A 28-year-old healthy female presented to her primary care physician with lymphadenopathy, fatigue, malaise, and night sweats. Symptoms persisted despite conservative treatment and eventually the patient underwent multiple lymph node resections and a bone marrow biopsy before a diagnosis of IgG4-related disease (IgG4-RD) was made. IgG4-RD is a relatively new disorder first histopathologically recognized within the last decade. As the disease can affect a single organ or multiple organs, symptoms can vary greatly among patients. With symptoms ranging from mild, such as lower extremity edema, to severe, such as spinal cord compression, IgG4-RD must be considered in appropriate patients. Diagnostic criteria have been proposed based on organ involvement, serum IgG4 levels, and histopathological criteria. Diagnosis can be difficult to make with many studies suggesting different values for diagnostic criteria, such as the level of tissue IgG4+/IgG+ cell ratio to delineate IgG4-RD. Treatment consists of high dose glucocorticoids as a first line therapy with some patients choosing instead to simply undergo observation. This case illustrates the difficulty in diagnosis and the need for increased awareness among medical professionals.
IgG4-RD is a relatively newly classified condition with unifying histopathologic features recognized only since the early 2000s [
A 28-year-old female with no significant past medical history presented to her primary care physician with lymphadenopathy, night sweats, fatigue, and malaise. She was treated empirically and partially responded to a short course of glucocorticoids and an antibiotic. When initial laboratory workup was unrevealing for an obvious etiology and symptoms persisted, computed tomography (CT) of the neck and chest with contrast was performed that showed diffuse adenopathy (Figure
CT neck with contrast revealed diffuse cervical adenopathy (arrows demonstrate lymphadenopathy).
Hematoxylin and eosin stain of a resected lymph node, 2x magnification. This preparation shows nonspecific reactive follicular hyperplasia (arrow demonstrates secondary follicle with prominent germinal center).
However, when her symptoms again worsened, she was referred to Infectious Disease who entertained a broad differential including Kikuchi’s syndrome, Epstein-Barr virus (EBV), cytomegalovirus (CMV), toxoplasmosis, or human immunodeficiency virus (HIV) infection. Extensive serological testing was unrevealing and a second lymph node was removed, again without an obvious etiology. Rheumatology was then consulted and expanded the differential to include systemic lupus erythematosus, Sjögren’s syndrome, Castleman’s disease, autoimmune lymphoproliferative syndrome, and IgG4-related disease (IgG4-RD). Table
Differential diagnosis with pertinent laboratory findings*.
Lymphoma | Bone marrow and lymph node biopsy performed HTLV-1+2 antibodies (nonreactive) |
Castleman's disease |
HHV-8 lymph node stains negative |
Autoimmune Lymphoproliferative syndrome | Less than 1.5% double negative (CD4−CD8−) T-cell count on cytometry |
Mycobacterial infection | AFB culture of lymph node (negative) |
Systemic lupus erythematosus | ANA panel (1 : 160) |
Anti-dsDNA and anti-Sm antibodies (negative) | |
Complement levels C3, C4 within normal range | |
Viral infections |
EBV (nuclear Ag IgG positive, viral capsid IgG positive, viral capsid IgM negative), |
CMV (IgM negative, IgG negative), parvovirus B19 (IgM negative, IgG negative), | |
Hepatitis (HBs Ag negative, HBc Ab negative, HBs Ab negative, HCV Ab negative) | |
Cat scratch disease | Bartonella panel (negative) |
Sjögren's syndrome | SSA/SSB (negative) |
*HTLV-1+2: human T-lymphotropic virus type I and II, HHV-8: human herpes virus 8; AFB: acid-fast bacilli, ANA: antinuclear antibodies, Anti-dsDNA: antidouble-stranded DNA, Anti-Sm: anti-Smith; EBV = Epstein-Barr virus, CMV: cytomegalovirus, HBs Ag = hepatitis B surface antigen, and HBc Ab: hepatitis B core antibody IgG, HBs Ab = hepatitis B surface antibody, HCV Ab: hepatitis C virus antibody, SSA: anti-Ro/SSA antibodies, and SSB: anti-La/SSB antibodies.
IgG (a) and IgG4 (b) stains, 4x magnification. These stains show an IgG4+/IgG+ cell ratio estimated at 30% (black arrow head: IgG staining, solid black arrow = IgG4 staining).
The diagnosis of IgG4-RD can be difficult to make and misdiagnosis is common. One set of proposed diagnostic criteria as outlined in Table
Proposed comprehensive diagnostic criteria for IgG4-RD*.
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Definite = |
*Adapted from Umehara et al. [
While the diagnostic criteria discussed earlier suggest an IgG4+/IgG+ cell ratio of >40%, other proposed diagnostic criteria recommend more stringent requirements such as a ratio of >50%. Others suggest that some cases of IgG4-RD may present with an even lower ratio such as >30% [
Specificity and sensitivity of IgG4+/IgG+ cell ratio for diagnosis of IgG4-RD*.
IgG4+/IgG+ Cell ratio | Sensitivity | Specificity |
---|---|---|
>30% | 100% | 71.4% |
>40% | 94.4% | 85.7% |
>50% | 94.4% | 95.2% |
*Adapted from Masaki et al. [
Another aspect of the proposed diagnostic criteria state the serum IgG4 concentration should be >135 mg/dL. However, the serum IgG4 level can be misleading, with approximately 30% of patients with otherwise classic findings for this disease having normal serum IgG4 concentrations [
Tissue biopsy and evaluation play a central role in diagnosis. Although IgG4-RD can manifest in nearly any organ system, it shares unique histologic findings regardless of location including dense lymphoplasmacytic infiltrate rich in IgG4-positive plasma cells, storiform fibrosis which is that of an irregularly whorled pattern, obliterative phlebitis, and an eosinophilic infiltrate [
Diagnosis can be difficult but the most important first step is a high clinical suspicion. This disease requires specific testing to be recognized and therefore must be sought out, not revealing itself on routine labs or biopsy. Furthermore, because of some shortcomings in the current diagnostic criteria, one must thoroughly consider other disorders in the differential diagnosis. In our case of unexplained generalized lymphadenopathy, fatigue, and night sweats, the differential diagnosis included various infections (EBV, CMV, toxoplasmosis, HIV, and mycobacterium), lymphoma/leukemia, metastatic neoplasia, systemic lupus erythematous, Castleman’s disease, autoimmune lymphoproliferative syndrome, and Sjögren’s syndrome [
Treatment strategies have not yet been validated by large randomized controlled trials. Recommendations are currently limited to case reports and consensus statements, with glucocorticoids considered first. Several glucocorticoid sparing regimens have also been suggested, with rituximab showing efficacy even in refractory disease [
IgG4-RD is a new disease that has been present for many years but only better appreciated within the last decade. The currently proposed diagnostic criteria incorporate organ involvement, the serum IgG4 level, and tissue evaluation with IgG4+/IgG+ ratio and IgG4 cells/HPF. These criteria must be interpreted in the right clinical setting and diagnosis made only after a thorough consideration and exclusion of alternative diagnoses. Clinical features of the disease can be difficult to piece together given the wide variety of potential systems that can be involved and, therefore, the physician must have a high clinical suspicion. Treatment based on case reports and consensus consists mainly of glucocorticoids or similar agents that suppress lymphocytes. As the disease definition and our understanding of it continues to evolve, greater physician awareness is needed so that this diagnosis is not overlooked in future patients. Ongoing study of patient’s with IgG4-RD will provide a better understanding of this disorder, how to best approach treatment, and potentially a more refined diagnostic scheme.
The authors would like to thank Dr. Geoffrey Sasaki for his help in obtaining and interpreting the histopathology provided in the figures of this paper. The views expressed in this material are those of the authors and do not reflect the official policy or position of the US Government, the Department of Defense, or the Department of the Air Force.