IgG4-Related Lymphadenopathy: a Distinct Clinicopathological Entity That Is Associated with IgG4-Related Sclerosing Diseases

Background: Autoimmune pancreatitis (AIP) and its related diseases, such as sclerosing cholangitis, sclerosing sialadenitis, interstitial nephritis and retroperitoneal fibrosis, share IgG4-related abnormalities including elevated serum IgG4 level and numerous IgG4- positive plasma cells in the affected tissues. All of these diseases are now wrapped into a new clinicopathological entity, and is designated as IgG4-related sclerosing diseases (IgG4-SD). Lymphadenopathy is not uncommon in patients with IgG4-SD, but so far as we know, there has been only one study that describes the clinicopathological features of IgG4-related lymphadenopathy (IgG4-LN). In order to clarify whether IgG4-LN is a distinct and clinically significant entity, we reviewed lymph node biopsies which had been pathologically diagnosed as reactive or inflammatory. We also reviewed patients with IgG4-SD who had had CT and/or PET/CT scans to see if the extent of lymphadenopathy affects serum levels of IgG and IgG4.

Design: The study protocol consists of two parts. The first part is a clinicopathological review of 713 lymph node biopsies which had been diagnosed as reactive or inflammatory. In our preliminary study with enlarged lymph nodes seen around pancreata with AIP or submaxillary glands with sclerosing sialadenitis, we had found that follicular hyperplasia and plasmacytic hyperplasia were characteristic. Thus we selected 87 lymph nodes with predominantly follicular and/or plasmacytic hyperplasia for the immunostains for IgG1 and IgG4. Lymph nodes were diagnosed to be IgG4-LA if

1. IgG4-positive plasma cells were numerous (more than 10/high power field in average), and

2. the number of IgG4- positive plasma cells was larger than or was comparable to that of IgG1-positive plasma cells.

The second part of the study is a clinical review of 27 patients with IgG4-SD who had CT and/or PET/CT scans. They consisted of 15 cases with AIP, 4 with sclerosing sialadenitis, 2 with interstitial pneumonia, 6 with IgG4-LA (the cases included in the first part). By reviewing CT and/or PET/CT scan images, the number of regions with lymphadenopathy was evaluated according to the Ann Arbor stage, and was compared with serum levels of IgG and IgG4.

Results: 11 cases fulfilled the criteria of IgG4-LA. The average age of the patients was 65.8 (range, 48–77) years; 9 were male. Three cases each were initially diagnosed as plasma cell type of Castleman’s disease and florid follicular hyperplasia; the rests were biopsied after we had recognized IgG4-LA. After the initial workup or in the followup, 5 cases were found to have other IgG4-SD, such as AIP, sclerosing sialadentitis, interstitial pneumonia, interstitial nephritis and retroperitoneal fibrosis. The serum level of IgG and IgG4 were 1366–6534 mg/dl (average, 4405) and 219–2750 mg/dl (average, 1363), respectively. Among the 27 cases in the second part of the study, the serum level of IgG and IgG4 were 1366–7953 mg/dl (average, 3243) and 122–4140 mg/dl (average, 1043), respectively. CT and/or PET/CT scan depicted lymphadenopathy in every case. The number of regions with lymphadenopathy was 3.43 in average (range, 1–8). The serum levels of both IgG and IgG4 significantly correlated with the number of regions with lymphadenopathy. The existence of lymphadenopathy in the cervical, mediastinal, axillary, paraaortic, iliac, and inguinal areas also correlated with the serum level of IgG and IgG4.

Conclusions: We suggest that IgG4-related lesion exists in the lymph node, and that IgG4-LA is a proper name for it. Our proposal is justified by the observation that patients with IgG4-LA revealed elevated serum IgG4 level and occasional coexistence of other IgG4-SD. IgG4-LA might be included previously in plasma cell type of Castleman’s disease and florid follicular hyperplasia. We found that the extent of lymphadenopathy in patients with IgG4-SD correlated with serum level of IgG and IgG4, suggesting that the extent of lymphadenopathy may indicate the disease activity of IgG4-SD.