Skin cancer risk in CHEK2 mutation carriers.

CHEK2 mutations have been linked with an increased risk of breast cancer. A unique challenge for oncodermatologists and oncologists is in the monitoring and counselling of patients regarding skin cancer risk due to CHEK2 mutation carrier status. In this review, we highlight current information in the literature on the risk of melanoma and non-melanoma skin cancers in CHEK2 mutation carriers. On the molecular level, CHEK2 is a cell cycle regulator that has been linked to cancer pathogenesis, though evidence from clinical studies regarding skin cancer risk has been inconsistent and conflicting. For melanoma, one study has demonstrated a statistically significant twofold risk of melanoma in individuals with CHEK2 mutations, particularly the CHEK2*1100delC variant. Five other studies did not show an association. For non-melanoma skin cancer, fewer data exist, with one prevalence study of CHEK2 mutations in a cohort of patients with basal cell carcinomas. Although there are currently no known studies of CHEK2 and cutaneous squamous cell carcinoma (SCC), data from other disciplines associating CHEK2 with head and neck SCCs are emerging. Overall, while there is currently not enough evidence to make conclusive statements regarding increased risk of melanoma and non-melanoma skin cancers in CHEK2 carriers, a molecular mechanism associating the mutation with cutaneous malignancy pathogenesis is evident, and further work is needed. Patient with CHEK2 mutations may benefit from screening dermatologic examinations with particular attention to skin cancers.

De novo subacute cutaneous lupus erythematosus-like eruptions in the setting of programmed death-1 or programmed death ligand-1 inhibitor therapy: clinicopathological correlation.

Immune checkpoint inhibitors (ICI) may cause eruptions resembling cutaneous autoimmune diseases. There are six cases of immunotherapy-associated subacute cutaneous lupus erythematosus (SCLE) in the literature. We present details of five patients referred to the Skin Toxicity Program at the Dana-Farber Cancer Institute/Brigham and Women's Cancer Center who developed de novo immunotherapy-associated SCLE-like eruptions, along with clinicopathological correlation and highlight potential mechanistic features and important diagnostic points. Two patients were maintained on topical corticosteroids, antihistamines and photoprotection. One had complete clearance and two had improvement with addition of hydroxychloroquine. Four patients continued their immunotherapy uninterrupted, while one had immunotherapy suspended for a month before restarting at full dose. Histopathologically, this series illustrates the temporal evolution of ICI-induced immune cutaneous reactions with SCLE subtype. Looking beyond the universally present lichenoid infiltrate, features of evolving SCLE were evident. We hypothesize that programmed death-1 blockade may induce immunological recognition of previously immunologically tolerated drug antigens, leading to epitope spreading and the SCLE phenotype.

Pityriasis rubra pilaris-like erythroderma secondary to phosphoinositide 3-kinase inhibition.

BACKGROUND: Phosphoinositide 3-kinase (PI3K) inhibitors are a class of small-molecule inhibitors approved for the treatment of certain leukaemias and lymphomas. Their dermatological adverse event profile is poorly described. AIM: To characterize a rare cutaneous adverse event from PI3K inhibitors in order to help dermatologists and oncologists identify and effectively manage such eruptions. METHODS: This was a retrospective analysis of patients receiving PI3K inhibitors referred to the Skin Toxicities Program in The Center for Cutaneous Oncology. RESULTS: Three patients on PI3K inhibitors for treatment of malignancy developed diffuse erythroderma and keratoderma. Clinical and histopathological findings were consistent with pityriasis rubra pilaris (PRP)-like reactions. All patients improved with topical and oral corticosteroids, oral acitretin, and drug discontinuation. CONCLUSIONS: PRP-like cutaneous eruptions may develop secondary to PI3K inhibition. Early dermatological evaluation of cutaneous toxicities to PI3K inhibitors as well as rapid initiation of disease-specific treatments may help keep patients on life-prolonging anti-cancer therapies.

Ixazomib-induced cutaneous necrotizing vasculitis.

Ixazomib is a second-generation proteasome inhibitor that has been approved in the combination treatment of multiple myeloma and is currently under clinical investigation for the management of Waldenstrom's macroglobulinemia. While cutaneous adverse events secondary to proteasome inhibitors have been reported, the side effect profile of ixazomib remains to be documented. We report two patients, one with multiple myeloma and one with Waldenstrom's macroglobulinemia, who developed cutaneous necrotizing vasculitis after the initiation of ixazomib. Both patients exhibited no signs of systemic vasculitis and completed their anti-cancer regimens with resolution of their respective eruptions following dose reductions in ixazomib and initiation of low-dose prednisone. A collaborative effort towards the characterization of such cutaneous toxicities facilitates early intervention, maintenance of life-preserving anti-cancer therapy, and allows clinicians opportunity to better understand the pathophysiology of vasculitis. Moreover, appropriate identification and characterization of cutaneous toxicities from novel therapies allows providers to accurately identify safety concerns, treat toxicity, and improve patient quality of life.

Managing toxicities associated with immune checkpoint inhibitors: consensus recommendations from the Society for Immunotherapy of Cancer (SITC) Toxicity Management Working Group.

Cancer immunotherapy has transformed the treatment of cancer. However, increasing use of immune-based therapies, including the widely used class of agents known as immune checkpoint inhibitors, has exposed a discrete group of immune-related adverse events (irAEs). Many of these are driven by the same immunologic mechanisms responsible for the drugs' therapeutic effects, namely blockade of inhibitory mechanisms that suppress the immune system and protect body tissues from an unconstrained acute or chronic immune response. Skin, gut, endocrine, lung and musculoskeletal irAEs are relatively common, whereas cardiovascular, hematologic, renal, neurologic and ophthalmologic irAEs occur much less frequently. The majority of irAEs are mild to moderate in severity; however, serious and occasionally life-threatening irAEs are reported in the literature, and treatment-related deaths occur in up to 2% of patients, varying by ICI. Immunotherapy-related irAEs typically have a delayed onset and prolonged duration compared to adverse events from chemotherapy, and effective management depends on early recognition and prompt intervention with immune suppression and/or immunomodulatory strategies. There is an urgent need for multidisciplinary guidance reflecting broad-based perspectives on how to recognize, report and manage organ-specific toxicities until evidence-based data are available to inform clinical decision-making. The Society for Immunotherapy of Cancer (SITC) established a multidisciplinary Toxicity Management Working Group, which met for a full-day workshop to develop recommendations to standardize management of irAEs. Here we present their consensus recommendations on managing toxicities associated with immune checkpoint inhibitor therapy.

Fatal disseminated Acanthamoeba infection in a liver transplant recipient immunocompromised by combination therapies for graft-versus-host disease.

Immunosuppressed solid organ transplant recipients are at increased risk for acquisition of opportunistic pathogens, with potentially fatal consequences. With the introduction of novel immunosuppressive agents used to prevent organ rejection and to treat the sequelae of transplantation, severity and rates of infection with unusual opportunistic pathogens may increase. Various monoclonal antibodies are now being used in the treatment of severe, acute graft-versus-host disease (GVHD), including rituximab, daclizumab, and alemtuzumab. These therapies, particularly when used in combination and with other traditional forms of immunosuppression, may have profound effects on the immune system. Acanthamoeba species are ubiquitous, free-living protozoa that rarely cause disseminated disease in the immunocompromised host. We report a fatal case of disseminated Acanthamoeba infection with a dramatic cutaneous presentation in a liver transplant recipient severely immunocompromised by sequential standard and novel therapies used to successfully treat life-threatening acute GVHD. This case illustrates the current major limitation of these therapies, discusses the cutaneous findings in disseminated acanthamoebiasis, and highlights the need to maintain vigilance for the presence of unusual infection in patients receiving similar therapeutic regimens.