Nivolumab-Induced Sarcoid-Like Granulomatous Reaction in a Patient With Advanced Melanoma

doi:10.1016/j.chest.2015.10.082

Chest

Volume 149, Issue 5, May 2016, Pages e133-e136

https://doi.org/10.1016/j.chest.2015.10.082 Get rights and content

To our knowledge, we report the first case of sarcoid-like granulomatous reaction induced by nivolumab, a fully human IgG4 anti-programmed death 1 (PD-1) immune checkpoint inhibitor antibody. A 57-year-old man was treated with nivolumab 3 mg/kg for 2 weeks for a desmoplastic melanoma stage III American Joint Commission on Cancer, with no BRAF, NRAS, and cKit mutations. At 10 months, although melanoma complete response was achieved, he developed sarcoid-like granulomatous reaction in the mediastinal lymph node and skin, which resumed after nivolumab arrest. Melanoma did not relapse after 12 months of follow-up. Considering the recently demonstrated role of activated PD-1/PDL-1 axis in sarcoidosis, granulomatous reaction in the patient seems to be a paradoxical reaction, but similar observations have been reported with ipilimumab, another immune checkpoint inhibitor. Sarcoid-like granulomatous reaction during immunotherapy treatment could be a manifestation of cell-mediated immunity induced by these drugs. Impact of granulomatous reaction induced by immune checkpoint inhibitor on melanoma progression is not known and requires further study. Melanoma patients treated by immunotherapy (anti-cytotoxic T-lymphocyte-associated protein-4/anti-PD-1) should be considered for developing sarcoid-like granulomatous reaction that must not be confused with tumor progression.

Section snippets

Case Report

A 57-year-old patient was diagnosed in 2011 with an invasive desmoplastic melanoma of the right nasolabial fold (Breslow thickness, 4.0 mm; Clark level, 5), for which he underwent wide local resection.

In May 2013, he developed an unresectable relapse involving on the right nasolabial fold. MRI showed a 27 × 43 mm necrotic tumor, expanding to the outer canthus, lower eyelid region, and lacrimal sac, with a deep extension to the nasal cavity. Whole-body tomodensitometry and cerebral MRI did not

Discussion

To our knowledge, this is the first report of nivolumab-induced sarcoid-like granulomatous reaction. Nivolumab improves overall survival of patients with advanced melanoma in first-line treatment in BRAF wild-type melanoma patients.¹ Nivolumab is a fully human IgG4 anti-PD-1 immune checkpoint inhibitor antibody that selectively blocks the interaction of the PD-1 receptor with its two known programmed death ligands, PD-L1 and PD-L2, disrupting the negative signal that regulates T-cell activation

Conclusion

Cutaneous, lymph node, or pulmonary lesion during immunotherapy is not always related to disease progression, but sometimes to sarcoid-like granulomatous reaction. Further studies should aim to investigate predisposing factors for immunotherapy-induced sarcoid-like granulomatous reaction and the impact on melanoma progression.

Acknowledgments

Author contributions: F.-X. D., C. P., B. B., M. M., A. T., and C. L. undertook the concept and design; F.-X. D., C. P., L. V., M. Battistella, A. T., and C. L. undertook analysis and interpretation; and C. P., M. Battistella, M. Bagot, A. T., and C. L. undertook drafting the manuscript for important intellectual content.

Financial/nonfinancial disclosures: C. P. and C. L. has participated to advisory boards for BMS. None declared (F.-X. D., C. P., B. B., L. V., M. Battistella, M. M., M. J., M.

References (20)

R.B. Reule et al.
Cutaneous and pulmonary sarcoidosis-like reaction associated with ipilimumab
J Am Acad Dermatol
(2013)
C. Robert et al.
Nivolumab in previously untreated melanoma without BRAF mutation
N Engl J Med
(2015)
M.C. Iannuzzi et al.
Sarcoidosis
N Engl J Med
(2007)
P. Seve et al.
Sarcoidosis and melanoma: a referral center study of 1,199 cases
Dermatology
(2009)
A. Eckert et al.
Anti-CTLA4 monoclonal antibody induced sarcoidosis in a metastatic melanoma patient
Dermatology
(2009)
C. Tissot et al.
Sarcoidosis complicating anti-cytotoxic T-lymphocyte-associated antigen-4 monoclonal antibody biotherapy
Eur Respir J
(2013)
W.V. Vogel et al.
Ipilimumab-induced sarcoidosis in a patient with metastatic melanoma undergoing complete remission
J Clin Oncol
(2012)
G. Berthod et al.
Pulmonary sarcoid-like granulomatosis induced by ipilimumab
J Clin Oncol
(2012)
S. Wilgenhof et al.
Sarcoidosis in a patient with metastatic melanoma sequentially treated with anti-CTLA-4 monoclonal antibody and selective BRAF inhibitor
Anticancer Res
(2012)
K.P. Murphy et al.
New-onset mediastinal and central nervous system sarcoidosis in a patient with metastatic melanoma undergoing CTLA4 monoclonal antibody treatment
Oncol Res Treat
(2014)

There are more references available in the full text version of this article.

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Citation Excerpt :
This patient had persistent hypermetabolic mediastinal and bilateral hilar lymphadenopathy as well as diffuse skin and breast lesions 13 months after first imaging manifestation of sarcoidosis, suggesting that pre-existing sarcoidosis may predispose the patient to prolonged duration of this adverse event. Danlos et al. reviewed nine case reports of sarcoid-like reaction induced by ipilimumab after treating metastatic melanoma and found that 44% (4/9) patients received corticosteroid treatment with subsequently regression of sarcoidosis-like reaction.8 Chorti et al. reported that most patients were asymptomatic and thus no treatment was required in their study.22
To assess the frequency of radiographically evident drug-induced sarcoidosis-like reaction (DISR) in patients treated with anti-cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) therapy, anti-programmed cell death protein 1 (PD-1) therapy, or a combination of both in a single centre.
The images and medical records of 457 patients with metastatic melanoma or head and neck cancer treated with either anti-CTLA-4 therapy, anti-PD-1 therapy, or a combination of both at University of California medical centre were reviewed retrospectively and the incidence of radiological manifestations of DISR was assessed among these treatment groups.
Radiological manifestations of DISR were found in 19/457 patients (4.1%). The mean interval from the initiation of immunotherapy to development of DISR was 5.5 months (range 2.3–13.5 months). Mean interval from radiological detection of DISR to imaging evidence of resolution was 5.8 months (range 1.6–18.3 months). Three patients out of 81 (3.7%), 11/297 (3.7%), and 5/79 (6.3%) developed sarcoidosis-like reaction after treatment with anti-CTLA-4 antibody, anti-PD-1 antibody, and a combination of both, respectively. Most patients with DISR were asymptomatic and did not require systemic therapy. Most patients did not demonstrate concomitant increased maximum standardised uptake value (SUVmax) in other organs on their integrated 2-[¹⁸F]-fluoro-2-deoxy-d-glucose (FDG) positron-emission tomography (PET)/computed tomography (CT).
In the present retrospective study of patients treated with immune checkpoint inhibitors (ICIs), DISR occurred in approximately 3.7% of patients treated with either anti-CTLA-4 or anti-PD-1 antibody and 6.3% of patients treated with a combination of both.
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Chest

Selected ReportsNivolumab-Induced Sarcoid-Like Granulomatous Reaction in a Patient With Advanced Melanoma

Section snippets

Case Report

Discussion

Conclusion

Acknowledgments

J Am Acad Dermatol

Nivolumab in previously untreated melanoma without BRAF mutation

N Engl J Med

Sarcoidosis

N Engl J Med

Sarcoidosis and melanoma: a referral center study of 1,199 cases

Dermatology

Anti-CTLA4 monoclonal antibody induced sarcoidosis in a metastatic melanoma patient

Dermatology

Sarcoidosis complicating anti-cytotoxic T-lymphocyte-associated antigen-4 monoclonal antibody biotherapy

Eur Respir J

Ipilimumab-induced sarcoidosis in a patient with metastatic melanoma undergoing complete remission

J Clin Oncol

Pulmonary sarcoid-like granulomatosis induced by ipilimumab

J Clin Oncol

Sarcoidosis in a patient with metastatic melanoma sequentially treated with anti-CTLA-4 monoclonal antibody and selective BRAF inhibitor

Anticancer Res

New-onset mediastinal and central nervous system sarcoidosis in a patient with metastatic melanoma undergoing CTLA4 monoclonal antibody treatment

Oncol Res Treat

Selected Reports
Nivolumab-Induced Sarcoid-Like Granulomatous Reaction in a Patient With Advanced Melanoma