避免中和抗丙型干擾素自體抗體導致的淋巴結病變在病理學上被誤診為淋巴瘤

Abstract

成人發病的免疫缺陷症候群，其特徵為中和抗丙型干擾素自體抗體（AIGA），常常帶來診斷上的挑戰，往往導致誤診。其中一種突出的表現為發燒性淋巴結腫大，需要進行全面的臨床病理分析，以釐清AIGA患者淋巴結腫大的複雜情況。此外，由於AIGA的非特異性臨床表現以及與某些淋巴瘤類型相似，包括淋巴濾泡輔助細胞型T細胞淋巴瘤-血管免疫芽型（nTFHL-AI），對AIGA的診斷也變得困難。 首先，我們進行了一項回顧性病例系列，分析與AIGA相關的淋巴結腫大，涵蓋了來自一家醫療中心的16名AIGA患者的26個淋巴結樣本。所有患者同時出現全身性非結核分枝桿菌感染，其中31％最初被臨床診斷為淋巴瘤。組織形態學模式分為良好形成的肉芽腫（46％），化膿性炎症或組織細胞凝集（31％）和淋巴增生性疾患（LPD）（23％）。 AIGA-LPD呈現異質性，可能與惡性T細胞淋巴瘤、IgG4相關疾病和多中心Castleman病相似。 LPD樣本的一半具有單株T細胞，其中33.3％與nTFHL-AI難以區分。抗生素治療導致LPD特徵消散，無需進行細胞毒性化療或免疫治療，對於惡性診斷產生疑慮。中位追蹤時間為4.3年。 接著，為了找出可靠的診斷方法，我們將研究人口擴大到一項多機構病例對照研究，包括13例AIGA-LPD和24例nTFHL-AI。首先，通過使用NanoString nCounter平台進行全癌病原體免疫分析，我們發現CXCL9和PDCD1在AIGA中的表達明顯下調，相較於nTFHL-AI。 CXCL9免疫組織化學（IHC）證實其在高診斷準確性（92.3％敏感性，100％特異性）方面區分AIGA-LPD和nTFHL-AI的能力。 總之，在AIGA的背景下區分淋巴瘤和良性淋巴腫大仍然是一項挑戰。全面的臨床病理分析強調了在臨床醫生和病理學家之間進行更多警覺和多學科討論的必要性，以獲得最佳的診斷和管理。 CXCL9的下調成為區分AIGA和nTFHL-AI等相似狀況的強大生物標記，提供可靠的診斷方法，以防止誤診，確保及時和準確的診斷。

Adult-onset immunodeficiency associated with neutralizing anti-interferon γ autoantibodies (AIGA) presents diagnostic challenges, often resulting in misdiagnoses. One of its prevalent manifestations is febrile lymphadenopathy, necessitating a comprehensive clinicopathological analysis to unravel the complexities of lymphadenopathy in AIGA patients. Additionally, diagnosing AIGA proves challenging due to its nonspecific clinical presentation and its resemblance to certain lymphoma types, including nodal T follicular helper cell lymphoma, angioimmunoblastic type (nTFHL-AI). Firstly, we conducted a retrospective case series analyzing AIGA-related lymphadenopathy, encompassing 26 lymph node biopsy specimens from 16 AIGA patients in a single medical center. All patients presented with concurrent disseminated nontuberculous mycobacterial infections, with 31% initially receiving a clinical diagnosis of lymphoma. Histomorphological patterns were categorized into well-formed granuloma (46%), suppurative inflammation or histiocytic aggregates (31%), and lymphoproliferative disorder (LPD) (23%). AIGA-LPD exhibits heterogeneity and can resemble malignant T-cell lymphoma, IgG4-related disease, and multicentric Castleman disease. Half of the LPD specimens featured monoclonal T cells, with 33% indistinguishable from nTFHL-AI. Antibiotic treatment led to the regression of LPD features without the need for cytotoxic chemotherapy or immunotherapy, casting doubt on a malignant diagnosis. The median follow-up time was 4.3 years. Next, to identify reliable diagnostic methods, we expanded the study population into a multi-institutional case-control study involving 13 AIGA-LPD and 24 nTFHL-AI cases. Initially, through immune transcriptomic analysis with the NanoString nCounter platform using PanCancer immune profiling, we discovered significant downregulation of CXCL9 and PDCD1 compared to nTFHL-AI. CXCL9 immunohistochemistry demonstrated its ability to differentiate AIGA-LPD from nTFHL-AI with high diagnostic accuracy (92% sensitivity, 100% specificity). In conclusion, differentiating between lymphoma and benign lymphadenopathy in the context of AIGA remains a challenge. The comprehensive clinicopathological analysis underscores the necessity for increased vigilance and multidisciplinary discussions among clinicians and pathologists for optimal diagnosis and management. The downregulation of CXCL9 emerges as a robust biomarker for differentiating AIGA from nTFHL-AI and similar conditions, providing a reliable diagnostic approach to prevent misdiagnosis and ensure a timely and accurate diagnosis.