tubular variant), sebaceous carcinoma, and eccrine carcinoma. Importantly, the patient was under continuous oncologic surveillance, with no evidence of a primary internal tumor to suggest metastasis. Despite negative carcinoembryonic antigen staining, the immunohistochemical and histopathologic findings fit best with a primary cutaneous malignant eccrine tumor, specifically microcystic adnexal carcinoma (MAC), in which p63 typically stains peripheral cells but solid variants have been described.³

Eccrine carcinoma is exceedingly rare, reported in 0.01% of diagnosed cutaneous malignancies, and demonstrates overlapping features to other malignant eccrine tumors. It possesses an inconsistent immunohistochemical staining profile, making the distinction from other malignant sweat gland tumors challenging.⁴ Given that the morphologic features were otherwise classic for MAC in our patient, we favored a clear-cell variant.

Sixteen years prior to the current presentation, our patient presented to urology with a history of prostatitis and increasing prostate-specific antigen levels. Biopsies were negative until prostate-specific antigen reached 13 ng/mL, confirming stage 1A prostate cancer. The patient subsequently underwent a robot-assisted radical prostatectomy. At age 63 years, dysphagia that was unresponsive to antibiotics led to a tonsillar biopsy revealing T2N2bM0 stage IVA SCC of the right tonsil with confirmed HPV type 16 with extracapsular extension. The patient underwent transoral robotic radical tonsillectomy and right neck dissection, followed by adjuvant chemoradiation consisting of intensity-modulated radiation therapy (IMRT) to a total dose of 63 Gy in 33 fractions, with concurrent weekly cisplatin. At age 67 years, dyspepsia, dysphagia, pyrosis, and gastroesophageal reflux prompted endoscopy, revealing T1aNxMx esophageal adenocarcinoma. Three months later, the patient underwent laparoscopic-assisted esophagectomy, with no recurrence. At age 68 years, an atypical intramelanocytic proliferation was found on the left cheek and was treated with Mohs micrographic surgery.

At age 71 years, acral lentiginous malignant melanoma (Breslow thickness 0.8 mm; Clark level IV; American Joint Committee on Cancer T1b) was diagnosed on the left plantar foot and treated with Mohs micrographic surgery. Sentinel lymph node biopsy was negative. Squamous cell carcinoma in situ on the frontal scalp and nodular BCC on the right upper back also were diagnosed.

While there are no guidelines for surveillance of individuals with POT1, recommendations were given in consensus from a medical genetics team,¹ including comprehensive monitoring—specifically baseline imaging utilizing brain and full-body magnetic resonance imaging. Furthermore, considering the crucial role of POT1 in maintaining telomeres, it was advised to measure telomere length as part of the surveillance process. Given the patient’s susceptibility to CLL, routine complete blood count assessments were recommended. Additionally, we advised close monitoring for seizures and consideration of genetic testing in first-degree relatives.

Literature Review

Given our patient’s history of multiple skin cancers, including the most recent MAC, we sought to conduct a review of the literature to evaluate existing skin cancer associations and reports for patients with known POT1 mutations to guide recommendations for dermatologic surveillance (Table). A search of PubMed articles indexed for MEDLINE through April 2023 using the terms microcystic adnexal carcinoma, POT1, melanoma, basal cell carcinoma, squamous cell carcinoma, and skin cancer yielded no reported cases of MAC associated with POT1 mutations. POT1 is one of 6 proteins (TERF1, TERF2, RAP1, TIN2, TPP1, and POT1) belonging to the shelterin complex, which plays a crucial role in telomeric DNA remodeling and regulation of telomere length.⁵ Mutation in the POT1 gene disrupts the shelterin complex, causing telomeres to become elongated and unstable, resulting in chromosomal abnormalities and promoting cancer development.⁵

While our literature review did not reveal any associations between the shelterin complex genes and MAC, mutations in the POT1 gene have been studied in other types of skin cancer, particularly melanoma.¹ One of the earliest studies was conducted in 2014 by Shi et al,⁶ in which whole-exome sequencing was performed on families with a history of melanoma. Multiple POT1 gene pathogenic variants associated with increased telomere length and fragility were identified in unrelated families. Subsequent studies have confirmed POT1 variants in melanoma-prone families,⁷ supporting an association between increased telomere length and melanoma risk^8-11; however, other studies have yielded nonsignificant findings.^12,13 Further investigation also has identified morphologic characteristics consistent with POT1 mutation, including spitzoid morphology.¹⁴

The association between POT1 mutations and nonmelanoma skin cancers has been relatively understudied. While a few studies have explored this link, results have shown mixed findings. Some studies have suggested a potential role for POT1 mutations in cutaneous SCC risk,¹⁵ while other studies have shown no significant associations for both BCC and SCC risk and telomere gene mutations.¹⁶ Additionally, mRNA levels of POT1 were upregulated in BCC cases compared to normal tissue in a gene expression.¹⁷

Comment

In the literature, POT1 mutations are well established as high-penetrance alterations associated with melanoma.^9,18,19 However, the correlation between POT1 and other forms of skin cancer is not yet delineated. Recent insights suggest that POT1 mutations play a major role in promoting melanoma progression through telomere elongation, an established driver of melanoma progression, thereby extending the proliferative capacity of incipient cancer cells.²⁰ This notion is supported by observations of increased telomere length in melanomaprone families with POT1 mutations. Given this association, research has focused on examining the relationship between telomere length and skin cancer.

Several studies have examined the relationship between telomere length and the risk for various types of skin cancer, including melanoma, BCC, and SCC. Prior investigations have suggested that shorter telomere length is associated with a decreased risk for melanoma and an increased risk for BCC, while no significant association has been observed for SCC.¹⁶ However, subsequent reports analyzing POT1 variants have failed to reveal any conclusive associations between BCC and SCC and telomere length.^16,21

In contrast, other genetic variants associated with melanoma susceptibility have demonstrated notable associations with BCC and SCC; for instance, the CDKN2A (cyclin-dependent kinase inhibitor 2A) gene, which is the first gene linked to high-risk familial melanoma, exhibits an increased presence of mutations in individuals with BCC and SCC.²² Similarly, the MC1R (melanocortin 1 receptor) variant, a gene involved in human pigmentation and known to increase the risk for melanoma, carries a statistically significantly higher risk for BCC (summary odds ratio, 1.39; 95% CI, 1.15-1.69) and SCC (summary odds ratio, 1.61; 95% CI, 1.35-1.91) when at least one variant is present and an even greater risk with 2 or more variants.²³

Considering the potential importance of POT1 mutations and their association with melanoma, as well as the inconsistencies surrounding POT1 mutations and their associations with BCC and SCC, further research may clarify the impact of POT1 mutations on the development and progression of different types of skin cancers and improve understanding of the complex interplay among telomere length, genetic variants, and skin cancer susceptibility. Given the established risk for melanoma with POT1 mutations, regular dermatology surveillance seems prudent. Dermatologists should consider referring patients with multiple skin cancers (especially melanoma) and any strong family history of internal malignancies to genetic testing for POT1. Though melanoma, CLL, angiosarcoma, and gliomas are the most commonly associated malignancies with POT1 mutations, as our case demonstrates, presentations can be heterogeneous, and the spectrum of malignancies associated with POT1 may be more expansive than previously thought.

For our patient, the current surveillance plan is fullbody skin examinations every 3 months. Given no prior family history of malignancies, presumably our patient’s case was a spontaneous mutation. Interestingly, despite his many primary cancer diagnoses and metastases, our patient has responded well to all treatments without recurrence. It is unclear if these characteristics and treatment successes are features of POT1associated cancers. Further research is needed to refine recommendations for screening and management of patients with identified POT1 mutations.

Conclusion

This case report highlights a rare occurrence of MAC in a patient with a POT1 mutation. Given the limited research conducted on investigating POT1 mutations and skin cancer, it is important to consider various forms of skin cancer, in addition to melanoma, when treating patients with a POT1 mutation.