Immunotherapy-induced exclusively cutaneous sarcoid-like reaction

Abstract

Sarcoid-like reactions (SLRs) are rare, granulomatous inflammatory reactions to immune checkpoint inhibitors (ICIs) that can involve any organ but frequently affect the lungs, mediastinal lymph nodes and skin. We present a rare case of an exclusively cutaneous SLR due to pembrolizumab that clinically resembled dermatomyositis. A literature review yielded only 12 previously reported cases of ICI-induced cutaneous SLR without any systemic involvement. Our case highlights the diversity of presentations of cutaneous SLR and emphasises the importance of histological evaluation of new cutaneous eruptions.

Background

Immune checkpoint inhibitors (ICIs) are the frontline treatment for several malignancies, but they are associated with various immune-related adverse events (irAEs), such as sarcoid-like reactions (SLRs).¹ SLRs are inflammatory granulomatous reactions of unclear aetiology that frequently occur in the setting of cancer or antineoplastic therapy.² SLRs most commonly involve the mediastinal or hilar lymph nodes, lungs and skin, and can get mistaken for cancer progression.¹

Here, we report a rare case of cutaneous SLRs without systemic involvement, a review of the literature involving other cases of ICI-induced cutaneous SLR, diagnostic challenges and treatment options.

Case presentation

A woman in her 70s with a history of triple-negative metastatic breast adenocarcinoma with programmed cell death ligand-1 (PD-L1) expression presented to the dermatology clinic with a 3-month history of an asymptomatic eruption on her face and arms. Treatment with carboplatin, gemcitabine and pembrolizumab had been initiated 1 month prior to rash onset. Physical examination revealed shiny red-brown to violaceous patches and plaques on her malar cheeks, nasolabial folds, forehead and chin, along with flat-topped papules over her dorsal upper extremities (figure 1). Oedema of the upper eyelids with faint erythema was also appreciated.

Figure 1.

Shiny red to brown patches and plaques on the face. Flat-topped, brown to purple indurated papules on the dorsal upper extremities.

Investigations

Punch biopsy of a representative papule on the left dorsal wrist was performed, and histopathological examination revealed dermal epithelioid histiocytes arranged in well-defined granulomas consistent with a granulomatous/sarcoidosis-like reaction (figure 2).

Figure 2.

H&E-stained section from left dorsal wrist. Dermal epithelioid histiocytes arranged in well-defined granulomas consistent with a granulomatous/sarcoidosis-like reaction: (A) 10× magnification and (B) 20× magnification.

Differential diagnosis

Initially, the distribution was suspicious for an autoimmune connective tissue disease, especially dermatomyositis given the nasolabial fold involvement. However, the deep colour was more concerning for sarcoidosis. Histopathology confirmed the diagnosis of an SLR, which was most likely secondary to pembrolizumab given the timing of her eruption. Whole-body CT imaging was negative for evidence of extracutaneous sarcoidal granulomas.

Treatment

Initially her oncologist held the pembrolizumab due to concerns of a drug reaction.

After confirmation of the diagnosis by histopathology, she was started on mometasone 0.1% ointment and tacrolimus 0.1% ointment to the face two times per day, and clobetasol 0.05% ointment for the upper extremities two times per day.

Outcome and follow-up

Given the exclusive cutaneous involvement of the patient’s SLR, pembrolizumab was restarted with careful monitoring for extracutaneous SLRs with imaging.

Significant improvement of the patient’s skin lesions with topical treatments was noted at her 1-month and 5-month follow-up dermatology clinic visit. At her 10-month oncology follow-up visit, she remains without systemic involvement of her SLR.

Discussion

Drug-induced SLRs are granulomatous inflammatory reactions that frequently involve the lungs and mediastinal lymph nodes but can affect almost every organ, including the skin. These reactions are most associated with antiretroviral therapy, tumour necrosis factor alpha antagonists, interferons and ICIs.³ ICIs are powerful anticancer therapies that target and inhibit cytotoxic T-lymphocyte-associated protein-4 (CTLA-4: ipilimumab), programmed cell death-1 (PD-1: pembrolizumab, nivolumab and cemiplimab) or PD-L1 (atezolizumab, avelumab and durvalumab). These drugs cause cytotoxic T-cell activation and help prevent cancer cells from evading the immune system.⁴ However, activating antitumour responses can lead to various irAEs. Cutaneous adverse reactions are the most common irAEs, and usually present as maculopapular eruptions, pruritus and vitiligo-like lesions.¹

Granulomatous/SLRs are rare irAEs that most commonly involve the mediastinal and hilar lymph nodes, and are associated with melanoma 81% of the time.⁵ The median time of SLR onset is 3–6 months after initiation of ICI therapy.^{3 6} The PD-1 inhibitor pembrolizumab is the most implicated ICI, contributing to 28.7% of cases.⁵ Most ICI-induced sarcoid-like skin lesions coexist with extracutaneous manifestations and only 12 cases of exclusive cutaneous involvement have been reported (table 1).^{5 7} Although carboplatin and gemcitabine have been associated with cutaneous adverse effects, there has only been one published case report of carboplatin-induced extracutaneous sarcoidosis and no reported cases of cutaneous sarcoidosis or SLRs.⁸ Thus, it is likely that our patient’s SLR was due to pembrolizumab. Our case adds to the limited number of reported cases of exclusively cutaneous ICI-induced SLRs. Previously reported cases usually involve the extremities and present as subcutaneous nodules or papules, similar to the lesions on our patient’s arms.⁷ However, our case shows that these cutaneous lesions can vary in morphology and presentation, involve atypical sites such as the face and resemble other dermatological diseases.

Table 1.

Summary of ICI-induced exclusively cutaneous SLRs

Sex/age	Primary disease	Agent	Onset after initiation of ICI (doses)	Clinical presentation	Management of SLR	Outcome of SLR	Study
F/60	Lung adenocarcinoma	Ipilimumab+nivolumab	7 months (3 doses ipilimumab, 10 doses nivolumab)	1–4 mm pink papules, some coalescing into plaques on posterior neck, upper arms and malar cheeks	Topical corticosteroids	Improvement but not resolution	Suozzi et al17
F/63	Lung adenocarcinoma	Nivolumab	3.5 months (7 doses)	2–6 mm scaly, erythematous papules coalescing into plaques on bilateral periorbital area and posterior neck, progressing to red-brown plaques involving glabella and nasal bridge	No improvement with TCS, ICI held for 1 cycle, systemic corticosteroids, hydroxychloroquine	Resolution	Birnbaum et al18
F/57	Ovarian carcinoma	Ipilimumab+nivolumab	10 months	1–3 cm tender, subcutaneous nodules on lower extremities, forearm and hip	D/c ICI	Resolved	Tetzlaff et al19
F/39	Melanoma	Nivolumab	3 months (6 doses)	Painful subcutaneous nodules on bilateral lower extremities and buttocks	D/c ICI, systemic steroids, hydroxychloroquine	Resolution	Tetzlaff et al19
F/56	Melanoma	Nivolumab	4+ months	FDG-avid subcutaneous nodules	Excision	Not reported	Ogawa et al20
M/72	Melanoma	Pembrolizumab	22 months	Subcutaneous nodules	None	Not resolved	Dimitriou et al21
M/64	Melanoma	Pembrolizumab	2 months	2 mm pigmented nodule on right submandibular area	None	Not reported	Woodbeck et al22
M/67	Melanoma	Ipilimumab	2 years	Coalescent papular lesions on back, face, arms, legs, hands, feet, groin and hips	D/c ICI, systemic, intramuscular and topical corticosteroids	Resolved	Cervantes et al23
F/49	Renal cell carcinoma	Ipilimumab+nivolumab	1 month (1 dose)	Subcutaneous nodules on left forearm and elbow	D/c ICI	Improving	Mobini et al7
M/58	Melanoma	Ipilimumab	1 month	Erythematous, scaly tender papules, plaques and nodules on black tattooed areas on chest, shoulders, upper back, left forearm and right thigh	D/c ICI, topical, intramuscular and systemic corticosteroids	Improving	Mobini et al7
M/57	Melanoma	Nivolumab or ipilimumab+nivolumab	1.3 months	Cutaneous lesions	Not reported, ICI continued	Resolved	Chorti et al24
M/36	Melanoma	Nivolumab (exacerbated by addition of BRAF‐inhibitor)	19 months	Micropapules in axilla and inguinal crease	Hydroxychloroquine, D/c BRAF‐inhibitor	Resolved	Pham et al15
F/70	Breast adenocarcinoma	Pembrolizumab	1 month	Shiny, pink to brown patches and plaques on the face, flat-topped, red-brown to violaceous indurated papules on dorsal upper extremities	Topical corticosteroids, topical calcineurin inhibitors	Improving	Current study

D/c, discontinue; F, female; ICI, immune checkpoint inhibitor; M, male; SLRs, sarcoid-like reactions; TCS, topical corticosteroids.

Cutaneous involvement in non-drug induced sarcoidosis occurs in up to 20% of cases and most commonly presents as red-brown or violaceous papules or plaques on the face, trunk and extremities.⁹ Cutaneous sarcoidosis may also present non-specifically as erythema nodosum which is a type of panniculitis characterised by tender, erythematous subcutaneous nodules on the pretibial areas.⁹ Due to the variety of presenting skin lesions, a biopsy is often necessary as the clinical differential diagnosis depends on the type and distribution of lesions. The histopathological differential diagnosis includes infections causing granulomatous inflammation such as fungal or mycobacterial infections, foreign body reactions and cutaneous Crohn’s disease.¹⁰ Drug-induced SLRs are clinically and histopathologically indistinguishable from sarcoidosis, but they often occur after starting a new drug and may improve or resolve after discontinuation.¹¹

The pathogenesis of sarcoidosis is not well understood but is theorised to involve dysregulation of macrophages and Type 1 helper T (Th1) cells by an extrinsic antigen which leads to non-caseating granuloma formation.^{9 12} These extrinsic antigens may be infectious, environmental or medications.¹² Interactions between these antigens and an individual’s immunogenetic response influence the development and progression of the disease.^{9 12} The granulomas in sarcoidosis composed of various cell types which indicate involvement of multiple innate and adaptive immune system pathways in the inflammatory cascade.¹² Granulomas are formed by macrophage which differentiate into epithelioid histiocytes and form multinucleated giant cells.¹² CD4+T helper cells exist within the granuloma while CD8+T cells, regulatory T (Treg) cells, fibroblasts and B cells are in the periphery.¹²

Like sarcoidosis, the pathogenesis of drug-induced SLRs is unclear but likely involves hyperactivity of the innate and adaptive immune systems since many of the implicated drugs modulate the immune system. ICI-induced SLRs have been studied over the past two decades and there are several hypotheses to explain this phenomenon. Increased immunosurveillance caused by ICIs can lead to activation of pro-inflammatory innate immune cells as well as activation of Th1 and Type 17 helper T (Th17) cells, which are involved in granulomatous reactions.³ Additionally, Th17 cells have been identified in the bronchoalveolar lavage and blood of patients with active sarcoidosis and are key producers of interleukin 17 (IL-17), which is essential for granuloma formation.^{5 13} CTLA-4 inhibitors are associated with the expansion of Th17 cells, and PD-1/PD-L1 inhibitors can cause Th17 cell hyperactivity and increased IL-17 expression.¹³ Blockage of the PD-1/PD-L1 pathway has also been shown to activate the phosphoinositide 3 kinase (PI3K)/mammalian target of rapamycin (mTOR) pathway in macrophages and T cells, which causes dysfunction of Treg cells and further increases IL-17 secretion and granuloma formation.³

ICI-induced SLRs are diagnostically challenging due to varied clinical presentations and radiographical findings that may mimic cancer recurrence instead of a drug reaction. The granulomas of SLRs appear as fluorodeoxyglucose (FDG)-avid lesions on imaging and are difficult to differentiate from malignancy without a biopsy. While thoracic biopsies are invasive and challenging, the coexistence of cutaneous lesions, which can be easily biopsied, can help confirm the diagnosis quickly and safely.⁵ Histopathological examination will show non-caseating, epithelioid granulomas.

Management of SLRs is dependent on the extent of involvement. Cutaneous lesions may be managed with topical corticosteroids and calcineurin inhibitors, while oral prednisone may be used for widespread lesions or systemic sarcoidosis. Cutaneous lesions often precede pulmonary involvement, so patients should be regularly monitored with imaging. While ICIs being stopped in response to SLRs is reported in 55% of cases, discontinuation should be avoided if possible due to documented reduced metastasis and survival benefits.⁵ It is postulated that SLRs to ICIs represent a robust immune response which is beneficial for targeting cancer cells.⁵ Limiting excessive iatrogenic systemic immunosuppression is also recommended since it can impede ICI therapeutic potency.⁵ Use of more than 7.5 mg of prednisone daily has been shown to decrease the efficacy of ICIs.¹⁴ For patients unresponsive to low-dose systemic steroids, hydroxychloroquine can be used as an alternative therapy which does not cause immunosuppression and has been shown to enhance anticancer therapies by inhibiting autophagy.^{13 15 16}

Our case adds to the limited reports of exclusively cutaneous ICI-induced SLR and highlights the diversity of presentations and morphologies of these skin lesions. Patients on ICI therapy should be regularly monitored for adverse cutaneous reactions. Dermatologists should include SLRs in the differential for these patients and have a low threshold for punch biopsy for further workup.

Learning points.

• Patients on immunotherapy with programmed cell death-1/programmed cell death ligand-1 or cytotoxic T-lymphocyte-associated protein-4 inhibitors can develop a sarcoid-like reaction (SLR), which commonly involves the mediastinal lymph nodes, lungs and skin.

• Biopsy must be done to confirm the diagnosis of immune checkpoint inhibitor (ICI)-induced SLRs because they have varied clinical presentations and radiographical findings that may mimic cancer recurrence instead of a drug reaction.

• Exclusively cutaneous SLRs are rare and can be treated topically without discontinuation of immunotherapy.

• Patients on ICI therapy should be regularly monitored for adverse cutaneous reactions, such as SLR.

• Dermatologists should include SLRs in their differential for these patients and have a low threshold for punch biopsy for non-specific skin lesions.

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