Presence of concurrent sarcoid-like granulomas indicates better survival in cancer patients: a retrospective cohort study

Mukunthan Murthi, Keiichiro Yoshioka, Jeong Hee Cho, Sixto Arias, Elio Danna, Moe Zaw, Greg Holt, Koichiro Tatsumi, Takeshi Kawasaki, Mehdi Mirsaeidi, Mukunthan Murthi, Keiichiro Yoshioka, Jeong Hee Cho, Sixto Arias, Elio Danna, Moe Zaw, Greg Holt, Koichiro Tatsumi, Takeshi Kawasaki, Mehdi Mirsaeidi

Abstract

Introduction: An increased risk of sarcoidosis and sarcoid-like reactions in subjects with a history of malignancy has been suggested. We assessed the incidence and clinical characteristics of cancer patients with biopsies containing sarcoid-like granulomas on cancer metastasis and patient survival.

Methods: This is a retrospective, multicentre, observational study involving endobronchial ultrasound transbronchial needle aspiration and a melanoma patient dataset at the University of Miami, USA, and a sarcoidosis patient database at Chiba University, Japan. Subjects with a confirmed diagnosis of cancer and who subsequently developed granulomas in different organs were enrolled. The study was registered at Clinicaltrials.gov (NCT03844698).

Results: 133 patients met the study's criteria. The most common primary cancer sites were the skin (22.5%), breast (20.3%) and lymph node (12.8%). 24 (18%) patients developed sarcoid-like granulomas within 1 year of cancer diagnosis, 54 (40.6%) between 1 and 5 years and 49 (36.8%) after 5 years. Imaging showed possible sarcoid-like granulomas in lymph nodes in 51 cases (38.3%) and lung tissue and mediastinal lymph nodes in 73 cases (54.9%); some parenchymal reticular opacity and fibrosis was found in 5 (3.7%) and significant parenchymal fibrosis in 2 (1.5%) subjects. According to logistic regression analysis, the frequency of metastatic cancer was significantly lower in patients with sarcoid-like granulomas than in controls. Moreover, multivariate Cox proportional hazard analysis showed a significant survival advantage in those with sarcoid-like granuloma.

Conclusion: Sarcoid-like granulomas are uncommon pathology findings in cancer patients. There is a significant association between the presence of granulomas and reduced metastasis and increased survival. Further study is warranted to understand the protective mechanism involved.

Conflict of interest statement

Conflict of interest: M. Murthi has nothing to disclose. Conflict of interest: K. Yoshioka has nothing to disclose. Conflict of interest: J.H. Cho has nothing to disclose. Conflict of interest: S. Arias has nothing to disclose. Conflict of interest: E. Donna has nothing to disclose. Conflict of interest: M. Zaw has nothing to disclose. Conflict of interest: G. Holt has nothing to disclose. Conflict of interest: K. Tatsumi has nothing to disclose. Conflict of interest: T. Kawasaki has nothing to disclose. Conflict of interest: M. Mirsaeidi has nothing to disclose.

Copyright ©ERS 2020.

Figures

FIGURE 1
FIGURE 1
Flowchart showing the selection of cases of cancer with sarcoid-like granuloma. UM: University of Miami; EBUS-TBNA: endobronchial ultrasound transbronchial needle aspiration.
FIGURE 2
FIGURE 2
Logistic regression with stepwise elimination for factors affecting stage 4 metastasis; p-value from Hosmer and Lemeshow goodness-of-fit test=0.107. The rhombus shape indicates the odds ratio (OR), and the horizontal line indicates the confidence interval (CI). The arrow indicates that the 95% CI is outside the range shown. MAB: monoclonal antibody therapy
FIGURE 3
FIGURE 3
Multivariate Cox proportional hazard analysis of survival of cancer patients with and without sarcoid-like granulomas.
FIGURE 4
FIGURE 4
Logistic regression with stepwise elimination for factors affecting survival; p-value from Hosmer and Lemeshow goodness-of-fit test=1.000. The rhombus shape indicates the odds ratio (OR), and the horizontal line indicates the confidence interval (CI). The arrow indicates that the 95% CI is outside the range shown. MAB: monoclonal antibody therapy.
FIGURE 5
FIGURE 5
Kaplan–Meier survival analysis showing the survival curve for the most common cancers among controls and cases. a) Breast cancer (granuloma=8, no granuloma=37, OR 0.55, 0.24–1.3); b) Melanoma (granuloma=5, no granuloma=18, OR 0.79, 0.27–2.25); c) Lymphoma (granuloma=6, no granuloma=15, OR 1.19, 0.43–3.28); d) Lung cancer (granuloma=6, no granuloma=30, OR 0.52, 0.2–1.34). The curves illustrate the proportion of subjects at each time point who were alive. The p-value was calculated by the log-rank test.

References

    1. Ma Y, Gal A, Koss MN. The pathology of pulmonary sarcoidosis: update. Semin Diagn Pathol 2007; 24: 150–161. doi:10.1053/j.semdp.2007.06.002
    1. Soler P, Basset F, Bernaudin JF, et al. . Morphology and distribution of the cells of a sarcoid granuloma: ultrastructural study of serial sections. Ann N Y Acad Sci 1976; 278: 147–160. doi:10.1111/j.1749-6632.1976.tb47026.x
    1. Askling J, Grunewald J, Eklund A, et al. . Increased risk for cancer following sarcoidosis. Am J Respir Crit Care Med 1999; 160: 1668–1672. doi:10.1164/ajrccm.160.5.9904045
    1. Bonifazi M, Bravi F, Gasparini S, et al. . Sarcoidosis and cancer risk: systematic review and meta-analysis of observational studies. Chest 2015; 147: 778–791. doi:10.1378/chest.14-1475
    1. Cohen PR, Kurzrock R. Sarcoidosis and malignancy. Clin Dermatol 2007; 25: 326–333. doi:10.1016/j.clindermatol.2007.03.010
    1. Schweitzer M, Salamo O, Mirsaeidi M, et al. . Increased risk of sarcoidosis among breast cancer patients; breast cancer – sarcoidosis syndrome. Eur Respir J 2017; 50: Suppl. 61, PA361.
    1. Steinfort DP, Tsui A, Grieve J, et al. . Sarcoidal reactions in regional lymph nodes of patients with early stage non–small cell lung cancer predict improved disease-free survival: a pilot case-control study. Hum Pathol 2012; 43: 333–338. doi:10.1016/j.humpath.2011.05.006
    1. Tomimaru Y, Higashiyama M, Okami J, et al. . Surgical results of lung cancer with sarcoid reaction in regional lymph nodes. Jpn J Clin Oncol 2007; 37: 90–95. doi:10.1093/jjco/hyl141
    1. O'Connell MJ, Schimpff SC, Kirschner RH, et al. . Epithelioid granulomas in Hodgkin disease: a favorable prognostic sign? JAMA 1975; 233: 886–889. doi:10.1001/jama.1975.03260080048020
    1. Sacks EL, Donaldson SS, Gordon J, et al. . Epithelioid granulomas associated with Hodgkin's disease: clinical correlations in 55 previously untreated patients. Cancer 1978; 41: 562–567. doi:10.1002/1097-0142(197802)41:2<562::AID-CNCR2820410224>;2-X
    1. Brincker H. Sarcoid reactions and sarcoidosis in Hodgkin's disease and other malignant lymphomata. Br J Cancer 1972; 26: 120–123. doi:10.1038/bjc.1972.18
    1. Kiess AP, Wang H, Travis WD, et al. . Sarcoid in cancer patients: clinical characteristics and associated disease status. Sarcoidosis Vasc Diffuse Lung Dis 2015; 32: 200–207.
    1. Butt S, Alzebdeh R, Kable T, et al. . Non-caseating granulomas in patients after the diagnosis of cancer: clinical characteristics and outcome. Sarcoidosis Vasc Diffuse Lung Dis 2011; 28: 44–49.
    1. Hunt BM, Vallières E, Buduhan G, et al. . Sarcoidosis as a benign cause of lymphadenopathy in cancer patients. Am J Surg 2009; 197: 629–632. doi:10.1016/j.amjsurg.2009.01.004
    1. Arish N, Kuint R, Sapir E, et al. . Characteristics of sarcoidosis in patients with previous malignancy: causality or coincidence? Respiration 2017; 93: 247–252. doi:10.1159/000455877
    1. Spiekermann C, Kuhlencord M, Huss S, et al. . Coexistence of sarcoidosis and metastatic lesions: a diagnostic and therapeutic dilemma. Oncol Lett 2017; 14: 7643–7652.
    1. Iannuzzi MC, Rybicki BA, Teirstein AS. Sarcoidosis. N Engl J Med 2007; 357: 2153–2165. doi:10.1056/NEJMra071714
    1. Grados A, Ebbo M, Bernit E, et al. . Sarcoidosis occurring after solid cancer: a nonfortuitous association: report of 12 cases and review of the literature. Medicine (Baltimore) 2015; 94: e928. doi:10.1097/MD.0000000000000928
    1. Dagaonkar RS, Choong CV, Asmat AB, et al. . Significance of coexistent granulomatous inflammation and lung cancer. J Clin Pathol 2017; 70: 337–341. doi:10.1136/jclinpath-2016-203868
    1. Kamiyoshihara M, Hirai T, Kawashima O, et al. . Sarcoid reactions in primary pulmonary carcinoma: report of seven cases. Oncol Rep 1998; 5: 177–180.
    1. Merchant TE, Filippa DA, Yahalom J. Sarcoidosis following chemotherapy for Hodgkin's disease. Leuk Lymphoma 1994; 13: 339–347. doi:10.3109/10428199409056299
    1. Sanan P, Lu Y. Multiorgan involvement of chemotherapy-induced sarcoidosis mimicking progression of lymphoma on FDG PET/CT. Clin Nucl Med 2017; 42: 702–703. doi:10.1097/RLU.0000000000001735
    1. Gkiozos I, Kopitopoulou A, Kalkanis A, et al. . Sarcoidosis-like reactions induced by checkpoint inhibitors. J Thorac Oncol 2018; 13: 1076–1082. doi:10.1016/j.jtho.2018.04.031
    1. Heyder T, Kohler M, Tarasova NK, et al. . Approach for identifying human leukocyte antigen (HLA)-DR bound peptides from scarce clinical samples. Mol Cell Proteomics 2016; 15: 3017–3029. doi:10.1074/mcp.M116.060764
    1. Wahlström J, Dengjel J, Persson B, et al. . Identification of HLA-DR–bound peptides presented by human bronchoalveolar lavage cells in sarcoidosis. J Clin Invest 2007; 117: 3576–3582. doi:10.1172/JCI32401
    1. Wahlström J, Dengjel J, Winqvist O, et al. . Autoimmune T cell responses to antigenic peptides presented by bronchoalveolar lavage cell HLA-DR molecules in sarcoidosis. Clin Immunol 2009; 133: 353–363. doi:10.1016/j.clim.2009.08.008
    1. Mor-Vaknin N, Punturieri A, Sitwala K, et al. . Vimentin is secreted by activated macrophages. Nat Cell Biol 2003; 5: 59–63. doi:10.1038/ncb898
    1. Eberhardt C, Thillai M, Parker R, et al. . Proteomic analysis of Kveim reagent identifies targets of cellular immunity in sarcoidosis. PLoS One 2017; 12: e0170285.
    1. Sarker AB, Akagi T, Yoshino T, et al. . Expression of vimentin and epithelial membrane antigen in human malignant lymphomas. Acta Pathol Jpn 1990; 40: 581–587.
    1. Kidd ME, Shumaker DK, Ridge KM. The role of vimentin intermediate filaments in the progression of lung cancer. Am J Respir Cell Mol Biol 2014; 50: 1–6.
    1. Sanchez-Cespedes M, Esteller M, Hibi K, et al. . Molecular detection of neoplastic cells in lymph nodes of metastatic colorectal cancer patients predicts recurrence. Clin Cancer Res 1999; 5: 2450–2454.

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