mTOR Inhibitor-Induced Transient Acantholytic Dermatitis

A 61-year-old Caucasian male with a medical history of metastatic carcinoid presented to dermatology with a new onset severely pruritic “breakouts” on the arms, neck, and chest. Approximately ten years prior, he was diagnosed with a small bowel carcinoid tumor and liver metastases treated with a combination of resection and ablation. Treatment for the following eight years consisted of monthly octreotide injections in response to a notable increase in the number and intensity of liver metastases on octreoscan. Ultimately, recurrence of the carcinoid tumor in the small bowel and increased liver metastases were noted on imaging and second line therapy with oral everolimus therapy daily was initiated. Within one month of starting treatment, the patient experienced the onset of a pruritic rash that at first was responsive to topical desonide cream, but ultimately persisted resulting in a referral to dermatology. Physical exam revealed erythematous eroded papules circumscribing his neck, chest, and arms (Figure 1). Histopathology from a representative papule revealed abrupt cutaneous ulceration, granulation tissue, as well as focal acantholytic dyskeratosis consistent with transient acantholytic dermatitis (TAD) (Figure 2). The patient responded well to high potency topical steroids, betamethasone, and clobetasol, as well as copious emollient therapy, and his symptoms promptly resolved with minimal post inflammatory hyperpigmentation.

TAD is an acantholytic vesiculobullous disorder characterized by severely pruritic and fragile vesicles that rapidly evolve into crusted erosions; TAD vesicles are predominately ruptured due to their fragility and underlying dyskeratosis. TAD commonly occurs on actinically damaged skin, tends to occur more frequently in older men with lighter skin types, and is exacerbated by heat and sweat. Histopathology typically reveals focal dyskeratosis and ulcerations, reminiscent of intraepidermal immunobullous conditions but lacking any significant DIF findings. Reports in the literature highlight the anecdotal nature of treatment for TAD, including systemic corticosteroids, topical steroids, topical antibiotics, isotretinoin, dapsone, and emollients.^1,2

While TAD is common, the association with the mTOR inhibitor everolimus is unique. mTOR is an increasingly significant therapeutic target for numerous indications including post-transplant immunosuppression as well as numerous malignancies such as carcinoid tumors. mTOR inhibitors bind immuniphilin FK506 inactivating kinases that phosphorylate the mTOR1 and mTOR2 complexes. Everolimus is more selective for the mTOR1 complex, which is associated with immunosuppression more so than the mTOR2 complex, which also affects glucose metabolism.³ Various rapamycin analogs are now FDA approved including everolimus, sirolimus, temsirolimus, and ridaforolimus. As these drugs become increasingly used in clinical practice, the incidence of adverse effects, like TAD, is expected to rise. The dermatologic adverse events associated with mTOR inhibitors were recently reviewed highlighting their association with acne, folliculitis, pruritus, exfoliative dermatitis, aphthous stomatitis, vasculitis, and onychopathy.⁴ Similarly, Beer et al summarized chemotherapy-induced TAD, mTOR inhibitors were not listed as a drug induced etiology as either a) this class may not be categorized as a “chemotherapy,” or b) this is an under-recognized adverse reaction.⁵