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Clinical and Histopathologic Features of Immune Checkpoint Inhibitor-related Pneumonitis

Larsen, Brandon T. MD, PhD*; Chae, June M. MD; Dixit, Anuj S. MD; Hartman, Thomas E. MD; Peikert, Tobias MD; Roden, Anja C. MD§

The American Journal of Surgical Pathology: October 2019 - Volume 43 - Issue 10 - p 1331–1340
doi: 10.1097/PAS.0000000000001298
Original Articles
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Immune checkpoint inhibitors (ICIs) have revolutionized oncology, but are associated with immune-related adverse events. Clinically, pneumonitis is a well-recognized complication, but its histopathologic features are poorly understood. Institutional archives were searched for patients having ICI therapy and subsequent lung tissue sampling. After excluding infectious cases, 9 patients (5 women, median: 59 y) were identified with clinically suspected ICI-related pneumonitis. Clinical history, imaging, and pathology slides were reviewed. Patients received pembrolizumab (6 cases), nivolumab (1), ipilimumab followed by pembrolizumab (1), or pembrolizumab followed by nivolumab (1); the latter experienced pneumonitis with both agents. Treatment duration ranged from 1 to 33 cycles (median: 8). Three patients received concurrent chemotherapy and 1 received radiation; the remainder received ICI monotherapy. Symptoms were nonspecific; 2 patients were asymptomatic. Thoracic imaging showed bilateral ground glass or nodular opacities in all cases, often with pleural effusion. Histologically, organizing pneumonia was seen in 7 patients, all with subclinical or mild disease, admixed with vague non-necrotizing airspace granulomas in 3 cases; all 6 patients with follow-up did well. One patient had acute fibrinous pneumonitis and 1 had diffuse alveolar damage; both died. All 9 cases showed foamy macrophages and pneumocyte vacuolization; 6 had rare eosinophils. ICI-related pneumonitis presents as bilateral ground-glass opacities or nodules, and usually manifests as organizing pneumonia histopathologically, often with vague non-necrotizing airspace granulomas. Foamy macrophages and pneumocyte vacuolization are characteristic and rare eosinophils are often seen. Less commonly, acute fibrinous pneumonitis or diffuse alveolar damage can occur, which may be fatal.

*Department of Laboratory Medicine and Pathology, Mayo Clinic, Scottsdale, AZ

Division of Pulmonary and Critical Care Medicine

Departments of Radiology

§Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN

Conflicts of Interest and Source of Funding: The authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article.

Correspondence: Brandon T. Larsen, MD, PhD, Department of Laboratory Medicine and Pathology, Mayo Clinic Arizona, 13400 E. Shea Blvd., Scottsdale, AZ 85259 (e-mail: larsen.brandon@mayo.edu).

In just a few years, immune checkpoint inhibitors (ICIs) have dramatically impacted the field of oncology and are revolutionizing the treatment of many advanced malignancies, by harnessing and unleashing the power of the immune system to target neoplastic cells. To date, all ICIs approved for clinical use in the United States are monoclonal antibodies, directed against key co-inhibitory molecules of the immune synapse that regulate the adaptive cytotoxic immune response. These inhibitors have been approved for a variety of indications and include agents targeting programmed cell death receptor 1 (PD-1) (pembrolizumab and nivolumab), programmed cell death ligand 1 (PD-L1) (atezolizumab, avelumab, and durvalumab), and cytotoxic T-lymphocyte–associated antigen 4 (CTLA-4) (ipilimumab). Despite their clinical benefits, these agents are associated with a unique spectrum of immune-related adverse events (irAEs).1 Most irAEs can be managed with prompt diagnosis, drug cessation, and immunosuppression, but severe irAEs can occur and are sometimes fatal, with pneumonitis being the most frequent cause of death related to anti-PD-1/PD-L1 immunotherapy.2

Early data from clinical trials and other studies reported ICI-related pneumonitis in only 3% to 7% of patients,3–8 but more recently this phenomenon was reported to occur in nearly 20% of patients with non–small cell lung cancer who received one or more of these agents outside of clinical trials, and this was associated with decreased survival.9 It has been postulated that ICI-related pneumonitis may be clinically under-recognized and under-reported, for a variety of reasons, and the true rate of ICI-related pneumonitis may be even higher.10 Recently, a growing body of literature has emerged that details the clinical manifestations of ICI-related pneumonitis,2,8,9,11–13 but published descriptions of the histologic features thereof are limited and the surgical pathology of this phenomenon remains poorly understood. Here, we report our institutional experience with ICI-related pneumonitis in a series of patients, all of whom had lung tissue available for review, to detail the spectrum of histopathologic changes that can be seen with this phenomenon and their association with clinical and imaging findings.

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MATERIALS AND METHODS

This study was approved by the appropriate Institutional Review Board (#18-003820). To identify potential cases of ICI-related pulmonary toxicity, institutional electronic medical records and laboratory databases were searched for patients receiving ICI therapy, who underwent subsequent lung tissue sampling by biopsy or at autopsy. The consultation files of one of the authors (B.T.L.) were also searched for additional cases of putative ICI-related pulmonary toxicity. Available medical records in each case were reviewed for pertinent aspects of the patient’s medical history, including age, sex, race, smoking status, history of preexisting autoimmune disorders, other underlying medical conditions, medication history, and pertinent laboratory results including serologic testing and cultures. The oncologic history in each case was also reviewed, including the type of malignancy necessitating ICI therapy, duration of ICI therapy, and details of other chemotherapies and radiotherapy. Presenting signs and symptoms and the duration thereof were tabulated. All available thoracic imaging studies were reviewed by 2 thoracic radiologists (T.E.H. and A.S.D.). Details of treatment approaches for ICI-related pneumonitis and patient outcomes were also tabulated.

All available slides of lung tissue from each case meeting inclusion criteria were retrieved from institutional pathology archives and reviewed by 2 thoracic pathologists (B.T.L. and A.C.R.), and original diagnoses were confirmed on routine hematoxylin and eosin (H&E)-stained sections. Special stains for microorganisms were also reviewed, including Grocott-Gomori methenamine silver (GMS) and Ziehl-Neelsen stains for acid-fast bacilli (AFB). Pertinent histologic features and patterns were evaluated.

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RESULTS

Initial database searches identified 13 patients who had lung tissue sampled after receiving ICI therapy. Upon further review of clinical information, 5 of these patients were found to have active fungal infections in the lung that were not present before initiating ICI therapy, including 4 presenting with a solitary lung nodule or mass. The latter 4 patients all had clinical suspicion for infection or recurrent/metastatic malignancy, and none had clinical suspicion for ICI-related pneumonitis. Biopsies confirmed the presence of fungal organisms including Histoplasma (1 case), Blastomyces (1), Mucor (1), and nonspecific Aspergillus-like hyphae with negative fungal cultures (1). The remaining patient died of acute bronchopneumonia due to aspiration, and was found to have Candida in the lungs at the time of autopsy. These 5 patients with fungal infections were excluded from further study. The remaining 9 patients were clinically suspected to have ICI-related pneumonitis with a negative infectious disease workup and no alternative explanation for pneumonitis, and were enrolled in the study.

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Clinical and Imaging Features

Of the 9 patients with clinically suspected ICI-related pneumonitis, 5 were women. The mean age of the patients was 59.4±13.3 years (median: 59, range: 32 to 72 y) at the time of initial treatment with an ICI agent. Pertinent clinical details are summarized in Table 1. Indications for ICI therapy included advanced-stage non–small cell lung carcinomas (4 patients, including 3 with adenocarcinoma and 1 with squamous cell carcinoma), metastatic Merkel cell carcinoma (2), metastatic melanoma (1), classic Hodgkin lymphoma of nodular sclerosing type (1), and metastatic basaloid squamous cell carcinoma from the skin (1).

TABLE 1

TABLE 1

Treatment regimens and outcomes varied among the subjects, and are summarized in Table 2. Most patients received only one ICI agent including pembrolizumab (6 cases) or nivolumab (1), but one patient received both agents sequentially, beginning with pembrolizumab but eventually switching to nivolumab 14 months later after experiencing transient pneumonitis with pembrolizumab requiring discontinuation of this agent. Interestingly, this patient developed pneumonitis again, 57 days later, after switching to nivolumab. The last patient received ipilimumab and tolerated it well, but experienced progression of metastatic disease and ipilimumab was stopped. After completing stereotactic body radiotherapy to her metastatic lung lesion, she was switched to pembrolizumab, and developed pneumonitis 11 months later.

TABLE 2

TABLE 2

Duration of ICI therapy before developing symptoms was known in 8 episodes of pneumonitis in 7 patients (including the patient with 2 separate bouts of ICI-related pneumonitis), and ranged from 1 to 33 cycles (mean: 11 cycles, median: 8 cycles). The time when symptoms developed was variable, with a mean time of presentation 237±178 days (median: 244 d, range: 14 to 540 d) from initiating ICI therapy. Three patients were treated concurrently with carboplatin and pemetrexed (all with pulmonary adenocarcinoma), and 1 patient was treated concurrently with radiation to the mediastinum for Merkel cell carcinoma during his first 2 cycles of pembrolizumab therapy, but completed his radiation therapy and continued receiving pembrolizumab alone after that point. The remaining 5 patients did not receive any concurrent chemotherapy or radiation, and were treated with an ICI agent alone.

Clinical presentations varied, but symptoms were nonspecific, including shortness of breath and dyspnea on exertion (4 cases), low-grade fever (4), arthralgias (2), nonproductive cough (2), fatigue (1), and diarrhea (1). Two patients were asymptomatic and evidence of pneumonitis was found incidentally on imaging studies performed for other reasons. Two patients had a history of psoriasis, one of whom also had hypothyroidism. One patient had a history of ulcerative colitis, and another patient had a history of peripheral spondyloarthritis and harbored the HLA-B27 antigen. The remaining 5 patients had no reported history of autoimmune disease. Smoking status was available in 8 patients, including 2 current smokers, 3 former smokers, and 3 patients with no history of smoking.

Thoracic imaging results showed bilateral ground glass and/or nodular consolidative opacities in all cases, and pleural effusion was seen in 4 patients, 2 of whom had bilateral effusions. Representative imaging findings are illustrated in Figure 1 and summarized in Table 3.

FIGURE 1

FIGURE 1

TABLE 3

TABLE 3

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Histopathologic Findings

All available H&E slides were evaluated from each case (mean: 2 H&E slides, range: 1 to 7), and special stains for microorganisms were reviewed. Histologic material included core biopsies (5 cases), transbronchial forceps biopsies (3), and lung tissue obtained at autopsy (1). Microscopic evaluation revealed evidence of acute lung injury in all cases, but the patterns of injury and degrees of severity varied. Organizing pneumonia was the most common histologic pattern seen (7 cases), and occurred in all patients presenting with subclinical, mild, or subacute disease (Fig. 2), but this was often intimately admixed with vague non-necrotizing granulomas in the airspaces (3 cases), producing a more unusual hybrid pattern of organizing granulomatous pneumonitis. In contrast, the 2 patients presenting more acutely showed histologic changes more in keeping with severe acute lung injury (Fig. 3), including 1 patient showing a pattern of acute fibrinous pneumonitis, wherein alveolar septal edema and abundant airspace fibrin were the most prominent histologic changes, and 1 patient presenting in acute respiratory failure who was found to have a pattern of acute and organizing diffuse alveolar damage (DAD) at the time of autopsy, with abundant eosinophilic hyaline membranes. Interestingly, all 9 cases showed patchy accumulation of foamy macrophages in airspaces and vacuolization of type II pneumocytes, in a pattern resembling adverse reactions to amiodarone or other medications. Rare scattered eosinophils were seen in 6 cases, but were never a prominent feature. No case showed viral inclusions, fungal organisms, neutrophilic infiltrates, or other specific histologic evidence of infection, and AFB and GMS stains and microbiologic cultures were negative in all cases. Histopathologic findings are summarized in Table 3.

FIGURE 2

FIGURE 2

FIGURE 3

FIGURE 3

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Outcomes

Patient outcomes varied, and were associated with the pattern of histopathologic changes that were present. Clinically, all cases were suspected to represent an adverse reaction to ICI therapy and the ICI agent was discontinued in all cases, with 2 patients receiving supportive care only (one of whom was asymptomatic, and the other having a mild fever only). The remaining 7 patients all received corticosteroids and broad-spectrum antibiotics. Follow-up information was available in 8 patients, 6 of whom had organizing pneumonia with or without granulomas. All 6 of the latter patients did well, with complete resolution of symptoms and imaging abnormalities, and remained without clinical or imaging evidence of pneumonitis at the time of last follow-up (mean: 21.0±15.0 mo later, median: 21 mo, range: 2 to 47 mo). Oncologic responses to ICI therapy were available in 5 of these 6 cases, and included 3 patients with a complete response and no clinical or radiologic evidence of residual malignancy, 1 patient with stable metastatic disease, and 1 patient with slowly progressing disease. The patients with acute fibrinous pneumonitis and DAD both died, 9 days and 8 days after developing symptoms, respectively.

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DISCUSSION

Pneumonitis is a feared complication of ICI therapy and its clinical features are well-documented in the literature.8,9,12–14 Clinical manifestations of ICI-related pneumonitis vary widely, ranging from an insidious onset of respiratory symptoms with subacute or even subclinical asymptomatic disease, to severe and rapidly progressive acute respiratory failure that may be fatal.8 The histopathologic features of ICI-related pneumonitis are less well understood, but it is not surprising that the few available pathologic descriptions in the literature tend to mirror the wide spectrum of clinical manifestations that can occur with these agents. To date, several well-documented single cases have been reported that showed organizing pneumonia,15–17 DAD,18,19 granulomas,19 acute fibrinous and organizing pneumonia,20 and chronic interstitial lymphocytic infiltrates21 as histologic manifestations of this phenomenon, but many patients with clinically suspected ICI-related pneumonitis are never biopsied. Indeed, in one of the largest published series of patients with ICI-related pneumonitis to date, less than half of the patients underwent lung biopsy, and the pathologic findings in these biopsied patients were only available in a small subset.8 Our series corroborates the spectrum of pathologic changes that was reported by Naidoo et al,8 and advances our understanding of this phenomenon by incorporating the clinical and radiologic features in each case. To our knowledge, the present study is the first to systematically detail the histopathologic features of ICI-related pneumonitis and to correlate these findings with clinical and imaging findings, in a series of patients with a variety of malignancies and co-morbidities. Our study is also the first to document foamy macrophage accumulation and pneumocyte vacuolization as essentially universal findings in this context.

Adverse drug reactions remain one of the most challenging diagnoses to establish to a reasonable degree of clinical certainty. In his classic monograph on the subject,22 Irey defined requirements that must be met when a drug reaction is suspected. There must be proof of drug administration, temporal eligibility (ie, exposure to the drug before developing symptoms), and an appropriate latency period between drug administration and development of symptoms. In addition, empiric correlation between the drug and suspected reaction is supported when other possibilities have been eliminated by appropriate clinical and laboratory investigations (eg, a negative workup for infections and autoimmune disorders) or temporal ineligibility (eg, exclusion of other drugs). Empiric correlation is also supported when symptoms improve with discontinuation, when only one drug was given, and/or when the pattern of clinical symptoms is consistent with toxicity. Recurrence of symptoms with reexposure to the drug can further support a putative association, but a drug rechallenge may be unethical and is usually avoided. Using these criteria, 5 degrees of certainty were proposed by Irey (“Causative,” “Probable,” “Possible,” “Coincidental,” and “Negative”). In reality, proving a causal link between a drug and a suspected reaction can be very difficult if not impossible, even after all alternative explanations have been excluded, and cases with the strongest evidence generally fall at most into the “Probable” category. Fortunately, this degree of certainty is sufficient for clinical purposes, to prompt discontinuation of the drug and appropriate therapy.

Like irAEs in other organ systems, ICI-related pneumonitis is a highly unusual type of drug reaction that differs mechanistically from conventional types of adverse drug reactions, likely involving overactivation of the immune system with autoreactive T cells and production of interleukin-17 and other proinflammatory cytokines,1 unlike the various types of hypersensitivity reactions or direct nonimmunologic, cytotoxic, or idiosyncratic reactions that occur with other agents.23 Other potential mechanisms may include modulation of humoral immunity with increasing levels of preexisting autoantibodies, enhanced complement-mediated inflammation due to direct binding of the ICI antibody to CTLA-4 expressed on normal cells, or cross-reactivity with related antigens in normal tissue.1 Whether irAEs should be regarded as true drug reactions in the traditional sense of the term or something else entirely is unclear, but the principles underlying their diagnosis do not depend on the underlying mechanism and Irey’s criteria also apply to irAEs, despite the highly unusual nature of these events. In this study, all of the current cases fulfill Irey’s criteria for ICI agents being a “Probable” cause of the suspected adverse pulmonary reaction. Each patient received ICI therapy before developing symptoms, each showed histologic evidence suggesting an adverse drug reaction (prominent foamy macrophages and pneumocyte vacuolization, often with rare eosinophils), and an appropriate latency period (known to be widely variable with ICI-related pneumonitis8). Each case also fulfills at least one criterion for empiric correlation, including resolution of symptoms or imaging abnormalities with discontinuation, exclusion of infection and other potential causes with an appropriate clinical and laboratory workup, elimination of other drug possibilities, and/or clinical and radiographic findings consistent with a drug reaction. In addition, an ICI agent was the only medication class that was common to all cases. Lastly, 1 patient (case 2) experienced an adverse reaction with pembrolizumab that resolved when the drug was discontinued, followed by a very similar reaction with subsequent nivolumab therapy. These are not identical agents, but they are both directed against the same target (PD-1), and it could be argued that this represents a form of drug rechallenge. We believe these cases fulfill sufficient criteria to suggest a causal link between ICI therapy and the clinical and histopathologic manifestations in the lungs, consistent with Irey’s “Probable” category of certainty.22

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Differential Diagnoses

As with other drug reactions in the lung, the histopathologic manifestations of ICI-related pneumonitis are nonspecific, and the diagnosis is one of exclusion. Whether organizing pneumonia, granulomas, acute fibrinous pneumonitis, DAD, or other patterns of injury are seen, the differential diagnosis is similar and primarily includes infection, an acute exacerbation or flare of underlying systemic connective tissue disease, and a reaction to some other drug or therapeutic modality (eg, radiation). Clinically, the first and most important distinction to be made is between infection and other causes that may respond to corticosteroid therapy, as this binary decision will influence all subsequent clinical management. It should be remembered that infection always leads the differential diagnosis in the immunocompromised host, and this is often relevant in patients with advanced malignancy and prior chemotherapy. Special stains (eg, GMS and AFB stains or their equivalent) should be utilized liberally to rule in or rule out infection, preferably in combination with microbiologic cultures. Despite the presence of vague granulomas in some cases of ICI-related pneumonitis, necrosis was never seen, and it should be remembered that the probability of infection is high when necrotizing granulomas are present in the lung. If necrosis is seen, other ancillary testing for infectious diseases (eg, serologic and molecular testing) should be considered if cultures and special stains are negative.

Distinguishing de novo ICI-related pneumonitis from pneumonitis related to acute exacerbation of preexisting autoimmune disease is a challenge, as both represent autoimmune phenomena and may be inseparable from a practical standpoint. Fortunately, this distinction may not be critical as both are treated in a similar manner with steroids and immunomodulatory agents if necessary. More important is the question of whether ICI agents can be utilized safely in patients with a preexisting autoimmune disorder. The potential risk of potentiating acute flares of autoimmune disease with ICI therapy is well recognized, but data on the safety and efficacy of ICI agents in these patients is limited. Current evidence suggests that acute flares and irAEs are common in patients with preexisting autoimmune disease, and are usually mild and easily managed and do not necessarily require cessation of ICI therapy, but they can be fatal in rare cases.24,25 In our series, 4 patients had underlying autoimmune disease but none had prior pulmonary manifestations, suggesting that their pneumonitis represented a de novo irAE from ICI therapy, rather than an acute flare of autoimmune disease. Nevertheless, it is certainly possible that these reactions were driven by their underlying immunologic disorders and simply potentiated by ICI therapy.

Distinguishing ICI-related pneumonitis from pneumonitis induced by other drugs or therapeutic modalities is particularly challenging, and is not possible on histologic grounds alone. The list of medications known to cause pulmonary toxicity is long, and many agents can cause DAD, organizing pneumonia, granulomatous inflammation, and other patterns of injury in the lungs. Many agents are also associated with foamy macrophage accumulation, pneumocyte vacuolization, and eosinophil accumulation, and to date, no specific histologic features have been noted with any one agent. Furthermore, foamy macrophages, pneumocyte vacuolization, and eosinophil accumulation are not specific to drug reactions, and can be seen with acute lung injury from a variety of other causes.26–28 Foamy macrophages and eosinophils can be histologic clues that suggest an adverse drug reaction in an appropriate clinical context, but our cases demonstrate that the histopathologic features of ICI-related pneumonitis overlap considerably with those reported with many other drugs and other causes of acute lung injury. Furthermore, drug toxicities can be potentiated by the concomitant administration of other agents or radiation, and it may be difficult to separate the relative contribution of each suspected culprit in a patient who has received multiple medications or other therapies. Indeed, since the early days of ICI clinical trials and continuing to this day, there has been widespread concern about the potential for increased pulmonary toxicity when ICI therapy is combined with radiotherapy and this remains an area of intense investigation, but remains poorly understood.29,30 In our series, several patients received concomitant chemotherapy or radiation, and this is an obvious limitation of our study but is also consistent with a growing body of evidence of increased toxicity with combined immunotherapy and radiation,31 and the potential risk for developing toxicity with combined regimens that include an ICI cannot be ignored. Ultimately, distinguishing ICI-related pneumonitis from pneumonitis caused by some other agent requires a complete medication history, and may only be possible by careful clinicopathologic correlation after a trial of drug discontinuation and clinical follow-up.

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CONCLUSIONS

Pneumonitis is a potentially life-threatening complication of ICI therapy, but a positive outcome is aided by its early recognition and prompt drug discontinuation. ICI-related pneumonitis is a diagnosis of exclusion requiring high clinical suspicion and sometimes requiring a lung biopsy. The histopathologic manifestations of ICI-related pneumonitis are nonspecific and varied. Biopsies from patients with ICI-related pneumonitis often show a pattern of organizing pneumonia that can be admixed with vague non-necrotizing granulomas in airspaces, and patients with these findings tend to do well, but acute fibrinous pneumonitis or DAD can also occur. In our series, the latter 2 patterns were associated with fatal outcomes. Foamy macrophages and pneumocyte vacuolization are universally seen, and rare eosinophils are frequently encountered. These features are also nonspecific, but their presence may be an important histologic clue that provides additional supportive evidence when ICI-related pneumonitis is suspected. Perhaps even more importantly, in cases where a drug reaction is not clinically suspected, histopathologic features may be the first clue that a patient is experiencing an adverse reaction to an ICI. It would behoove surgical pathologists to be aware of these manifestations to prevent unnecessary delays in the diagnosis, particularly given the rapidly expanding use of ICIs for a variety of indications, and the increasing frequency of irAEs with these agents.

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Keywords:

immunotherapy; pembrolizumab; nivolumab; drug reaction

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