Systemic sarcoidosis is a granulomatous disease characterized by a hyperactive T-helper-1 (Th-1) immune response leading to the formation of non-caseating granulomas in involved organs. Idiopathic sarcoidosis can present in many ways and can involve any organ, but most commonly affects the lymph nodes, lungs, skin, eyes and joints. Treatment, if any, is usually guided by the extent of underlying organ involvement and severity of symptoms. Cases of ir-sarcoidosis, although rare, have been reported with multiple immune checkpoint inhibitors, across a span of different cancers, and with a variety of clinical presentations.
How does ir-Sarcoidosis present?
Majority of cases of presumed ir-sarcoidosis published in the literature have presented with involvement of the lymph nodes, lung and/or skin with less common organs including the central nervous system, spleen, bone, eyes and pituitary gland. Multi-organ involvement (most commonly skin and lung) is common. There have also been reports of other granulomatous reactions including granulomatous panniculitis, granulomatous dermatitis and granulomatous foreign body reaction.
In a systematic review of case reports of ir-sarcoidosis, the median time to development was 8.7 months after starting immunotherapy but ranged from 3 weeks to 22 months. In 22% of cases, ir-sarcoidosis was found incidentally on routine follow-up imaging with either CT scan or FDG PET imaging showing hypermetabolic lymph nodes +/- worsening or new lung nodularity. Clinical features may include; hypercalcemia, hypercalciuria, elevated ACE levels, and Koebner’s phenomenon.
How is ir-sarcoidosis diagnosed?
Most patients with ir-sarcoidosis, especially with lung or lymph node involvement are largely asymptomatic. Constitutional symptoms, if present, can often be blamed on background malignancy. Imaging, including new nodules or lymph nodes on CT scans and metabolically active lesions on PET scans, can mimic tumor progression. Traditional laboratory parameters such as inflammatory markers are often not helpful as they can be elevated due to cancer itself. Although there are reported cases with elevated angiotensin converting enzyme (ACE) levels, the significance is unknown in ir-sarcoidosis.
As such, Ir-sarcoidosis can be difficult to distinguish from active tumor based on symptoms and imaging alone and requires a high index of suspicion, particularly if the clinical/radiographic findings are unexpected. The mainstay of diagnosis is biopsy. Cutaneous lesions are more amenable to biopsy and should be considered first, when possible.
How is ir-SLR treated?
Similar to idiopathic sarcoidosis, treatment depends on type and severity of organ involvement. In some cases, despite being asymptomatic, patients/oncologists might prefer systemic treatment of ir-sarcoidosis in order to allow more accurate tumor surveillance.
In majority of reported cases, ir-sarcoidosis has demonstrated an excellent response, with or without treatment, particularly in mild cases. In 10-15% of reported cases, patients with mild, asymptomatic disease had complete resolution despite continuing immunotherapy without steroids or other immunosuppression.
In those with moderate to severe disease, treatment options include temporarily holding immunotherapy, systemic or intra-lesional corticosteroids, and in severe cases, steroid-sparing agents such as hydroxychloroquine, methotrexate and infliximab. There is no standard practice with regards to dose or duration of systemic steroids, but many reported cases had good response to prednisone 40mg daily tapering over 1-3 months. Majority of reported cases in the literature have had near complete resolution of ir-SLR regardless of treatment.
- The data we have on ir-sarcoidosis comes mostly from individual case reports (n < 70) published in the literature. Of these, the largest case series includes only 5 patients, from a national retrospective cohort, across multiple clinical sites.
- For each published case report, there are likely multiple unpublished cases, which may differ in terms of presentation, response to treatment and clinical course.
- Majority of published case reports of ir-sarcoidosis (~ 80%) have been reported in patients with melanoma. This is likely due to multiple factors including early and high prevalence of ICI use in metastatic melanoma. However, it may be also be confounded by the fact that there seems to be an independent relationship with certain cancers (particularly melanoma and hematologic cancers) and the development of sarcoidosis. As such, with our limited experience to date, some might argue that de novo development of sarcoid-like reactions after immune checkpoint inhibitor therapy in melanoma patients is different than other irAE as it is not unique to immunotherapy and may be associated with the tumor itself.
Last updated by Dr. Shahin Jamal February 2021: See sarcoidosis module for references