Diagnostic Approach to the Complexity of IgG4-Related Disease

doi:10.1016/j.mayocp.2015.03.020

Mayo Clinic Proceedings

Volume 90, Issue 7, July 2015, Pages 927-939

https://doi.org/10.1016/j.mayocp.2015.03.020 Get rights and content

Abstract

IgG4-related disease (IgG4-RD) is a systemic disease characterized by the infiltration of IgG4-bearing plasma cells and, more importantly, distinctive histopathological features: storiform fibrosis, obliterative phlebitis, a lymphoplasmacytic infiltrate, and mild-to-moderate tissue eosinophilia. The diagnostic approach is complex and relies on the coexistence of various clinical, laboratory, and histopathological findings, none of which is pathognomonic in and of itself. IgG4-related disease should be suspected in patients presenting with unexplained enlargement or swelling of 1 or more organs or tissue organs. Four laboratory abnormalities often provide initial clues to the diagnosis of IgG4-RD: peripheral eosinophilia, hypergammaglobulinemia, elevated serum IgE levels, and hypocomplementemia. Elevated serum IgG4 levels provided critical information in identifying the first cases of IgG4-RD, but recent studies have reported substantial limitations to the measurement of serum IgG4 concentrations, precluding reliance on serum IgG4 concentrations for diagnostic purposes. In contrast, new studies have suggested a promising role of flow cytometry studies in the diagnosis and longitudinal management of IgG4-RD. Demonstration of the classic histopathological features of IgG4-RD remains crucial to diagnosis in most cases, and biopsy proof is preferred strongly by most disease experts before the initiation of treatment. Of note, the multiorgan nature of IgG4-RD was first established in 2003. This review intends to provide most recent knowledge about the clinical, laboratory, radiological, and pathological characteristics of IgG4-RD that may guide the physician to establish an early diagnosis. We searched PubMed and MEDLINE for relevant articles published between January 1, 2000, and November 1, 2014, using the search terms IgG4 and IgG4-related.

Section snippets

Clinical Suspicion

The signs and symptoms of IgG4-RD at presentation are diverse and may be divided into general and organ-specific signs and symptoms.

Routine Tests

Routine laboratory tests such as complete blood cell counts and biochemical profiles often provide nonspecific indications of organ involvement that require further investigation. In particular, abnormalities of liver function tests that suggest biliary obstruction should focus diagnostic efforts on the pancreas and biliary tree, whereas elevated serum creatinine levels or proteinuria may signal renal disease. Mild-to-moderate peripheral eosinophilia is found in 34% of patients (Table 1), but

Imaging Studies

Cross-sectional imaging studies using computed tomography (CT) or magnetic resonance imaging (MRI) play an important diagnostic role. Organ lesions of IgG4-RD frequently lead to the finding of organ enlargement or frank pseudotumors on CT. These same lesions usually generate low signal intensity on T2-weighted MRI.26, 27 Some studies have suggested a potential diagnostic role of 18F-fluorodeoxyglucose positron emission tomography/CT .28, 29 A recent study identified a more extensive disease

Histopathological Approach

Histopathological analysis of specimens from the organ involved remains the diagnostic cornerstone of IgG4-RD. Needle biopsies are generally useful in excluding malignancies but often provide insufficient quantities of tissue to confirm a diagnosis of IgG4-RD.⁴⁹

Flow Cytometry

Blood plasmablast concentrations may be superior to serum IgG4 concentrations for the diagnosis of IgG4-RD and offer important possibilities to follow disease activity in the longitudinal evaluation of patients. Untreated patients with IgG4-RD have a marked elevation in blood plasmablast concentrations.12, 64 Plasmablasts can be identified through flow cytometry analysis of peripheral blood, gating on cells that are CD19^lowCD38⁺CD20⁻CD27⁺.¹² Of note, increased plasmablasts showing CD19⁺CD38⁺CD20

Differential Diagnosis

The first diagnostic challenge is to differentiate whether the clinical picture owes to IgG4-RD or to malignancy, especially when the disease affects a single organ and is either diagnosed unexpectedly in pathological specimens or identified incidentally on radiological studies. It is essential to differentiate single-organ IgG4-RD from pancreatic cancer, cholangiocarcinoma, lung adenocarcinoma, prostate cancer, and lymphoma. Similarly, multiorgan IgG4-RD may mimic lymphoma or a metastatic

Diagnostic Criteria

The diagnostic approach is heterogeneous, and the first proposed sets of criteria centered on specific organs rather than IgG4-RD as a whole. The best examples of organ-specific criteria are those created for IgG4-related pancreatitis, sclerosing cholangitis, kidney disease, and major salivary gland disease. In 2012, Umehara et al⁷¹ proposed a set of criteria for the diagnosis of systemic IgG4-RD designed to be used independently of the predominant organ involvement but exclusively focused on

Conclusion

IgG4-related disease is an increasingly recognized systemic disease in adults, with a heterogeneous clinical, laboratory, and histological presentation affecting a wide range of organ systems. The diagnostic approach is complex and should include not only IgG4-related tests (serum levels of IgG4 and immunohistochemical studies) but also an extensive evaluation of the patient’s condition including epidemiological, clinical, laboratory, imaging, and typical pathological features; the more

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A case report of multisite IgG4-related disease diagnosed by ultrasound-guided biopsies of the kidney and prostate
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IgG4-related disease mimicking gynecologic malignancy
2023, Gynecologic Oncology Reports
Immunoglobulin G4 (IgG4) related disease is a systemic disease that causes fibrosis, tumor-like nodules, and lymphoid hyperplasia with infiltration of IgG4 positive plasma cells. It can manifest in many organ systems; however, there are few cases that report gynecologic organ involvement. It is crucial to correctly diagnose IgG4-related disease versus malignancy because the former is treated with glucocorticoids or rituximab. In this case report, we describe two patients in which IgG4-related disease mimics gynecologic cancer. In the first case, an 85 year old woman presented with diffuse lymphadenopathy and a uterine mass concerning for malignancy. Biopsies were negative for carcinoma. Inguinal lymph node biopsy demonstrated IgG4 positive plasma cells and the patient was treated with rituximab therapy given concurrent severe rheumatoid arthritis. In the second case, a 35 year old woman under surveillance for Stage IB2 squamous cell carcinoma of the cervix (status post definitive chemoradiation therapy) presented with fluorodeoxyglucose (FDG) avid paraaortic lymph nodes on positron emission tomography (PET) imaging with subsequent negative paraaortic lymph node biopsies. Serial imaging and biopsies remained inconclusive despite ongoing diffuse lymphadenopathy and clinical concern for recurrence. Supraclavicular lymph node excision was performed which demonstrated lymphoid hyperplasia with increased IgG4 plasma cells and no evidence of carcinoma, supporting the diagnosis of IgG4-related disease. The patient was treated with high dose steroids with clinical improvement and resolution of abnormal imaging findings. We demonstrate that IgG4-related disease can present with FDG-avid lesions on PET imaging and lymphadenopathy that mimics primary or recurrent gynecologic malignancy. While rare, we conclude the IgG4-related disease is an important differential diagnosis to consider in the workup of primary or recurrent gynecologic malignancy and highlights the value of PET imaging to identify unusual patterns of lymphadenopathy and guide histologic confirmation of disease.
Successful azathioprine treatment in a male with IgG4 related disease. Case report
2022, Revista Medica Clinica Las Condes
reporte de caso de enfermedad relacionada con IgG4 tratada exitosamente con azatioprina. Caso clínico: varón de 53 años con proptosis, cefalea y masa extraocular derecha visible por tomografía, el estudio anatomopatológico concluyó en enfermedad relacionada con IgG4. Se inició tratamiento con prednisona en dosis altas con descenso progresivo, añadiendo azatioprina a los 3 meses para inducción rápida de remisión. Resultados: se observó una mejoría significativa a los 6 meses de tratamiento mixto con prednisona y azatioprina, observándose ausencia de masa extraocular derecha en la resonancia magnética cerebral. Conclusiones: se puede optar por terapia doble con prednisona y azatioprina en un paciente con masa orbitaria debido a enfermedad relacionada con IgG4, ello con la intención de remisión rápida de la enfermedad.
case report of IgG4-related disease successfully treated with azathioprine. Clinical case: 53-year-old male with proptosis, headache and right extraocular mass visible by tomography, the pathological study concluded in IgG4-related disease. Treatment with high-dose prednisone was started with progressive reduction, adding azathioprine at 3 months for rapid induction of remission. Results: significant improvement was observed after 6 months of mixed treatment with prednisone and azathioprine, observing the absence of a right extraocular mass in the magnetic resonance imaging brain. Conclusions: dual therapy with prednisone and azathioprine can be chosen in a patient with an orbital mass due to IgG4-related disease, with the intention of rapid remission of the disease.
Follicular lymphoma with hepatic accumulation on FDG-PET/CT masquerading IgG4-related disease
2021, Radiology Case Reports
Follicular lymphoma is clinically classified as a common type of indolent non-Hodgkin's lymphoma, and its clinical diagnosis is difficult because B symptoms and elevated soluble interleukin-2 receptor (sIL-2R) levels are less frequent in follicular lymphoma than in other lymphomas. We report a case of follicular lymphoma masquerading immunoglobulin G4-related disease (IgG4-RD) with elevated IgG4 levels. A 67-year-old man presented to our hospital with a 1-year history of deep right supraclavicular and para-aortic lymph node lymphadenopathy on plain computed tomography (CT) findings along with elevated IgG4 levels, and the ¹⁸F-fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) scan showed heterogeneous diffuse FDG uptake in the liver, and FDG uptake was noted at multiple sites in the enlarged right supraclavicular and para-aortic lymph nodes. Excisional biopsy of the right supraclavicular lymph node, performed under general anesthesia, showed a tumor-like structure mimicking a normal germinal center in the lymphoid follicle; immunostaining was positive for B-cell lymphoma 2 and CD10 proteins with some plasma cells stained with IgG, only 30% of them were positive for IgG4, and no marked fibrosis characteristic of IgG4-RD was observed; therefore, follicular lymphoma was diagnosed, and all symptoms, including FDG uptake, improved with rituximab monotherapy. Differential diagnoses of slowly progressive generalized lymphadenopathy over the years with elevated serum IgG4 levels include IgG4-RD, Castleman's disease, and indolent lymphoma. Multiple accumulation in the liver on FDG-PET/CT, if found, may suggest indolent lymphoma among them.
IgG4-Related Infiltrative Kidney Disease without Extrarenal Organ Involvement: A Case Report
2024, Journal of the Medical Association of Thailand
IgG4-related disease: an update on pathology and diagnostic criteria with a focus on salivary gland manifestations
2024, Virchows Archiv

View all citing articles on Scopus

: Grant Support: The work was supported by the Josep Font Research Fellow Award, Hospital Clinic, Barcelona, Spain (P.B.-Z.).

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ReviewDiagnostic Approach to the Complexity of IgG4-Related Disease

Abstract

Section snippets

Clinical Suspicion

Routine Tests

Imaging Studies

Histopathological Approach

Flow Cytometry

Differential Diagnosis

Diagnostic Criteria

Conclusion

Semin Diagn Pathol

Autoimmun Rev

J Autoimmun

Dig Liver Dis

Mod Pathol

Mod Pathol

J Mol Biol

Gastroenterology

Semin Arthritis Rheum

Kidney Int

Mod Pathol

Pancreatology

Semin Diagn Pathol

Hum Pathol

Kidney Int

J Allergy Clin Immunol

Immunity

Clin Chim Acta

Lancet

IgG4-related disease

N Engl J Med

IgG4-related disease

Annu Rev Pathol

IgG4-related systemic disease: features and treatment response in a French cohort: results of a multicenter registry

Medicine (Baltimore)

IgG4-related disease in a Chinese cohort: a prospective study

Scand J Rheumatol

Clinical and pathological characteristics of IgG4-related sclerosing sialadenitis

Laryngoscope

The diagnostic utility of serum IgG4 concentrations in IgG4-related disease

Ann Rheum Dis

IgG4-related disease: baseline clinical and laboratory features in 125 patients with biopsy-proven disease

Arth Rheumatol

Plasmablasts as a biomarker for IgG4-related disease, independent of serum IgG4 concentrations

Ann Rheum Dis

The utility of serum IgG4 concentrations as a biomarker

Int J Rheumatol

Serum immunoglobulin G4 associated with number and distribution of extrapancreatic lesions in type 1 autoimmune pancreatitis patients

J Gastroenterol Hepatol

Brief Report: spuriously low serum IgG4 concentrations caused by the prozone phenomenon in patients with IgG4-related disease

Arthritis Rheumatol

Distinct clinical, serological, and sonographic characteristics of Hashimoto’s thyroiditis based with and without IgG4-positive plasma cells

J Clin Endocrinol Metab

IgG4-related chronic rhinosinusitis: a new clinical entity of nasal disease

Acta Otolaryngol

Prevalence of atopy, eosinophilia, and IgE elevation in IgG4-related disease

Allergy

Immunoglobulin G4-related lung disease: clinicoradiological and pathological features

Respirology

Incidence of malignancies in patients with IgG4-related disease

Intern Med

Location and frequency of lesions in patients with IgG4-related ophthalmic diseases

Graefes Arch Clin Exp Ophthalmol

Review
Diagnostic Approach to the Complexity of IgG4-Related Disease