Tab Application Banner
  • Users Online: 211
  • Home
  • Print this page
  • Email this page
Home About us Editorial board Ahead of print Current issue Search Archives Submit article Instructions Subscribe Contacts Login 

Ahead of print publication  

Immunoglobulin G4-related isolated cervical lymphadenopathy

1 Department of Pathology, Star Hospitals, Hyderabad, Telangana, India
2 Department of Rheumatology and Clinical Immunology, Star Hospitals, Hyderabad, Telangana, India
3 Department of Pathology, Nizam's Institute of Medical Sciences, Hyderabad, Telangana, India
4 Department of ENT, Star Hospitals, Hyderabad, Telangana, India

Date of Submission27-Mar-2021
Date of Decision31-Mar-2021
Date of Acceptance05-Sep-2021
Date of Web Publication21-Apr-2022

Correspondence Address:
Nayan Patel Sureja,
Department of Rheumatology and Clinical Immunology, Star Hospitals, Banjara Hills, Hyderabad - 500 034, Telangana
Login to access the Email id

Source of Support: None, Conflict of Interest: None

DOI: 10.4103/injr.injr_61_21

How to cite this URL:
Sureja VP, Sureja NP, Paul TR, Sistla SK, Tagore KR. Immunoglobulin G4-related isolated cervical lymphadenopathy. Indian J Rheumatol [Epub ahead of print] [cited 2023 Feb 7]. Available from:

Dear Editor,

Immunoglobulin G4-related disease (IgG4-RD) is an immune-mediated condition causing fibroinflammatory lesions in nearly any tissue.[1]. Lymphadenopathy is frequently associated with IgG4-RD, and often occurs simultaneously or subsequently after the development of extranodal lesions. Lymphadenopathy can sometimes be the initial manifestation but often develops to involve other organs.[2] Occasionally, the disease remains limited to the lymph nodes.[3] Isolated IgG4-related cervical lymphadenopathy is extremely uncommon, and results in a diagnostic dilemma.[4],[5]

A 47-year-old woman had a right submandibular swelling for 3 years. In December 2020, she presented with an increase in the size of swelling without any local or systemic symptoms. In 2018 medical records, the swelling was confirmed as cervical lymphadenopathy, and lymph node biopsy was suggestive of reactive follicular hyperplasia [Figure 1]a and [Figure 1]b. Oral antibiotics did not help, whereas the swelling transiently reduced with a short course of oral corticosteroids (CS).
Figure 1: Immunoglobulin G4-related cervical lymphadenopathy. Histopathology of the cervical lymph node showing (a) hyperplastic lymphoid follicles with prominent germinal centres (×40), and (b) inter-follicular prominence of plasma cells (×100). Image showing (c) right submandibular lymphadenopathy. Immunohistochemical stains showing (d) CD3 positivity in the paracortical T-lymphocytes, (e) CD20 positivity within the follicles, (f) Bcl2 positivity in the periphery of follicles, (g) CD138 positivity within the follicles and interfollicular areas, (h) IgG positivity in few plasma cells, and (i) IgG4 positivity in 80–100 plasma cells per high-power field

Click here to view

On examination, the swelling was evident in the right submandibular region [[Figure 1]c: arrow]. Neck palpation revealed bilateral cervical lymphadenopathy. The rest of the physical examination was normal. Erythrocyte sedimentation rate and C-reactive protein were elevated. Complete blood counts, urine examination, serum angiotensin-converting enzyme, and chest radiograph were normal. Hepatitis B surface antigen, anti-hepatitis C virus, and human immunodeficiency virus antibodies were negative. Antinuclear antibodies by immunofluorescence assay and anti-extractable nuclear antigen antibodies by line immunoassay were negative.

Possibilities of IgG4-RD and Castleman disease were considered. Histopathological review of the previous biopsy slides failed to provide additional clues. Whole-body positron-emission tomography–computed tomography showed abnormal accumulation of fluorodeoxyglucose only in the cervical lymph nodes (bilateral Ib, and right II, III, IV). Serum IgG4 was elevated (404 mg/dl) more than two times the upper normal limit. Immunohistochemistry (IHC) of the lymph node biopsy tissue revealed CD3 positivity in the paracortical T-lymphocytes [Figure 1]d, CD20 within the follicles [Figure 1]e, Bcl2 in the periphery of follicles [Figure 1]f, and CD138 within the follicles and interfollicular areas [Figure 1]g. IgG was positive in few plasma cells [Figure 1]h, whereas a large number of IgG4-positive plasma cells (80–100 cells/hpf) were seen within the follicles and interfollicular areas [Figure 1]i. The ratio of IgG4 to IgG positive plasma cells was approximately 50%. The patient satisfied the 2011 comprehensive diagnostic criteria,[6] and the 2019 American College of Rheumatology/European League Against Rheumatism classification criteria for IgG4-RD.[1] With a diagnosis of IgG4-related lymphadenopathy (IgG4-RLAD), oral CS was initiated at 0.6 mg/kg. After 1 month, lymphadenopathy resolved, azathioprine was added, and CS was gradually tapered.

Histological findings of IgG4-RD, such as storiform fibrosis and obliterative phlebitis, are usually absent in IgG4-RLAD. Histologically, IgG4-RLAD is divided into five subgroups: Type I: multicentric Castleman's disease like; Type II: reactive follicular hyperplasia like; Type III: interfollicular expansion and immunoblastosis; Type IV: progressively transformed germinal center type; and Type V: inflammatory pseudotumor like.[2] The present case had Type II pattern, which is also commonly seen in reactive lymphadenopathy secondary to other etiologies. Thus, high clinical suspicion and liberal use of IHC are required for the diagnosis.

The number of IgG4 cells/hpf required for diagnosing IgG4-RLAD remains controversial. While there is no provision for IgG4-RLAD in both the available diagnostic criteria,[1],[6] Bookhout and Rollins-Raval[7] have recommended >100 IgG4 cells/hpf for diagnosing isolated IgG4-RLAD without any other organ involvement.

We found only eight published cases of IgG4-related isolated cervical lymphadenopathy,[3],[4],[5] satisfying the 2011 diagnostic criteria for IgG4-RD. All the patients had unilateral involvement. Sato et al.[3] described IgG4-RLAD in 40 Japanese patients (all had cervical lymphadenopathy) using >100 IgG4 cells/hpf as an inclusion criterion. Twelve patients satisfying the criteria had isolated cervical lymphadenopathy, of which nine progressed to involve nodes in other regions and/or extranodal organs over a median follow-up of 36 months (range: 12–132). In the remaining three patients, the disease remained limited to the cervical nodes over a period of 5, 10, and 26 months. Bilateral involvement was unique to the present case.

This case along with previously published cases emphasizes the importance of considering IgG4-RLAD in the differential diagnosis of isolated cervical lymphadenopathy.


Written informed consent was obtained from the patient.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient has given her consent for her images and other clinical information to be reported in the journal. The patient understands that name and initials will not be published and due efforts will be made to conceal identity, but anonymity cannot be guaranteed.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.

  References Top

Wallace ZS, Naden RP, Chari S, Choi H, Della-Torre E, Dicaire JF, et al. The 2019 American College of Rheumatology/European League Against Rheumatism classification criteria for IgG4-related disease. Arthritis Rheumatol 2020;72:7-19.  Back to cited text no. 1
Sato Y, Yoshino T. IgG4-related lymphadenopathy. Int J Rheumatol 2012;2012:572539.  Back to cited text no. 2
Sato Y, Inoue D, Asano N, Takata K, Asaoku H, Maeda Y, et al. Association between IgG4-related disease and progressively transformed germinal centers of lymph nodes. Mod Pathol 2012;25:956-67.  Back to cited text no. 3
Kawaguchi M, Kato H, Kito Y, Mizuta K, Aoki M, Kato K, et al. Imaging findings of primary immunoglobulin G4-related cervical lymphadenopathy. Neuroradiology 2017;59:1111-9.  Back to cited text no. 4
Nakamura M, Iwamoto O, Chino T, Todoroki K, Kusukawa J. Diagnostic dilemma of IgG4-related primary localized cervical lymphadenopathy associated with aberrant IL-6 expression level. Diagn Pathol 2016;11:43.  Back to cited text no. 5
Umehara H, Okazaki K, Masaki Y, Kawano M, Yamamoto M, Saeki T, et al. Comprehensive diagnostic criteria for IgG4-related disease (IgG4-RD), 2011. Mod Rheumatol 2012;22:21-30.  Back to cited text no. 6
Bookhout CE, Rollins-Raval MA. Immunoglobulin G4-related lymphadenopathy. Surg Pathol Clin 2016;9:117-29.  Back to cited text no. 7


  [Figure 1]


     Search Pubmed for
    -  Sureja VP
    -  Sureja NP
    -  Paul TR
    -  Sistla SK
    -  Tagore KR
    Access Statistics
    Email Alert *
    Add to My List *
* Registration required (free)  

  In this article
Article Figures

 Article Access Statistics
    PDF Downloaded17    

Recommend this journal