Successful treatment of pulmonary lymphomatoid granulomatosis with PD-1 inhibitor-based regimen: A Case Report and Literature Review

Successful treatment of pulmonary lymphomatoid granulomatosis with PD-1 inhibitor-based regimen: A Case Report and Literature Review | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Case Report Successful treatment of pulmonary lymphomatoid granulomatosis with PD-1 inhibitor-based regimen: A Case Report and Literature Review Qi Gao, Xiaoyan Liu, Feifei Wu, Junli Jia, Li Cao, Qingfeng Yu, and 3 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-3929733/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Pulmonary lymphomatoid granulomatosis (PLG) is a rare and aggressively progressive tumor characterized by atypical clinical manifestations and pathological features. This condition is notably susceptible to misdiagnosis and underdiagnosis. The absence of standardized treatment regimens has led to various recommendations in the literature, predominantly favoring, Rituximab-based regimens. However, the prognosis for these patients has been consistently poor, with a median survival time of only 14 months. Recently, we encountered a case of PLG exhibiting PD-1/PD-L1 and P53 expression. We administered a programmed cell death-1 (PD-1) inhibitor-based regimen. Remarkably, the patient had an overall survival (OS) of 40 months as of the most recent follow-up, without disease progression. This case stands as a notable observation, particularly, because the utilization of a PD-1 inhibitor-based regimen has not been previously reported for PLG treatment. We hope this case could contribute significantly to enhancing physicians' comprehension of PLG and provide new potential treatment strategy. pulmonary lymphomatoid granulomatosis PD-1 inhibitor treatment strategy survival time Figures Figure 1 Figure 2 Introduction Lymphomatoid granulomatosis (LYG) is a rare B-cell clonal lymphoproliferative disorder, frequently associated with the Epstein-Barr virus (EBV) infection according to current studies[ 1 ]. Initially described in 1972 by Liebow et al[ 2 ], LYG presents clinical manifestations akin to granulomatosis with polyangiitis (GPA), with histological features resembling lymphoma. LYG manifests as a multi-system disorder, potentially affecting the kidneys (45%), skin (25–50%), and central nervous system (25–50%). Notably, the lung emerges as the predominant organ involved, exceeding 90% incidence, categorizing it as a type of Primary pulmonary B-cell lymphomas (PP-BCLs)[ 3 ]. The limited understanding of the pathogenesis, the scarcity of reported cases, and the absence of an established treatment protocol for LYG have contributed to its poor prognosis, with a median survival time of only 14 months[ 4 ]. We recently diagnosed a case presented with PD-1/PD-L1 and P53 expression, and treated with PD-1 inhibitor-based regimen, with an overall survival of approximately 40 months. To our knowledge, LYG treated with PD-1 inhibitor-based regimen has not been previously described. We herein report the case as follow. Case Report A 69-year-old male patient was initially admitted to the thoracic surgery department of our hospital in May 2021 due to a mass in the right upper lung for over 8 months. He reported no symptoms such as fever, cough, expectoration, shortness of breath, night sweats, or weight loss, and had a history of good health. On physical examination, no abnormalities were detected in either lungs, and there were no findings of superficial lymphadenophathy and hepatosplenomegaly. Routine blood tests and lung cancer tumor markers did not show any significant abnormalities. EBV-DNA could not be detected in plasma. Pulmonary function was within the normal range. A Positron Emission Tomography Computed Tomography (PET-CT) scan revealed a metabolically active soft tissue mass in the upper lobe of the right lung with a maximum standardized uptake value (SUVmax) of approximately 19.8 and a maximum diameter of 5.3cm plus 6.7cm. Nodules in both lungs, enlarged lymph nodes in the right hilum, enlarged lymph nodes in the mediastinum (region 4–5), and the left hilum were metabolic activeity, with SUVmax ranging from 4.3 to 21.1, indicative of metastasis (Fig. 1 a). A fiberoptic bronchoscopic needle aspiration biopsy was conducted, extracting a neoplastic specimen from the right upper lobe and right middle bronchial opening. Subsequent histopathological examination revealed chronic inflammation of the bronchial mucosa. For further diagnosis, a CT-guided fine-needle aspiration biopsy of the right upper lung tissue indicated granulomatous inflammation with necrosis, which tended to be tuberculosis. However, TB-DNA detection was negative. Given the uncertainty regarding tuberculosis infection, the patient underwent a temporary course of classical quadruple anti-tuberculosis empirical treatment for 32 days. A follow-up CT examination a month later showed no change in the lesion. Another CT-guided needle biopsy of the mass in the right upper lung was performed to explore the possibility of neoplastic disease. The pathology, lymphoid immunophenotype, EBER ISH, and immunocytochemistry (Fig. 2 ) collectively demonstrated disruption of tissue structure in one of the nodular foci in the lung tissue, which was completely replaced by lymphoid cells (the background lymphocytes were immunophenotyped as CD3-positive). There appeared to be localized necrosis, and the lymphocytes grew in a mixed pattern. Under high magnification, the mixture of cells was seen to be composed of small lymphocyte-like cells, histiocytes, plasma cells and medium- or large nucleated kernel cells, resembling immunoblast or large R-S-like cells of Hodgkin's lymphoma, which lymphoid immunophenotype was CD20-positive and CD79a-positive, and partly infiltrated the blood vessels. Immunohistochemistry showed positivity for P53, PD-1/PD-L1 and EBER. The Ki-67 index was about 30% positive. Next-generation sequencing reveals IGHD gene rearrangement. For these pathologic features, the patient was diagnosed of lymphomatoid granuloma, grade 3, with the upper lobe of the right lung, multiple nodules in both lungs, lymph nodes in the right hilar, mediastinum and left hilar lung were infiltrated. Subsequently, flow cytology and lymphocyte subsets analysis showed a decreased number of T cells in bone marrow biopsy, although no abnormal tumor cells. Initially, the patient declined chemotherapy. Therefore, a therapeutic regimen comprising “rituximab (an anti-CD20 monoclonal antibody, R) plus sintilimab (an PD-1 inhibitor)” was administered. Enhanced CT scans were performed during the treatment period, revealing a partial response (PR) after two cycles (Fig. 1 b) and stable disease (SD) after four cycles (Fig. 1 c). However, a subsequent PET-CT scans after six cycles indicated an enlargement of the lesions, indicating progressive disease (PD) (Fig. 1 d). The patient refused further rituximab treatment due to the economic constraints, leading to an adjustment in the treatment strategy to “sintilimab plus GemOx (Gemcitabine, Oxaliplatin)”. Enhanced CT assessments after eight (Fig. 1 e) and twelve cycles (Fig. 1 f) demonstrated a noticeable reduction in lesion size, ultimately yielding a maximum diameter of hilar lesions less than 2.0cm (Fig. 1 g), indicative of a PR. Subsequently, the patient received sintilimab as maintenance therapy for a duration of 14 months, spanning from April 15, 2022 to June 8, 2023. At the last follow-up, the patient remained alive with an overall survival (OS) of approximately 40 months (From September 8, 2020 to January 15, 2024), and notable, without disease progression. Discussion LYG is a rare clinical disease that predominantly affects middle-aged male (range: 30 to 50 years old). Laboratory results were generally normal[ 5 ], and imaging features, such as multiple lamellar and nodular shadows, are similar to those observed in infections or tumors[ 6 ]. Therefore, treatment is frequently delayed due to misdiagnosis of the disease. Although the performance of fiberoptic bronchoscopy or CT-guided percutaneous lung aspiration biopsy, there remains a great possibility of inconclusive diagnosis due to factors such as sampling[ 5 ]. Our patient was initial diagnosed as tuberculosis (TB) for both immunohistochemistry tests (the fiberoptic bronchoscopic needle aspiration biopsy and the CT-guided fine-needle aspiration biopsy) showed granulomatous inflammation with necrosis, although a negative TB-DNA result. Subsequently, he underwent anti-TB treatment, which, unfortunately, proved to be uneffective. Based on its pathologic features, PLG has been categorized as a distinct mature B-cell neoplasm in the revision of WHO classification of lymphoid neoplasms in 2016 [ 7 ]. The patient’s diagnosis of PLG, grade 3, was established by observing a substantial proportion of large atypical EBV + B cells in the microscopic field[ 8 ], according to the criteria proposed by Katzenstein et al. in 2010[ 9 ]. Although high expression of P53 protein was detected by immunochemistry, next-generation sequencing (NGS) analysis of the patient's tumor tissue did not show a mutation in the P53 gene. In 2015, the WHO stipulated that grade 3 PLG disease could be managed akin to diffuse large B-cell lymphoma (DLBCL) [ 10 ], with a rituximab-based regimen as a first-line treatment option. Therefore, patients with PLG were presently treated with rituximab-based strategies[ 11 ], but the median survival time is disappointingly short, approximately 14 months. The suitability of this treatment approach for PLG remains a topic of controversy. At present, the etiology and pathogenesis of PLG remain incompletely understood. Numerous studies propose a close association between the disease and EBV infection, highlighting EBV’s capacity to bind to the CD21 receptor on B cells surface, leading to monoclonal proliferation of B lymphocytes, particularly in immunodeficient states[ 3 ]. In this case, both bone marrow flow cytometry and the lymphocyte subsets analyses showed a reduced number of T cells, potentially facilitating immune escape by abnormal B cells and their eventually transformation into malignant tumors[ 12 ]. As for tumor immune escape, Berger[ 13 ] concluded that PD-1, an immune checkpoint belonging to the immunoglobulin B7-CD28 family, plays a negative regulatory role in the human immune response by inhibiting T cell activation, proliferation, and inducing T cell death[ 13 ]. Suppression of PD-1 results in a significant reduction in T cells numbers, leading to immune evasion by tumor cells[ 14 ]. Therefore, PD-1 blockade can attenuate the inhibitory effect on T cell activation, fostering the activation of the endogenous anti-tumor immune response and providing a novel therapeutic pathway for tumor patients. However, until now, there has been no report on the expression of PD-1/PD-L1 in LYG. The immunohistochemistry findings indicated a high PD-1/PD-L1 expression in our patient. Thus, we initiated a PD-1 inhibitor-based regimen. To date, the patient has undergone 14 months of treatment and remains alive, with an overall survival of 26 months longer than the reported median survival time. Further research indicates that this upregulation of PD-1 expression may also be associated with mutations or deletions in the p53 gene, an important tumor suppressor. Upregulated p53 mediates cell cycle arrest and apoptosis, eliminating damaged cells[ 15 ] when oncogenic signals are present. In contrast, mutated p53 may increase PD-L1 expression by activating various cytokines, leading to the conversion of infiltrating T into depleted CD8 + T cells, counteracting the effects of PD-1 inhibitors[ 14 ]. However, our patient showed high P53 expression in immunohistochemistry, while intriguingly, NGS analysis did not reveal any mutation in the P53 gene. Consequently, this observation underscores the necessity for further investigation into the relationship between P53 and PD-1. PLG is an aggressive disease that has been reported to be in long-term remission without treatment in 14–27% of cases. Conversely, it proves fatal in 63.5% of patients, with a reported median survival time of 14 months[ 4 ]. To date, treated with PD-1 inhibitor-based therapy, our patient has received 14 months of treatment and remains alive, with an overall survival of 26 months longer than the median survival time reported. We speculated that the PD-1 inhibitor-based regimen may provide alternative therapeutic option for PLG. Declarations Author contribution Qi Gao, Xiaoyan Liu: data collection, analysis and interpretation; Qi Gao: writing original draft; Xiaoyan Liu: critical revision of the article; Feifei Wu, Junli Jia, Li Cao, Qingfeng Yu: data collection; Dandan Zhang and Wugan Zhao; providing pathology figures; Jie Ma: conceptualization, supervision, writing – review & editing. All authors read and approved the final manuscript. Ethical approval This article does not contain any studies with human participants or animals performed by any of the authors. Consent to participate Informed consent was obtained from all individual participants included in the study. Consent to publish The participant has consented to the submission of the case report to the journal. Conflict of interest The authors declare that they have no competing interests. Funding The work was supported by the Henan Provincial Science and Technology Research Project (NO.LHGJ20230240). References Swerdlow SH, Harris ECNL, Jaffe ES, Pileri AS (eds) WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues.2008 Liebow AA, Carrington CR, Friedman PJ (1972) Lymphomatoid granulomatosis. Hum Pathol 3:457–558. http://dx.doi.org/10.1016/s0046-8177(72)80005-4 Sanguedolce F, Zanelli M, Zizzo M et al (2021) Primary Pulmonary B-Cell Lymphoma: A Review and Update. Cancers (Basel) 13. http://dx.doi.org/10.3390/cancers13030415 Fauci AS, Haynes BF, Costa J et al (1982) Lymphomatoid Granulomatosis. Prospective clinical and therapeutic experience over 10 years. N Engl J Med 306:68–74. http://dx.doi.org/10.1056/NEJM198201143060203 Borie R, Wislez M, Antoine M, Cadranel J (2017) Lymphoproliferative Disorders of the Lung. Respiration 94:157–175. http://dx.doi.org/10.1159/000477740 Hare SS, Souza CA, Bain G et al (2012) The radiological spectrum of pulmonary lymphoproliferative disease. Br J Radiol 85:848–864. http://dx.doi.org/10.1259/bjr/16420165 Swerdlow SH, Campo E, Pileri SA et al (2016) The 2016 revision of the World Health Organization classification of lymphoid neoplasms. Blood 127:2375–2390. http://dx.doi.org/10.1182/blood-2016-01-643569 Swerdlow S (2017) WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues Katzenstein AL, Doxtader E, Narendra S (2010) Lymphomatoid granulomatosis: insights gained over 4 decades. Am J Surg Pathol 34:e35–48. http://dx.doi.org/10.1097/PAS.0b013e3181fd8781 Travis WDB, Burke E, Marx AP, Nicholson A (2015) A.G. WHO Classification of Tumours of the Lung, Pleura, Thymus and Heart Jung KH, Sung HJ, Lee JH et al (2009) A case of pulmonary lymphomatoid granulomatosis successfully treated by combination chemotherapy with rituximab. Chemotherapy 55:386–390. http://dx.doi.org/10.1159/000237745 Pina-Oviedo S, Weissferdt A, Kalhor N, Moran CA (2015) Primary Pulmonary Lymphomas. Adv Anat Pathol 22:355–375. http://dx.doi.org/10.1097/PAP.0000000000000090 Berger KN, Pu JJ (2018) PD-1 pathway and its clinical application: A 20year journey after discovery of the complete human PD-1 gene. Gene 638:20–25. http://dx.doi.org/10.1016/j.gene.2017.09.050 Liu S, Liu T, Jiang J et al (2023) p53 mutation and deletion contribute to tumor immune evasion. Front Genet 14:1088455. http://dx.doi.org/10.3389/fgene.2023.1088455 Engeland K (2018) Cell cycle arrest through indirect transcriptional repression by p53: I have a DREAM. Cell Death Differ 25:114–132. http://dx.doi.org/10.1038/cdd.2017.172 Additional Declarations No competing interests reported. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-3929733","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Case Report","associatedPublications":[],"authors":[{"id":272963184,"identity":"85a0b91b-a2a5-4057-ad55-3295c57dc2ed","order_by":0,"name":"Qi Gao","email":"","orcid":"","institution":"The First Affiliated Hospital of Zhengzhou University","correspondingAuthor":false,"prefix":"","firstName":"Qi","middleName":"","lastName":"Gao","suffix":""},{"id":272963185,"identity":"4142954a-3e3e-4416-a104-112c90e6d15d","order_by":1,"name":"Xiaoyan Liu","email":"","orcid":"","institution":"The First Affiliated Hospital of Zhengzhou University","correspondingAuthor":false,"prefix":"","firstName":"Xiaoyan","middleName":"","lastName":"Liu","suffix":""},{"id":272963186,"identity":"3c7bca49-2400-4405-a298-1a9e69ae1116","order_by":2,"name":"Feifei Wu","email":"","orcid":"","institution":"The First Affiliated Hospital of Zhengzhou University","correspondingAuthor":false,"prefix":"","firstName":"Feifei","middleName":"","lastName":"Wu","suffix":""},{"id":272963187,"identity":"28bd6f83-07ba-405c-98da-551f67d1d819","order_by":3,"name":"Junli Jia","email":"","orcid":"","institution":"The First Affiliated Hospital of Zhengzhou University","correspondingAuthor":false,"prefix":"","firstName":"Junli","middleName":"","lastName":"Jia","suffix":""},{"id":272963188,"identity":"59a85cda-840e-4b45-83f4-51e6c97a66bc","order_by":4,"name":"Li Cao","email":"","orcid":"","institution":"The First Affiliated Hospital of Zhengzhou University","correspondingAuthor":false,"prefix":"","firstName":"Li","middleName":"","lastName":"Cao","suffix":""},{"id":272963189,"identity":"60a00c0b-fb4d-4c6d-8035-00bfebc2d234","order_by":5,"name":"Qingfeng Yu","email":"","orcid":"","institution":"The First Affiliated Hospital of Zhengzhou University","correspondingAuthor":false,"prefix":"","firstName":"Qingfeng","middleName":"","lastName":"Yu","suffix":""},{"id":272963190,"identity":"f9db6dd9-65c6-41ff-9bdd-e4497414dbb2","order_by":6,"name":"Dandan Zhang","email":"","orcid":"","institution":"The First Affiliated Hospital of Zhengzhou University","correspondingAuthor":false,"prefix":"","firstName":"Dandan","middleName":"","lastName":"Zhang","suffix":""},{"id":272963191,"identity":"83d2f70a-38f5-4c79-b912-d5ca0f391745","order_by":7,"name":"Wugan Zhao","email":"","orcid":"","institution":"The First Affiliated Hospital of Zhengzhou University","correspondingAuthor":false,"prefix":"","firstName":"Wugan","middleName":"","lastName":"Zhao","suffix":""},{"id":272963192,"identity":"b9c38826-c233-44d7-97ed-f6cfdf5642fd","order_by":8,"name":"Jie Ma","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA0ElEQVRIiWNgGAWjYBAC9gYQyWMjB+GyEaGF5wCYTDMmVQvD4cQG4rWwH3664YcMc/r8/jMGDB/KDjPwz24goIUnzexmDw9bbmPDGQPGGecOM0jcOYBfi70ED9sNHh6e3GbGHgNm3rbDDAYSCQRsAWq5+YdHIp2NmceA+S+xWm7z8Bgk8LABtTASpQXol9syPAmGM3jYCg72nEvnkbhBSAv74Wc33/b8l5fvP7zxwY8yazn+GQS0gAFjD4Q+ADKDCPUg8INIdaNgFIyCUTAyAQClOjoiAwUPzQAAAABJRU5ErkJggg==","orcid":"","institution":"The First Affiliated Hospital of Zhengzhou University","correspondingAuthor":true,"prefix":"","firstName":"Jie","middleName":"","lastName":"Ma","suffix":""}],"badges":[],"createdAt":"2024-02-05 03:33:43","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-3929733/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-3929733/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":51236940,"identity":"71f54b34-74bb-471f-83ad-b69740169f79","added_by":"auto","created_at":"2024-02-16 16:43:42","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":2519386,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003e(a) \u003c/strong\u003ePET-CT of the patient at diagnosis. \u003cstrong\u003e(b)\u003c/strong\u003eEnhanced CT after the patients had two cycles of treatment. \u003cstrong\u003e(c) \u003c/strong\u003eEnhanced CT after the patients had four cycles of treatment. \u003cstrong\u003e(d)\u003c/strong\u003e PET-CT after he had six cycles of treatment. The metabolically active mass was still present, and the SUVmax was about 39.1 and the maximum diameter was 3.5cm plus 3.9cm. \u003cstrong\u003e(e)\u003c/strong\u003eEnhanced CT of the hilar lesions after the patient had eight cycles of chemotherapy. \u003cstrong\u003e(f) \u003c/strong\u003eEnhanced CT of the hilar lesions after the patient had twelve cycles of chemotherapy. \u003cstrong\u003e(g)\u003c/strong\u003e Enhanced CT of the patient in the last follow-up time (March 3, 2020).\u003c/p\u003e","description":"","filename":"Fig1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-3929733/v1/1badf036dd19bccbced165fb.jpg"},{"id":51236942,"identity":"41f87f71-3233-4fdf-9340-d72e54cac145","added_by":"auto","created_at":"2024-02-16 16:43:42","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":4091043,"visible":true,"origin":"","legend":"\u003cp\u003eThe pathological photograph in this case. \u0026nbsp;\u003cstrong\u003e(a) \u003c/strong\u003eLow magnification shows typical necrotic zones. \u003cstrong\u003e(b) \u003c/strong\u003eHigher magnification of an infiltrated artery shows a predominantly large lymphoid cell infiltrate. \u003cstrong\u003e(c) \u003c/strong\u003eThe large lymphoid cells stain with CD20. \u003cstrong\u003e(d) \u003c/strong\u003ethe more numerous small lymphocytes stain with CD3. \u003cstrong\u003e(e) \u003c/strong\u003eNumerous EBV-positive cells are seen by ISH. The needle biopsies in this patient were positive for EBER by ISH. EBER indicates Epstein-Barr virus encoded RNA; ISH, in-situ hybridization. \u003cstrong\u003e(f) \u003c/strong\u003eImmunohistochemical stains for P53. \u003cstrong\u003e(g)\u003c/strong\u003e Immunohistochemical stains for PD-1. \u003cstrong\u003e(h) \u003c/strong\u003eImmunohistochemical stains for PD-L1.\u003c/p\u003e","description":"","filename":"Fig2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-3929733/v1/a261eab905005a6c8acf4398.jpg"},{"id":88596614,"identity":"ac059a5b-0f46-4dd7-b473-c588caf99a01","added_by":"auto","created_at":"2025-08-08 07:02:18","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":6963646,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-3929733/v1/ba66738c-d50b-4f7b-a9f0-d1d2f5e2cdc9.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Successful treatment of pulmonary lymphomatoid granulomatosis with PD-1 inhibitor-based regimen: A Case Report and Literature Review","fulltext":[{"header":"Introduction","content":"\u003cp\u003eLymphomatoid granulomatosis (LYG) is a rare B-cell clonal lymphoproliferative disorder, frequently associated with the Epstein-Barr virus (EBV) infection according to current studies[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Initially described in 1972 by Liebow et al[\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e], LYG presents clinical manifestations akin to granulomatosis with polyangiitis (GPA), with histological features resembling lymphoma. LYG manifests as a multi-system disorder, potentially affecting the kidneys (45%), skin (25\u0026ndash;50%), and central nervous system (25\u0026ndash;50%). Notably, the lung emerges as the predominant organ involved, exceeding 90% incidence, categorizing it as a type of Primary pulmonary B-cell lymphomas (PP-BCLs)[\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. The limited understanding of the pathogenesis, the scarcity of reported cases, and the absence of an established treatment protocol for LYG have contributed to its poor prognosis, with a median survival time of only 14 months[\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. We recently diagnosed a case presented with PD-1/PD-L1 and P53 expression, and treated with PD-1 inhibitor-based regimen, with an overall survival of approximately 40 months. To our knowledge, LYG treated with PD-1 inhibitor-based regimen has not been previously described. We herein report the case as follow.\u003c/p\u003e"},{"header":"Case Report","content":"\u003cp\u003eA 69-year-old male patient was initially admitted to the thoracic surgery department of our hospital in May 2021 due to a mass in the right upper lung for over 8 months. He reported no symptoms such as fever, cough, expectoration, shortness of breath, night sweats, or weight loss, and had a history of good health. On physical examination, no abnormalities were detected in either lungs, and there were no findings of superficial lymphadenophathy and hepatosplenomegaly. Routine blood tests and lung cancer tumor markers did not show any significant abnormalities. EBV-DNA could not be detected in plasma. Pulmonary function was within the normal range. A Positron Emission Tomography Computed Tomography (PET-CT) scan revealed a metabolically active soft tissue mass in the upper lobe of the right lung with a maximum standardized uptake value (SUVmax) of approximately 19.8 and a maximum diameter of 5.3cm plus 6.7cm. Nodules in both lungs, enlarged lymph nodes in the right hilum, enlarged lymph nodes in the mediastinum (region 4\u0026ndash;5), and the left hilum were metabolic activeity, with SUVmax ranging from 4.3 to 21.1, indicative of metastasis (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003ea).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eA fiberoptic bronchoscopic needle aspiration biopsy was conducted, extracting a neoplastic specimen from the right upper lobe and right middle bronchial opening. Subsequent histopathological examination revealed chronic inflammation of the bronchial mucosa. For further diagnosis, a CT-guided fine-needle aspiration biopsy of the right upper lung tissue indicated granulomatous inflammation with necrosis, which tended to be tuberculosis. However, TB-DNA detection was negative. Given the uncertainty regarding tuberculosis infection, the patient underwent a temporary course of classical quadruple anti-tuberculosis empirical treatment for 32 days. A follow-up CT examination a month later showed no change in the lesion.\u003c/p\u003e \u003cp\u003eAnother CT-guided needle biopsy of the mass in the right upper lung was performed to explore the possibility of neoplastic disease. The pathology, lymphoid immunophenotype, EBER ISH, and immunocytochemistry (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e) collectively demonstrated disruption of tissue structure in one of the nodular foci in the lung tissue, which was completely replaced by lymphoid cells (the background lymphocytes were immunophenotyped as CD3-positive). There appeared to be localized necrosis, and the lymphocytes grew in a mixed pattern. Under high magnification, the mixture of cells was seen to be composed of small lymphocyte-like cells, histiocytes, plasma cells and medium- or large nucleated kernel cells, resembling immunoblast or large R-S-like cells of Hodgkin's lymphoma, which lymphoid immunophenotype was CD20-positive and CD79a-positive, and partly infiltrated the blood vessels. Immunohistochemistry showed positivity for P53, PD-1/PD-L1 and EBER. The Ki-67 index was about 30% positive. Next-generation sequencing reveals IGHD gene rearrangement. For these pathologic features, the patient was diagnosed of lymphomatoid granuloma, grade 3, with the upper lobe of the right lung, multiple nodules in both lungs, lymph nodes in the right hilar, mediastinum and left hilar lung were infiltrated. Subsequently, flow cytology and lymphocyte subsets analysis showed a decreased number of T cells in bone marrow biopsy, although no abnormal tumor cells.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eInitially, the patient declined chemotherapy. Therefore, a therapeutic regimen comprising \u0026ldquo;rituximab (an anti-CD20 monoclonal antibody, R) plus sintilimab (an PD-1 inhibitor)\u0026rdquo; was administered. Enhanced CT scans were performed during the treatment period, revealing a partial response (PR) after two cycles (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eb) and stable disease (SD) after four cycles (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003ec). However, a subsequent PET-CT scans after six cycles indicated an enlargement of the lesions, indicating progressive disease (PD) (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003ed).\u003c/p\u003e \u003cp\u003eThe patient refused further rituximab treatment due to the economic constraints, leading to an adjustment in the treatment strategy to \u0026ldquo;sintilimab plus GemOx (Gemcitabine, Oxaliplatin)\u0026rdquo;. Enhanced CT assessments after eight (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003ee) and twelve cycles (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003ef) demonstrated a noticeable reduction in lesion size, ultimately yielding a maximum diameter of hilar lesions less than 2.0cm (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eg), indicative of a PR. Subsequently, the patient received sintilimab as maintenance therapy for a duration of 14 months, spanning from April 15, 2022 to June 8, 2023. At the last follow-up, the patient remained alive with an overall survival (OS) of approximately 40 months (From September 8, 2020 to January 15, 2024), and notable, without disease progression.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eLYG is a rare clinical disease that predominantly affects middle-aged male (range: 30 to 50 years old). Laboratory results were generally normal[\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e], and imaging features, such as multiple lamellar and nodular shadows, are similar to those observed in infections or tumors[\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. Therefore, treatment is frequently delayed due to misdiagnosis of the disease. Although the performance of fiberoptic bronchoscopy or CT-guided percutaneous lung aspiration biopsy, there remains a great possibility of inconclusive diagnosis due to factors such as sampling[\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eOur patient was initial diagnosed as tuberculosis (TB) for both immunohistochemistry tests (the fiberoptic bronchoscopic needle aspiration biopsy and the CT-guided fine-needle aspiration biopsy) showed granulomatous inflammation with necrosis, although a negative TB-DNA result. Subsequently, he underwent anti-TB treatment, which, unfortunately, proved to be uneffective.\u003c/p\u003e \u003cp\u003eBased on its pathologic features, PLG has been categorized as a distinct mature B-cell neoplasm in the revision of WHO classification of lymphoid neoplasms in 2016 [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. The patient\u0026rsquo;s diagnosis of PLG, grade 3, was established by observing a substantial proportion of large atypical EBV\u0026thinsp;+\u0026thinsp;B cells in the microscopic field[\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e], according to the criteria proposed by Katzenstein et al. in 2010[\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. Although high expression of P53 protein was detected by immunochemistry, next-generation sequencing (NGS) analysis of the patient's tumor tissue did not show a mutation in the P53 gene.\u003c/p\u003e \u003cp\u003eIn 2015, the WHO stipulated that grade 3 PLG disease could be managed akin to diffuse large B-cell lymphoma (DLBCL) [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e], with a rituximab-based regimen as a first-line treatment option. Therefore, patients with PLG were presently treated with rituximab-based strategies[\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e], but the median survival time is disappointingly short, approximately 14 months. The suitability of this treatment approach for PLG remains a topic of controversy.\u003c/p\u003e \u003cp\u003eAt present, the etiology and pathogenesis of PLG remain incompletely understood. Numerous studies propose a close association between the disease and EBV infection, highlighting EBV\u0026rsquo;s capacity to bind to the CD21 receptor on B cells surface, leading to monoclonal proliferation of B lymphocytes, particularly in immunodeficient states[\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. In this case, both bone marrow flow cytometry and the lymphocyte subsets analyses showed a reduced number of T cells, potentially facilitating immune escape by abnormal B cells and their eventually transformation into malignant tumors[\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. As for tumor immune escape, Berger[\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e] concluded that PD-1, an immune checkpoint belonging to the immunoglobulin B7-CD28 family, plays a negative regulatory role in the human immune response by inhibiting T cell activation, proliferation, and inducing T cell death[\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. Suppression of PD-1 results in a significant reduction in T cells numbers, leading to immune evasion by tumor cells[\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. Therefore, PD-1 blockade can attenuate the inhibitory effect on T cell activation, fostering the activation of the endogenous anti-tumor immune response and providing a novel therapeutic pathway for tumor patients. However, until now, there has been no report on the expression of PD-1/PD-L1 in LYG. The immunohistochemistry findings indicated a high PD-1/PD-L1 expression in our patient. Thus, we initiated a PD-1 inhibitor-based regimen. To date, the patient has undergone 14 months of treatment and remains alive, with an overall survival of 26 months longer than the reported median survival time.\u003c/p\u003e \u003cp\u003eFurther research indicates that this upregulation of PD-1 expression may also be associated with mutations or deletions in the p53 gene, an important tumor suppressor. Upregulated p53 mediates cell cycle arrest and apoptosis, eliminating damaged cells[\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e] when oncogenic signals are present. In contrast, mutated p53 may increase PD-L1 expression by activating various cytokines, leading to the conversion of infiltrating T into depleted CD8\u0026thinsp;+\u0026thinsp;T cells, counteracting the effects of PD-1 inhibitors[\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. However, our patient showed high P53 expression in immunohistochemistry, while intriguingly, NGS analysis did not reveal any mutation in the P53 gene. Consequently, this observation underscores the necessity for further investigation into the relationship between P53 and PD-1.\u003c/p\u003e \u003cp\u003ePLG is an aggressive disease that has been reported to be in long-term remission without treatment in 14\u0026ndash;27% of cases. Conversely, it proves fatal in 63.5% of patients, with a reported median survival time of 14 months[\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. To date, treated with PD-1 inhibitor-based therapy, our patient has received 14 months of treatment and remains alive, with an overall survival of 26 months longer than the median survival time reported. We speculated that the PD-1 inhibitor-based regimen may provide alternative therapeutic option for PLG.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAuthor contribution\u003c/strong\u003e\u0026nbsp; Qi Gao, Xiaoyan Liu: data collection, analysis and interpretation; Qi Gao: writing original draft; Xiaoyan Liu: critical revision of the article; Feifei Wu, Junli Jia, Li Cao, Qingfeng Yu: data collection; Dandan Zhang and Wugan \u0026nbsp;Zhao; providing pathology figures; Jie Ma: conceptualization, supervision, writing \u0026ndash; review \u0026amp; editing. All authors read and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthical approval\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThis article does not contain any studies with human participants or animals performed by any of the authors.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent to participate\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eInformed consent was obtained from all individual participants included in the study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent to publish\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe participant has consented to the submission of the case report to the journal.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflict of interest\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe work was supported by the Henan Provincial Science and Technology Research Project (NO.LHGJ20230240).\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eSwerdlow SH, Harris ECNL, Jaffe ES, Pileri AS (eds) WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues.2008\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLiebow AA, Carrington CR, Friedman PJ (1972) Lymphomatoid granulomatosis. 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Cell Death Differ 25:114\u0026ndash;132. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttp://dx.doi.org/10.1038/cdd.2017.172\u003c/span\u003e\u003cspan address=\"10.1038/cdd.2017.172\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"pulmonary lymphomatoid granulomatosis, PD-1 inhibitor, treatment strategy, survival time","lastPublishedDoi":"10.21203/rs.3.rs-3929733/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-3929733/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003ePulmonary lymphomatoid granulomatosis (PLG) is a rare and aggressively progressive tumor characterized by atypical clinical manifestations and pathological features. This condition is notably susceptible to misdiagnosis and underdiagnosis. The absence of standardized treatment regimens has led to various recommendations in the literature, predominantly favoring, Rituximab-based regimens. However, the prognosis for these patients has been consistently poor, with a median survival time of only 14 months. Recently, we encountered a case of PLG exhibiting PD-1/PD-L1 and P53 expression. We administered a programmed cell death-1 (PD-1) inhibitor-based regimen. Remarkably, the patient had an overall survival (OS) of 40 months as of the most recent follow-up, without disease progression. This case stands as a notable observation, particularly, because the utilization of a PD-1 inhibitor-based regimen has not been previously reported for PLG treatment. We hope this case could contribute significantly to enhancing physicians' comprehension of PLG and provide new potential treatment strategy.\u003c/p\u003e","manuscriptTitle":"Successful treatment of pulmonary lymphomatoid granulomatosis with PD-1 inhibitor-based regimen: A Case Report and Literature Review","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-02-16 16:43:38","doi":"10.21203/rs.3.rs-3929733/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"4e79874e-ac06-42ac-89b1-6d55dc9f1a71","owner":[],"postedDate":"February 16th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-08-08T06:54:07+00:00","versionOfRecord":[],"versionCreatedAt":"2024-02-16 16:43:38","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-3929733","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-3929733","identity":"rs-3929733","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}