Mixed Topics

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.

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.

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.

THE DIAGNOSIS: Mycobacteria infection

Despite the initial biopsy for tissue culture showing no growth, a subsequent biopsy performed 1 month later yielded a positive result. Mycobacterium marinum was identified through organism genome sequencing. The patient was further treated by infectious disease with clarithromycin and ethambutol, with complete resolution of the lesions.

Although initial staining with acid-fast bacilli and tissue culture were negative, we suspected a diagnosis of mycobacterial infection with sporotrichoid spread of multiple nodular and ulcerated lesions that was unresponsive to antibiotics. Performing a tissue culture is crucial for diagnosing mycobacterial skin and soft-tissue infections, as an acid-fast bacilli stain alone cannot distinguish between different mycobacterial species. Lowenstein-Jensen agar is a selective medium specifically used for the culture and isolation of Mycobacterium species. The strict temperature requirement of 30 °C to 32 °C (86-89.6 °F) for the growth of this organism suggests that the infection predominantly affects the limbs, which tend to have a slightly lower temperature compared to the core of the body.¹ In our case, the histologic findings and clinical history suggested granulomatous involvement due to fungi or mycobacteria.

Cutaneous leishmaniasis is characterized by ulcers with possible accompanying nodular lymphangitis; however, the patient did not have relevant travel history. Leishmaniasis results from a parasite transmitted by a sandfly, with most cases occurring in Afghanistan, Algeria, Brazil, Iran, Pakistan, Peru, Saudi Arabia, and Syria.²

Ecthyma gangrenosum is characterized by tender necrotic plaques seen predominantly in immunocompromised patients and is associated with Pseudomonas aeruginosa bacteremia.³ Our patient had lesions present for a duration of 5 months, which is inconsistent with the more rapidly progressing course of ecthyma gangrenosum.

Leukocytoclastic vasculitis may manifest with palpable purpura of the lower extremities. An infectious trigger, such as Mycobacterium, may lead to a leukocytoclastic vasculitis. The histopathologic findings classically demonstrate neutrophil deposition in vessel walls, deposition of fibrin in the vessel lumen, and nuclear debris.⁴

Despite the presence of granulomatous changes in our patient, the presentation of ulcerated nodules in a sporotrichoid pattern on one extremity suggests a diagnosis of infectious etiology rather than sarcoidosis.

THE DIAGNOSIS: Mycobacteria infection

Despite the initial biopsy for tissue culture showing no growth, a subsequent biopsy performed 1 month later yielded a positive result. Mycobacterium marinum was identified through organism genome sequencing. The patient was further treated by infectious disease with clarithromycin and ethambutol, with complete resolution of the lesions.

Although initial staining with acid-fast bacilli and tissue culture were negative, we suspected a diagnosis of mycobacterial infection with sporotrichoid spread of multiple nodular and ulcerated lesions that was unresponsive to antibiotics. Performing a tissue culture is crucial for diagnosing mycobacterial skin and soft-tissue infections, as an acid-fast bacilli stain alone cannot distinguish between different mycobacterial species. Lowenstein-Jensen agar is a selective medium specifically used for the culture and isolation of Mycobacterium species. The strict temperature requirement of 30 °C to 32 °C (86-89.6 °F) for the growth of this organism suggests that the infection predominantly affects the limbs, which tend to have a slightly lower temperature compared to the core of the body.¹ In our case, the histologic findings and clinical history suggested granulomatous involvement due to fungi or mycobacteria.

Cutaneous leishmaniasis is characterized by ulcers with possible accompanying nodular lymphangitis; however, the patient did not have relevant travel history. Leishmaniasis results from a parasite transmitted by a sandfly, with most cases occurring in Afghanistan, Algeria, Brazil, Iran, Pakistan, Peru, Saudi Arabia, and Syria.²

Ecthyma gangrenosum is characterized by tender necrotic plaques seen predominantly in immunocompromised patients and is associated with Pseudomonas aeruginosa bacteremia.³ Our patient had lesions present for a duration of 5 months, which is inconsistent with the more rapidly progressing course of ecthyma gangrenosum.

Leukocytoclastic vasculitis may manifest with palpable purpura of the lower extremities. An infectious trigger, such as Mycobacterium, may lead to a leukocytoclastic vasculitis. The histopathologic findings classically demonstrate neutrophil deposition in vessel walls, deposition of fibrin in the vessel lumen, and nuclear debris.⁴

Despite the presence of granulomatous changes in our patient, the presentation of ulcerated nodules in a sporotrichoid pattern on one extremity suggests a diagnosis of infectious etiology rather than sarcoidosis.

THE DIAGNOSIS: Mycobacteria infection

Despite the initial biopsy for tissue culture showing no growth, a subsequent biopsy performed 1 month later yielded a positive result. Mycobacterium marinum was identified through organism genome sequencing. The patient was further treated by infectious disease with clarithromycin and ethambutol, with complete resolution of the lesions.

Although initial staining with acid-fast bacilli and tissue culture were negative, we suspected a diagnosis of mycobacterial infection with sporotrichoid spread of multiple nodular and ulcerated lesions that was unresponsive to antibiotics. Performing a tissue culture is crucial for diagnosing mycobacterial skin and soft-tissue infections, as an acid-fast bacilli stain alone cannot distinguish between different mycobacterial species. Lowenstein-Jensen agar is a selective medium specifically used for the culture and isolation of Mycobacterium species. The strict temperature requirement of 30 °C to 32 °C (86-89.6 °F) for the growth of this organism suggests that the infection predominantly affects the limbs, which tend to have a slightly lower temperature compared to the core of the body.¹ In our case, the histologic findings and clinical history suggested granulomatous involvement due to fungi or mycobacteria.

Cutaneous leishmaniasis is characterized by ulcers with possible accompanying nodular lymphangitis; however, the patient did not have relevant travel history. Leishmaniasis results from a parasite transmitted by a sandfly, with most cases occurring in Afghanistan, Algeria, Brazil, Iran, Pakistan, Peru, Saudi Arabia, and Syria.²

Ecthyma gangrenosum is characterized by tender necrotic plaques seen predominantly in immunocompromised patients and is associated with Pseudomonas aeruginosa bacteremia.³ Our patient had lesions present for a duration of 5 months, which is inconsistent with the more rapidly progressing course of ecthyma gangrenosum.

Leukocytoclastic vasculitis may manifest with palpable purpura of the lower extremities. An infectious trigger, such as Mycobacterium, may lead to a leukocytoclastic vasculitis. The histopathologic findings classically demonstrate neutrophil deposition in vessel walls, deposition of fibrin in the vessel lumen, and nuclear debris.⁴

Despite the presence of granulomatous changes in our patient, the presentation of ulcerated nodules in a sporotrichoid pattern on one extremity suggests a diagnosis of infectious etiology rather than sarcoidosis.

THE DIAGNOSIS: Angiolymphoid Hyperplasia With Eosinophilia

Angiolymphoid hyperplasia with eosinophilia (ALHE) is a rare, benign, inflammatory vascular proliferation with lymphocytic and eosinophilic infiltration. Bleeding and pruritus associated with ALHE can substantially affect a patient’s quality of life, necessitating correct diagnosis and effective treatment.¹ The etiopathogenesis of ALHE is poorly understood, and it often is attributed to an underlying vascular malformation or local trauma. Vascular proliferation due to hyperestrogenemia could explain why pregnancy is considered a predisposing factor for ALHE.^1,2

Angiolymphoid hyperplasia with eosinophilia typically manifests with solitary or multiple pink to red-brown, dome-shaped papules or nodules occurring most frequently on the head and neck. Lesions may be either asymptomatic or associated with pruritus, pain, and spontaneous bleeding.¹ Dermoscopy is crucial to diagnosis. The most frequent dermoscopic findings include a polymorphic vascular pattern such as dotted and linear irregular vessels over a pink background, white lines, white dots, white structureless areas, and red-purple lacunae.^2,3 Histopathology will demonstrate a vascular proliferation with plump epithelioid endothelial cells showing abundant eosinophilic cytoplasm, accompanied by a variable lymphocytic and eosinophilic inflammatory infiltrate (Figure 1).¹

In our case, dermoscopic-histopathologic correlation suggested that the polymorphic vascular pattern and clods on a pink background corresponded to thin- and thick-walled vessels containing plump endothelial cells and intraluminal erythrocytes within the superficial and deep dermis. White structures could represent underlying fibrosis and altered dermal collagen due to vascular proliferation. The brown pigment network and peripheral brownish pigmentation were most likely secondary to increased melanin and accentuation of the pigment network in the setting of Fitzpatrick skin types IV to V, although pruritic trauma with postinflammatory hyperpigmentation may also have contributed, making dermoscopic-histopathologic correlation challenging.

Surgical excision is considered the primary treatment modality for ALHE, with the lowest recurrence rates.¹ Alternative therapeutic options include intralesional steroids, cryotherapy, sclerotherapy, radiofrequency, pulsed dye laser, and carbon dioxide laser, with varying efficacy reported.¹ Our patient was treated with a combination of a long-pulse Nd:YAG laser (pulse width of 30 ms) to target the vascular component, followed by a single session with an ablative Er:YAG laser. After 4 weeks, healing with good cosmetic results was observed (Figure 2). At 6-month follow-up, there was no recurrence of the lesions.

Kimura disease, often considered the closest differential diagnosis for ALHE, is a rare lymphoproliferative fibroinflammatory condition. Patients present with subcutaneous nodules on the head and neck, often associated with lymphadenopathy. Elevated serum IgE levels and peripheral blood eosinophilia are common.¹ Another consideration in the differential diagnosis is cutaneous bacillary angiomatosis caused by Bartonella species, a vascular proliferative condition that mostly affects individuals with HIV, transplant recipients, and those taking immunosuppressive medications.⁴ Pyogenic granuloma, also known as lobular capillary haemangioma, is another benign vascular proliferation that resembles ALHE. Clinically, it manifests as a solitary, painless, flesh-colored to erythematous papulonodule; however, multiple grouped lesions also can occur. The lesions often are associated with bleeding and erosions.⁵ Epithelioid hemangioendothelioma is a rare vascular tumor most frequently manifesting in the liver, lungs, or bones, and very rarely is limited to skin. Cutaneous epithelioid hemangioendothelioma mimics ALHE and may manifest as a solitary erythematous mass, multiple dome-shaped masses, or dermal nodules.⁶

THE DIAGNOSIS: Angiolymphoid Hyperplasia With Eosinophilia

Angiolymphoid hyperplasia with eosinophilia (ALHE) is a rare, benign, inflammatory vascular proliferation with lymphocytic and eosinophilic infiltration. Bleeding and pruritus associated with ALHE can substantially affect a patient’s quality of life, necessitating correct diagnosis and effective treatment.¹ The etiopathogenesis of ALHE is poorly understood, and it often is attributed to an underlying vascular malformation or local trauma. Vascular proliferation due to hyperestrogenemia could explain why pregnancy is considered a predisposing factor for ALHE.^1,2

Angiolymphoid hyperplasia with eosinophilia typically manifests with solitary or multiple pink to red-brown, dome-shaped papules or nodules occurring most frequently on the head and neck. Lesions may be either asymptomatic or associated with pruritus, pain, and spontaneous bleeding.¹ Dermoscopy is crucial to diagnosis. The most frequent dermoscopic findings include a polymorphic vascular pattern such as dotted and linear irregular vessels over a pink background, white lines, white dots, white structureless areas, and red-purple lacunae.^2,3 Histopathology will demonstrate a vascular proliferation with plump epithelioid endothelial cells showing abundant eosinophilic cytoplasm, accompanied by a variable lymphocytic and eosinophilic inflammatory infiltrate (Figure 1).¹

In our case, dermoscopic-histopathologic correlation suggested that the polymorphic vascular pattern and clods on a pink background corresponded to thin- and thick-walled vessels containing plump endothelial cells and intraluminal erythrocytes within the superficial and deep dermis. White structures could represent underlying fibrosis and altered dermal collagen due to vascular proliferation. The brown pigment network and peripheral brownish pigmentation were most likely secondary to increased melanin and accentuation of the pigment network in the setting of Fitzpatrick skin types IV to V, although pruritic trauma with postinflammatory hyperpigmentation may also have contributed, making dermoscopic-histopathologic correlation challenging.

Surgical excision is considered the primary treatment modality for ALHE, with the lowest recurrence rates.¹ Alternative therapeutic options include intralesional steroids, cryotherapy, sclerotherapy, radiofrequency, pulsed dye laser, and carbon dioxide laser, with varying efficacy reported.¹ Our patient was treated with a combination of a long-pulse Nd:YAG laser (pulse width of 30 ms) to target the vascular component, followed by a single session with an ablative Er:YAG laser. After 4 weeks, healing with good cosmetic results was observed (Figure 2). At 6-month follow-up, there was no recurrence of the lesions.

Kimura disease, often considered the closest differential diagnosis for ALHE, is a rare lymphoproliferative fibroinflammatory condition. Patients present with subcutaneous nodules on the head and neck, often associated with lymphadenopathy. Elevated serum IgE levels and peripheral blood eosinophilia are common.¹ Another consideration in the differential diagnosis is cutaneous bacillary angiomatosis caused by Bartonella species, a vascular proliferative condition that mostly affects individuals with HIV, transplant recipients, and those taking immunosuppressive medications.⁴ Pyogenic granuloma, also known as lobular capillary haemangioma, is another benign vascular proliferation that resembles ALHE. Clinically, it manifests as a solitary, painless, flesh-colored to erythematous papulonodule; however, multiple grouped lesions also can occur. The lesions often are associated with bleeding and erosions.⁵ Epithelioid hemangioendothelioma is a rare vascular tumor most frequently manifesting in the liver, lungs, or bones, and very rarely is limited to skin. Cutaneous epithelioid hemangioendothelioma mimics ALHE and may manifest as a solitary erythematous mass, multiple dome-shaped masses, or dermal nodules.⁶

THE DIAGNOSIS: Angiolymphoid Hyperplasia With Eosinophilia

Angiolymphoid hyperplasia with eosinophilia (ALHE) is a rare, benign, inflammatory vascular proliferation with lymphocytic and eosinophilic infiltration. Bleeding and pruritus associated with ALHE can substantially affect a patient’s quality of life, necessitating correct diagnosis and effective treatment.¹ The etiopathogenesis of ALHE is poorly understood, and it often is attributed to an underlying vascular malformation or local trauma. Vascular proliferation due to hyperestrogenemia could explain why pregnancy is considered a predisposing factor for ALHE.^1,2

Angiolymphoid hyperplasia with eosinophilia typically manifests with solitary or multiple pink to red-brown, dome-shaped papules or nodules occurring most frequently on the head and neck. Lesions may be either asymptomatic or associated with pruritus, pain, and spontaneous bleeding.¹ Dermoscopy is crucial to diagnosis. The most frequent dermoscopic findings include a polymorphic vascular pattern such as dotted and linear irregular vessels over a pink background, white lines, white dots, white structureless areas, and red-purple lacunae.^2,3 Histopathology will demonstrate a vascular proliferation with plump epithelioid endothelial cells showing abundant eosinophilic cytoplasm, accompanied by a variable lymphocytic and eosinophilic inflammatory infiltrate (Figure 1).¹

In our case, dermoscopic-histopathologic correlation suggested that the polymorphic vascular pattern and clods on a pink background corresponded to thin- and thick-walled vessels containing plump endothelial cells and intraluminal erythrocytes within the superficial and deep dermis. White structures could represent underlying fibrosis and altered dermal collagen due to vascular proliferation. The brown pigment network and peripheral brownish pigmentation were most likely secondary to increased melanin and accentuation of the pigment network in the setting of Fitzpatrick skin types IV to V, although pruritic trauma with postinflammatory hyperpigmentation may also have contributed, making dermoscopic-histopathologic correlation challenging.

Surgical excision is considered the primary treatment modality for ALHE, with the lowest recurrence rates.¹ Alternative therapeutic options include intralesional steroids, cryotherapy, sclerotherapy, radiofrequency, pulsed dye laser, and carbon dioxide laser, with varying efficacy reported.¹ Our patient was treated with a combination of a long-pulse Nd:YAG laser (pulse width of 30 ms) to target the vascular component, followed by a single session with an ablative Er:YAG laser. After 4 weeks, healing with good cosmetic results was observed (Figure 2). At 6-month follow-up, there was no recurrence of the lesions.

Kimura disease, often considered the closest differential diagnosis for ALHE, is a rare lymphoproliferative fibroinflammatory condition. Patients present with subcutaneous nodules on the head and neck, often associated with lymphadenopathy. Elevated serum IgE levels and peripheral blood eosinophilia are common.¹ Another consideration in the differential diagnosis is cutaneous bacillary angiomatosis caused by Bartonella species, a vascular proliferative condition that mostly affects individuals with HIV, transplant recipients, and those taking immunosuppressive medications.⁴ Pyogenic granuloma, also known as lobular capillary haemangioma, is another benign vascular proliferation that resembles ALHE. Clinically, it manifests as a solitary, painless, flesh-colored to erythematous papulonodule; however, multiple grouped lesions also can occur. The lesions often are associated with bleeding and erosions.⁵ Epithelioid hemangioendothelioma is a rare vascular tumor most frequently manifesting in the liver, lungs, or bones, and very rarely is limited to skin. Cutaneous epithelioid hemangioendothelioma mimics ALHE and may manifest as a solitary erythematous mass, multiple dome-shaped masses, or dermal nodules.⁶

Practice Gap

Chronic localized granulomatous inflammation can be difficult to manage, particularly when manifesting on the face. Intralesional corticosteroids may lead to atrophy and dyspigmentation and therefore must be used cautiously in cosmetically sensitive areas.¹ Surgical removal can lead to recurrence, and systemic agents may carry risks disproportionate to disease burden. Although tumor necrosis factor (TNF) α inhibitors are effective systemically, their localized use in cutaneous granulomatous dermatoses remains underreported.^1-3 We describe a technique using intralesional injection of adalimumab to treat chronic refractory cutaneous granulomatous inflammation.

The Technique

A 69-year-old woman presented with a crusted erythematous papule with surrounding inflammation on the left nasal ala of 5 years’ duration (Figure 1). Histopathology demonstrated a localized cutaneous granulomatous process. There was no clinical, radiographic, or laboratory evidence of systemic sarcoidosis. Infectious causes were excluded through negative tissue cultures and special stains, including auramine-rhodamine. Over a 3-month period following initial presentation, the lesion proved refractory to intralesional 5-fluorouracil, intralesional triamcinolone acetonide, pentoxifylline, N-acetylcysteine, and shave excision (Figure 2).

At 3-month follow-up, given the lesion’s persistence despite local and systemic anti-inflammatory approaches and our intent to avoid repeated corticosteroid exposure or more aggressive surgery in a cosmetically sensitive facial site, we attempted treatment with intralesional adalimumab. A 40-mg/0.4-mL dose of adalimumab was withdrawn directly from a prefilled autoinjector and placed into a sterile container, then transferred to a syringe fitted with a 30-gauge needle. Finally, the full 0.4 mL was injected intralesionally (Figure 3) until complete blanching of the lesion was achieved.

At 1-month follow-up, the lesion demonstrated decreased erythema and crusting (Figure 4A). The patient subsequently underwent 12 adalimumab injections over an 18-month period with marked reduction in size and erythema of the lesion without complications (Figure 4B). In addition, doxycycline 100 mg/d was started 11 months after the first adalimumab injection to address mild residual inflammation (Figure 4C); after 4 months, the dose was reduced to 50 mg/d due to gastrointestinal adverse effects. Doxycycline was maintained for 3 additional months with persistent improvement of the lesion.

Practice Implication

Intralesional administration of adalimumab may represent a useful therapeutic option for localized refractory granulomatous inflammation, particularly in sensitive areas such as the face, where conventional therapies may be limited by adverse effects or suboptimal response. Localized delivery of TNF-α inhibition directly to the site of inflammation may allow for clinical improvement while minimizing systemic exposure associated with biologic therapy.² This approach may be particularly advantageous in cases in which repeated intralesional corticosteroid injections raise concern for atrophy or dyspigmentation, or when surgical intervention carries a risk for recurrence or cosmetic morbidity.^1,2 Given the established role of TNF-α in granuloma formation and maintenance, intralesional adalimumab provides a biologically plausible targeted therapeutic strategy. Further studies are needed to evaluate the potential applications in other cutaneous granulomatous dermatoses.^2,3

Practice Gap

Chronic localized granulomatous inflammation can be difficult to manage, particularly when manifesting on the face. Intralesional corticosteroids may lead to atrophy and dyspigmentation and therefore must be used cautiously in cosmetically sensitive areas.¹ Surgical removal can lead to recurrence, and systemic agents may carry risks disproportionate to disease burden. Although tumor necrosis factor (TNF) α inhibitors are effective systemically, their localized use in cutaneous granulomatous dermatoses remains underreported.^1-3 We describe a technique using intralesional injection of adalimumab to treat chronic refractory cutaneous granulomatous inflammation.

The Technique

A 69-year-old woman presented with a crusted erythematous papule with surrounding inflammation on the left nasal ala of 5 years’ duration (Figure 1). Histopathology demonstrated a localized cutaneous granulomatous process. There was no clinical, radiographic, or laboratory evidence of systemic sarcoidosis. Infectious causes were excluded through negative tissue cultures and special stains, including auramine-rhodamine. Over a 3-month period following initial presentation, the lesion proved refractory to intralesional 5-fluorouracil, intralesional triamcinolone acetonide, pentoxifylline, N-acetylcysteine, and shave excision (Figure 2).

At 3-month follow-up, given the lesion’s persistence despite local and systemic anti-inflammatory approaches and our intent to avoid repeated corticosteroid exposure or more aggressive surgery in a cosmetically sensitive facial site, we attempted treatment with intralesional adalimumab. A 40-mg/0.4-mL dose of adalimumab was withdrawn directly from a prefilled autoinjector and placed into a sterile container, then transferred to a syringe fitted with a 30-gauge needle. Finally, the full 0.4 mL was injected intralesionally (Figure 3) until complete blanching of the lesion was achieved.

At 1-month follow-up, the lesion demonstrated decreased erythema and crusting (Figure 4A). The patient subsequently underwent 12 adalimumab injections over an 18-month period with marked reduction in size and erythema of the lesion without complications (Figure 4B). In addition, doxycycline 100 mg/d was started 11 months after the first adalimumab injection to address mild residual inflammation (Figure 4C); after 4 months, the dose was reduced to 50 mg/d due to gastrointestinal adverse effects. Doxycycline was maintained for 3 additional months with persistent improvement of the lesion.

Practice Implication

Intralesional administration of adalimumab may represent a useful therapeutic option for localized refractory granulomatous inflammation, particularly in sensitive areas such as the face, where conventional therapies may be limited by adverse effects or suboptimal response. Localized delivery of TNF-α inhibition directly to the site of inflammation may allow for clinical improvement while minimizing systemic exposure associated with biologic therapy.² This approach may be particularly advantageous in cases in which repeated intralesional corticosteroid injections raise concern for atrophy or dyspigmentation, or when surgical intervention carries a risk for recurrence or cosmetic morbidity.^1,2 Given the established role of TNF-α in granuloma formation and maintenance, intralesional adalimumab provides a biologically plausible targeted therapeutic strategy. Further studies are needed to evaluate the potential applications in other cutaneous granulomatous dermatoses.^2,3

Practice Gap

Chronic localized granulomatous inflammation can be difficult to manage, particularly when manifesting on the face. Intralesional corticosteroids may lead to atrophy and dyspigmentation and therefore must be used cautiously in cosmetically sensitive areas.¹ Surgical removal can lead to recurrence, and systemic agents may carry risks disproportionate to disease burden. Although tumor necrosis factor (TNF) α inhibitors are effective systemically, their localized use in cutaneous granulomatous dermatoses remains underreported.^1-3 We describe a technique using intralesional injection of adalimumab to treat chronic refractory cutaneous granulomatous inflammation.

The Technique

A 69-year-old woman presented with a crusted erythematous papule with surrounding inflammation on the left nasal ala of 5 years’ duration (Figure 1). Histopathology demonstrated a localized cutaneous granulomatous process. There was no clinical, radiographic, or laboratory evidence of systemic sarcoidosis. Infectious causes were excluded through negative tissue cultures and special stains, including auramine-rhodamine. Over a 3-month period following initial presentation, the lesion proved refractory to intralesional 5-fluorouracil, intralesional triamcinolone acetonide, pentoxifylline, N-acetylcysteine, and shave excision (Figure 2).

At 3-month follow-up, given the lesion’s persistence despite local and systemic anti-inflammatory approaches and our intent to avoid repeated corticosteroid exposure or more aggressive surgery in a cosmetically sensitive facial site, we attempted treatment with intralesional adalimumab. A 40-mg/0.4-mL dose of adalimumab was withdrawn directly from a prefilled autoinjector and placed into a sterile container, then transferred to a syringe fitted with a 30-gauge needle. Finally, the full 0.4 mL was injected intralesionally (Figure 3) until complete blanching of the lesion was achieved.

At 1-month follow-up, the lesion demonstrated decreased erythema and crusting (Figure 4A). The patient subsequently underwent 12 adalimumab injections over an 18-month period with marked reduction in size and erythema of the lesion without complications (Figure 4B). In addition, doxycycline 100 mg/d was started 11 months after the first adalimumab injection to address mild residual inflammation (Figure 4C); after 4 months, the dose was reduced to 50 mg/d due to gastrointestinal adverse effects. Doxycycline was maintained for 3 additional months with persistent improvement of the lesion.

Practice Implication

Intralesional administration of adalimumab may represent a useful therapeutic option for localized refractory granulomatous inflammation, particularly in sensitive areas such as the face, where conventional therapies may be limited by adverse effects or suboptimal response. Localized delivery of TNF-α inhibition directly to the site of inflammation may allow for clinical improvement while minimizing systemic exposure associated with biologic therapy.² This approach may be particularly advantageous in cases in which repeated intralesional corticosteroid injections raise concern for atrophy or dyspigmentation, or when surgical intervention carries a risk for recurrence or cosmetic morbidity.^1,2 Given the established role of TNF-α in granuloma formation and maintenance, intralesional adalimumab provides a biologically plausible targeted therapeutic strategy. Further studies are needed to evaluate the potential applications in other cutaneous granulomatous dermatoses.^2,3

Hidradenitis suppurativa (HS) is a chronic inflammatory skin condition characterized by painful nodules, abscesses, scarring, and sinus tracts that commonly manifest in the axillary, inguinal, perianal, and inframammary regions.¹ Hidradenitis suppurativa has been associated with several metabolic and cardiovascular comorbidities as well as polycystic ovary syndrome (PCOS)(recently renamed polyendocrine metabolic ovarian syndrome),^2,3 a condition characterized by hyperandrogenism, chronic anovulation, and polycystic ovaries.² Multiple comorbidities of PCOS overlap with those of HS, including type 2 diabetes, cardiovascular disease, and metabolic syndrome.^1,3-5 While HS may be associated with PCOS, there is limited literature analyzing the association between these conditions. This study aimed to analyze the association between HS and PCOS using data from the National Institute of Health’s All of Us Research Program database (https://allofus.nih.gov/). While other studies have looked at the association between HS and PCOS, ours is among the first to analyze the relationship between multiple race/ ethnicity groups, which is especially important given racial disparities in HS and comorbid diseases.

Methods

A cross-sectional, population-based study of females included in the All of Us Research Program database was conducted. Patients with HS were identified using the Systematized Nomenclature of Medicine–Clinical Terms (SNOMED CT) code 59393003, while PCOS was identified with the code 237055002. Type 2 diabetes was identified with the following SNOMED CT codes: 44054006, 313436004, 237599002, 199230006, 359642000, and 81531005. Obesity was identified with the following codes: 414916001, 238136002, 190966007, 296526005, 294493008, 238134004, 83911000119104, and 415530009. Male patients and those who did not answer questions regarding sociodemographic variables were excluded from the final analysis. P values were calculated using Pearson χ² tests. Multivariate logistic regression was used to calculate adjusted odds ratios and unadjusted odds ratios to analyze the association between HS and PCOS while controlling for age, race/ethnicity, smoking status, type 2 diabetes, and obesity. Statistical analyses were conducted using a 95% CI.

Results

The final analysis included 78,742 patients. The prevalence of PCOS was 5.64% in the HS group vs 0.93% in the non-HS group (eTable 1). Individuals with HS had higher rates of smoking cigarettes (57.71% vs 37.67%), obesity (51.08% vs 17.22%), and type 2 diabetes (20.73% vs 9.11%) than individuals without HS, respectively.

Multivariate logistic regression analyses revealed that individuals with HS were 2.06 times more likely to have PCOS after adjusting for sociodemographic variables and comorbidities (95% CI, 1.41-3.02; P<.001). Adjusted subgroup analyses by race/ethnicity did not yield statistically significant results; however, unadjusted analyses revealed that individuals with HS had significantly increased odds of PCOS across all race/ethnicity groups (eTable 2). Interaction terms analysis to determine if the relationship between HS and PCOS differs by race/ ethnicity did not yield statistically significant results. However, independent of HS status, non-Hispanic Black and Hispanic patients were less likely to have PCOS compared to White individuals (adjusted odds ratio, 0.37 and 0.56, respectively; P<.001). Disparities in access to care could have led to underdiagnosis of PCOS among non-Hispanic Black and Hispanic patients. Lastly, individuals with type 2 diabetes were 10.43 times more likely to have PCOS than those without, while patients with obesity were 11.14 times more likely to have PCOS than those without.

Comment

This study demonstrated that females with HS are 2.06 times more likely to have PCOS than those without HS, even after controlling for important sociodemographic variables and comorbidities. While adjusted subgroup analyses did not yield statistically significant results, unadjusted analyses demonstrated increased odds of PCOS in patients with HS across all race/ethnicity groups, suggesting that sociodemographic variables and comorbidities substantially influence the relationship between HS and PCOS; for instance, patients with type 2 diabetes and obesity are approximately 10- to 11-fold more likely to have PCOS than patients without these conditions. Non-Hispanic Black and Hispanic patients were less likely to have PCOS compared with White patients, indicating possible underdiagnosis of PCOS in these populations and highlighting the need for increased PCOS screening. Limitations of this study include the reliance on SNOMED CT codes, which may have led to underdiagnosis of HS or PCOS, as well as the inability to differentiate between mild and severe HS in the database.

Hyperandrogenism is believed to contribute to the pathogenesis of both HS and PCOS, supporting the potential use of antiandrogen therapies, such as spironolactone, in managing both conditions.^2,3 Furthermore, oral contraceptives may have a role in managing both conditions. In HS, oral contraceptives help to mitigate flares associated with hormonal changes during menstruation, while in PCOS, they are used to regulate the hormonal cycle and reduce hirsutism.^2-4 However, not all women experience menstrual flares of HS, suggesting that variations in HS phenotypes may influence individual responses to hormonal changes.¹ Additionally, the considerable overlap in metabolic and cardiovascular comorbidities between HS and PCOS indicates that shared pathomechanisms may contribute to the association between these conditions.^1,2 For example, proinflammatory adipokines released in both HS and PCOS may contribute to inflammation, cardiovascular disease, and insulin resistance.^3,5

Conclusion

Further research is needed to better understand the shared pathophysiology that links these 2 diseases and to identify targeted approaches for optimizing management and improving patient outcomes. The association between HS and PCOS highlights the importance of screening for metabolic and reproductive comorbidities in patients with HS. Early recognition and management of both HS and PCOS can improve long-term outcomes.

Hidradenitis suppurativa (HS) is a chronic inflammatory skin condition characterized by painful nodules, abscesses, scarring, and sinus tracts that commonly manifest in the axillary, inguinal, perianal, and inframammary regions.¹ Hidradenitis suppurativa has been associated with several metabolic and cardiovascular comorbidities as well as polycystic ovary syndrome (PCOS)(recently renamed polyendocrine metabolic ovarian syndrome),^2,3 a condition characterized by hyperandrogenism, chronic anovulation, and polycystic ovaries.² Multiple comorbidities of PCOS overlap with those of HS, including type 2 diabetes, cardiovascular disease, and metabolic syndrome.^1,3-5 While HS may be associated with PCOS, there is limited literature analyzing the association between these conditions. This study aimed to analyze the association between HS and PCOS using data from the National Institute of Health’s All of Us Research Program database (https://allofus.nih.gov/). While other studies have looked at the association between HS and PCOS, ours is among the first to analyze the relationship between multiple race/ ethnicity groups, which is especially important given racial disparities in HS and comorbid diseases.

Methods

A cross-sectional, population-based study of females included in the All of Us Research Program database was conducted. Patients with HS were identified using the Systematized Nomenclature of Medicine–Clinical Terms (SNOMED CT) code 59393003, while PCOS was identified with the code 237055002. Type 2 diabetes was identified with the following SNOMED CT codes: 44054006, 313436004, 237599002, 199230006, 359642000, and 81531005. Obesity was identified with the following codes: 414916001, 238136002, 190966007, 296526005, 294493008, 238134004, 83911000119104, and 415530009. Male patients and those who did not answer questions regarding sociodemographic variables were excluded from the final analysis. P values were calculated using Pearson χ² tests. Multivariate logistic regression was used to calculate adjusted odds ratios and unadjusted odds ratios to analyze the association between HS and PCOS while controlling for age, race/ethnicity, smoking status, type 2 diabetes, and obesity. Statistical analyses were conducted using a 95% CI.

Results

The final analysis included 78,742 patients. The prevalence of PCOS was 5.64% in the HS group vs 0.93% in the non-HS group (eTable 1). Individuals with HS had higher rates of smoking cigarettes (57.71% vs 37.67%), obesity (51.08% vs 17.22%), and type 2 diabetes (20.73% vs 9.11%) than individuals without HS, respectively.

Multivariate logistic regression analyses revealed that individuals with HS were 2.06 times more likely to have PCOS after adjusting for sociodemographic variables and comorbidities (95% CI, 1.41-3.02; P<.001). Adjusted subgroup analyses by race/ethnicity did not yield statistically significant results; however, unadjusted analyses revealed that individuals with HS had significantly increased odds of PCOS across all race/ethnicity groups (eTable 2). Interaction terms analysis to determine if the relationship between HS and PCOS differs by race/ ethnicity did not yield statistically significant results. However, independent of HS status, non-Hispanic Black and Hispanic patients were less likely to have PCOS compared to White individuals (adjusted odds ratio, 0.37 and 0.56, respectively; P<.001). Disparities in access to care could have led to underdiagnosis of PCOS among non-Hispanic Black and Hispanic patients. Lastly, individuals with type 2 diabetes were 10.43 times more likely to have PCOS than those without, while patients with obesity were 11.14 times more likely to have PCOS than those without.

Comment

This study demonstrated that females with HS are 2.06 times more likely to have PCOS than those without HS, even after controlling for important sociodemographic variables and comorbidities. While adjusted subgroup analyses did not yield statistically significant results, unadjusted analyses demonstrated increased odds of PCOS in patients with HS across all race/ethnicity groups, suggesting that sociodemographic variables and comorbidities substantially influence the relationship between HS and PCOS; for instance, patients with type 2 diabetes and obesity are approximately 10- to 11-fold more likely to have PCOS than patients without these conditions. Non-Hispanic Black and Hispanic patients were less likely to have PCOS compared with White patients, indicating possible underdiagnosis of PCOS in these populations and highlighting the need for increased PCOS screening. Limitations of this study include the reliance on SNOMED CT codes, which may have led to underdiagnosis of HS or PCOS, as well as the inability to differentiate between mild and severe HS in the database.

Hyperandrogenism is believed to contribute to the pathogenesis of both HS and PCOS, supporting the potential use of antiandrogen therapies, such as spironolactone, in managing both conditions.^2,3 Furthermore, oral contraceptives may have a role in managing both conditions. In HS, oral contraceptives help to mitigate flares associated with hormonal changes during menstruation, while in PCOS, they are used to regulate the hormonal cycle and reduce hirsutism.^2-4 However, not all women experience menstrual flares of HS, suggesting that variations in HS phenotypes may influence individual responses to hormonal changes.¹ Additionally, the considerable overlap in metabolic and cardiovascular comorbidities between HS and PCOS indicates that shared pathomechanisms may contribute to the association between these conditions.^1,2 For example, proinflammatory adipokines released in both HS and PCOS may contribute to inflammation, cardiovascular disease, and insulin resistance.^3,5

Conclusion

Further research is needed to better understand the shared pathophysiology that links these 2 diseases and to identify targeted approaches for optimizing management and improving patient outcomes. The association between HS and PCOS highlights the importance of screening for metabolic and reproductive comorbidities in patients with HS. Early recognition and management of both HS and PCOS can improve long-term outcomes.

Hidradenitis suppurativa (HS) is a chronic inflammatory skin condition characterized by painful nodules, abscesses, scarring, and sinus tracts that commonly manifest in the axillary, inguinal, perianal, and inframammary regions.¹ Hidradenitis suppurativa has been associated with several metabolic and cardiovascular comorbidities as well as polycystic ovary syndrome (PCOS)(recently renamed polyendocrine metabolic ovarian syndrome),^2,3 a condition characterized by hyperandrogenism, chronic anovulation, and polycystic ovaries.² Multiple comorbidities of PCOS overlap with those of HS, including type 2 diabetes, cardiovascular disease, and metabolic syndrome.^1,3-5 While HS may be associated with PCOS, there is limited literature analyzing the association between these conditions. This study aimed to analyze the association between HS and PCOS using data from the National Institute of Health’s All of Us Research Program database (https://allofus.nih.gov/). While other studies have looked at the association between HS and PCOS, ours is among the first to analyze the relationship between multiple race/ ethnicity groups, which is especially important given racial disparities in HS and comorbid diseases.

Methods

A cross-sectional, population-based study of females included in the All of Us Research Program database was conducted. Patients with HS were identified using the Systematized Nomenclature of Medicine–Clinical Terms (SNOMED CT) code 59393003, while PCOS was identified with the code 237055002. Type 2 diabetes was identified with the following SNOMED CT codes: 44054006, 313436004, 237599002, 199230006, 359642000, and 81531005. Obesity was identified with the following codes: 414916001, 238136002, 190966007, 296526005, 294493008, 238134004, 83911000119104, and 415530009. Male patients and those who did not answer questions regarding sociodemographic variables were excluded from the final analysis. P values were calculated using Pearson χ² tests. Multivariate logistic regression was used to calculate adjusted odds ratios and unadjusted odds ratios to analyze the association between HS and PCOS while controlling for age, race/ethnicity, smoking status, type 2 diabetes, and obesity. Statistical analyses were conducted using a 95% CI.

Results

The final analysis included 78,742 patients. The prevalence of PCOS was 5.64% in the HS group vs 0.93% in the non-HS group (eTable 1). Individuals with HS had higher rates of smoking cigarettes (57.71% vs 37.67%), obesity (51.08% vs 17.22%), and type 2 diabetes (20.73% vs 9.11%) than individuals without HS, respectively.

Multivariate logistic regression analyses revealed that individuals with HS were 2.06 times more likely to have PCOS after adjusting for sociodemographic variables and comorbidities (95% CI, 1.41-3.02; P<.001). Adjusted subgroup analyses by race/ethnicity did not yield statistically significant results; however, unadjusted analyses revealed that individuals with HS had significantly increased odds of PCOS across all race/ethnicity groups (eTable 2). Interaction terms analysis to determine if the relationship between HS and PCOS differs by race/ ethnicity did not yield statistically significant results. However, independent of HS status, non-Hispanic Black and Hispanic patients were less likely to have PCOS compared to White individuals (adjusted odds ratio, 0.37 and 0.56, respectively; P<.001). Disparities in access to care could have led to underdiagnosis of PCOS among non-Hispanic Black and Hispanic patients. Lastly, individuals with type 2 diabetes were 10.43 times more likely to have PCOS than those without, while patients with obesity were 11.14 times more likely to have PCOS than those without.

Comment

This study demonstrated that females with HS are 2.06 times more likely to have PCOS than those without HS, even after controlling for important sociodemographic variables and comorbidities. While adjusted subgroup analyses did not yield statistically significant results, unadjusted analyses demonstrated increased odds of PCOS in patients with HS across all race/ethnicity groups, suggesting that sociodemographic variables and comorbidities substantially influence the relationship between HS and PCOS; for instance, patients with type 2 diabetes and obesity are approximately 10- to 11-fold more likely to have PCOS than patients without these conditions. Non-Hispanic Black and Hispanic patients were less likely to have PCOS compared with White patients, indicating possible underdiagnosis of PCOS in these populations and highlighting the need for increased PCOS screening. Limitations of this study include the reliance on SNOMED CT codes, which may have led to underdiagnosis of HS or PCOS, as well as the inability to differentiate between mild and severe HS in the database.

Hyperandrogenism is believed to contribute to the pathogenesis of both HS and PCOS, supporting the potential use of antiandrogen therapies, such as spironolactone, in managing both conditions.^2,3 Furthermore, oral contraceptives may have a role in managing both conditions. In HS, oral contraceptives help to mitigate flares associated with hormonal changes during menstruation, while in PCOS, they are used to regulate the hormonal cycle and reduce hirsutism.^2-4 However, not all women experience menstrual flares of HS, suggesting that variations in HS phenotypes may influence individual responses to hormonal changes.¹ Additionally, the considerable overlap in metabolic and cardiovascular comorbidities between HS and PCOS indicates that shared pathomechanisms may contribute to the association between these conditions.^1,2 For example, proinflammatory adipokines released in both HS and PCOS may contribute to inflammation, cardiovascular disease, and insulin resistance.^3,5

Conclusion

Further research is needed to better understand the shared pathophysiology that links these 2 diseases and to identify targeted approaches for optimizing management and improving patient outcomes. The association between HS and PCOS highlights the importance of screening for metabolic and reproductive comorbidities in patients with HS. Early recognition and management of both HS and PCOS can improve long-term outcomes.