Progressive nodular histiocytosis with dramatic response to cobimetinib.

Introduction

The cutaneous and mucocutaneous group—that is, group C—of non-Langerhans cell histiocytosis (non-LCH) include a wide variety of rare entities characterized by the presence or absence of systemic involvement. Among several other histiocytoses, group C includes progressive nodular histiocytosis (PNH), which was first described by the presence of yellowish papules and dermal nodules with or without mucosal involvement, and generalized eruptive histiocytosis (GEH). Though difficult to treat, there have been significant developments in describing the pathogenesis and mutational landscape of histiocytic disorders., We describe a woman with overlapping features of eruptive and progressive nodular non-LCH with a remarkable response to targeted therapy identified with mutational analysis.

Report of case

A 71-year-old woman presented to dermatology with a 10-year history of evolving skin eruptions. They initially started as purpuric patches which resolved with topical corticosteroids. Approximately 6 years later, she developed papules and nodules with histopathology demonstrating noncaseating granulomatous inflammation consistent with sarcoidosis; further workup with imaging and ophthalmology evaluation were unremarkable. Despite attempting several treatments, her skin lesions progressively worsened. These included hydroxychloroquine 400mg daily and triamcinolone 0.1% ointment, methotrexate 15mg weekly for 3 months, prednisone 40mg daily for several months, and infliximab 5 mg/kg once, limited by admission for sepsis. Eighteen months later, she presented with extensive violaceous nodules and plaques with notable sparing of the palms and soles (Fig 1) along with macules and papules on her legs. Per patient history, there was an initial slow progression followed by an eruptive progression. The lesions were first noted on her left axilla and knee and progressed to involve most of her body, and eventually her face and eyelids. Punch biopsies of arm lesions demonstrated diffuse proliferation of epithelioid histiocytes with focal lymphocytes extending to subcutaneous tissue (Fig 2, A and B). A lysozyme stain was performed and was negative, excluding histiocytoid Sweet syndrome. Immunohistochemical stains were also performed, and the histiocytes were positive for CD68, CD4, and PU.1 (Fig 2, C and D) and negative for CD14, S100, CD163, CD7, CD123, CD1a, Langerin, EBER, lysozyme, factor XIIIa, AE1/AE3, ALK1, CD56, CD30, CD19. BRAF V600E mutation and PDL1 were negative. A bone marrow biopsy and PET scan were negative with exception of hypermetabolic activity of the superficial skin nodules. Based upon clinical, histopathologic, and systemic work-up negative for systemic disease, a diagnosis of eruptive nodular non-LCH was made.

Fig 1

Clinical photographs of progressive nodular histiocytosis and improvement with cobimetinib therapy. Dermal nodules coalescing into plaques on the upper portion of the back and neck (A) and shoulders (C) with improvement after 10 cycles of cobimetinib (B, D).

Fig 2

Histopathology of progressive nodular histiocytosis. Proliferation of epithelioid histiocytes in the dermis with focal infiltration of lymphocytes in the subcutaneous tissue (A, Hematoxylin-eosin stain; original magnifications: ×2). Epithelioid histiocytes in the dermis (B, Hematoxylin-eosin stain; original magnification: ×20). Immunohistochemical stains demonstrated that the cells were positive for CD4 (C, Original magnification: ×20) and PU.1 (D, Original magnification: ×20).

Next generation sequencing was performed from the skin biopsy and demonstrated mutations of more than 40% allele frequency in several genes including MAP3K1 and JAK2, prompting initiation of the MEK inhibitor, cobimetinib, which was titrated to 60mg daily for 21 days in 28-day cycles. Within five months there was a noticeable response to therapy based on clinical assessment, although improvement of face and neck nodules were not noted until ten months of treatment (Fig 1, C and D). Dosing was adjusted for elevated creatine phosphokinase during treatment. Monitoring for ocular and cardiac toxicities was performed. The patient has been on therapy for approximately 24 months, and when lapses occurred, she did notice some recurrence.

Discussion

Histiocytic disorders comprise a heterogeneous group of over one hundred subtypes that have recently been classified into five categories: Langerhans (L), cutaneous and mucocutaneous (C), malignant (M), Rosai-Dorfman disease (R), and hemophagocytic lymphohistiocytosis (H). The C group are non-LCH with broad clinical spectrums and shared overlapping histopathologic features., They are further classified by the absence or presence of xanthogranulomas—benign dermal neoplasms with histopathology characterized by large, foamy-appearing, lipid-laden macrophages—and systemic involvement. This group of histiocytoses also ranges from benign and self-limiting to eruptive and debilitating. Juvenile xanthogranuloma, the most common group C non-LCH, is usually benign with one or several centimeter-sized yellow nodules which both presents and remits within the first years of life. Another group C non-LCH, xanthoma disseminatum, is characterized by chronic and persistent cutaneous and mucosal lesions, often with a visceral component. Mucosal sites (i.e., around the eyes) are involved in half of the cases and diabetes insipidus in nearly 40%. Others in group C include generalized eruptive histiocytosis, progressive nodular histiocytosis, and Rosai-Dorfman disease.

Management of nodular non-LCH is difficult. Surgical ablation and excision have been recommended but are not always feasible, as in this case, and may have aesthetic and/or functional impact., There are cases of successful medical management, yet the regimens used—methotrexate, systemic steroids—remain an unreliable approach with treatment failures reported both in the literature and with our patient.

More recently, mutational analysis-directed therapy has shown promising results. In patients with BRAF V600E-positive mutations, vemurafenib has proven to be effective, particularly in the LCH and Erdheim-Chester disease. In the 50% of patients with histiocytic neoplasms without BRAF mutations, MAPK signaling is the primary driver of unregulated cellular proliferation. In a phase II clinical trial of MEK inhibition (i.e. cobimetinib) the overall response and 1-year progression-free rates were 89% and 94%.

The remarkable response of our patient to cobimetinib further supports the dependence of histiocytic neoplasms on MAPK signaling. Mutational analysis and molecular-directed therapy offer a promising treatment approach to patients with this heterogenous group of disorders and uncommon diseases.

Conflicts of interest

None disclosed.