Exclusive Cutaneous and Subcutaneous Sarcoidal Granulomatous Inflammation due to Immune Checkpoint Inhibitors: Report of Two Cases with Unusual Manifestations and Review of the Literature

Abstract

Recent emergence of immune checkpoint inhibitors (ICIs) has revolutionized the treatment of cancers and produced prolonged response by boosting the immune system against tumor cells. The primary target antigens are cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4), a downregulator of T-cell activation, and programmed cell death-1 receptor (PD-1), a regulator of T-cell proliferation. This enhanced immune response can induce autoimmune adverse effects in many organs. Although skin toxicities are the most common, sarcoidal inflammation with exclusive cutaneous involvement is a rare occurrence with only 6 cases reported to date. We report 2 cases with unusual features. One patient is a female who was treated for metastatic renal cell carcinoma with combination of ipilimumab (anti-CTLA-4) and nivolumab (anti-PD-1). She developed deep nodules showing sarcoidal dermatitis and panniculitis on histopathologic exam. The second patient is a male with melanoma of eyelid conjunctiva who was treated prophylactically with ipilimumab. He presented with papules/plaques confined to black tattoos, where the biopsy revealed sarcoidal dermatitis. By a comprehensive literature review, we intend to raise awareness about this potential skin side effect in the growing number of patients receiving targeted immunotherapies. It is crucial to have a high index of suspicion and perform timely biopsies to implement appropriate management strategies.

European recommendations for management of immune checkpoint inhibitors‐derived dermatologic adverse events. The EADV task force ‘Dermatology for cancer patients’ position statement

“…• Whereas pulmonary granulomata and hilar/mediastinal lymphadenopathy are a well-established irAE, cutaneous granulomatous/sarcoid-like eruptions (GE) have been also described in the context of ICI treatment. 99,100 Eighty cases of ICI-induced GE have been reported with both anti-CTLA-4, anti-PD-1 or in combination, and mostly in patients with melanoma. Exclusive cutaneous/subcutaneous involvement is uncommon, noted in only 8/80 patients.…”

“…Exclusive cutaneous/subcutaneous involvement is uncommon, noted in only 8/80 patients. 99,100 The median time of onset is 6 months. 100 The most common site of skin involvement is upper and lower extremities.…”

“…99,100 The median time of onset is 6 months. 100 The most common site of skin involvement is upper and lower extremities. As in primary sarcoidosis, localisation to prior scars or tattoos has been described, as well as panniculitis.…”

“…Consider replacing antihistamines with GABA analogs, e.g., gabapentin100-300 mg tid or pregabalin, 50-100 mg tid (titrate) Continue ICI at current dose Reassess after 2-4 weeks; if reactions worsen or do not improve, proceed to next step IV † B Persistent Grade 2 Additional systemic antipruritics Consider neurokinine 1 receptor antagonists e.g., aprepitant 125 mg day 1, 80 mg day 3, 80 mg day 5 or V C Consider omalizumab 300 mg s.c. every 4 weeks ‡ Reassess after 2-4 weeks; if reactions worsen or do not improve, proceed to next step Consider systemic corticosteroids (e.g. prednisone 0.5-1 mg/kg body weight/day, 14-day taper) †,# IV † B GABA analogs, e.g.…”

Ichthyosiform red-brown plaques on bilateral shins

“…Both ipilimumab (anti–CTLA-4) and nivolumab (anti–PD-1) have been reported individually (and in combination) to cause cutaneous sarcoidosis. 5 Clinicians should maintain a high index of suspicion for medication-induced cutaneous sarcoidosis in patients on immune checkpoint inhibitor therapy who present with sarcoidal lesions.…”