CHALLENGES AND PITFALLS IN THE DIAGNOSIS OF IgG4-RELATED DISEASE

Available online 15 November 2023

Author links open overlay panel, ABSTRACT

IgG4-related disease (IgG4-RD) is a relatively novel fibroinflammatory condition characterised typically by dense lymphoplasmacytic inflammation, storiform fibrosis and obliterative venulitis, together with prominent IgG4+ plasma cells and an IgG4+/IgG+ plasma cell ratio of >40%. The diagnosis is usually made on a combination of clinical and serological features together with characteristic radiological and histological appearances. The condition may be limited to a single tissue/organ (e.g., autoimmune pancreatitis) or may be multicentric in nature – four clinical ‘patterns’ of disease distribution have recently been described. The diagnosis of IgG4-RD can be challenging, particularly when the clinical presentation is unusual and/or when the histological features are not typical. A diagnosis of IgG4-RD may still be achieved in these situations, after careful clinicopathological discussion e.g., at a specialist multidisciplinary team meeting. However, a wide range of other conditions (neoplastic and non-neoplastic) can mimic IgG4-RD, clinically and/or on histological examination. The relationship between IgG4-RD and non-IgG4-RD associated conditions in some clinical situations is particularly complex. This review describes the role of histological examination in the diagnosis of IgG4-RD, discusses some of the practical difficulties that may be encountered and provides an insight into the range of non-IgG4-RD associated conditions that can mimic IgG4-RD on clinical and/or histological grounds. The requirement for interpretation of histological features in the context of the global clinical picture of the patient is highlighted and emphasised.

Section snippetsHistological criteria

IgG4-related disease (IgG4-RD) is a relatively recently described condition that is characterised by the presence of chronic inflammation and fibrosis within involved tissues.1 These processes may involve an organ or tissue diffusely, leading to organ dysfunction, or in a localised manner, leading to masses that may simulate neoplasia.1 Three key histopathological characteristics were agreed upon during the first international IgG4-RD symposium in Boston in 2011.2 These are (1) dense

THE IMPORTANCE OF CLINICOPATHOLOGICAL CORRELATION

While histopathological assessment is important in suggesting and/or supporting a diagnosis of IgG4-RD, clinicopathological correlation and a sound clinical judgement remains crucial. There must be a careful dialogue between the treating clinician and the reporting pathologist to guide interpretation of histological findings. This is particularly important (1) when trying to distinguish IgG4-RD from other inflammatory, infective and malignant conditions that may have an elevated serum and/or

CLINICAL DIAGNOSTIC CRITERIA AND PATHOLOGY

The diagnosis of IgG4-RD is challenging, as it presents to multiple different specialists with often disconnected features and mimics a number of important malignant and inflammatory processes. There have been a number of consensus systemic disease and organ-specific criteria developed over the last 15 years to increase the accuracy of diagnosing IgG4-RD.

The Consensus Histopathological Criteria (2011) are valuable for the histopathological assessment of biopsy and/or resection specimens. This

EVOLUTION OF HISTOLOGICAL FEATURES OVER TIME

It is very likely that the histological features of IgG4-RD evolve over time in a similar way to that seen with other fibroinflammatory conditions. While the classical morphology includes the presence of dense lymphoplasmacytic chronic inflammation and storiform fibrosis, more established lesions may show less intense and/or patchy inflammation and fibrosis that has a less cellular and more hyaline quality. Therefore, a diagnosis of IgG4-RD on histological grounds may be more difficult to make

THE IMPORTANCE OF SAMPLING VARIABILITY

Achieving a diagnosis of IgG4-RD may be more challenging on biopsy material than it is when examining surgical resections, since sampling variability can affect the likelihood of identifying the characteristic histological features.4,53 The absence of storiform fibrosis and obliterative venulitis within biopsy samples is most common source of diagnostic difficulty. When examining tissues where the changes of IgG4-RD may be particularly patchy in distribution e.g., portal tract involvement in

IDENTIFYING POSSIBLE IgG4-RD AT NEW SITES

We now appreciate four broad clinical disease subsets, defined by the predominant pattern of organ involvement: (1) hepato-pancreato-biliary, (2) retroperitoneum and aorta, (3) limited head and neck, and (4) systemic disease with Mikulicz disease, although there are many overlapping features between these groups.18 Within these, there are 11 classical organs described to be involved in patients with IgG4-RD. However, there are case series and reports of many less typical organs presenting with

RELATING HISTOPATHOLOGY TO CLINICAL FEATURES AND FOLLOW-UP

It has become increasingly important to follow up patients with IgG4-RD both in those with diagnostic certainty and those with a degree of uncertainty, so as to increase understanding of the disease and the pitfalls and challenges. On review of 100 consecutive histopathological cases with high IgG4 infiltrates, it was clear with careful clinical correlation that IgG4-positive plasma cells was not specific for an IgD4-RD diagnosis, with significant numbers present in those with other

SUMMARY

Histological examination of potentially involved tissues is a very important component of diagnosis in IgG4-RD. However, accurate diagnosis relies on careful clinicopathological assessment e.g., in a multidisciplinary team setting. Histological examination of affected tissues in IgG4-RD may reveal features that are highly characteristic of the condition. Even in this situation, it is important to exclude histological mimics of the disease. The finding of non-diagnostic histological features can

Declaration of Competing Interest

ELC consults for Horizon Therapeutics, Zenus BioPharma, and Sanofi for IgG4-RD

ELC receives funding from the National Institute for Health Research (NIHR) Biomedical Research Centre (BRC) Oxford

ACB – none

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