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      Eruptive squamous cell carcinomas in metastatic melanoma: An unintended consequence of immunotherapy

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          Abstract

          Introduction With the increasing use of immune-targeted therapy in metastatic melanoma over the last decade and the continued discovery of new targets, it is important to consider not only the efficacy and tolerability of these interventions but also their potential to impact other nontargeted pathways. Currently, in the clinical trial phase, Dynavax (Berkley, CA) is developing SD-101, a TLR9 agonist designed to elicit a potent and focused immune response to solid tumors and hematologic malignancies. Dynavax has been shown to have antitumor activities when used alone and in combination with immune checkpoint inhibitors. 1 Here we report a case of the development of 10 invasive cutaneous squamous cell carcinomas (cSCC) after the initiation of SD101 injected peritumorally in combination with pembrolizumab to treat metastatic melanoma. Case report An 84-year-old white man with recently diagnosed ulcerated malignant melanoma (Breslow depth at least 2.5 mm) of his right second toe presented to our dermatology department in 2012 for surgical evaluation and treatment recommendations. The patient underwent amputation of his distal second toe with histopathology showing melanoma within the bone and right ilioinguinal lymph node dissection positive in 1 of 10 nodes resulting in initial stage IIIC (T3b, N1b, M0) designation. Following external beam radiation to the right inguinal region, he was closely monitored clinically along with surveillance positron emission tomography imaging. Over the next 2 years, he had 2 cutaneous melanoma metastases, which were adequately surgically treated with wide local excision. Beginning in 2017, following development of multiple in-transit melanoma metastases across the right lower extremity, he was started on immune therapy with pembrolizumab. Because of disease progression, the patient was subsequently enrolled in a phase II clinical trial with SD101, a TLR9 agonist, injected peritumorally into a melanoma metastasis on his right anterior thigh, and concomitant pembrolizumab. However, within 4 months of enrolling, 10 pink scaly papules and plaques developed across the body (Fig 1), which were biopsy-proven invasive cSCCs, without signs of viral cytopathic changes (Fig 2). Seven of the 10 cSCCs were located on bilateral distal lower extremities and not localized to TLR9 injection site. The remaining 3 cSCCs were found on photo-exposed sites on left temple and bilateral upper extremities. As cutaneous melanoma metastases continued to develop in addition to cSCCs, he was discontinued from the trial and started on nivolumab with acitretin for cSCC prevention. Since initiating acitretin, the patient has not had new nonmelanoma skin cancers. Fig 1 Clinical presentation. Multiple pink scaly papules and plaques across the body, which were biopsy-proven invasive SCCs. Fig 2 A, Histopathology. Skin, left temple, shave biopsy. Invasive SCC, well differentiated, presented on the deep margin. The tumor is at least 3.5 mm in thickness and extends into the mid reticular dermis. No perineural or lymphovascular invasion is seen. (Original magnification: ×4.) B, Histopathology. Skin, right dorsal foot, shave biopsy. Invasive SCC, well differentiated, presented on the deep margin. The tumor is at least 2.5 mm in thickness and extends into at least the mid reticular dermis. No perineural or lymphovascular invasion is seen. (Original magnification: ×4.) Discussion The skin continuously interfaces with the external environment and serves as the first line of defense, both as a physical barrier and as a key component of the immune system. 2 Toll-like receptors (TLRs) expressed by keratinocytes and melanocytes are responsible for inducing an inflammatory response to help eliminate pathogens but, in doing so, can inadvertently contribute to the development of skin cancer. 2 When TLR9 is activated, it is found to enhance invasion and promote proliferation of malignant cells via COX-2 and NFkB activation.2, 3 Although TLR expression on tumor cells may allow tumors to evade immune surveillance, TLRs are also being developed as targets for anticancer interventions that result in the recognition and destruction of tumor cells. 2 TLR agonists specifically targeting TLR7, 8, and 9, have been developed as treatment options for difficult-to-treat melanoma and basal cell carcinoma, functioning by recruiting dendritic cells and inducing a robust T-cell response. 2 By stimulating the natural immune response, these TLR agonists have the potential to be broadly effective in multiple tumor types. 1 Mouse tumor model studies have found that intratumorally administered SD-101 can increase the quantity and quality of tumor specific CD8+ T cells in patients previously nonresponsive to programmed cell death protein 1 (PD-1) blockade. 1 SD-101 activates plasmacytoid dendritic cells via TLR9 and is used to stimulate both interferon-γ production and activate tumor-specific cytotoxic CD8+ cells.1, 2 In preliminary studies when used in conjunction with PD-1 blockade, an increase in immune cell infiltrates in the tumor microenvironment have been reported. 1 However, TLRs can potentiate chronic inflammation, which can ultimately contribute to squamous cell carcinoma (SCC) development.1, 3 One study found that TLR9 mediated the invasion of in vitro oral SCC, and that its expression was an independent predictor of poor prognosis. 3 At this time, however, it is currently unknown if any association exists between TLR9 agonists, such as SD-101, and the development of cSCC. Numerous case reports demonstrate how the PD-1 inhibitors, pembrolizumab and nivolumab, can induce several cutaneous immune-related adverse events including bullous pemphigoid, cutaneous sarcoidosis, vitiligo, and psoriasis.4, 5, 6, 7, 8 There are also reports of PD-1 inhibitors, particularly pembrolizumab, inducing keratoacanthomas. 9 However, despite these reports, the CARSKIN trial found that pembrolizumab can be used to successfully treat advanced cSCC, 10 and the US Food and Drug Administration recently approved a new PD-1 inhibitor cemiplimab for the treatment of metastatic cSCC. In the presented case, this patient did not have any adverse reactions to pembrolizumab when used as a monotherapy. However, it is possible that combining pembrolizumab with SD-101 may have altered the tumor microenvironment leading to the development of 10 cSCCs. One proposed mechanism (Fig 3) in this case is that the use of SD-101 led to increased expression of matrix-metalloproteinase 13 as seen in oral SCC and increased invasion and migration of a previously undiagnosed cSCC. 3 We cannot completely rule out that the SCC development in this patient was related to either another medication or idiopathic disease. However, because SCC did not develop while treated solely with pembrolizumab therapy, we hypothesize that the TLR9 agonist activity of SD-101 either alone or in combination with pembrolizumab may have contributed to his disease progression. Fig 3 Proposed mechanism leading to cutaneous SCC development. The use of SD-101 led to increased expression of matrix-metalloproteinase 13 as seen in oral SCC and increased invasion and migration of a previously undiagnosed cutaneous SCC. 3 As our understanding of the signaling pathway of melanoma grows, observed cutaneous and systemic side effects may bring to light the interactions between distinct disease processes. Clinicians must continue to be aware of potential immune-related adverse events as immune checkpoint inhibitors and TLR agonists become more frequently utilized members of our oncology treatment arsenal. Moving forward, it will be imperative to document cases of SCC arising in patients treated with immunotherapy and to develop strategies that do not interfere with antitumor responses.

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          Pembrolizumab-associated sarcoidosis

          Introduction Pembrolizumab is a humanized antibody that targets the programmed cell death-1 (PD-1) receptor. It is currently approved by the US Food and Drug Administration for patients with advanced melanoma and metastatic non–small cell lung cancer. As an immune checkpoint inhibitor, pembrolizumab augments a patient's immune system against an underlying malignancy. Systemic toxicities associated with use of PD-1 inhibitors such as fatigue, pyrexia, chills, and infusion reactions have been commonly reported. 1 We report a case of sarcoidosis flare associated with pembrolizumab, which is, to our knowledge, the first reported case of sarcoidosis linked to PD-1 inhibition. Case report A 72-year-old woman with refractory, stage IV Hodgkin lymphoma diagnosed in 2014 was placed on pembrolizumab, 200 mg intravenously every 3 weeks. Twelve years prior, the patient had gallstone pancreatitis, and a chest x-ray at that time found bilateral hilar adenopathy. Subsequent mediastinoscopy and lymph node biopsy were notable for sarcoidosis, although the patient was never symptomatic and was never treated. Approximately 6 months after starting pembrolizumab, the patient presented to the dermatology clinic with slowly enlarging, asymptomatic subcutaneous nodules on her arms. Physical examination found 2 nontender, subcutaneous nodules on the right extensor forearm without overlying erythema, with the largest nodule measuring 10 cm in diameter (Fig 1, A). There was a similar, smaller nodule on the left forearm. Punch biopsy of the larger right forearm nodule found mild lymphohistiocytic perivascular dermatitis with a focal, dermal epithelioid granuloma (Fig 2, A and B). Infectious stains and tissue cultures were negative. Based on the clinical presentation and medical history, a diagnosis of cutaneous sarcoidosis was made. Pembrolizumab was held for the progressing skin lesions and a positron emission tomography/computed tomography scan was performed to reassess the status of the lymphoma. The imaging found new bilateral pulmonary parenchymal patchy ground glass opacities with septal thickening. There were also new hypermetabolic areas within multiple bones, including the left side of the scapula (Fig 3, A), sternum, and the right side of the iliac. Interval increases in fludeoxyglucose (FDG)-avid mediastinal and bilateral hilar lymph nodes (Fig 3, B), compared with 3 months prior were seen. It was unclear whether these changes were secondary to lymphoma or sarcoidosis. Soon thereafter, the patient had left eye pain, and evaluation by an ophthalmologist found acute iritis attributable to sarcoidosis. In addition, she had dyspnea and was referred to cardiothoracic surgery for consideration of video-assisted thoracoscopic surgery to determine the etiology of the dyspnea and adenopathy. However, the patient declined to pursue lung/lymph node biopsy. A decision was made to initiate an empiric trial of prednisone at a dose of 60 mg orally daily, to see if there would be a favorable clinical/radiographic response, based on the presumption that sarcoidosis induced by pembrolizumab, and not lymphoma, was the etiologic culprit for the clinical and imaging features. Shortly after the initiation of prednisone, the left eye pain and dyspnea resolved, and within 1 month, the skin nodules resolved (Fig 1, B). Reimaging performed approximately 3 months after the prior scans (1 month after starting prednisone) found complete resolution of the FDG-avid skeletal regions previously noted (Fig 3, C) as well as resolution of the hilar and mediastinal adenopathy (Fig 3, D). The patient's lymphoma is currently in complete remission since she stopped taking pembrolizumab for the last 4 months. Discussion Early reports of the PD-1 inhibitors pembrolizumab and nivolumab described exacerbation of psoriasis for patients with a previous history of skin disease and de novo development of psoriasis in patients who lacked both a personal and family history.2, 3, 4 More severe cutaneous toxicities such as Stevens-Johnson syndrome have also been reported. 5 A retrospective review of 82 patients treated with PD-1 inhibitors for metastatic melanoma found that 49% (40 of 82) of treated patients had some form of adverse cutaneous event, with lichenoid dermatitis (17%), eczematous dermatitis (17%), and vitiligo (15%) being the most common dermatoses. 6 In an additional retrospective case series of 83 patients, pembrolizumab use was associated with skin toxicity in 42% (35 of 83), with papular eruptions (29%) most common, followed by pruritus (12%), and hypopigmentation (8%). 7 Of particular concern, based on the method by which PD-1 inhibitors are effective in unleashing an individual's immune system against an underlying cancer, would be the exacerbation or de novo development of autoimmune disorders, cutaneous and systemic. Although there is evidence that patients with diseases such as Churg-Strauss can be treated successfully with PD-1 inhibition for melanoma without subsequent flare of their vasculitis, 8 there are also cases in which PD-1 inhibitor use has led to rapid progression of previously stable patients with autoimmune diseases such as myasthenia gravis. 9 Recent reports of the development of autoimmune blistering skin disorders such as bullous pemphigoid from PD-1 blockade provide additional concerns about the risk of autoimmune sequelae from immune checkpoint inhibitors. 10 Our case is notable beyond the fact that it is, to our knowledge, the first reported case of sarcoidosis flare associated with PD-1 blockade. It highlights the diagnostic difficulty of discerning the etiology of adverse events that may radiographically mimic the disease for which the PD-1 inhibitor is being used; sarcoidosis, like lymphoma, presents with increased FDG avidity on positron emission tomography/computed tomography scans. Our patient's skin nodules were bothersome, but the acute iritis and dyspnea necessitated prednisone use, which eventually led to the resolution of the clinical and imaging features. Without tissue confirmation of sarcoid involving the skin and the development of sarcoidal iritis, it is conceivable that the mediastinal, pulmonary, and skeletal lesions could have been falsely attributed to progression of the lymphoma. While our patient had a history of asymptomatic pulmonary sarcoidosis, the development of dyspnea, iritis, and subcutaneous nodules after several months of pembrolizumab use implicates PD-1 blockade in the progression of sarcoidosis in this circumstance. This case highlights the importance of being mindful of the spectrum of toxicities associated with PD-1 inhibitors and ensuring that these toxicities don't obfuscate a favorable clinical response. More importantly, it should raise awareness that PD-1 inhibition, although helpful in redeploying an individual's immune response against an underlying malignancy, may exacerbate underlying autoimmune conditions such as sarcoidosis, as an unexpected consequence.
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            Immune-related sarcoidosis observed in combination ipilimumab and nivolumab therapy

            Introduction Immune checkpoint inhibitors show remarkable antitumor activity across multiple tumor types, with approval of programmed death–1 (PD-1) inhibitors for non–small cell lung cancer and melanoma. A recent clinical trial found median progression-free survival of 11.5 months for combined nivolumab plus ipilimumab therapy for metastatic melanoma compared with 6.9 months (nivolumab alone) or 2.9 months (ipilimumab alone). 1 Nivolumab, a fully human IgG4 PD-1 antagonist antibody, and ipilimumab, a fully human IgG1 cytotoxic T-lymphocyte–associated antigen 4 (CTLA-4) antagonist antibody, act by relieving suppression of antitumor T cells. CTLA-4 inhibition (ipilimumab) potentiates early T-cell activation during antigen presentation. PD-1 inhibition (nivolumab) acts primarily on T cells that have already been activated and subsequently suppressed via PD-1 signaling at sites of T cell destination. Both CTLA-4 and PD-1 signaling normally dampen the immune system to protect against excessive inflammation and development of autoimmunity; however, in the setting of malignancy, they can be co-opted by tumors to allow immune evasion. Blocking such signaling has profound antitumor effects in some patients. Adverse effects associated with immune checkpoint inhibitor therapy are termed immune-related adverse events (irAEs) (Fig 1). Here we discuss a rare irAE, sarcoidosis, in the setting of combined ipilimumab/nivolumab therapy for lung adenocarcinoma. Report of a case A 60-year-old white woman with lung adenocarcinoma metastatic to her lymph nodes and brain, receiving ipilimumab plus nivolumab for 7 months, presented to her oncologist with nausea, vomiting, aphasia, and confusion. She was admitted to the hospital with differential diagnoses including progressive brain metastases, radiation necrosis at an intracranial site of prior radiosurgery, or an adverse reaction to ipilimumab or nivolumab. This patient was diagnosed with lung cancer 9 months prior after experiencing dysarthria and worsening balance. Brain imaging found a left frontal lobe lesion. Chest imaging uncovered a right upper lobe lung mass with subcarinal and paratracheal lymphadenopathy. Bronchoscopic biopsy confirmed poorly differentiated lung adenocarcinoma, with histology findings negative for epidermal growth factor receptor, anaplastic lymphoma kinase (ALK) gene rearrangement, Kirsten rat sarcoma viral oncogene homolog (KRAS) gene mutation and human homolog of v-ROS avian UR2 sarcoma virus oncogene (ROS1) rearrangement. She subsequently underwent uncomplicated gamma knife surgery to the left frontal lobe brain lesion. She then initiated combination immunotherapy with ipilimumab every 6 weeks plus nivolumab every 2 weeks (dosing for both drugs was 1 mg/kg) according to trial protocol. Two weeks into treatment a mildly pruritic maculopapular rash developed; this was diagnosed by her oncologist as ipilimumab-associated cutaneous eruption and treated using oral diphenhydramine and topical triamcinolone 0.1% cream with resolution and no interruption in immunotherapy. Follow-up imaging per study protocol at 2 months found regression of cancer outside the brain but also found progression of the left frontal lobe lesion or treatment effect (ie, radiation necrosis). Immunotherapy was held, and she underwent intracranial resection, which found primarily radiation necrosis. She restarted immunotherapy 2 weeks after surgery, receiving a total of 3 ipilimumab and 10 nivolumab treatments prior to her current presentation. At presentation to the emergency room, her vital signs were stable, but she was in diabetic ketoacidosis (serum glucose, 766 mg/dL) and was transferred to the intensive care unit, where an insulin drip was started and proved effective. On hospital day 7, the dermatology department was consulted to evaluate a rash on the neck. On examination, the patient had greater than fifty 1- to 3-mm skin-colored to pink firm papules, some coalescing into annular plaques (Fig 2, A). Her bilateral malar cheeks also had approximately 10 thin pale pink 2- to 4-mm papules. Some papules had umbilicated appearance. There was no apple jelly color appreciated on diascopy. No cervical or axillary lymphadenopathy or lacrimal gland hyperplasia was appreciated. Skin biopsy of lesion on the posterior neck revealed a dermal granulomatous infiltrate consistent with sarcoidosis (Fig 2, B). A small focus of polarizable material was seen. This finding was noted in a previous case of ipilimumab-associated cutaneous sarcoidosis. 2 A diagnosis of cutaneous sarcoidosis was made and was considered an irAE secondary to ipilimumab, nivolumab, or the combination. She was treated with topical clobetasol 0.05% ointment twice daily for 2 weeks with some improvement but not resolution of the lesions. Brain magnetic resonance imaging during the hospitalization found interval increase in the left frontal lobe metastasis, with sustained response to immunotherapy outside the brain. Subsequent intracranial resection found metastatic lung adenocarcinoma. The patient declined further treatment and died 3 months later. Discussion Sarcoidosis is a rare irAE, with only 11 cases reported to date (Table I). Most occurred during ipilimumab treatment of metastatic melanoma, with a single report (limited detail) of sarcoidosis with anti–PD-L1 antibody treatment. None have been reported during treatment of lung cancer. Of these cases, sarcoidosis occurred predominantly in the lung (67% of the time) and less so in the skin (25%). The timing of sarcoidosis onset ranged anywhere from 2 cycles to 10 cycles of therapy. There is evidence supporting a positive association between irAEs and clinical response, specifically for vitiligo during melanoma treatment 13 ; however, there does not seem to be a correlation between development of sarcoidosis and treatment response (Table I). Sarcoidosis can be systemic, involving lung, skin, central nervous system, or kidney.2, 9 Clinicians should be aware of the association between immunotherapy and sarcoidosis, because systemic sarcoidosis can be mistaken for progression of malignancy on clinical examination and in imaging studies. Fluorodeoxyglucose positron emission tomography/computed tomography (PET/CT), for example, can highlight inflammatory cells in sarcoidosis and be misinterpreted as cancer progression. This finding has the potential to adversely impact decisions on patient treatment and management. The diagnosis of sarcoidosis was delayed in many of the cases analyzed in Table I because systemic involvement was thought to represent progression of malignancy. In our patient, when her brain magnetic resonance image showed an enlarging left frontal lobe mass, systemic sarcoidosis was considered in the differential diagnosis and led to the recommendation for definitive tissue sampling; unfortunately, in this instance, malignancy was confirmed. Our patient experienced 2 other adverse events related to immunotherapy: macular papular cutaneous eruption, also called ipilimumab-associated cutaneous eruption (discrete, erythematous, minimally scaly, pruritic papules that can coalesce into thin plaques, most often involving the trunk and extremities) and insulin-dependent diabetes (in the setting of PD-1 inhibition may develop over a time ranging from 1 week to 5 months8, 14). The rash usually occurs early in treatment, 3 to 4 weeks after the first dose, as occurred for our patient, and responds to topical steroids. 15 The rash can worsen with subsequent cycles and be associated with a significant increase in peripheral eosinophilia (neither occurred in this patient). Conclusion With increased use of immune checkpoint inhibitors for cancer treatment, physicians are seeing a variety of irAEs (Fig 1). In some cases, the irAE provides insight into disease pathogenesis. For example, validating findings in mice, it appears that PD-1 inhibition unmasks genetic susceptibility to diabetes. 16 The pathomechanism of sarcoidosis is poorly understood, but dysregulated cellular immunity could play a key role through a T helper–1 T-cell–mediated response to an unknown antigen (possibly mycobacterial),17, 18 and this response could be potentiated by checkpoint inhibitors. It is not clear without further scientific research whether specifically the ipilimumab or nivolumab (or both) contributed to the pathogenesis of sarcoidosis in our patient. If ipilimumab drives sarcoidosis alone, as it may be in melanoma cases, our observation then suggests the PD-1 pathway is either not involved, or not able to abrogate, the CTLA-4 pathway effect.
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              Nivolumab-related cutaneous sarcoidosis in a patient with lung adenocarcinoma

              Introduction Immune checkpoint inhibitors are able to harness and stimulate the immune system's innate antitumor capabilities. One of these targeted checkpoints is the programmed cell death-1 (PD-1) pathway. When PD-1 is bound to its ligands, it transduces a coinhibitory signal to activated T cells allowing for immune system dampening and peripheral tolerance. Cancer cells exploit this pathway by expressing their own PD-1 ligands enabling them to evade immune system recognition and elimination.1, 2 Nivolumab is a PD-1 antibody that disrupts this T-cell inhibitory pathway. It is approved by the US Food and Drug Administration for the treatment of metastatic melanoma, non–small cell lung cancer, renal cell carcinoma, and classical Hodgkin lymphoma. 1 Immune-related adverse events (irAEs), such as colitis, endocrinopathies, and dermatitis, have been well documented in patients treated with checkpoint inhibitors. 3 We report a case of immune-related cutaneous sarcoidosis in a patient with lung adenocarcinoma on nivolumab monotherapy. Case report A 63-year-old African-American woman had stage IV epidermal growth factor receptor mutation-negative lung adenocarcinoma diagnosed 2 years before presentation. The patient was started on 4 cycles of carboplatin (area under the curve 6), 900 mg, paclitaxel, 200 mg/m2, and bevacizumab, 15 mg/kg every 3 weeks, followed by bevacizumab, 15 mg/kg maintenance therapy every 3 weeks. Fourteen months later, imaging showed an increase in pleural metastatic disease, and the patient was started on nivolumab, 3 mg/kg every 2 weeks. After 7 cycles of nivolumab, the patient presented to the dermatology department with a 3-week history of a severely pruritic waxing and waning cutaneous eruption on the periorbital skin and posterior neck. On examination, the patient had around fifteen 2- to 4-mm scaly, erythematous papules coalescing into plaques on the periorbital areas bilaterally (Fig 1). There were also around twenty 4- to 6-mm scaly, erythematous papules coalescing into plaques on the posterior neck (Fig 1). The patient was prescribed fluocinonide 0.05% ointment to the neck twice daily and hydrocortisone 2.5% ointment to the face twice daily for suspected contact dermatitis. On follow-up 2 weeks later, the patient did not improve, and the lesions had progressed to red-brown plaques now involving the glabella and nasal bridge. Given the lack of improvement and progression, a punch biopsy of the neck lesion was performed, which found nodular collections of epithelioid and multinucleated histiocytes surrounded by a sparse lymphocytic infiltrate throughout the dermis (Fig 1). Fite and periodic acid–Schiff–diastase staining were negative for atypical mycobacterial and fungal infection. Considering the patient's nivolumab history, the diagnosis was therapy-related cutaneous sarcoidosis. The patient's nivolumab infusion was held for 1 cycle, and she was started on methylprednisolone, 24 mg for 1 day, and tapered down to 4 mg/d over the next 6 days. The lesions initially regressed after 48 hours but flared up around 48 hours after completing the steroid taper. Although some research has found that systemic corticosteroids do not seem to diminish the efficacy of immunotherapy, the patient was treated with low-dose prednisone, 10 mg once daily. However, the patient only showed complete resolution after hydroxychloroquine, 200 mg twice daily, was added. She was able to continue her nivolumab therapy and has shown stable disease on a follow-up positron emission tomography scan 1 month later. Discussion To date, several cases of immune checkpoint-induced sarcoidosis have been reported, most occurring in melanoma patients treated with ipilimumab, a cytotoxic T-lymphocyte–associated protein 4 (CTLA-4) inhibitor. 2 Two cases involved nivolumab as a monotherapy, both of which were in patients with melanoma.2, 4 Another case reported nivolumab-related sarcoidosis in a lung cancer patient, but the patient was on ipilimumab and nivolumab combination therapy. 3 In this case, suppressing both PD-1 and CTLA-4 obscured the pathway responsible for the observed irAE. Our case of immune-related cutaneous sarcoidosis in a lung cancer patient on nivolumab monotherapy further supports the theory that PD-1 blockade may contribute to the pathogenesis of immune-related sarcoidosis independently from CTLA-4 blockade. The PD-1 pathway and its role in immunity are exceedingly complex. Once activated, T cells, B cells, macrophages, and dendritic cells all express the PD-1 receptor. The corresponding PD-1 ligands (PD-L1 and PD-L2) can be induced on many cells, particularly on antigen-presenting cells. 5 The PD-1–PD-L1 interaction inhibits T-cell proliferation and the production of key inflammatory cytokines such as interferon-γ, tumor necrosis factor-α, and interleukin-2. 5 PD-1 also contributes to immunologic peripheral tolerance by aiding in the conversion of T cells into regulatory T cells. 6 In addition to its role in the PD-1 pathway, PD-L1 serves as an analog to CTLA-4, allowing it to participate in a second, parallel immunoinhibitory pathway. 7 In our patient, nivolumab blocked PD-1's immune suppression leading to sustained or increased immunogencity. However, CTLA-4 and PD-L1 were unaffected and free to continue causing T-cell inhibition via the CTLA-4 pathway. This PD-1 inhibition, in the absence of CTLA-4 inhibition, provides some insight into the pathogenesis of sarcoidosis. However, an overly simplistic paradigm may be inaccurate because there is also paradoxical evidence of PD-1's role in sarcoidosis. A recent study found that PD-1 was upregulated on CD4+ T cells in sarcoidosis patients compared with healthy controls. 8 The authors posit that PD-1 overexpression may decrease T-cell proliferative capacities leading to the immunologic derangements associated with sarcoidosis. This finding is counter to what our case exhibits with PD-1 blockade appearing to be involved in the pathogenesis of sarcoidosis (Fig 2). The PD-1 upregulation, however, may be a secondary response rather than the initiating event in the case of sarcoidosis; thus, more research is needed. The salient clinical correlate to therapy-related sarcoidosis is the concept of tumor pseudoprogression and its impact on patient management. Although our patient did not present with pulmonary sarcoidosis, clinicians must be cautious not to mistake a granulomatous irAE, which can be highlighted on positron emission tomography/computed tomography scan, for progression of a treated cancer or metasteses. 9 This is important for all malignancies but especially critical in the treatment of lung cancer. Most therapy-related sarcoidosis cases respond to topical or systemic steroids and regress. 4 It is encouraging that our patient's sarcoidosis is improving on hydroxychloroquine, as it is nonimmunosuppressive and has even been theorized to have anticancer effects by inhibiting autophagy, a cellular defense mechanism against metabolic stress. 10 Conclusion Clinicians must continue to be aware of potential irAEs as immune checkpoint inhibitors remain a part of our oncology armament. Although the clear mechanisms on how PD-1 is related to sarcoidosis remain elusive, its general participation in the disease process becomes more evident as new cases of PD-1 inhibitor-related sarcoidosis are reported.
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                Author and article information

                Contributors
                Journal
                JAAD Case Rep
                JAAD Case Rep
                JAAD Case Reports
                Elsevier
                2352-5126
                08 June 2019
                June 2019
                08 June 2019
                : 5
                : 6
                : 514-517
                Affiliations
                [a ]Philadelphia College of Osteopathic Medicine, Philadelphia, Pennsylvania
                [b ]Department of Dermatology, University Hospitals Cleveland Medical Center, Cleveland, Ohio
                Author notes
                []Correspondence to: Gregory R. Delost, DO, Department of Dermatology, UH Cleveland Medical Center, 11100 Euclid Avenue, Lakeside 3500, Cleveland, OH 44106. Gregory.Delost@ 123456UHhospitals.org
                Article
                S2352-5126(19)30117-1
                10.1016/j.jdcr.2019.03.014
                6558268
                © 2019 by the American Academy of Dermatology, Inc. Published by Elsevier, Inc.

                This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

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