Diverse types of dermatologic toxicities from immune checkpoint blockade therapy.

Immunomodulatory drugs that leverages host immune mechanisms to destroy tumor cells have been met with great promise in the treatment of cancer. Immunotherapy, targeting cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) and the programmed cell death 1 (PD-1) receptor and its ligand (PD-L1) have shown tremendous improvements in the survival of patients with advanced solid tumors. However, the development of dermatologic toxicity (DT) is a consequence to immunotherapy. Review of published reports of the DT to immunotherapy revealed patients receiving anti-CTCLA-4 antibody or anti-PD-1/PD-L1 antibody often develop a DT of any type and grade. In this article, of the 3825 patients who were treated with anti-PD-1 and of 556 patients receiving anti-PD-L1, DT of any type and grade were reported in 1474 (∼39%) and 95 (∼17%) of patients, respectively. The emergence of specific types of DT to immunotherapy is beginning to be recognized can be categorized into four groups: (a) inflammatory, (b) immunobullous, (c) alteration of keratinocytes and (d) alteration of melanocytes. Lichenoid dermatitis and bullous pemphigoid appear to be DT more associated with anti-PD-1/PD-L1 antibody. The DT profile in patients receiving immunotherapy is diverse, and early recognition of specific types of DT that clinicians may encounter is critical for optimal patient care.

Cutaneous histoplasmosis with prominent parasitization of epidermal keratinocytes: report of a case.

Disseminated histoplasmosis most commonly occurs in immunosuppressed individuals and involves the skin in approximately 6% of patients. Cutaneous histoplasmosis with an intraepithelial-predominant distribution has not been described. A 47-year-old man was admitted to our institution with fever and vancomycin-resistant enterococcal bacteremia. He had been diagnosed with T-cell prolymphocytic leukemia 4 years earlier and had undergone matched-unrelated-donor stem cell transplant 2 years earlier; on admission, he had relapsed disease. His medical history was significant for disseminated histoplasmosis 6 months before admission, controlled with multiple antifungal regimens. During this final hospitalization, the patient developed multiple 2-5 mm erythematous papules, a hemorrhagic crust across the chest, shoulders, forearms, dorsal aspect of the fingers, abdomen and thighs. Skin biopsy revealed clusters of oval yeast forms mostly confined to the cytoplasm of keratinocytes and within the stratum corneum; scattered organisms were present in the underlying superficial dermis without any significant associated inflammatory infiltrate. Special stains and immunohistochemical studies confirmed these to be Histoplasma organisms. We highlight this previously unrecognized pattern of cutaneous histoplasmosis to ensure its prompt recognition and appropriate antifungal therapy.

Autoimmune dermatologic toxicities from immune checkpoint blockade with anti-PD-1 antibody therapy: a report on bullous skin eruptions.

Monoclonal antibodies against the immune checkpoint programmed cell death receptor 1 (PD-1) improve the hosts' antitumor immune response and have showed tremendous promise in the treatment of advanced solid tumors and hematologic malignancies. Reports of serious autoimmune dermatologic toxicities from immune checkpoint blockade therapy, however, are emerging. We report our experience with five patients who presented with pruritic vesicles and blisters on the skin while treated with anti-PD-1 antibody immunotherapy with either nivolumab or pembrolizumab. Four of the patients' skin biopsies revealed subepidermal bullae with immunohistochemical study for type IV collagen labeling the floor of the blister cavity and direct immunofluorescence studies (in three of the four patients tested) decorated linear IgG and C3 immune deposits on the blister roof, diagnostic of bullous pemphigoid. One patient developed bullous erythema multiforme. All patients had partial or complete resolution of skin lesions following treatment with systemic corticosteroid and cessation of checkpoint blockade. Recognition and treatment of rare immune-related bullous dermatologic toxicities will become increasingly important as more patients are treated with effective and newer immune checkpoint blockade therapy.

Pigmented extramammary Paget disease of the thigh mimicking a melanocytic tumor: report of a case and review of the literature.

IMPORTANCE: Extramammary Paget disease (EMPD) is an uncommon tumor that presents in apocrine-rich skin as an irregular, pruritic plaque. Histopathologically, EMPD consists of an intraepidermal proliferation of atypical epithelioid cells. Rarely, the tumor cells contain intracytoplasmic melanin pigment, and the lesion clinically and histopathologically can mimic a melanocytic proliferation. OBSERVATIONS: A 51-year-old female with a history of breast carcinoma presented with a pigmented patch on her right thigh of 6 months duration. The clinical impression was an atypical melanocytic nevus. Histopathologic examination revealed an intraepidermal proliferation of epithelioid cells along the dermal-epidermal junction with pagetoid migration. The tumor cells exhibited increased cytoplasm containing conspicuous melanin pigment and enlarged oval-irregular nuclei. Immunohistochemical studies showed the tumor cells to be strongly and diffusely positive for cytokeratin 8/18, cytokeratin 7 and p63; focally and weakly positive for epithelial membrane antigen (EMA), but negative for cytokeratin 5/6, Cam5.2, carcinoembryonic antigen (CEA), human melanoma black 45 (HMB-45), tyrosinase and Sox-10, supporting the diagnosis of pigmented EMPD. The lesion was subsequently excised, and the patient is free of disease after 24 months. CONCLUSION: We present this unusual case of pigmented EMPD arising on the thigh to draw attention to the entity and to underscore the potentially misleading clinical, histopathologic and immunophenotypic features that mimic other cutaneous intraepidermal lesions.

Update on topical antibiotics in dermatology.

Topical antibiotics are used for various purposes in dermatology. Some of the most common uses include treatment of acne, treatment and prevention of wound infection(s), impetigo or impetiginized dermatitis, and staphylococcal nasal carrier state. It is important for the dermatologist to be familiar with the spectrum of activity, the mechanism of action, and the variables that may interfere with the antibiotic of choice. The following discussion will review an update on topical antibiotic use in acne, wound care, impetigo, and in staphylococcal nasal carriers.

Palliative treatment of paraneoplastic acanthosis nigricans and oral florid papillomatosis with retinoids.

Malignant acanthosis nigricans (MAN) with oral florid papillomatosis is a rare paraneoplastic condition affecting the skin and mucocutaneous tissues associated with an underlying malignancy. It is characterized by proliferation of keratinocytes resulting in papillomatous change and hyperpigmentation of the skin and multiple confluent warty or verrucous lesions of the oral mucous membranes. The oral involvement can interfere with the patient's ability to eat and drink. There is no specific therapy for this complication. Treatment of the underlying malignancy can lead to improvement of symptoms, but the degree of improvement varies. Here, the authors present a case of MAN with oral florid papillomatosis associated with gastric adenocarcinoma that was treated with oral retinoids resulting in significant clinical improvement of the hyperkeratosis and hyperpigmentation as well as improved patient functionality.

Cutaneous Rosai-Dorfman disease.

Sinus histiocytosis with massive lymphadenopathy, or Rosai-Dorfman disease, is a benign idiopathic histiocytic proliferative disorder that commonly involves the lymph nodes but secondarily may involve the skin. However, purely cutaneous disease without lymphadenopathy or internal organ involvement rarely may occur. We present case reports of three patients who presented with asymptomatic nonspecific enlarging skin nodules without evidence of lymphadenopathy or internal disease. Histopathologic examination of skin lesions in all patients showed proliferation of large histiocytes with phagocytosed inflammatory cells characteristic of Rosai-Dorfman disease. However, the diagnoses of dermatofibroma, other spindle cell neoplasm, infectious granulomatous process, and other xanthohistiocytic proliferations were also considered due to the presence of storiform spindle cells and foamy cells in the first case. One patient experienced regression during a course of oral steroids, while another patient cleared spontaneously. In the absence of massive lymphadenopathy characteristic of Rosai-Dorfman disease, the diagnosis of purely cutaneous Rosai-Dorfman disease may be complicated by the rarity, non-specific clinical appearance of skin lesions, and broad histopathological differential diagnosis of this disorder. A high index of suspicion of the clinician and pathologist is often required.