Clinicopathological characteristics of new primary melanomas in patients receiving immune checkpoint inhibitor therapy for metastatic melanoma.

BACKGROUND: Immune checkpoint inhibitors have improved survival in advanced stage melanoma patients. Rates of new primary melanomas (NPM) in patients with prior melanoma have been reported to be as high as 12%. Little is currently known regarding the frequency or characteristics of NPMs occurring in melanoma patients treated with immune checkpoint inhibitors. AIM: To determine the frequency and describe clinicopathologic characteristics of NPMs diagnosed in patients during or after treatment with immune checkpoint inhibitors for metastatic melanoma. METHODS: A retrospective analysis of prospectively collected data from the Melanoma Institute Australia and Westmead Hospital Dermatology databases. Clinicopathological data for the initial primary melanoma (IPM) and NPM were compared. RESULTS: Between 2013-2017, 14 NPMs in 13 patients (out of a total of 1047) treated with checkpoint inhibitors were identified. NPMs were significantly thinner than the IPM (median Breslow thickness 0.35 mm vs 2.0 mm, P = 0.0003), less likely to be ulcerated (0/14 vs 6/13, P = 0.004) and less likely to have nodal metastases (0/14 vs 6/13, P = 0.004). NPMs were significantly more likely to be detected in the in-situ stage (6/14 vs 0/13, P = 0.0016). CONCLUSION: NPMs are infrequent in patients treated with checkpoint inhibitors. When they occur, they are usually detected at an early stage and have features associated with a favourable prognosis, most likely reflecting close surveillance. Further study is required to determine long-term risk in patients achieving a durable response to immune checkpoint inhibitors, and to determine whether the immunotherapy itself influences both their development and biology.

Stewart-Bluefarb syndrome following traumatic arteriovenous malformation.

Stewart-Bluefarb syndrome is a rare angioproliferative disorder that presents as violet plaques on the extremities, due to an underlying arteriovenous malformation (AVM). We report the case of a 12-year-old boy who developed a traumatic AVM in a bicycle accident and presented seven years later with exophytic, violet plaques. This is the first instance of a traumatic AVM preceding Stewart-Bluefarb syndrome in a pediatric patient in the literature. Given the typically long period required to establish this diagnosis, it is crucial for clinicians to actively interrogate a history of preceding trauma in patients presenting with acroangiodermatitis.

Anti-programmed cell death-1 therapy-associated bullous disorders: a systematic review of the literature.

Bullous disorders are rare adverse events associated with anti-programmed cell death-1 (anti-PD1) therapy. This paper presents two new cases of bullous disorders under anti-PD1 therapy and systematically reviewed the literature to foster a better understanding of the presentation and pathogenesis of bullous disorders under anti-PD1. A systematic review of the literature was completed using MEDLINE, Embase, PubMed and LILACS databases. We identified 29 cases of bullous disorders under anti-PD1 therapy, including our two new cases. This includes 18 cases of bullous pemphigoid (BP), five cases of toxic epidermal necrolysis (TEN)/Stevens-Johnson syndrome (SJS) spectrum, one case of erythema multiforme (EM), four cases of bullous lichenoid reactions and one case of vesiculobullous eczema. In BP, blistering occurred by a median of 23 weeks after anti-PD1 therapy initiation and is often preceded by a prodrome, which lasts for a median of 9.5 weeks. Limbs and trunk were the most frequently involved body sites. Most cases (76%) achieved remission. In TEN/SJS/EM, blistering was usually preceded by a prodrome of interface dermatitis that lasted for a median of 1.5 weeks. Most cases (80%) died from either TEN/SJS or disease progression. Bullous disorders under anti-PD1 may be classified clinically as BP, SJS/TEN/EM, bullous lichenoid reactions and vesiculobullous eczema and histologically by intraepidermal splitting and subepidermal splitting. BP is usually preceded by a pruritic eruption and has a relatively good prognosis. SJS/TEN is usually preceded by a maculopapular eruption and has a very poor prognosis.

Incidence of Basal Cell Carcinoma and Squamous Cell Carcinoma in Patients on Antiprogrammed Cell Death-1 Therapy for Metastatic Melanoma.

Systemic melanoma therapies have the potential to affect basal cell carcinoma (BCC) and cutaneous squamous cell carcinoma (cuSCC) development. In this study, we aim to compare the incidence of BCC and cuSCC in patients with metastatic melanoma treated with antiprogrammed cell death-1 (anti-PD1), BRAF inhibitor (BRAFi) monotherapy or dabrafenib and trametinib combination therapy (CombiDT) with a group of control patients having similar risk factors. We reviewed the records of melanoma patients on anti-PD1, BRAFi, or CombiDT, and patients from the High-Risk Melanoma Clinic, Westmead Hospital. We also performed an immunohistochemical analysis of BCCs under anti-PD1 compared with controls using PD1, PD-L1, CD3, CD8, and CD20 stains. For the results, in all, 340 patients were included; 82 on anti-PD1, 134 on BRAFi, 69 on CombiDT, and 55 controls. BRAFi had the highest incidence of BCC (12.7%), followed by CombiDT (10.1%) and anti-PD1 (2.4%). The incidence of BCC was significantly lower in patients on anti-PD1 (2.4% vs. 19.4%; P<0.001) compared with controls. Patients on anti-PD1 were 8.54 times less likely to develop BCC than the controls [hazard ratio, 0.117 (95% confidence interval, 0.026-0.526), P=0.005]. BRAFi and CombiDT showed no significant differences in BCC incidence compared with controls. BRAFi had the highest cuSCC incidence (23.9%), followed by anti-PD1 (7.3%) and CombiDT (2.9%). The incidence of cuSCC was significantly higher in patients on BRAFi (23.9% vs. 3.5%; P<0.001) compared with controls, but anti-PD1 and CombiDT showed no differences in cuSCC incidence compared with controls. Immunohistochemistry analysis of 10 BCC from under anti-PD1 and 8 BCC from controls patients showed that while all BCC had negative PD-L1 staining, the percentage of PD1 staining in anti-PD1 group is significantly lower than that of the control group (independent t test, 8% vs. 26%; P<0.001). In conclusion, our study suggests that anti-PD1 therapy decreases the incidence of BCC, as a result of the PD1/PD-L1 blockade. Future studies investigating the role of anti-PD1 in suppressing or treating BCC may be warranted.

Intracorneal pustular drug eruption, a novel cutaneous adverse event in anti-programmed cell death-1 patients that highlights the effect of anti-programmed cell death-1 in neutrophils.

The introduction of anti-programmed cell death-1 (anti-PD1) monoclonal antibodies has revolutionized the treatment of various advanced malignancies. Despite its efficacy, anti-PD1 therapy is accompanied by a variety of cutaneous adverse events. A 79-year-old man developed erythematous scaly plaques and pustules of the forehead, legs and arms after four cycles of nivolumab infusions every 2 weeks. Histology showed intracorneal pustules with dermal neutrophils and eosinophils. He was treated successfully with topical corticosteroids without discontinuation of nivolumab. We report subcorneal pustular eruption as a novel cutaneous adverse event in patients on anti-PD1 therapy. Other neutrophilic eruptions (psoriasis, Sweet's syndrome, acute generalized pustulosis) have been reported in patients on anti-PD1 treatments, suggesting the neutrophil as another cell type modulated by anti-PD1 antibodies.

Melanocytic lesion evolution patterns with targeted therapies and immunotherapies for advanced metastatic melanoma: An observational study.

BACKGROUND/OBJECTIVES: Various cutaneous side-effects have been reported with anti-melanoma systemic therapies. This study investigated the changes in melanocytic lesion pigmentation in patients on four different therapies. METHODS: We analysed the serial dermatoscopic photographs of atypical melanocytic lesions taken from patients with advanced metastatic melanoma on four different systemic therapies (selective BRAF-inhibitor monotherapy, dabrafenib combined with trametinib [D&T], anti-programmed cell death protein 1 [anti-PD1] therapies, and anti-PD1 combined with ipilimumab) seen from February 2013 to May 2016. We compared these changes with the melanocytic lesions of 10 control patients. RESULTS: In the control group, 19% of naevi lightened, 64% did not change and 17% darkened. Only the BRAF inhibitor group showed more darkened lesions than controls (37%, P < 0.001). Meanwhile, there were more lightened naevi in the D&T therapy group (86%, P < 0.001) as well as the anti-PD1 and ipilimumab groups (59%, P < 0.001) than controls. Patients on anti-PD1 monotherapy had more lightened (49%) and fewer darkened naevi (9%) than controls, but differences were not significant. CONCLUSIONS: Our study showed that different anti-melanoma systemic therapies have different effects on the pigmentation of melanocytic lesions. BRAF inhibitor may have the propensity to cause darkening while D&T therapy and anti-PD1 caused lightening compared with controls. The findings emphasise the importance of regular dermatological monitoring in specialised clinics for patients on anti-melanoma systemic therapy. Clinicians should expect changes in the global pigmentation of melanocytic lesions but be suspicious of lesions with structural changes.