Shaun Chou

Cutaneous adverse events (AEs) of anti-programmed cell death (PD)-1 therapy in patients with metastatic melanoma: A single-institution cohort

BACKGROUND Anti-programmed cell death (PD)-1 therapy is emerging as the backbone of new standard of care immunotherapy for metastatic melanoma. Immune-related cutaneous events are observed in these patients. OBJECTIVE We sought to describe cutaneous adverse events observed in patients with metastatic melanoma on anti-PD-1 therapy. METHODS We reviewed the clinical and histologic information of all patients treated with single-agent anti-PD-1 therapy for metastatic melanoma at Westmead Hospital, Sydney, Australia, from May 2012 to February 2015. RESULTS Of the 82 patients included in the study, 34 had dermatology assessments. Forty (49%) developed a form of anti-PD-1-associated cutaneous adverse events. In all, 17% developed lichenoid reactions and eczema, and 15% developed vitiligo. An estimated 25% of patients were expected to develop their first lichenoid reactions within 8.3 months, and eczema and vitiligo within 10.3 months of therapy. These adverse events tend to appear together in patients on anti-PD-1 therapy. LIMITATIONS The study was from a single center and clinical information was reviewed retrospectively in patients not referred to dermatology. CONCLUSION Anti-PD-1 therapy is associated with the development of immune-related cutaneous events. Lichenoid reactions, eczema, and vitiligo are the 3 most prevalent lesions observed in our population. There is a tendency for lichenoid reactions and eczema to occur with vitiligo.

A case of bullous pemphigoid in a patient with metastatic melanoma treated with pembrolizumab.

The innovative blockade of immune checkpoints with targeted immunotherapies, such as monoclonal antibodies against programmed cell death-1, is pioneering the treatment for advanced melanoma. Potential adverse events of particular interest associated with immunotherapy are of an inflammatory or immune-related nature. Reported dermatological side effects mostly comprise nonspecific rash and pruritus. This is a report of a 75-year-old man with metastatic melanoma who was initially administered pembrolizumab at 10 mg/kg every 3 weeks. He developed spongiotic dermatitis that was partially treated with topical steroids after cycle 3. Pembrolizumab cycles were stopped because of disease progression after cycle 6. On the 30-day follow-up, the patient presented with extensive erythematous papules and plaques, in addition to a few intact and ruptured vesicles and bullae over the upper and lower limbs, especially over the knees and elbows. Both punch skin biopsies (haematoxylin and eosin and direct immunofluorescence studies) confirmed a bullous pemphigoid diagnosis. He was treated with a tapering dose of oral prednisone, resulting in rapid clinical improvement after only a week of treatment, which was switched to dexamethasone following the diagnosis of new brain metastases.

Cutaneous Toxic Effects of BRAF Inhibitors Alone and in Combination With MEK Inhibitors for Metastatic Melanoma.

IMPORTANCE The cutaneous adverse effects of the BRAF inhibitors vemurafenib and dabrafenib mesylate in the treatment of metastatic melanoma have been well reported. The addition of a MEK inhibitor to a BRAF inhibitor improves the blockade of the mitogen-activated protein kinase pathway. The combination of dabrafenib with the MEK inhibitor trametinib dimethyl sulfoxide (CombiDT therapy) increases response rate and survival compared with a BRAF inhibitor alone. Clinical trials have suggested that CombiDT therapy induces fewer cutaneous toxic effects than a single-agent BRAF inhibitor. To our knowledge, a direct comparison has not been performed before. OBJECTIVE To compare the cutaneous toxic effects of BRAF inhibitor monotherapy and CombiDT therapy in a large cohort of patients. DESIGN, SETTING, AND PARTICIPANTS We performed a retrospective cohort study from September 1, 2009, through November 30, 2013. The study population included 185 Australian patients with unresectable stages IIIC and IV melanoma referred from Crown Princess Mary Cancer Care Centre who underwent review at the Department of Dermatology, Westmead Hospital. Of these, 119 patients received dabrafenib; 36, vemurafenib; and 30, CombiDT therapy. Data analysis were performed in December 2013. MAIN OUTCOMES AND MEASURES Multiple cutaneous adverse effects between BRAF inhibitor monotherapy and CombiDT therapy were identified and compared in a cohort of patients who underwent the same dermatologic assessment. RESULTS The most common cutaneous adverse effects seen in patients receiving the single-agent BRAF inhibitor dabrafenib or vemurafenib included Grover disease (51 patients [42.9%] and 14 [38.9%], respectively [P = .67]), plantar hyperkeratosis (47 [39.5%] and 14 [38.9%], respectively [P = .95]), verrucal keratosis (79 [66.4%] and 26 [72.2%], respectively [P = .51]), and cutaneous squamous cell carcinoma (31 [26.1%] and 13 [36.1%], respectively [P = .54]). Photosensitivity was more common with vemurafenib (14 patients [38.9%]) compared with dabrafenib (1 [0.8%]; P < .001). Compared with dabrafenib, CombiDT therapy showed a higher frequency of folliculitis (12 patients [40.0%] vs. 8 [6.7%]; P < .001) and a significant decrease of cutaneous squamous cell carcinoma (0 vs. 31 [26.1%]; P < .001), verrucal keratosis (0 vs. 79 [66.4%]; P < .001), and Grover disease (0 vs. 51 [42.9%]; P < .001). CONCLUSIONS AND RELEVANCE This study confirms that the prevalence of cutaneous toxic effects differs among vemurafenib, dabrafenib, and CombiDT therapies. Cutaneous squamous cell carcinoma is the most concerning cutaneous toxic effect related to BRAF inhibitor monotherapy that did not appear with CombiDT therapy. Although CombiDT therapy has an improved profile of cutaneous toxic effects, continuous dermatologic assessments should be provided for all patients when receiving these treatments.

Bullous pemphigoid, an autoantibody-mediated disease, is a novel immune-related adverse event in patients treated with anti-programmed cell death 1 antibodies.

Anti-programmed cell death 1 (anti-PD1) antibodies such as pembrolizumab have shown improved progression-free and overall survival in patients with advanced melanoma. Of 124 patients reviewed in Westmead Hospital from May 2012 to November 2015, treated with pembrolizumab for advanced melanoma, we encountered three cases of bullous pemphigoid (BP). We have previously reported a case of BP. In two recent cases, BP was diagnosed early and treated promptly with potent topical or oral steroid. Patients on anti-PD1 antibodies are at a higher risk of developing cutaneous immune-related adverse events such as lichenoid reactions, eczema and vitiligo. No cases of BP were encountered in the previously published cohort of 260 melanoma patients treated with BRAF inhibitors; as such, it appears that BP is associated with anti-PD1 treatment rather than metastatic melanoma. BP appears to be another immune-related adverse event, and clinicians should have a low threshold for performing cutaneous biopsies and immunofluorescence studies in patients on anti-PD1 therapies.

Panniculitis in patients treated with BRAF inhibitors: a case series.

Abstract:Panniculitis is a rare complication of BRAF inhibitor therapy that is used to treat patients with BRAF-mutated metastatic melanoma. We present a clinicopathologic review of 9 patients who developed panniculitis while on BRAF inhibitor therapy. In 13% of patients on vemurafenib, 3% of patients on dabrafenib and 10% on combination of dabrafenib + trametinib, tender erythematous nodular lesions of panniculitis appeared on legs, arms and trunk. Histological evaluation of 8 biopsies from 7 patients showed predominantly neutrophilic infiltrate in 4, lymphocytic in 1, and mixed in 3. Lesions with neutrophilic infiltrate appeared in earlier stages of treatment than those with mixed or lymphocytic infiltrate. All biopsies showed lobular involvement and 5 also had a septal component. In addition, 1 biopsy had lichenoid inflammation in the epidermis and the other had evidence of vasculitis. Most patients responded to conservative medical management without the need to reduce or to stop BRAF inhibitor therapy. Panniculitis seems to be a rare class effect of BRAF inhibitors that is predominantly lobular and neutrophilic, although other patterns can be seen.

Extraventricular neurocytoma with atypical features and ganglionic differentiation

Extraventricular neurocytoma (EVN) is an unusual variant of central neurocytoma located outside the ventricular system. Both tumours share a similar histology characterised by monotonous populations of round-to-oval cells with scanty cytoplasm separated by neuropil and branching capillaries. We report an EVN arising from the right frontal lobe near the olfactory tract in a 34-year-old male with worsening chronic epilepsy. Our patients tumour exhibited many uncommon features including ganglionic differentiation, increased mitotic activity and a high proliferative index. We discuss the important differential diagnoses given the site of the tumour as well as the differentiating features from olfactory neuroblastoma, oligodendroglioma, anaplastic ganglioglioma and supra-tentorial primitive neuroectodermal tumour.

Eruptive naevi in a patient treated with LGX818 for BRAF mutant metastatic melanoma.

LGX818 is a new-generation BRAF inhibitor (BRAFi) that is currently undergoing phase 3 trials for the treatment of BRAF mutant metastatic melanoma patients (NCT01909453). Cutaneous toxicities associated with the administration of BRAF inhibitors are considered to be induced by the paradoxical activation of the mitogen-activated protein kinase pathway in wild-type BRAF cells. Changes in naevi, including new naevi, hyperpigmentation and fading of existing naevi, have also been reported. In addition, some patients receiving these therapies have developed second primary melanomas. As a consequence, the importance of sequential digital dermoscopy in all patients treated with a BRAFi to detect new primary melanomas has been emphasized. A 61-year-old man with BRAF mutant stage IV metastatic melanoma was commenced on the phase 1 trial of LGX818 at 300 mg daily in 2013. After 2 months of therapy, the patient was noted to have developed eruptive naevi, fading of existing naevi and darkening of other naevi. Excision of a new pigmented lesion from the back indicated a compound naevus. Immunohistochemistry showed that the naevus cells lacked a BRAF V600E mutation. This is the first reported case of eruptive naevi in a patient treated with LGX818. The absence of the BRAF V600E mutation within a changing naevus supports the theory that BRAFi stimulates the proliferation of wild-type BRAF cells. Close dermatological surveillance is important for all patients treated with any type of BRAFi.

Renal Anastomosing Hemangiomas With a Diverse Morphologic Spectrum: Report of Two Cases and Review of Literature.

Benign vascular lesions have a diverse appearance and can be extremely difficult to classify. We present renal anastomosing hemangiomas from 2 patients that exemplify the potential diverse range of appearances that can occur in this recently described, rare variant of capillary hemangioma. The lesion from one patient was an intravenous hemangioma with closely packed, fenestrated vascular channels that were reminiscent of the splenic red pulp. Also, the endothelial cells contained hyaline globules. On the other hand, the second patient had multifocal tumor. The lesions showed more extensive hyalinization and vascular ectasia reminiscent of cavernous hemangioma. Extramedullary hematopoiesis was a feature in all the tumors, particularly in the second patient where numerous immature blasts were present within vascular spaces.

Histologic Assessment of Lichenoid Dermatitis Observed in Patients With Advanced Malignancies on Antiprogramed Cell Death-1 (anti-PD-1) Therapy With or Without Ipilimumab.

Abstract: Lichenoid drug reaction is a common adverse reaction in patients taking immune-modulatory agents such as antiprogramed cell death (PD-1) and cytotoxic T lymphocyte antigen–4 agents. The authors describe the clinical and histologic features of lichenoid drug reaction in 20 biopsies from 15 patients on anti–PD-1 agents and 9 biopsies from 7 patients on anti–PD-1 plus ipilimumab therapy. Clinically, all except 2 patients presented with discrete, violaceous exanthematous papules to plaques. The lichenoid inflammation in the majority (18 of 29 biopsies) was florid although histology was quite heterogeneous. Nevertheless, there was frequent involvement of the superficial follicular epithelium and acrosyringium, and also a propensity to blister that occurred in approximately 20% of the biopsies. Occasional patients had disease closely resembling lichen planus, although all of these biopsies had some atypical features for lichen planus such as parakeratosis. Dermal eosinophils were common particularly in those with mild inflammation. The lichenoid reaction was responsive to topical steroid or oral systemic treatment in general, and the anti–PD-1 agent had to be ceased in only one patient.

PD-1 inhibitors induced bullous lichen planus-like reactions: a rare presentation and report of three cases.

The introduction of immunotherapy such as antiprogrammed death1 (anti-PD1) monoclonal antibodies has changed the scenario of treatment in cancer. Apart from their impressive efficacy profiles, they are better tolerated than the anticytotoxic T-lymphocyte-associated protein 4 antibodies. Dermatological adverse events such as pruritus and rash have been reported in various clinical trials. We report three cases of anti-PD1-induced bullous lichen planus (LP)-like reactions encountered in our institution. These patients developed LP-like papules and annular plaques with vesicles or crusted centres. Histology showed LP-like changes with negative immunofluorescence. Vesiculobullous lesions in patients treated with anti-PD1 therapies require a careful clinicopathological evaluation.