Risk of Nonkeratinocyte Skin Cancers in People Living with HIV during the Era of Antiretroviral Therapy.

Antiretroviral therapy may alter susceptibility to nonkeratinocyte skin cancers (NKSCs) by improving immunity in people living with HIV. Using linked data from HIV and cancer registries in 12 states/regions in the United States during the antiretroviral therapy era (1996‒2018), we calculated standardized incidence ratios for 27 NKSCs, comparing incidence with that of the general population. Risk factors for NKSCs were evaluated using Poisson regression. There were 2,743 NKSCs diagnosed in 585,706 people living with HIV followed for 4,575,794 person-years. Kaposi sarcoma was the most common cancer (82%), followed by melanoma (12%) and cutaneous lymphoma (2.6%). Incidence was elevated for virus-related NKSCs: Kaposi sarcoma (standardized incidence ratio = 147, 95% confidence interval = 141‒153), diffuse large B-cell lymphoma (standardized incidence ratio = 5.19, 95% confidence interval = 3.13‒8.11), and Merkel cell carcinoma (standardized incidence ratio = 3.15, 95% confidence interval = 1.93‒4.87); elevated incidence for diffuse large B-cell lymphoma and Merkel cell carcinoma was observed only among people living with HIV with a previously acquired immunodeficiency syndrome diagnosis. Kaposi sarcoma risk was highest among men who have sex with men. Incidence was not increased for melanoma, adnexal carcinomas, and sarcomas. Melanoma and Merkel cell carcinoma arose disproportionately on sun-exposed skin, supporting a role for UVR in their development. In conclusion, risk for most NKSCs was similar to that of the general population during the antiretroviral therapy era, suggesting that people living with HIV without NKSC risk factors may not require intensive skin surveillance.

Malignancy-associated acquired vulvar lymphangioma circumscriptum: A clinicopathologic study of 71 cases.

BACKGROUND: Acquired lymphangioma circumscriptum of the vulva is rare and can occur subsequent to malignancies of the anogenital and pelvic region. We sought to investigate the clinicopathologic characteristics of malignancy-associated acquired vulvar lymphangioma circumscriptum (AVLC). METHODS: We identified all cases of AVLC within our institution with history of prior malignancy between 2005 and 2021. A similar search was performed in the PubMed database to identify published cases to date. The clinical and histopathologic information was recorded. RESULTS: A total of 71 cases were identified. The most common preceding malignancy was cervical carcinoma (71.8%, 51/71). Radiation therapy was given to 91.4% (64/70) of the patients and lymph node dissection was made on 70.2% (40/57). Median interval between the diagnosis of malignancy and the AVLC was 10 years (range 0-32 years). AVLC frequently presented as vesicular (31.6%, 18/57) or verrucous (28.1%, 16/57) lesions clinically. Common treatments for AVLC included excision (53.1%, 26/49) and laser therapy (16.3%, 8/49), with an overall recurrence rate of 42.9% (24/56) at a median follow-up interval of 1.8 years (range 0.04-32.3 years). CONCLUSION: AVLC is a rare, late complication of anogenital and pelvic malignancies causing debilitating physical symptoms and psychological stress. Further studies are warranted to determine the most effective treatment modalities to mitigate recurrence.

Inhibition of the ATM/Chk2 axis promotes cGAS/STING signaling in ARID1A-deficient tumors.

ARID1A, a component of the chromatin-remodeling complex SWI/SNF, is one of the most frequently mutated genes in human cancer. We sought to develop rational combination therapy to potentiate the efficacy of immune checkpoint blockade in ARID1A-deficient tumors. In a proteomic analysis of a data set from The Cancer Genomic Atlas, we found enhanced expression of Chk2, a DNA damage checkpoint kinase, in ARID1A-mutated/deficient tumors. Surprisingly, we found that ARID1A targets the nonchromatin substrate Chk2 for ubiquitination. Loss of ARID1A increased the Chk2 level through modulating autoubiquitination of the E3-ligase RNF8 and thereby reducing RNF8-mediated Chk2 degradation. Inhibition of the ATM/Chk2 DNA damage checkpoint axis led to replication stress and accumulation of cytosolic DNA, which subsequently activated the DNA sensor STING-mediated innate immune response in ARID1A-deficient tumors. As expected, tumors with mutation or low expression of both ARID1A and ATM/Chk2 exhibited increased tumor-infiltrating lymphocytes and were associated with longer patient survival. Notably, an ATM inhibitor selectively potentiated the efficacy of immune checkpoint blockade in ARID1A-depleted tumors but not in WT tumors. Together, these results suggest that ARID1A's targeting of the nonchromatin substrate Chk2 for ubiquitination makes it possible to selectively modulate cancer cell-intrinsic innate immunity to enhance the antitumor activity of immune checkpoint blockade.