Lymphoproliferative Disease in CVID: a Report of Types and Frequencies from a US Patient Registry

Abstract

Purpose-Lymphoproliferative disease in common variable immunodeficiency disease (CVID) is heterogeneous in pathogenesis and ranges from non-malignant lymphoid hyperplasia to lymphoma. Methods-The United States Immunodeficiency Network (USIDNET) patient registry was queried for lymphoproliferative diseases reported in CVID patients. Diagnoses included as possible manifestations of lymphoproliferation included lymphadenopathy, lymphoid hyperplasia, lymphocytic inflammation, lymphocytosis, and gammopathy. Results-Among 1091 CVID patients, lymphoproliferative conditions were reported in 17.2% (N = 188). These conditions included lymphadenopathy (N = 192, 12.3%), lymphoid hyperplasia or lymphocytic inflammation (N = 50, 4.6%), lymphocytosis (N = 3, 0.3%), and gammopathies (N = 3, 0.3%). Of the 188 patients with lymphoproliferative conditions, 15 (8%) also had a diagnosis of lymphoma, while the remaining 173 (92%) did not. Nine (4.8%) had a diagnosis of nonlymphomatous malignancy including basal cell carcinoma (N = 3, 1.6%), thyroid carcinoma (N = 2, 1.1%), gynecologic cancer (N = 2, 1.1%), testicular cancer (N = 1), and vocal cord carcinoma (N = 1). CVID patients with lymphoma were older than patients with lymphoproliferative disease who did not have a diagnosis of lymphoma at the time of analysis (median age 49 vs. 35 years, p = 0.005). CVID patients with lymphoproliferative disease had 2.5 times higher odds of having chronic lung disease compared with those with lymphoma (OR = 0.4, p = 0.049). There were no significant differences in the frequency of autoimmune, gastrointestinal, hepatic, or granulomatous disease between these populations.

Lymphadenopathy at the crossroad between immunodeficiency and autoinflammation: An intriguing challenge

“…The risk of lymphoid neoplasms is higher in CVID patients with other features of lymphoproliferation [9,19,20], thus highlighting the need of an accurate diagnostic approach to lymph node enlargement in this disease. Although most lymphadenopathies in CVID are benign [11], in the absence of adequate non-invasive predictors of malignancy the finding of lymphadenopathy often requires STAT3 GOF [77] Reports of HL [1] and leukemia [1] Reports of squamous cell carcinoma STAT1 GOF [79] Reports of HL [2] SOCS1 deficiency [80] Report of HL [1] TET2 deficiency [60] NHL (2 B cell NHL, 1 T cell NHL) reported in all 3 described patients XLP-1 [99,100] Lymphoma (mainly B cell NHL) reported in up to 50% of the patients XMEN [94] EBV-associated lymphoma (> HL) reported in 12 of 36 of the described patients Report of Kaposi sarcoma [1] STK4 deficiency [88] Lymphoma (HL, NHL) reported in three of 15 of the described patients ITK deficiency [3,84] EBV-related lymphomas reported in 13 of 18 of the described patients (> HL)…”

State-of-the-art diagnostic evaluation of common variable immunodeficiency

“…One study of patients with CVID with lymphoproliferative disease found a 2.5-fold increased odds of having lymphoma compared to patients with CVID without lymphoproliferative disease. 56 In most cases, lymphomas are extranodal and appear in unusual locations such as the lung or mucosal-associated tissues. 23…”

Shared Pathogenetic Features Between Common Variable Immunodeficiency and Sjögren’s Syndrome: Clues for a Personalized Medicine

“…Even if the main site of B cell hyperplasia and lymphoma development in CVID is the lung, also salivary glands can be involved in some cases (50)(51)(52)(53)113). Data suggest that IFN gamma could upregulate BAFF both in peripheral blood and in lung tissue, and locally BAFF could promote B cell survival and proliferation (63,114).…”

“…The most common forms of benign lymphoid hyperplasia in CVID are splenomegaly and lymphadenopathy, but lymphoid hyperplasia and polyclonal lymphoproliferative infiltrations frequently affect other organs and tissues such as lungs and gastrointestinal. The lung represents the prevalent extranodal site for lymphoproliferative disorders, which include follicular bronchiolitis, lymphoid interstitial pneumonia, and pulmonary nodular lymphoid hyperplasia ( 50 ). Chapel et al.…”