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Immune-checkpoint inhibitors have profoundly changed cancer treatment, improving the prognosis of many oncologic patients. However, despite the good efficacy of these drugs, their mechanism of action, which involves the activation of the immune system, can lead to immune-related adverse events, which may affect almost all organs. Pulmonary adverse events are relatively common, and potentially life-threatening complications may occur. The diagnosis is challenging due to the wide and non-specific spectrum of clinical and radiological manifestations. The role of the radiologist is to recognize and diagnose pulmonary immune-related adverse events, possibly even in the early stages, to estimate their extent and guide patients' management. [ABSTRACT FROM AUTHOR]

Open in new tab Download slide OBJECTIVES CALGB140503, in which nodal sampling was mandated, reported non-inferior disease-free survival for patients undergoing sublobar resection (SLR) compared to lobectomy (L). Outside of trial settings, the adequacy of lymphadenectomy during SLR has been questioned. We sought to evaluate whether SLR is associated with suboptimal lymphadenectomy, differences in pathologic upstaging and survival in patients with 1.5- to 2.0-cm tumours using real-world data. MATERIALS AND METHODS Using the National Cancer Database(2018–2019), we evaluated patients with 1.5- to 2.0-cm non-small-cell lung cancer who underwent resection (sublobar versus lobectomy). We studied factors associated with nodal upstaging (logistic regression) and survival (Cox regression and Kaplan–Meier method) after propensity matching to adjust for differences among groups. RESULTS Among 3196 patients included, SLR was performed in 839 (26.3%) (of which 588 were wedge resections) and L was performed in 2357 (73.7%) patients. More patients undergoing SLR (21.7%) compared to L (2.1%) had no lymph nodes sampled (P  < 0.001). Those undergoing SLR had fewer total lymph nodes examined (4 vs 11, P  < 0.001) and were less likely to have pathologic nodal metastases (4.7% vs 9%, P  < 0.001) compared to L. Multivariable analysis identified L [adjusted odds ratio (aOR) 2.21, 95% confidence interval, 1.47–3.35] to be independently associated with pathologic N+ disease. Overall survival was not associated with the type of procedure but was significantly decreased in those with N+ disease. CONCLUSIONS Despite comparable overall survival to L, SLR is associated with suboptimal lymphadenectomy in patients with 1.5–2.0 cm non-small-cell lung cancer. Surgeons should be careful to perform adequate lymphadenectomy when performing SLR to mitigate nodal under-staging and to identify appropriate patients for systemic therapy. [ABSTRACT FROM AUTHOR]

Abstract An 81 year old male with Child‐Pugh A cirrhosis and metastatic hepatocellular carcinoma (HCC) treated with 3‐weekly atezolizumab and bevacizumab developed a pulmonary sarcoid‐like reaction (SLR) after 5 months. Atezolizumab, an immune checkpoint inhibitor, was identified as the likely culprit. He was treated with prednisolone, resulting in improvement, and was successfully rechallenged with both atezolizumab and bevacizumab.

An 81 year old male with Child‐Pugh A cirrhosis and metastatic hepatocellular carcinoma (HCC) treated with 3‐weekly atezolizumab and bevacizumab developed a pulmonary sarcoid‐like reaction (SLR) after 5 months. Atezolizumab, an immune checkpoint inhibitor, was identified as the likely culprit. He was treated with prednisolone, resulting in improvement, and was successfully rechallenged with both atezolizumab and bevacizumab. [ABSTRACT FROM AUTHOR]

Sarcoid Like Reaction (SLR) is a localized non-caseating epithelioid granulomatous reaction seen secondary to certain immunotherapies and malignancies. Invasive melanoma, while being associated with onset of sarcoidosis, has not shown to directly induce SLR in the literature. We present the case of a 68-year-old male with malignant melanoma, who was found to have SLR prior to starting immunotherapy, which worsened while on pembrolizumab. This case highlights the challenge of distinguishing between drug-induced SLR and melanoma-induced SLR, and the implications in terms of management.

BackgroundCoronavirus disease (COVID-19)-associated acute pericarditis has recently received much attention owing to its high frequency associated with pericardial tamponade (PT), showing unfavorable prognosis. However, early diagnosis and treatment remain challenging in cases of non-specific signs and symptoms.Case presentationA 64-year-old man was admitted to our hospital for acute osteomyelitis of the toes and was properly treated with antimicrobial agents. Three days after admission, the patient developed mild COVID-19 without pneumonia, for which early anti-COVID-19 agents were initiated. Nevertheless, the patient developed hemorrhagic PT due to acute pericarditis 2 weeks later, which was confirmed by cardiac magnetic resonance, requiring an urgent pericardiocentesis. Although cytological analysis of the hemorrhagic pericardial fluid strongly suggested adenocarcinoma, the atypical cells were eventually proven to be mesothelial cells with reactive atypia. Furthermore, lymph nodes swelling with abnormal 2-[18F]-fluoro-2-deoxy-D-glucose accumulation on imaging were suggestive of malignancy. However, biopsy examination revealed multiple non-caseating granulomas in the lymph node, unlikely due to malignancy. Eventually, the temporal association of the preceding COVID-19 with the occurrence of subacute PT without other identifiable cause led to a final diagnosis of COVID-19-associated acute pericarditis. With anti-inflammatory and corticosteroids treatment, the patient's symptoms involving the pericardial structure and function were completely resolved along with improvements in size of the affected lymphadenopathies.ConclusionsWe encountered a unique case of COVID-19-associated acute pericarditis exhibiting hemorrhagic PT. This case underscores the residual risk of delayed pericardial involvement even in patients with mild COVID-19 who receive early treatment, and the recognition that COVID-19 may cause various cytomorphological and histological features. Additionally, the importance of considering this rare entity as a cause of hemorrhagic pericardial effusions should be highlighted.

The association between sarcoidosis and autoimmunity has been reported for years. However, the significance of autoantibodies in the pathophysiology and clinical management of sarcoidosis is not well understood. No autoantibodies that can be used as serologic biomarkers to diagnose the disease, monitor the state of the disease, and predict the prognosis of patients are established. We performed a comprehensive analysis of serum autoantibodies and analyzed their associations with clinical features of sarcoidosis. Patients with systemic autoimmune rheumatic diseases-associated autoantibodies had a higher prevalence of advanced radiographic stage and consolidations in high-resolution computed tomography than patients without autoantibodies (p <.05). Age, sex, clinical history, pulmonary function tests, serum angiotensin-converting enzyme levels, rheumatoid factor, and the number of involved organs were not significantly different between the two groups. There may be an association between autoantibodies and more advanced pulmonary lesions in patients with sarcoidosis. Further investigations are needed to establish the significance of autoantibodies. [ABSTRACT FROM AUTHOR]

Pulmonary cavitary lesions visible on a chest radiograph can be a diagnostic challenge. It is necessary to take into consideration a wide differential diagnosis and to conduct a wide range of examinations to confirm their exact cause. A 44-year-old woman with a history of endometrial adenocarcinoma was admitted to the pulmonology department to diagnose mediastinal lymphadenopathy with coexisting nodules in the lung parenchyma. The X-ray and positron emission tomography (PET) showed cavitating lesions in the lungs, which could correspond to metastases, but the laboratory and histopathological tests did not confirm any neoplastic features. In specimens obtained by endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) and video-assisted thoracoscopic surgery (VATs) non-caseating granulomas were found, which suggested sarcoidosis or a sarcoid-like reaction. At an advanced stage of pulmonary changes, the presence of neoplastic cells was revealed in the sputum. Despite chemotherapy the patient died. Multiple pulmonary metastases were confirmed in the post-mortem examination. This case is an example of a rare sarcoid-like reaction in the mediastinum and lung parenchyma due to cancer located below the diaphragm. Differentiating between sarcoidosis, a sarcoid-like reaction and lung metastases in similar cases may be difficult. For this reason, it should be advisable to repeat diagnostic procedures in patients with malignancies in the past, including EBUS-TBNA and VATs.

Abstract Background Sarcoidosis is a systemic inflammatory disease that is characterized by non-caseating epithelioid-cell granulomas upon histology. However, similar histological findings may also be seen with certain infections. Thus, differentiation from infection is pivotal to ensure appropriate treatment. Here, we present a case of a disseminated infection with Mycobacterium genavense owing to an interleukin 12 receptor subunit beta 1 (IL-12Rβ1) associated immunodeficiency in a previously healthy female who was initially misdiagnosed with sarcoidosis. M. genavense is a nontuberculous mycobacterium which can cause lymphadenopathy, gastrointestinal and bone marrow infiltration in immunocompromised patients. With this case report we aim to highlight that an infection with M. genavense on the ground of a genetic defect of mycobacterial immune control may represent a rare differential diagnosis of sarcoidosis. Case presentation A 31-year-old female was referred to our hospital with progressive lymphadenopathy, hepatosplenomegaly, pancytopenia and systemic inflammation. She had previously been evaluated for generalized lymphadenopathy in another hospital. At that time, lymph node biopsies had revealed sarcoid-like lesions and a systemic corticosteroid treatment was initiated based on a putative diagnosis of sarcoidosis. When her condition worsened, she was transferred to our university clinic, where the diagnosis of disseminated M. genavense infection owing to an inborn interferonopathy was made. Her family history revealed that her brother had also suffered from IL-12Rβ1 deficiency and had died from a systemic infection with M. genavense at the age of 21. The patient received antimycobacterial treatment combined with subcutaneous type I interferon, which eventually led to a gradual improvement over the next months. Conclusions Differentiating between sarcoidosis and sarcoid-like lesions secondary to infections may be challenging, especially when pathogens are difficult to detect or not expected in an apparently immunocompetent patient. Patients with IL-12Rβ1-associated immunodeficiency may be asymptomatic until adulthood, and disseminated M. genavense infection on the grounds of an IL-12Rβ1-associated immunodeficiency may represent a rare differential diagnosis of sarcoidosis.

Sarcoidosis is a multisystemic and chronic inflammatory disorder characterized by the manifestation of epithelioid cell granulomas in various organs. Sarcoid-like reactions occur in patients who do not fulfill the diagnostic criteria for sarcoidosis but present with similar clinical and histological features. An 80-year-old man presented to our hospital with several subcutaneous nodules on the extremities. Based on clinical and pathological findings, the subcutaneous nodules were diagnosed as sarcoid nodules. However, the patient did not meet the diagnostic criteria for sarcoidosis. Positron emission tomography-computed tomography revealed abnormalities in several uptakes in the extremities that matched with the subcutaneous nodules and transverse colon. Additional examinations using lower gastrointestinal endoscopy, pathological examination, and contrast-enhanced computed tomography revealed tubular adenocarcinoma of the transverse colon. The patient underwent partial colon resection and lymph node dissection. The sarcoid nodules disappeared within 2 months postoperatively. Approximately 2 years later, there were no signs of recurrence of subcutaneous nodules, colon cancer, or additional findings suggestive of sarcoidosis. To our knowledge, this is the first report on a sarcoid-like reaction developing in the subcutaneous tissues of the extremities, associated with colon cancer, wherein the sarcoid nodules disappeared after the operation. [ABSTRACT FROM AUTHOR]

Sarcoidosis is a heterogeneous disease, which can affect virtually every body organ, even though lungs and intra thoracic lymph nodes are almost universally affected. The presence of noncaseating granulomas is the histopathological hallmark of the disease, and clinical picture depends on the organs affected. Data about interaction between sarcoidosis and comorbidities, such as cardiovascular and pulmonary diseases, autoimmune disorders, malignancy and drug-related adverse events are limited. Several lung conditions can be associated with sarcoidosis, such as pulmonary hypertension and fibrosis, making it difficult sometimes the differentiation between complications and distinctive pathologies. Their coexistence may complicate the diagnosis of sarcoidosis and contribute to the highly variable and unpredictable natural history, particularly if several diseases are recognised. A thorough assessment of specific disorders that can be associated with sarcoidosis should always be carried out, and future studies will need to evaluate sarcoidosis not only as a single disorder, but also in the light of possible concomitant conditions. Comorbidities in sarcoidosis are common, especially cardiovascular and pulmonary diseases. In the diagnostic workup, a distinction must be made between sarcoidosis-related complaints and complaints caused by other separate disorders. It can be very difficult to distinguish between complications of sarcoidosis and other concomitant conditions. The coexistence of multiple conditions may complicate the diagnosis of sarcoidosis, affect its natural course and response to treatment. [ABSTRACT FROM AUTHOR]

Background: Sarcoidosis is a systemic inflammatory disease that is characterized by non-caseating epithelioid-cell granulomas upon histology. However, similar histological findings may also be seen with certain infections. Thus, differentiation from infection is pivotal to ensure appropriate treatment. Here, we present a case of a disseminated infection with Mycobacterium genavense owing to an interleukin 12 receptor subunit beta 1 (IL-12Rβ1) associated immunodeficiency in a previously healthy female who was initially misdiagnosed with sarcoidosis. M. genavense is a nontuberculous mycobacterium which can cause lymphadenopathy, gastrointestinal and bone marrow infiltration in immunocompromised patients. With this case report we aim to highlight that an infection with M. genavense on the ground of a genetic defect of mycobacterial immune control may represent a rare differential diagnosis of sarcoidosis.Case Presentation: A 31-year-old female was referred to our hospital with progressive lymphadenopathy, hepatosplenomegaly, pancytopenia and systemic inflammation. She had previously been evaluated for generalized lymphadenopathy in another hospital. At that time, lymph node biopsies had revealed sarcoid-like lesions and a systemic corticosteroid treatment was initiated based on a putative diagnosis of sarcoidosis. When her condition worsened, she was transferred to our university clinic, where the diagnosis of disseminated M. genavense infection owing to an inborn interferonopathy was made. Her family history revealed that her brother had also suffered from IL-12Rβ1 deficiency and had died from a systemic infection with M. genavense at the age of 21. The patient received antimycobacterial treatment combined with subcutaneous type I interferon, which eventually led to a gradual improvement over the next months.Conclusions: Differentiating between sarcoidosis and sarcoid-like lesions secondary to infections may be challenging, especially when pathogens are difficult to detect or not expected in an apparently immunocompetent patient. Patients with IL-12Rβ1-associated immunodeficiency may be asymptomatic until adulthood, and disseminated M. genavense infection on the grounds of an IL-12Rβ1-associated immunodeficiency may represent a rare differential diagnosis of sarcoidosis. [ABSTRACT FROM AUTHOR]

Background: The drug-induced sarcoidosis-like reaction (DISR) is a condition clinically and pathologically similar to sarcoidosis but is induced by certain drugs. A few cases of DISR associated with the use of TNF-α antagonists have been reported in the literature., Case Report: A 49-year-old female patient with a diagnosis of Crohn's Disease under treatment with adalimumab presented with a 2-month-long ulcerated swelling in the left lower fornix. Histological analysis of the biopsy specimen revealed multiple non-caseating granulomas multinucleated cells and epithelioid macrophages surrounded by lymphocytes. The lesion is under symptomatic control with a topical corticosteroid, and the patient is being monitored for manifestation in other organs and systems., Conclusion: Lesions of DISR may occur isolated in the oral mucosa. Therefore, this complication must be considered in the differential diagnosis of oral granulomatous lesions in patients under treatment with anti-TNF-α drugs., Competing Interests: Declaration of Competing Interest The authors declare that there is no potential conflict of interest regarding this work., (Copyright © 2023 Elsevier Masson SAS. All rights reserved.)

A 48-year-old woman with regional recurrences of breast cancer in the axillar and supraclavicular regions was referred to our hospital. Under the diagnosis of recurrent luminal breast cancer with a high Ki-67 labeling index of >30% and a disease-free interval of 13 years, the patient began to receive palbociclib, letrozole, and luteinizing hormone-releasing hormone agonist, resulting in marked response of the supraclavicular lesion and stable disease of the axillar lesion on ultrasound (US) evaluation. Positron emission tomography (PET)/computed tomography of the axillar and supraclavicular foci showed high and no avidities before and after treatment, respectively. The unmovable neck lesion became movable with the treatment. The patient, therefore, underwent surgical resection of the 2 metastatic foci to examine the discordant therapeutic efficacy against the 2 metastatic foci on 2 image modalities, that is, US and PET, and to possibly get a cure of the breast cancer oligometastasis. Pathological examination showed marked fibrosis and scant cancer cell residuals with microcalcifications in the neck tumor and massive sarcoid-like reaction with scant cancer cell residuals in the axillary nodes. The residual cancer cells showed estrogen and progesterone receptor positivities, human epidermal growth factor receptor type 2 negativity, and an extremely low Ki-67 labeling index of 2.5%. The patient recovered uneventfully and has continued palbociclib-containing endocrine therapy for 1 year without any recurrences. Breast oncologists should well understand the basic principles of internal echo formation on US and take the presence of sarcoid-like reaction in the cancer cell clusters into consideration on the therapeutic evaluation of metastatic breast cancer.

The use of immune-checkpoint inhibitor (ICI) therapy has significantly improved patient outcomes in a wide variety of cancers and has become a cornerstone in the treatment of renal cell carcinoma. However, ICI treatment has the potential to cause a variety of immune-related adverse events (irAEs) that can affect any tissue or organ. This report describes the diagnostic dilemma of a patient with both RCC and diffuse large B-cell lymphoma who developed acute onset of fever and diffuse lymphadenopathy following treatment with combined ipilimumab and nivolumab. While diagnostic considerations included worsening lymphoma, hyperprogression of RCC, sarcoid-like reaction from immunotherapy, and fungal infection, his lymphadenopathy eventually resolved with treatment for histoplasmosis and discontinuation of immunotherapy. Despite only receiving two doses of immunotherapy, he has not required additional systemic therapy for RCC. This case demonstrates both the effectiveness of ICI therapy and the need for multidisciplinary approach to potential irAEs. [ABSTRACT FROM AUTHOR]

Abstract Background Sarcoid-like reaction (SLR) is a histological pattern of granulomatous inflammation that is clinically differentiated from sarcoidosis. Since SLR is known to occur in several neoplasias and occasionally causes lymphadenopathy and mimics metastatic malignancy, it needs to be considered whether lymphadenopathy is due to metastasis or SLR for the choice of cancer treatment. Few cases of hepatocellular carcinoma (HCC) with SLR have been reported. Here, a case of HCC with lymphadenopathy diagnosed as SLR without metastasis is presented. Case presentation A 69-year-old woman was admitted to our hospital because of upper abdominal pain. She tested positive for hepatitis C virus ribonucleic acid. Imaging modalities showed an 81 × 65-mm-sized tumor with multiple nodules in segment 3 and a 17 × 12-mm-sized tumor in segment 5 with a common HCC enhancement pattern. In addition, a lymph node in the hepatoduodenal ligament was enlarged at 13 mm in size, suggesting the metastasis of HCC. Hepatectomy of the lateral segment and segment 5 and lymph node dissection in the hepatoduodenal ligament were performed. Both tumors in segments 3 and 5 were pathologically diagnosed as HCC without vessel invasion. The tumors contained necrotic cells and epithelioid cell granulomas with multinucleated giant cells, which is typically observed in sarcoidosis. The dissected lymph nodes also contained epithelioid cell granulomas, as well as giant cells with asteroid bodies. There was no malignancy in the lymph nodes. The pathological findings suggested the coexistence of malignancy and sarcoidosis. However, since the patient did not show any typical findings of pulmonary or cardiac sarcoidosis, the case was diagnosed as HCC with SLR in the primary lesion and regional lymph nodes. Conclusions SLR needs to be considered in the differential diagnosis when a cancer patient develops lymphadenopathy. However, lymphadenopathy due to SLR is indistinguishable from that due to metastasis even when using multiple imaging modalities. Pathological examinations may be helpful for the diagnosis.

The use of immune-checkpoint inhibitor (ICI) therapy has significantly improved patient outcomes in a wide variety of cancers and has become a cornerstone in the treatment of renal cell carcinoma. However, ICI treatment has the potential to cause a variety of immune-related adverse events (irAEs) that can affect any tissue or organ. This report describes the diagnostic dilemma of a patient with both RCC and diffuse large B-cell lymphoma who developed acute onset of fever and diffuse lymphadenopathy following treatment with combined ipilimumab and nivolumab. While diagnostic considerations included worsening lymphoma, hyperprogression of RCC, sarcoid-like reaction from immunotherapy, and fungal infection, his lymphadenopathy eventually resolved with treatment for histoplasmosis and discontinuation of immunotherapy. Despite only receiving two doses of immunotherapy, he has not required additional systemic therapy for RCC. This case demonstrates both the effectiveness of ICI therapy and the need for multidisciplinary approach to potential irAEs.

Immune checkpoint inhibitor (ICI) treatment has dramatically revolutionized the landscape of therapeutic approaches in multiple cancers, particularly, non-small-cell lung cancer (NSCLC). With the increasing use of programmed death-1 (PD-1) inhibitors in the clinic, the emerging toxicity profile presents a novel learning curve for clinicians. Here we report the first case of an NSCLC patient displaying sarcoid/granulomatous-like reaction (SLR, also known as GLR) in the liver during an anti-PD-1 therapy which showed efficacious response of complete regression. Also, this is the first report describing the SLR induced by toripalimab, a novel PD-1 inhibitor. Given this kind of hepatic findings can be easily mistaken as metastasis, even resulting in premature use of second-line treatments. In particular, we briefly review the clinical features of all those cases reporting sarcoidosis and SLRs manifested on different organs during anti-PD-(L)1 therapy. We anticipate that these clinical cases would help to alert the attention of clinicians that SLRs, as a rare immune-related adverse event (irAE), is manageable and that histopathological analysis is necessary before interpreting it as disease progression. [ABSTRACT FROM AUTHOR]

Immune checkpoint inhibitor-induced sarcoid-like reactions and tertiary lymphoid structures (TLSs) are increasingly recognized but rarely reported in the same patient. We report a patient with lung adenocarcinoma who displayed sarcoid-like reactions in intrathoracic lymph nodes and tertiary lymphoid structures in surgical tumor after neoadjuvant therapy with nivolumab plus ipilimumab. Pathological examination revealed 50% residual tumor cells after treatment, and the CT evaluation of the primary tumor showed a stable disease. The patient experienced a recurrence eight months after surgery. To identify immune correlates of the limited response to immunotherapy, we conducted genomic and transcriptional assays, multiplex immunoassay, and multiplex immunohistochemistry on the pre- and post-immunotherapy tumor, lymph node, and plasma samples. TP53 R181C, KRAS G12C and SMAD4 R361H were identified as driver mutations of the tumor. In addition to abundant infiltrated lymphocytes, immunotherapy induced high levels of inhibitory components in post-treatment tissue samples, especially the FOXP3+ regulatory T cells in tumor and PD-L1 expression in the lymph node. Despite abundant TLSs in the post-treatment tumor, most TLSs were immature. Moreover, increasing levels of circulating checkpoint proteins BTLA, TIM-3, LAG-3, PD-1, PD-L1, and CTLA4 were observed during immunotherapy. Collectively, our observations revealed that high levels of immunosuppressive molecules in tumor, lymph nodes and/or in peripheral blood might indicate poor outcomes after immunotherapy, even in the setting of a patient with concurrent sarcoid-like reactions and tertiary lymphoid structures. [ABSTRACT FROM AUTHOR]

Introduction Testicular germ cell cancer has a relatively good prognosis even if visceral and/or lymph node metastases are present thanks to chemotherapy. Yet chemotherapy can lead to various adverse events. Therefore, it is crucial to distinguish whether a suspected metastatic disease is metastasis or not. Case presentation A 33‐year‐old male visited our hospital to receive subsequent therapy for suspected recurrent seminoma with a progressing pulmonary nodule and mediastinal lymphadenopathy after orchiectomy. The pathological diagnosis of needle aspiration and resected specimen of the several lesions was consistent with epithelioid cell granuloma without caseous necrosis. Based on these findings, the lung and mediastinal lymph node lesions were diagnosed as sarcoidosis. Conclusion In cases where the simultaneous occurrence of other benign or malignant diseases is suspected, pathological confirmation is necessary for appropriate decision‐making.

Immune checkpoint inhibitor (ICI) treatment has dramatically revolutionized the landscape of therapeutic approaches in multiple cancers, particularly, non-small-cell lung cancer (NSCLC). With the increasing use of programmed death-1 (PD-1) inhibitors in the clinic, the emerging toxicity profile presents a novel learning curve for clinicians. Here we report the first case of an NSCLC patient displaying sarcoid/granulomatous-like reaction (SLR, also known as GLR) in the liver during an anti-PD-1 therapy which showed efficacious response of complete regression. Also, this is the first report describing the SLR induced by toripalimab, a novel PD-1 inhibitor. Given this kind of hepatic findings can be easily mistaken as metastasis, even resulting in premature use of second-line treatments. In particular, we briefly review the clinical features of all those cases reporting sarcoidosis and SLRs manifested on different organs during anti-PD-(L)1 therapy. We anticipate that these clinical cases would help to alert the attention of clinicians that SLRs, as a rare immune-related adverse event (irAE), is manageable and that histopathological analysis is necessary before interpreting it as disease progression.

Immune checkpoint inhibitor-induced sarcoid-like reactions and tertiary lymphoid structures (TLSs) are increasingly recognized but rarely reported in the same patient. We report a patient with lung adenocarcinoma who displayed sarcoid-like reactions in intrathoracic lymph nodes and tertiary lymphoid structures in surgical tumor after neoadjuvant therapy with nivolumab plus ipilimumab. Pathological examination revealed 50% residual tumor cells after treatment, and the CT evaluation of the primary tumor showed a stable disease. The patient experienced a recurrence eight months after surgery. To identify immune correlates of the limited response to immunotherapy, we conducted genomic and transcriptional assays, multiplex immunoassay, and multiplex immunohistochemistry on the pre- and post-immunotherapy tumor, lymph node, and plasma samples. TP53 R181C, KRAS G12C and SMAD4 R361H were identified as driver mutations of the tumor. In addition to abundant infiltrated lymphocytes, immunotherapy induced high levels of inhibitory components in post-treatment tissue samples, especially the FOXP3+ regulatory T cells in tumor and PD-L1 expression in the lymph node. Despite abundant TLSs in the post-treatment tumor, most TLSs were immature. Moreover, increasing levels of circulating checkpoint proteins BTLA, TIM-3, LAG-3, PD-1, PD-L1, and CTLA4 were observed during immunotherapy. Collectively, our observations revealed that high levels of immunosuppressive molecules in tumor, lymph nodes and/or in peripheral blood might indicate poor outcomes after immunotherapy, even in the setting of a patient with concurrent sarcoid-like reactions and tertiary lymphoid structures.

Sarcoidosis and sarcoid-like reactions (SLR) have been repeatedly reported in patients with melanoma treated with BRAF and MEK inhibitors. In the current study we present three patients that developed SLR under treatment with BRAF and mitogen-activated protein kinase (MEK) inhibitors for melanoma. Two patients developed mediastinal lymphadenitis with histological features of an SLR while on targeted therapy in the adjuvant setting, whereas one patient with metastatic melanoma developed granulomatous nephritis while receiving combination treatment with BRAF/MEK inhibitors and atezolizumab. In addition, we review the published literature on the pathogenesis, clinical characteristics, histologic features, imaging findings, and other potential useful diagnostic tools. We also address the need for a common terminology for these cases and propose an algorithm for the accurate diagnosis of BRAF/MEK inhibitor-induced SLR. We also review the currently available data on the treatment of these patients and suggest a treatment approach for SLR in patients with melanoma, as well as for the management of melanoma when SLR emerges. [ABSTRACT FROM AUTHOR]

Drug-induced sarcoidosis-like reaction (DISR) is a condition almost indistinguishable from sarcoidosis, both clinically and microscopically, consisting of granulomatous tissue reaction associated with a specific therapy. Commonly affected sites are the lungs, hilar lymph nodes, and skin. This report aimed to describe a very uncommon case of DISR with an unique involvement of the oral cavity. A 63-year-old female with a history of rheumatoid arthritis, who was treated with a TNF-α antagonist (adalimumab), presented multiple ulcerative nodules on the hard palate. Laboratory tests and imaging studies failed to show any other alterations. The biopsy specimen demonstrated multiple noncaseating granulomas. Histochemical reactions were negative for acid-fast bacilli and fungi, and immunohistochemical assessment highlighted the presence of normal lymphocytes and histiocytes. With the diagnosis of DISR, adalimumab was discontinued, and complete clinical resolution of the lesions was achieved after 14 months. Although uncommon, DISR should be considered in differential diagnoses of oral granulomatous reactions, especially in cases where the patient is being treated with TNF-α antagonists. [ABSTRACT FROM AUTHOR]

A 48-year-old woman with regional recurrences of breast cancer in the axillar and supraclavicular regions was referred to our hospital. Under the diagnosis of recurrent luminal breast cancer with a high Ki-67 labeling index of >30% and a disease-free interval of 13 years, the patient began to receive palbociclib, letrozole, and luteinizing hormone-releasing hormone agonist, resulting in marked response of the supraclavicular lesion and stable disease of the axillar lesion on ultrasound (US) evaluation. Positron emission tomography (PET)/computed tomography of the axillar and supraclavicular foci showed high and no avidities before and after treatment, respectively. The unmovable neck lesion became movable with the treatment. The patient, therefore, underwent surgical resection of the 2 metastatic foci to examine the discordant therapeutic efficacy against the 2 metastatic foci on 2 image modalities, that is, US and PET, and to possibly get a cure of the breast cancer oligometastasis. Pathological examination showed marked fibrosis and scant cancer cell residuals with microcalcifications in the neck tumor and massive sarcoid-like reaction with scant cancer cell residuals in the axillary nodes. The residual cancer cells showed estrogen and progesterone receptor positivities, human epidermal growth factor receptor type 2 negativity, and an extremely low Ki-67 labeling index of 2.5%. The patient recovered uneventfully and has continued palbociclib-containing endocrine therapy for 1 year without any recurrences. Breast oncologists should well understand the basic principles of internal echo formation on US and take the presence of sarcoid-like reaction in the cancer cell clusters into consideration on the therapeutic evaluation of metastatic breast cancer. [ABSTRACT FROM AUTHOR]

Abstract Background The utilization of monoclonal antibodies has become more widespread over the past decade. However, the development of non-caseating granulomas with the use of monoclonal antibodies, such as ustekinumab, is not widely reported in the literature. Case presentation We report a case of a 50-year-old Caucasian male who presented complaining of weight loss and shortness of breath. He was receiving ustekinumab for refractory psoriasis but had no other significant medical comorbidities. On physical examination, reduced breath sounds on the right side were noted. Blood cultures were drawn on presentation and came back negative in 48 hours. A chest computed tomography scan revealed a large right lung mass in addition to right-sided pleural effusion. Therapeutic thoracocentesis was done; fluid cytology and analysis were negative for malignancy, acid-fast bacilli, or fungal infections. A positron emission tomography scan showed multifocal radiotracer uptake including within right lung mass, multiple bones, lymph nodes, liver and spleen. Biopsies showed hyalinized non-necrotizing granulomas. Immunohistochemical stains for AE1/AE3, cytokeratin 7 and 20, and thyroid transcription factor 1, were all negative. He was started on steroid therapy, and ustekinumab was discontinued and the follow-up computed tomography after a few months showed substantial improvement. However, over the course of next 4 months patient developed hepatic dysfunction and recurrent ascites and ultimately underwent transjugular intrahepatic portosystemic shunt placement. Furthermore, he was started on azathioprine and steroids were tapered. He improved clinically and was discharged from our hospital within a week. Conclusions This case highlights the need for careful consideration of patient medication history while evaluating the possible differential diagnoses that may contribute to a patient’s presentation.

Background: Sarcoid-like reaction (SLR) is a histological pattern of granulomatous inflammation that is clinically differentiated from sarcoidosis. Since SLR is known to occur in several neoplasias and occasionally causes lymphadenopathy and mimics metastatic malignancy, it needs to be considered whether lymphadenopathy is due to metastasis or SLR for the choice of cancer treatment. Few cases of hepatocellular carcinoma (HCC) with SLR have been reported. Here, a case of HCC with lymphadenopathy diagnosed as SLR without metastasis is presented. Case presentation: A 69-year-old woman was admitted to our hospital because of upper abdominal pain. She tested positive for hepatitis C virus ribonucleic acid. Imaging modalities showed an 81 × 65-mm-sized tumor with multiple nodules in segment 3 and a 17 × 12-mm-sized tumor in segment 5 with a common HCC enhancement pattern. In addition, a lymph node in the hepatoduodenal ligament was enlarged at 13 mm in size, suggesting the metastasis of HCC. Hepatectomy of the lateral segment and segment 5 and lymph node dissection in the hepatoduodenal ligament were performed. Both tumors in segments 3 and 5 were pathologically diagnosed as HCC without vessel invasion. The tumors contained necrotic cells and epithelioid cell granulomas with multinucleated giant cells, which is typically observed in sarcoidosis. The dissected lymph nodes also contained epithelioid cell granulomas, as well as giant cells with asteroid bodies. There was no malignancy in the lymph nodes. The pathological findings suggested the coexistence of malignancy and sarcoidosis. However, since the patient did not show any typical findings of pulmonary or cardiac sarcoidosis, the case was diagnosed as HCC with SLR in the primary lesion and regional lymph nodes. Conclusions: SLR needs to be considered in the differential diagnosis when a cancer patient develops lymphadenopathy. However, lymphadenopathy due to SLR is indistinguishable from that due to metastasis even when using multiple imaging modalities. Pathological examinations may be helpful for the diagnosis. [ABSTRACT FROM AUTHOR]

Sarcoidosis is a multisystem granulomatous disorder characterized by helper T cell inflammation. Sarcoid-like reaction (SLR) is a well-defined entity and may be related with several malignant disorders and/or their therapies. SLR has been reported more than 20 years ago and in recent years in cases treated by checkpoint inhibitors (CPIs). Better outcome has been reported in cases developing granulomatous reaction and/or SLRs during CPI treatments. However, these lesions clinically may be thought as disease progression and may cause to stop treatment or alterations. These therapeutic manipulations may be harmful for the patients. Clinicians should be aware of SLRs in cases treated by CPIs and tissues must be sampled and reviewed by an experienced pathologist to avoid misdiagnosis and also unnecessary CPI treatment cessations.Significance StatementClinicians should be aware of sarcoid-like reactions in cases treated by checkpoint inhibitors and tissues must be sampled and reviewed by an experienced pathologist to avoid misdiagnosis and CPI treatment stops. [ABSTRACT FROM AUTHOR]

Purpose: Sarcoidosis is a chronic idiopathic granulomatous inflammatory disease that can affect many major organ systems, primarily the lungs, and hence has remarkable clinical heterogeneity. At least 50% of patients with systemic sarcoidosis develop inflammatory eye disease, and in approximately 21% of cases, it may be the first clinical manifestation. Neuro-ocular involvement occurs in

Abstract Background In patients with esophageal cancer, differentiation between lymph node metastasis and lymphadenopathies from sarcoidosis or sarcoid-like reactions of lymph nodes is clinically important. Herein, we report two esophageal cancer cases with lymph node involvement of sarcoid-like reaction or sarcoidosis. Case presentation One patient received chemotherapy and the other chemoradiotherapy as initial treatments. In both cases, [18F]-fluorodeoxyglucose positron emission tomography–computed tomography (FDG-PET/CT) was performed before and after chemo(radio)therapy. After the treatment, FDG uptake was not detected in the primary tumor, but it was slightly reduced in the hilar and mediastinal lymph nodes in both cases. These non-identical responses to chemo(radio)therapy suggest the presence of sarcoid-like reaction of lymph nodes associated with squamous cell carcinoma of the esophagus. Curative surgical resection was performed as treatment. Conclusions These FDG-PET/CT findings may be helpful to distinguish between metastasis and sarcoidosis-associated lymphadenopathy in esophageal cancer.

Abstract Background Immune checkpoint inhibitors (ICI) target T cell inhibitory pathways that are responsible for cancer tolerance by down-modulating immune functions. ICI have revolutionized patients care with lung cancer. Nevertheless, restoring endogenous antitumor T-cell responses can induce immune related adverse events, such as sarcoidosis. Case presentation We report here the first case of a thoracic and cutaneous sarcoid-like reaction in a patient with a relapsing unresectable non-small cell lung cancer (NSCLC) treated with nivolumab, an anti-PD-1 mAb. The expression of PD-1 and its ligands, PD-L1 and PD-L2, was assessed by flow cytometry on peripheral blood mononuclear cells (PBMC) and compared to patients who had discontinued nivolumab therapy without having developed any immune related adverse events. PD-L1 expression was transiently increased on B cells, T cells and monocytes, whereas PD-L2 expression was not modulated. PD-1 was transiently undetectable when PD-L1 was maximal, before returning to basal level. Sarcoidosis spontaneously resolved, without corticotherapy. Conclusion This case sheds the light on a complex regulation of PD-L1 expression in vivo on PBMC after nivolumab arrest and triggers the question of monitoring the expression of immune checkpoint on immune cells during and after treatment with ICI.

Abstract Background Sarcoidosis is a multisystem, chronic granulomatous disease of unknown etiology that predominantly affects the lungs. Pulmonary sarcoidosis classically presents with constitutional symptoms and computed tomographic scan findings of bilateral, symmetric micronodules in a peribronchovascular distribution with upper and middle lung zone predominance accompanied by bilateral, symmetric hilar lymphadenopathy. A solitary lung mass is a rare finding for pulmonary sarcoidosis, and with its associated constitutional symptoms, it strongly mimics a malignancy. We aimed to provide further insight into the broad differential diagnosis of a lung mass by describing our experiences in the care of a patient who presented with clinical and radiographic features of lung cancer who was ultimately found to have an atypical manifestation of stage II pulmonary sarcoidosis. Case presentation A 44-year-old African American woman with a history of childhood asthma and type 2 diabetes mellitus presented with shortness of breath. After being treated for a presumed asthma exacerbation with prednisone, she experienced worsening dyspnea, night sweats, and unintentional weight loss. Further evaluation revealed a large left lower lobe mass and hilar lymphadenopathy. A computed tomography-guided biopsy of the lung mass revealed a multifocal non-necrotizing granuloma with multinucleated giant cells. Although consistent with sarcoidosis, this finding could represent a sarcoid-like reaction secondary to an occult malignancy. A more extensive repeat biopsy via bronchoscopy and mediastinoscopy revealed granulomatous inflammation without evidence of malignancy or infection. These procedures confirmed the diagnosis of pulmonary sarcoidosis, and she was started on treatment with high-dose prednisone. Her treatment course was complicated by hyperglycemia necessitating insulin therapy, but after 3 months of therapy, she reported improvement in her dyspnea, and repeat imaging revealed a significant decrease in the size of the lung mass and lymphadenopathy. Given her clinical and radiographic response, she was continued on a prednisone taper. Conclusions Atypical manifestations of pulmonary sarcoidosis are diagnostically challenging because the clinical and radiographic features of the disease mimic those of a malignancy. We aimed to illustrate a unique etiology of a lung mass and the importance of maintaining a broad differential diagnosis. Nonetheless, with the possibility of a malignancy, a high index of suspicion is necessary for timely diagnosis and optimal management.

Correctly distinguishing metastasis and sarcoid-like reaction in patients with mediastinal lymphadenopathy is clinically important in esophageal cancer. A patient was a 52-year-old Japanese woman with superficial esophageal squamous cell carcinoma and rare case of sarcoid-like reaction. The patient was admitted with pharyngeal discomfort and an upper gastrointestinal endoscopy detected a superficial tumor in the middle thoracic esophagus. Biopsy confirmed a diagnosis of squamous cell carcinoma. Chest computed tomography (CT) showed enlarged lymph nodes around the trachea and in the bilateral hilum of the lung that were found to accumulate label on positron emission tomography CT. One course of chemotherapy in 5-fluorouracil, docetaxel and cisplatin did not affect the lymphadenopathy, which suggested that it was reactive rather than metastatic. The patient had undergone thoracoscopic esophagectomy with lymph node dissection. The pathohistology of the dissected lymph nodes showed noncaseating epithelioid-cell granuloma and no malignant cells. No clinical findings indicative of systemic sarcoidosis were observed, leading to a diagnosis of sarcoid-like reaction with the esophageal cancer. The patient has survived without recurrence for 4 years after beginning the initial treatment. Monitoring the response to chemotherapy may be helpful in distinguishing between metastasis and sarcoidosis-associated lymphadenopathy in esophageal cancer. [ABSTRACT FROM AUTHOR]

Anti-tumor necrosis factor alpha (TNFα) therapy is widely used to treat various inflammatory conditions. Paradoxically, there are several case reports describing the development of bronchocentric granulomatosis treated with TNFα inhibitors, and it is difficult to determine the effect of treatment using conventional spirometry because the lesions are located in small airways. However, it has been reported that the forced oscillation technique (FOT) is useful in the evaluation of small airway disease in bronchial asthma or chronic obstructive pulmonary disease. We performed the FOT to determine the effect of treatment on bronchocentric granulomatosis and found it to be useful. We report the case of a 55-year-old female with ulcerative colitis who was treated with golimumab and who developed bronchocentric granulomatosis as a sarcoid-like reaction to golimumab. She was successfully treated with prednisone, and the treatment efficacy was confirmed by the FOT. The FOT may be useful in the evaluation of small airway disease in bronchocentric granulomatosis. This case may help inform clinicians of the usefulness of the FOT to assess small airway disease in various diseases.

The sarcoid-like reaction represents an autoinflammatory cause of mediastinal and hilar lymphadenopathy but may also involve other lymph node regions and organs. This rare phenomenon has mainly been reported in patients with Hodgkin’s lymphoma (HL) or solid tumors (particularly melanoma) undergoing immunotherapy and chemotherapy. Cases in non-Hodgkin’s lymphoma (NHL) are very uncommon. We present an uncommon case of a patient with primarily mediastinal diffuse large B-cell lymphoma (DLBCL) who showed a CT-based partial response in interim staging, whereas at end-of-treatment multiple newly enlarged and hypermetabolic mediastinal and bilateral hilar lymph nodes were detected by 18F-FDG PET/CT imaging. A subsequent histological workup determined a sarcoid-like reaction without any lymphomatous tissue. Therefore, sarcoid-like reactions should be considered as a potential pitfall in Deauville staging with 18F-FDG PET/CT imaging for patients with NHL.

Early detection of immune-related adverse events (irAEs) with immune checkpoint inhibitors (ICIs) is crucial, particularly when these are likely to mimic tumor progression, as well as sarcoid-like reactions. Here, we report the case of a 68-year woman, with a history of four primary cutaneous melanomas (thickest lesion with BRAF mutation removed from the left axilla 2 years before), who was diagnosed with BRAF V600E-mutant metastatic melanoma and treated by ICI targeting the PD-1 receptor. Follow-up whole-body positron emission tomography/computed tomography (PET/CT) using 18F-fluorodeoxyglucose ([18F]-FDG) was performed at 15 months, and FDG-avid subcutaneous nodules on her legs were detected. A biopsy from a lesion on her right leg was obtained, and histology strongly suggested erythema nodosum. Given the isolated nature of these lesions, the normal serum Angiotensin-Converting Enzyme and the context of ICI, an immune-related sarcoid-like reaction was retained as the most likely diagnosis. Recent literature in immune-oncology suggests that erythema nodosum could be directly related to ICI(s). Although erythema nodosum is a rare occurrence with imaging features overlapping with malignancy, it should be considered in the differential diagnosis of suspicious in-transit metastasis, especially when the patient is treated with ICIs and when lesions follow a bilateral distribution. In conclusion, nuclear medicine physicians should keep in mind this irAE when interpreting PET/CT scans in clinical practice in order to avoid false-positive findings.

Summary: The administration of target inhibitors is paramount to grant the longest survival in patients with ALK-positive non-small cell lung cancer (NSCLC). The eventual resistance to tyrosine kinase inhibitors (TKI) is monitored clinically and radiologically for prompt molecule shift to further generation TKI, if available. However, the early radiological detection of progression pattern (e.g. nodule onset) should be regarded with caution because overlaps exist with non-tumor cell proliferation and/or accumulation. Here we report the case of a stage IV ALK-rearranged NSCLC patient exposed to serial crizotinib, brigatinib, ceritinib, and lorlatinib (this latter brought to complete brain and leptomeningeal disease response), in a period of more than five years. During lorlatinib, the appearance of solid pulmonary nodules was obviously interpreted as disease progression. However, surgical biopsies of the pulmonary nodules revealed features of sarcoid-like granulomatous lymphadenitis, namely without tumor cell. This invasive approach, besides documenting for the first time a sarcoid-like reaction to ALK inhibitors, allowed to revert the radiological diagnosis and maintain lorlatinib, for the best patient outcome. The pragmatic relevance of these findings suggests a careful attitude towards the interpretation of radiologic patterns of disease progression in patients under TKI. [ABSTRACT FROM AUTHOR]

Purpose: This study aimed to assess the imaging features and natural course of hilar and mediastinal sarcoid-like reaction on 18F-fluorodeoxyglucose (FDG) PET/CT after the treatment of malignancies.Methods: Sixteen patients with the appearance of sarcoid-like reaction seen on 18F-FDG-PET/CT after treatment were included. Hilar and mediastinal lymph node metastases were pathologically or clinically ruled out. Posttreatment 18F-FDG-PET/CT imaging features were assessed.Results: The maximum standardized uptake values of sarcoid-like reaction were 3.8-13.6 (mean 6.8). FDG uptake of hilar nodes was symmetrical in 12 (75%) patients and asymmetrical in 4 (25%). The time interval between the initiation of therapy and appearance of sarcoid-like reaction was 9-86 months (median 27.1 months). Among 14 patients who underwent further follow-up using 18F-FDG-PET/CT, sarcoid-like reaction regressed in 11 (79%) patients and did not regress in 3 (21%) patients. The time interval between the appearance of sarcoid-like reaction and its regression was 3-80 months (median, 8.5 months).Conclusion: After the treatment of malignancies, benign sarcoid-like reaction was rarely observed during follow-up. Although sarcoid-like reaction appeared a long time after the treatment of malignancies, it frequently and spontaneously regressed in a relatively short period of time. [ABSTRACT FROM AUTHOR]

Background: Chronic beryllium disease (CBD) is a granulomatous disease that resembles sarcoidosis but is caused by beryllium. Clinical manifestations similar to those observed in CBD have occasionally been reported in exposure to dusts of other metals. However, reports describing the clinical, radiographic, and pathological findings in conditions other than beryllium-induced granulomatous lung diseases, and detailed information on mineralogical analyses of metal dusts, are limited. Case presentation: A 51-year-old Japanese man with rapidly progressing nodular shadows on chest radiography, and a 10-year occupation history of underground construction without beryllium exposure, was referred to our hospital. High-resolution computed tomography showed well-defined multiple centrilobular and perilobular nodules, and thickening of the intralobular septa in the middle and lower zones of both lungs. No extrathoracic manifestations were observed. Pathologically, the lung specimens showed 5–12 mm nodules with dust deposition and several non-necrotizing granulomas along the lymphatic routes. X-ray analytical electron microscopy of the same specimens revealed aluminum, iron, titanium, and silica deposition in the lung tissues. The patient stopped smoking and changed his occupation to avoid further dust exposure; the chest radiography shadows decreased 5 years later. Conclusion: The radiological appearances of CBD and sarcoidosis are similar, although mediastinal or hilar lymphadenopathy is less common in CBD and is usually seen in the presence of parenchymal opacities. Extrathoracic manifestations are also rare. Despite limited evidence, these findings are similar to those observed in pneumoconiosis with a sarcoid-like reaction due to exposure to dust other than of beryllium. Aluminum is frequently detected in patients with pneumoconiosis with a sarcoid-like reaction and is listed as an inorganic agent in the etiology of sarcoidosis. It was also detected in our patient and may have contributed to the etiology. Additionally, our case suggests that cessation of dust exposure may contribute to improvement under the aforementioned conditions.

Purpose: Sarcoidosis is a granulomatous disease of unknown etiology. Occasionally, triggering causes are identified, such as neoplasms, and they are termed sarcoid-like reactions, which may appear in any sarcoidotic target tissue. Choroidal metastases appear as part of widespread metastatic disease or as the first suggestion of neoplastic disease. They can also be a part of the differential diagnosis of a spectrum of inflammatory eye diseases. We present a case in which a lung carcinoma, pulmonary and eye sarcoid-like reactions, and choroidal metastasis take place in the same patient. Case report: A 60-year-old male with a past history of pulmonary sarcoidosis and associated anterior uveitis was diagnosed with a lung carcinoma with no regional lymph nodes extension, so that the resection surgery was performed without additional systemic treatment. At the same time, he complained of visual acuity loss and pain in his right eye. An intense ocular inflammatory reaction and a choroidal mass compatible with metastasis were identified. A vitrectomy with an accompanied histological exam of the lesion was deemed inconclusive. Ocular symptoms progressively worsened showing mass growth, and as a result, an enucleation was performed and the histological study subsequently revealed metastasis from his lung carcinoma. Conclusion: Sarcoid-like reactions may be due to incipient malignancies. Any diagnosis of sarcoidosis requires ruling out other diseases that can produce secondary sarcoid-like reactions. In addition, any choroidal mass suggestive of metastasis requires exclusion of metastatic disease even in the absence of clinical signs indicating tumor extension. [ABSTRACT FROM AUTHOR]