Erythema dyschromicum perstans-like eruptions induced by epidermal growth factor receptor inhibitors in patients with lung cancer.

INTRODUCTION: Cutaneous adverse reactions to epidermal growth factor receptor inhibitors (EGFRi) are some of the most common side effects that patients experience. However, cutaneous adverse reactions that cause dyspigmentation in patients have been rarely reported. Erythema dyschromicum perstans (EDP) is a rare pigmentary condition that causes ashy-grey hyperpigmented macules and patches, with a few cases reported from EGFRi in the literature. The disfiguration caused by this condition may negatively impact patients' quality of life. Our study aimed to describe the clinical characteristics of EDP induced by EGFRi to better recognize and manage the condition. METHODS: We conducted a multicenter retrospective review at three academic institutions to identify patients with EDP induced by EGFRi from 2017 to 2023 and included sixteen patients in our study. RESULTS: The median age of patients was 66 years old, with 63% female and 37% male (Table 1). The majority of our patients were Asian (88%). All patients had non-small cell lung cancer and most patients received osimertinib. Median time to EDP was 6 months. The most common areas of distribution were the head/neck region, lower extremities, and upper extremities. Various topical ointments were trialed; however, approximately less than half had improvement in their disease and most patients had persistent EDP with no resolution. All patients desired treatment except one with EDP on the tongue, and there was no cancer treatment discontinuation or interruption due to EDP. Table 1 Patient demographics and clinical characteristics of 16 patients with EDP induced by EGFRi Case no Demographics: age, race, and sex Fitzpatrick skin type Cancer type EGFR therapy Concomitant photosensitive drug(s) Time to EDP (months) Clinical features Distribution Symptoms Treatments and clinical course EDP status from most recent follow up 1 47 y/o Asian male III Stage IV NSCLC Erlotinib None Unknown Brown-blue-gray hyperpigmented patches Bilateral shins Left thigh Xerosis Pruritus Triamcinolone 0.1% ointment for 4 months, improvement of blue discoloration Tacrolimus 0.1% BID for 9 months, improvement but no resolution Ongoing 2 62 y/o Asian female IV Stage IV NSCLC Osimertinib None 4 Gray-brown hyperpigmented patches Bilateral arms Back Forehead Neck Right shin None Tacrolimus 0.1% ointment for 1 year with minor improvement Ongoing 3 69 y/o Asian female IV Stage IV NSCLC Osimertinib None 4 Gray-brown macules and patches Chest Face Forehead Bilateral legs None Tacrolimus 0.1% ointment for 10 months, no improvement Ongoing 4 79 y/o White male II Stage IV NSCLC Osimertinib None 15 Mottled grey-blue hyperpigmented patches and plaques with mild scaling Bilateral arms Back Forehead Neck None Photoprotection, no improvement Ongoing 5 69 y/o Asian female III Stage IV NSCLC Osimertinib Ibuprofen 4 Blue-grey hyperpigmented macules and patches Abdomen Bilateral arms None Tacrolimus 0.1% ointment for 7 months, no improvement Ongoing 6 65 y/o Asian male III Stage IV NSCLC Osimertinib None 20 Hyperpigmented blue gray macules and patches Helix Bilateral shins None Photoprotection, no improvement Ongoing 7 66 y/o Asian female IV Stage IV NSCLC Erlotinib TMP-SMX 6 Ashy grey-brown thin plaques Back Forehead None 2.5% hydrocortisone ointment for 8 months, resolved Resolved 8 82 y/o Asian male III Stage III NSCLC Erlotinib Simvastatin 20 Ash-grey hyperpigmented patches Dorsal feet Forehead Scalp None Photoprotection Ongoing 9 57 y/o Asian female III Stage II NSCLC Erlotinib None 1 Bue-grey discoloration Tongue None No intervention Ongoing 10 51 y/o Asian female III Stage IV NSCLC Osimertinib None 9 Blue-grey hyperpigmented macules and patches Bilateral arms Axillae Groin Neck Trunk None 2.5% hydrocortisone ointment, triamcinolone 0.1% ointment, photoprotection with mild improvement Ongoing 11 67 y/o Asian male III Stage IV NSCLC Osimertinib None 7 Gray-blue macules and patches with mild background erythema and scaling Bilateral arms Ears Face Bilateral shins None Triamcinolone 0.1% ointment, protection for 6 months with mild improvement Ongoing 12 75 y/o Asian female IV Stage III NSCLC Osimertinib TMP-SMX 3 Gray-blue hyperpigmented patches Bilateral arms Abdomen Back Face Bilateral shins Pruritus Triamcinolone 0.1% and betamethasone 0.01% with relief of pruritus, lesions unchanged Triluma cream 6 months, mild improvement Ongoing 13 42 y/o Asian male IV Stage IV NSCLC Afatinib TMP-SMX 24 Grey-brown hyperpigmented patches Back Face None Hydroquinone 4% cream for 2 years with mild improvement Ongoing 14 74 y/o White female III Stage II NSCLC Osimertinib Atorvastatin 4 Grey-brown hyperpigmented patches Bilateral legs Trunk None Photoprotection Ongoing 15 64 y/o Asian female IV Stage IV NSCLC Osimertinib None 3 Gray-brown hyperpigmentation Abdomen Bilateral arms Back Bilateral legs Pruritus Triamcinolone 0.1% cream; No change, minimal concern to patient Ongoing 16 52 y/o Asian female IV Stage IV NSCLC Osimertinib None 42 Gray hyperpigmented patches with digitate shape Abdomen Bilateral flanks None Triamcinolone 0.1% cream Ongoing NSCLC, non-small cell lung cancer, TMP-SMX, Trimethoprim/Sulfamethoxazole CONCLUSIONS: We highlight the largest case series describing EDP from EGFR inhibitors, which mostly affected Asian patients with lung malignancy and on EGFR tyrosine kinase inhibitors. Clinicians should be able to recognize this condition in their patients and assess how it is affecting their quality of life, and refer to dermatology to help with management.

Health Care Utilization and Costs in Systemic Therapies for Metastatic Melanoma from 2016 to 2020.

BACKGROUND: Widespread implementation of immune checkpoint inhibitors (ICI) and targeted therapies for metastatic melanoma has led to a decline in melanoma-related mortality but increased healthcare costs. We aimed to determine how healthcare utilization varied by systemic, non-adjuvant melanoma treatment from 2016 to 2020. PATIENTS AND METHODS: Adults with presumed stage IV metastatic melanoma receiving systemic therapy from 2016 to 2020 were identified in Optum, a nationwide commercial claims database. Treatment groups were nivolumab, pembrolizumab, ipilimumab+nivolumab (combination-ICI), or BRAF+MEK inhibitor (BRAFi+MEKi) therapy. Outcomes included hospitalizations, days hospitalized, emergency room (ER) visits, outpatient visits, and healthcare costs per patient per month (pppm). Multivariable regression models were used to analyze whether cost and utilization outcomes varied by treatment group, with nivolumab as reference. RESULTS: Among 2018 adult patients with metastatic melanoma identified, mean (SD) age was 67 (15) years. From 2016 to 2020, nivolumab surpassed pembrolizumab as the most prescribed systemic melanoma therapy while combination-ICI and BRAFi+MEKi therapies remained stable. Relative to nivolumab, all other therapies were associated with increased total healthcare costs (combination-ICI: ß = $47 600 pppm, 95%CI $42 200-$53 100; BRAFi+MEKi: ß = $3810, 95%CI $365-$7260; pembrolizumab: ß = $6450, 95%CI $4420-$8480). Combination-ICI and BRAFi+MEKi therapies were associated with more inpatient hospital days. CONCLUSIONS: Amid the evolving landscape of systemic therapy for advanced melanoma, nivolumab monotherapy emerged as the most used and least costly systemic treatment from 2016 to 2020. Its sharp increase in use in 2018 and lower costs relative to pembrolizumab may in part be due to earlier adoption of less frequent dosing intervals.

Immunotherapy for keratinocyte cancers. Part II: Identification and management of cutaneous side effects of immunotherapy treatments.

Keratinocytic cancers (KCs), specifically cutaneous squamous cell and basal cell carcinomas, can respond to topical, intralesional, or systemic immunotherapies, but cutaneous adverse events (CAEs) may occur. Understanding these risks, early recognition of these CAEs, and effective treatment may enable patients to continue their anticancer immunotherapies without dose impact. Immune checkpoint inhibitor-related CAEs after KCs can have multiple clinical presentations, with specific observed types including psoriasis and bullous pemphigoid. Cutaneous toxicities can require biopsies to confirm the diagnosis, especially in patients who are not responsive to topical or oral steroids, since the selection of biologic drugs depends on accurate diagnosis. Different types of CAEs from immune checkpoint inhibitors have been associated with different oncologic outcomes in various primary cancer types, and this remains to be determined for KC patients. CAE characterization and management after immune checkpoint inhibitors in KC patients is a rapidly growing field that needs specific and prospective studies.

Clinical features of drug-induced hypersensitivity syndrome to BRAF inhibitors with and without previous immune checkpoint inhibition: a review.

PURPOSE: Cutaneous reactions to BRAF inhibitors are common, but severe reactions resembling or consistent with drug-induced hypersensitivity syndrome (DIHS)/drug reaction with eosinophilia and systemic symptoms (DRESS) are relatively rare. Several reports suggest that cutaneous reactions including DRESS/DIHS to BRAF inhibitors are more frequent and severe in the setting of previous immune checkpoint inhibition (ICI). METHODS: To characterize existing literature on these reports, we queried the PubMed/MEDLINE database for cases of DIHS/DRESS to BRAF inhibitors. RESULTS: We identified 23 cases of DIHS to BRAF inhibitors following checkpoint inhibition and 14 cases without prior checkpoint inhibitor therapy. In both cohorts, DIHS occurred relatively early, with median time to onset from drug exposure of 8-10 days. Patients who received prior ICI were less likely to have peripheral eosinophilia (26% vs 71%), atypical lymphocytes (9% vs 50%), renal involvement (61% vs 79%), hepatic involvement (52% vs 86%), and lymphadenopathy (9% vs 43%) compared to patients who did not receive prior ICI. Thrombocytopenia was more common with prior ICI (17% vs 7%). Only patients who received prior ICI experienced hypotension (26%) during the course of their DIHS. All cases of BRAF-induced DIHS generally improved on systemic steroids/supportive care, and no cases of death were identified. CONCLUSION: Dermatologists should consider a diagnosis of DIHS following BRAF inhibitor initiation, particularly in the setting of past checkpoint inhibition, with atypical features including relatively rapid onset and steroid responsiveness, lack of peripheral eosinophilia, lymphocytosis, or lymphadenopathy, and increased risk of thrombocytopenia and hypotension.

Dermatologic toxicities of targeted antineoplastic agents and immune checkpoint inhibitor therapy in pediatric patients: A systematic review.

Cutaneous adverse events (cAEs) from targeted antineoplastic agents and immune checkpoint inhibitors are common in children with cancer and may lead to dose reduction or cessation of critical oncologic treatment. Timely diagnosis and proper management of cAEs in pediatric oncology patients is essential to optimize ongoing cancer-directed therapy and improve quality of life. This systematic review of published studies summarizes dermatologic toxicities to targeted anticancer treatments and immune checkpoint inhibitors.

Cutaneous cytomegalovirus - A case of disseminated cytomegalovirus presenting with extensive ulcerative skin lesions in a renal transplant recipient.

Cytomegalovirus (CMV) reactivation is common in organ transplant recipients and can lead to significant morbidity and mortality. Cutaneous CMV findings are rarely reported in the literature and diagnosis can be delayed if not clinically recognized. We describe a case of a female patient 20 years post renal transplant who presented with extensive ulcerative skin lesions and diarrhea. She rapidly deteriorated and died on day 5 of hospitalization. Autopsy noted extensive CMV involvement of skin and gastrointestinal (GI) tract by CMV-specific immunohistochemistry. These findings, along with high-grade CMV viremia, led to the final postmortem diagnosis of disseminated CMV infection. This case focuses on the cutaneous findings of disseminated CMV as recognition of CMV skin lesions can lead to earlier initiation of appropriate therapy in transplant recipients.

How we treat Merkel cell carcinoma: within and beyond current guidelines.

Merkel cell carcinoma (MCC) is an aggressive skin cancer associated with a high risk of local recurrence and distant metastasis. Optimal care of this potentially life-threatening cancer is critical but challenging because: physicians are often unfamiliar with its management due to rarity, and MCC management remains controversial, in part because it is rapidly evolving across multiple specialties. While guidelines offer a broad overview of management, they are often not sufficient when making decisions for individual patients. Herein, we present a literature review as well as practical approaches adopted at our institutions for staging, surveillance and therapy of MCC. Each of these areas are discussed in light of how they can be appropriately customized for prevalent but challenging situations. We also provide representative examples of MCC patient scenarios and how they were managed by a multidisciplinary team to identify suitable evidence-based, individualized treatment plans.

Lay abstract Merkel cell carcinoma (MCC) is a skin cancer with a high risk of recurrence and distant spread. Optimal care of this cancer is important. However, management is challenging because it is rare and its treatment is continuously evolving across multiple specialties. While treatment guidelines offer a broad overview of management, they are often not detailed enough to provide appropriate patient-specific assistance. Herein, we present a review of recent studies and our suggestions relevant to MCC staging, surveillance and treatment options. Each of these areas are discussed in light of how they can be appropriately customized for challenging situations often encountered by practitioners. We also provide representative examples of MCC patient scenarios and how they were managed by a multidisciplinary team to identify evidence-based, individualized treatment plans.

Competing risks analysis of Merkel cell carcinoma with concurrent chronic lymphocytic leukemia and non-Hodgkin lymphoma.

BACKGROUND: Although hematogenous malignancy is a risk factor for poorer prognosis in Merkel cell carcinoma (MCC), current guidelines make no specific recommendations for surveillance. OBJECTIVE: We aim to characterize MCC-specific mortality compared to other causes of death for patients with hematologic malignancy in MCC, which will guide workup and surveillance strategies. METHODS: The Surveillance, Epidemiology, and End Results-18 registry was queried for MCC patients with chronic lymphocytic leukemia (CLL) or non-Hodgkin lymphoma (NHL). RESULTS: Of 8519 patients with MCC, 146 (1.7%) had CLL and 234 (2.8%) had NHL. Chronic lymphocytic leukemia patients had 5-year cumulative incidence of MCC-specific mortality of 38.4% versus 28.4% in patients without CLL/NHL. For both cohorts, oncologic risk was highest within the first three years of diagnosis with competing risks favored thereafter. On competing risk regression, a history of CLL trended toward statistical significance with poorer MCC-specific mortality (subdistribution hazard ratio: 1.33, 95% CI: 0.963-1.834, P=0.084), while NHL was not prognostic. CONCLUSIONS: Merkel cell carcinoma patients with CLL may benefit from more aggressive initial management. Surveillance for similar length in CLL patients with MCC may be appropriate; this co-morbidity did not affect the timeframe by which the risk of competing causes of death exceeded oncologic risks.

Prognostic value of volumetric PET parameters at early response evaluation in melanoma patients treated with immunotherapy.

PURPOSE: The purpose of this study was to investigate the prognostic value of whole-body metabolic tumor volume (MTV) and other metabolic tumor parameters, obtained from baseline and first restaging 18F-FDG PET/CT scans in melanoma patients treated with immune checkpoint inhibitors (ICIs). METHODS: Eighty-five consecutive melanoma patients (M, 57; F, 28) treated with ICIs who underwent PET/CT scans before and approximately 3 months after the start of immunotherapy were retrospectively enrolled. Metabolic tumor parameters including MTV for all melanoma lesions were measured on each scan. A Cox proportional hazards model was used for univariate and multivariate analyses of metabolic parameters combined with known clinical prognostic factors associated with overall survival (OS). Kaplan-Meier curves for patients dichotomized based on median values of imaging parameters were generated. RESULTS: The median OS time in all patients was 45 months (95% CI 24-45 months). Univariate analysis demonstrated that MTV obtained from first restaging PET/CT scans (MTVpost) was the strongest prognostic factor for OS among PET/CT parameters (P < 0.0001). The median OS in patients with high MTVpost (≥ 23.44) was 16 months (95% CI 12-32 months) as compared with more than 60 months in patients with low MTVpost (< 23.44) (P = 0.0003). A multivariate model including PET/CT parameters and known clinical prognostic factors revealed that MTVpost and the presence of central nervous system lesions were independent prognostic factors for OS (P = 0.0004, 0.0167, respectively). One pseudoprogression case (1.2%) was seen in this population and classified into the high MTVpost group. CONCLUSION: Whole-body metabolic tumor volume from PET scan acquired approximately 3 months following initiation of immunotherapy (MTVpost) is a strong prognostic indicator of OS in melanoma patients. Although the possibility of pseudoprogression must be considered whenever evaluating first restaging PET imaging, it only occurred in 1 patient in our cohort.

Cutaneous pleomorphic fibromas arising in patients with germline TP53 mutations.

Pleomorphic fibromas are rare benign cutaneous neoplasms associated with deletion/loss of chromosomes 13q and 17p, where RB1 and TP53 are located, respectively. Herein, we report five cases of pleomorphic fibroma arising in patients with germline TP53 mutations, suggesting a potential link with Li-Fraumeni syndrome. All three patients were female and young (mean age 27) with a strong personal and/or family oncologic history and confirmed pathogenic germline TP53 mutations. In two patients, multiple pleomorphic fibromas were diagnosed. Clinically, the lesions arose at various cutaneous sites and were small (≤2 cm) and raised (4/5). Histopathologically, the tumors were paucicellular, composed of atypical spindled to stellate cells with hyperchromatic and variably pleomorphic nuclei. Mitotic activity was exceedingly low, although rare atypical mitotic figures were seen in one case. Immunohistochemically, the tumor cells were diffusely positive for p16 (3/3) and showed loss of Rb expression (5/5). All cases showed aberrant p53 expression (overexpression in 4, complete loss in 1). The tumors have followed a benign clinical course with no evidence of progression or recurrence. In conclusion, the development of multiple pleomorphic fibromas in a young patient may be a clue to an underlying genetic cancer syndrome involving TP53.