Jonathan S. Leventhal

Clinical and Histologic Features of Lichenoid Mucocutaneous Eruptions Due to Anti–Programmed Cell Death 1 and Anti–Programmed Cell Death Ligand 1 Immunotherapy

Importance Antagonist antibodies to programmed cell death 1 (PD-1) and programmed cell death ligand 1 (PD-L1) have shown remarkable activity in multiple tumor types. Recent US Food and Drug Administration approval of such agents for advanced melanoma, non-small cell lung cancer, and renal cell carcinoma has hastened the need to better characterize their unique toxicity profiles. Objective To provide a clinical and pathologic description of the lichenoid mucocutaneous adverse effects seen in patients receiving anti-PD-1/PD-L1 treatment. Design, Setting, and Participants Patients with advanced cancer who were referred to dermatology at Yale-New Haven Hospital, a tertiary care hospital, after developing cutaneous adverse effects while receiving an anti-PD-1 or PD-L1 antibody therapy either as monotherapy or in combination with another agent were identified. Medical records from 2010 to 2015 and available skin biopsy specimens were retrospectively reviewed. Main Outcomes and Measures Patient demographic characteristics, concurrent medications, therapeutic regimen, type of disease, previous oncologic therapies, clinical morphology of cutaneous lesions, treatment of rash, peripheral blood eosinophil count, tumor response, and skin histologic characteristics if biopsies were available. Results Patients were 13 men and 7 women, with a mean (range) age of 64 (46-86) years. The majority of cases (16 [80%]) had a clinical morphology consisting of erythematous papules with scale in a variety of distributions. Biopsies were available from 17 patients; 16 (94%) showed features of lichenoid interface dermatitis. Eighteen patients were treated with topical corticosteroids, and only 1 patient required discontinuation of anti-PD-1/PD-L1 therapy. Only 4 of 20 patients (20%) developed peripheral eosinophilia. Sixteen patients (80%) were concurrently taking medications that have been previously reported to cause lichenoid drug eruptions. Conclusions and Relevance Papular and nodular eruptions with scale, as well as mucosal erosions, with lichenoid features on histologic analysis were a distinct finding seen with anti-PD-1/PD-L1 therapies and were generally manageable with topical steroids. Concurrent medications may play a role in the development of this cutaneous adverse effect.

Nivolumab-associated vitiligo-like depigmentation in a patient with acute myeloid leukemia: A novel finding

Programmed cell death–1 receptor (PD-1) inhibitors enhance the antitumoral immune response via immune checkpoint inhibition. In a healthy immune system, the binding of ligands to PD-1 induces T-cell inactivation and prevents overactive immune responses. However, PD-1 ligands are also expressed by a variety of tumors, including melanomas, renal cell carcinomas, and brain tumors, in an effort to evade the host immune response. Although immune checkpoint inhibitors have revolutionized care for cancer patients, new cutaneous and systemic toxicities are still being discovered. Nivolumab is a humanized IgG4 anti–PD-1 monoclonal antibody that is currently approved by the US Food and Drug Administration for the treatment of melanoma, non–small cell lung cancer, renal cancer, and classical Hodgkin lymphoma.1 Several adverse effects of immune-targeting therapies are described and are referred to as immune-related adverse events (irAEs). Systemic irAEs include enterocolitis, pneumonitis, hepatitis, nephritis, hypophysitis, and autoimmune thyroid disease. In addition, dermatologic toxicity is the most common irAE of checkpoint inhibitors and ranges from pruritus and mild dermatoses to severe reactions including Stevens-Johnson syndrome and toxic epidermal necrolysis.2 Vitiligo-like depigmentation is well described in melanoma patients receiving immunotherapy with PD-1 inhibitors and may be associated with favorable outcomes.3 Here we report a case of vitiligo-like depigmentation in a patient with acute myeloid leukemia (AML) receiving nivolumab as part of a phase II clinical trial. To our knowledge, this is the first reported case of vitiligo-like depigmentation associated with PD-1 inhibitor treatment in a patient with a nonmelanoma malignancy. Previous reports of PD-1 inhibitor–associated vitiligo-like depigmentation have been exclusively described in patients being treated for melanoma.

Skin Conditions of Baseball, Cricket, and Softball Players

Each year in the United States over 80 million people participate in bat-and-ball sports, for example baseball and softball. Cricket, the world’s second most popular sport, is enjoyed by hundreds of millions of participants in such countries as India, Pakistan, Australia, New Zealand, Bangladesh, South Africa, West Indies, Sri Lanka, United Kingdom, and Zimbabwe. Although any player can develop skin disease as a result of participation in these bat-and-ball sports, competitive team athletes are especially prone to skin problems related to infection, trauma, allergy, solar exposure, and other causes. These diseases can produce symptoms that hinder individual athletic performance and participation. In this review, we discuss the diagnosis and best-practice management of skin diseases that can develop as a result of participation in baseball, softball, and cricket.

Treatment of melanoma in-transit metastases with combination intralesional interleukin-2, topical imiquimod, and tretinoin 0.1% cream

The treatment of in-transit and satellite melanoma metastases is challenging. Treatment options for these cutaneous and subcutaneous lesions include surgical excision, radiotherapy, isolated limb infusion/perfusion, electrochemotherapy, cryotherapy, laser therapy (pulsed dye or carbon dioxide), systemic treatment with interferon-α or interleukin-2 (IL-2), topical imiquimod, dinitrochlorobenzene, and intralesional immunotherapy with bacillus Calmette-Guerin vaccine, granulocyte macrophage colony-stimulating factor, IL-2, or talimogene laherparepvec.1 Response rates for these therapies are often suboptimal. Topical imiquimod has been used for the treatment of both melanoma in situ (in patients who are either poor surgical candidates or have positive margins after excision) and in-transit metastases.1, 2 There are reports of regression of locoregional melanoma metastases after topical imiquimod to cutaneous lesions.1, 2 Combination therapy using intralesional IL-2 together with topical imiquimod and tretinoin may increase the efficacy of IL-2.3 Here we report the case of a patient with in-transit metastatic melanoma treated with intratumoral IL-2 together with topical imiquimod and tretinoin cream.

Generalized lichen nitidus-like eruption in the setting of mogamulizumab and tremelimumab

Generalized lichen nitidus is a rare condition that typically manifests with clusters of multiple, discrete, shiny, 1-3-mm papules that are flesh-colored to pink or brown [1, 2]. Histopathologically, it is characterized by a dense lymphohistiocytic infiltrate within dermal papillae [1]. While the etiology is unknown, genetic and immunologic factors have been implicated in disease pathogenesis [1, 2]. Herein, we present a case of generalized lichen nitidus-like eruption in the setting of immunotherapy [...]

Gemcitabine-associated acute lipodermatosclerosislike eruption: An underrecognized phenomenon

Gemcitabine is a commonly used chemotherapy for the treatment of various solid tumors as well as sarcomas and hematologic malignancies. Although side effects such as bone marrow suppression are well described, cutaneous side effects are less recognized. Certain gemcitabine-associated cutaneous reactions have been categorized under the umbrella terminology pseudocellulitis, including lipodermatosclerosislike and erysipeloid reactions, sclerodermalike changes, and radiation recall events.1, 2 Additionally, these reactions are often confused with other diagnoses, in particular, infectious cellulitis, which may subject patients to unnecessary treatment with antibiotics, hospitalizations, and interruption of chemotherapy. Given the widespread use of gemcitabine and the relatively few reported cases of associated acute lipodermatosclerosis (ALDS), we believe that the condition is underrecognized and underreported. We propose using a more specific diagnosis for cutaneous reactions to gemcitabine that will guide appropriate management. In this series, we report 4 cases of gemcitabine-associated ALDS-like eruptions and a literature review of 16 similar cases. To the best of our knowledge, this is the largest case series review reported for gemcitabine-associated ALDS-like eruptions.

The skin as a window to the blood: Cutaneous manifestations of myeloid malignancies

Cutaneous manifestations of myeloid malignancies are common and have a broad range of presentations. These skin findings are classified as specific, due to direct infiltration by malignant hematopoietic cells, or non-specific. Early recognition and diagnosis can have significant clinical implications, as skin manifestations may be the first indication of underlying hematologic malignancy, can reflect the immune status and stage of disease, and cutaneous reactions may occur from conventional and targeted agents used to treat myeloid disease. In addition, infections with cutaneous involvement are common in immunocompromised patients with myeloid disease. Given the varying presentations, dermatologic findings associated with myeloid malignancies can pose diagnostic challenges for hematologists and dermatologists. In this clinical review intended for the practicing hematologist/oncologist, we discuss the presentation, diagnosis, treatment, and prognostic value of the most common cutaneous manifestations associated with myeloid malignancies using illustrative macro- and microscopic figures and with a special emphasis on practical considerations.

Reactive granulomatous dermatitis presenting as subcutaneous nodules and cords in a patient with advanced myelodysplastic syndrome

Dear Editor, A 72-year-old woman with history of a myelodysplastic syndrome with multilineage dysplasia (MDS-MLD) presented with new onset, firm, slightly tender, subcutaneous nodules (1–10 cm) on the posterior neck, upper and lower extremities, and abdomen, with overlying erythematous patches and several subcutaneous linear cords on the torso and proximal extremities (Fig. 1). The lesions developed suddenly over the course of several weeks. At the time of evaluation, she reported ongoing fatigue and bruising but no other systemic symptoms. On exam, she had no hepatosplenomegaly or palpable lymphadenopathy. Her lower-riskMDSwas diagnosed 5 years earlier when a bone marrow (BM) assessment showed multilineage dysplasia, no increase in blasts, and deletion 20q by cytogenetics, classified then as refractory cytopenia with multilineage dysplasia (RCMD). After failing erythropoiesis-stimulating agents for anemia, she received azacitidine for 3 years but had worsening cytopenias and developed a del(20q) clone with monosomy 7 but with a low blast count. Ineligible for allogeneic hematopoietic stem cell transplantation, she then received decitabine for 2 years. Other comorbidities included diabetes, hyperlipidemia, gout, and chronic obstructive pulmonary disease (COPD). There were no new medications in the months preceding the onset of the eruption. Punch biopsies were obtained at initial presentation and 1 month later, which both demonstrated deep dermal and subcutaneous palisades of histiocytes around altered collagen and clusters of neutrophils and nuclear dust (Fig. 1). The findings were not consistent with myeloid sarcoma or Sweet’s syndrome. GMS, acid-fast bacillus, Gram, and PAS stains were negative for infectious organisms. Deep tissue cultures were negative for bacterial, fungal, and mycobacterial organisms. CT scan revealed no cavitary changes in the lungs. A repeat BM assessment again showed myelodysplastic syndrome without increased blasts, while cytogenetic studies detected only the del(20q) abnormality. She was diagnosed with MDS-associated paraneoplastic granulomatous dermatitis. Treatment with lenalidomide was initiated but withdrawn after 1 week subsequent to worsening pancytopenia and renal function. A course of prednisone 10 mg daily was then started and resulted in substantial clinical improvement with decrease in size and number of subcutaneous lesions. Unfortunately, the patient’s pancytopenia progressed with symptomatic anemia requiring blood transfusions. She was hospitalized with pulmonary infiltrates shortly thereafter and passed away after several days in the setting of lactic acidosis, sepsis, and multiorgan failure. Myelodysplastic syndromes are hematopoietic neoplasms associated with clonal cytogenetic abnormalities, dysplasia in the myeloid lineages, ineffective hematopoiesis leading to cytopenias, and a variable risk of leukemic progression [1, 2]. Granulomatous dermatitis has been rarely reported to herald onset of MDS, leukemic progression, or worsening of cytopenias, as seen in this case [3–8]. With no alternative etiology, this presentation was attributed to a paraneoplastic manifestation of progressing MDS. Development of resistance to epigenetic therapy with increasing transfusion requirements and worsening pancytopenia placed her at risk for infectious complications [1, 2]. Although an infectious process was carefully * Jonathan Leventhal Jonathan.Leventhal@yale.edu

Recurrent Coxsackievirus Infection in a Patient with Lamellar Ichthyosis.

We describe a case of coxsackievirus (CV) A6 infection in a patient with lamellar ichthyosis followed by subsequent CV A8 infection within the same year. Atypical cutaneous features characterized the infection. This observation, combined with the rapidity with which reinfection occurred, suggests that the natural history of CV infection may be altered in patients with underlying ichthyoses.

Bullous disorders associated with anti-PD-1 and anti-PD-L1 therapy: A retrospective analysis evaluating the clinical and histopathologic features, frequency, and impact on cancer therapy

Background: Bullous disorders associated with anti–programmed cell death 1 (PD‐1)/programmed cell death ligand 1 (PD‐L1) therapy are increasingly reported and may pose distinct therapeutic challenges. Their frequency and impact on cancer therapy are not well established. Objective: To evaluate the clinical and histopathologic findings, frequency, and impact on cancer therapy of bullous eruptions due to anti–PD‐1/PD‐L1 therapy. Methods: We retrospectively reviewed the medical records of patients evaluated by the oncodermatology clinic and consultative service of Yale New Haven Hospital from 2016 to 2018. Results: We identified 9 of 853 patients who developed bullous eruptions (˜1%) that were treated with an–PD‐1/PD‐L1 therapy at our institution during the study period: 7 presented with bullous pemphigoid, 1 presented with bullous lichenoid dermatitis, and 1 presented with linear IgA bullous dermatosis in the context of vancomycin therapy. In all, 8 patients required systemic steroids, 5 required maintenance therapy, and 8 required interruption of immunotherapy. All 9 patients had an initial positive tumor response or stable disease, but 4 went on to develop disease progression. Limitations: This was a retrospective study from a single tertiary care center. Conclusions: Bullous disorders developed in approximately 1% of patients treated with anti–PD‐1/PD‐L1 therapy at our institution and frequently resulted in interruption of immune therapy and management with systemic corticosteroids and occasionally steroid‐sparing agents.