2.9: IgG4-related disease
Santosh P. Rai, Saubhagya Srivastava, Yvette Kirubha Jayakar, DavidLivingstone
Background
Immunoglobulin G4 (IgG4)-related disease is a recently established clinical–pathologic entity that is characterized by infiltration of IgG4-positive plasma cells and lymphocytes with associated fibro-inflammatory lesions, producing tumefactive lesions in one or more organ systems. Elevated serum IgG4 concentrations are also frequently encountered in patients. IgG4-related disease is recognized as a systemic disease and is found capable of affecting multiple organ systems including the pancreas, biliary tract, renal system, retroperitoneum, lungs, lymph nodes, periorbital tissues, salivary and lacrimal glands, thyroid gland, prostate gland, testicles, breasts and pituitary gland. Although the exact mechanism of pathogenesis is not completely understood, the common findings are suggestive of an autoimmune and an allergic aetiology. Imaging plays a key role in diagnosis of IgG4-related disease by demonstration of enlargement of affected organs along with infiltration. Being a multisystem disease, the radiological workup should include whole-body examinations. It is not uncommon for a patient to present with development of a mass in the affected organ or a diffuse enlargement of the affected organ, which can be mistaken for a neoplastic process. This makes it crucial for a radiologist to be able to differentiate between IgG4-related disorders and neoplastic processes and be able to consider several inflammatory and neoplastic processes as differentials in every anatomic location. IgG4-related disorders generally show excellent response to corticosteroid therapy, which makes it important for the radiologist to corelate clinical and radiological manifestations to facilitate an early diagnosis, appropriate management of the patient.
History
1995 – Yoshida et al. first suggested the concept of Autoimmune Pancreatitis (AIP), and described it as a chronic pancreatitis of autoimmune aetiology.
2001 – Hamano et al. identified a link between patients of sclerosing pancreatitis (Type 1 AIP) and elevated serum IgG4 concentrations along with infiltration by IgG4-positive plasma cells in pancreatic specimens.
2003 – Kamisawa et al. identified AIP as part of a spectrum of multisystem IgG4 disease.
Ever since, similar IgG4-related lesions have been found in many extrapancreatic organs such as the biliary tract, gallbladder, lymph nodes, retroperitoneum, mesentery, renal system, pulmonary system, breasts, prostate, thyroid, salivary and lacrimal glands, periorbital tissues, testicles and skin.
Various terms such as IgG4-related systemic disease, IgG4-related plasmacytic syndrome, IgG4-related sclerosing disease and IgG4-related autoimmune disease have been used to describe this clinical–pathological entity. However, due to the reason that fibro-inflammatory lesions are characteristically found in some organs and rarely in other organs, and the disease may be systemic or only found in one organ, terms such as systemic and sclerosing are not considered accurate in describing this spectrum of disease. Recently, a set of Japanese investigators reached a consensus to unify different nomenclatures and use the term ‘IgG4-related disease’.
The same panel of Japanese investigators also described three major diagnostic criteria for the diagnosis of IgG4-related disease:
A diagnosis of IgG4-related disease is definitive only when all three criteria are met. The diagnosis is considered to be probable if only the first and second criteria are met. It is very difficult to establish criteria that include all IgG4-related conditions, as the clinical features and histopathological features depend on the location of the lesion. Therefore, the mentioned criteria are not organ specific but aid physicians in differentiating IgG4-related disease from other neoplastic or inflammatory processes. The most commonly affected organ in IgG4-related disease is the pancreas in the form of type 1 autoimmune pancreatitis (lymphoplasmacytic sclerosing pancreatitis). However, because cases with only extra pancreatic involvement without AIP have been reported, pancreatic involvement, although present in most patients with IgG4-related disease, is not essential to the diagnosis.
Points favouring a diagnosis of IgG4-related disease
- • IgG4-positive plasma cells’ presence is essential for a definitive diagnosis of IgG4-related disease. However, IgG4-positive plasma cells may be found in other inflammatory conditions as well.
- • A ratio of IgG4 to IgG plasma cells >40% (IgG4/IgG > 40%) favours a diagnosis of IgG4-related disease.
- • Elevated serum IgG4 concentration is a common serologic finding; however, it is not specific to IgG4-related disease.
Clinical symptoms of IgG4-related conditions are generally mild. Fever and CRP elevation are usually absent. IgG4-related disease is often incidentally found when an organ enlargement is detected on radiological examinations. Patients of IgG4-related disease generally show an extremely positive response to corticosteroid therapy with resolution of clinical and radiological features seen within 2 weeks.
Abdominal manifestations of IgG4-related disease
IgG4-related autoimmune pancreatitis
Autoimmune pancreatitis (AIP) is a rare and specific form of chronic pancreatitis that occurs secondary to an autoimmune fibro-inflammatory process. There are two distinct subtypes of autoimmune pancreatitis:
Type 1 AIP (lymphoplasmacytic sclerosing pancreatitis) is IgG4-related pancreatic manifestation of IgG4-related disease. Type 2 AIP is a distinct clincopathological entity without any association to IgG4 (Table 2.9.1).
| Type 1 AIP (IgG4-related) | Type 2 AIP (non-IgG4-related) | |
|---|---|---|
| Epidemiology | ||
| Signs and symptoms | ||
| Extrapancreatic involvement | ||
| Histopathology | IgG4-rich periductal lymphoplasmacytic infiltrates | Granulocyte epithelial lesions (GELs) |
| Serum IgG4 concentration | Elevated | Normal |
| Response to steroids | Excellent | Excellent |
| Recurrence | Common | Rare |
Type 1 AIP
Incidence
- • IgG4-AIP has an estimated overall prevalence of 4.6 per 100,000 population and an estimated annual incidence of 1.4 per 100,000 population, supported by clinic-epidemiological data.
- • IgG4-related autoimmune pancreatitis is found in 2%–8% of patients with chronic pancreatitis.
- • It is seen more commonly in middle-aged and elderly men (95% of patients are older than 45 years of age).
- • Male to female ratio is 2.9–3.7:1.
Clinical presentation
Patients with IgG4-related pancreatitis usually have no specific symptoms. However, some patients may present with the following:
Diagnosis
As mentioned before, three major criteria are used for diagnosis of IgG4-related disease that are as follows:
- (i) Clinical – this includes the clinical history, physical examination and imaging appearances.
- (ii) Immunological/Serological – serum IgG4 > 135 mg/dL and/or an IgG4/IgG positive plasma cells > 40%
- (iii) Histopathological – periductal infiltration by IgG4-positive plasma cells, lymphoplasmacytic infiltration and storiform fibrosis.
Periductal infiltration by IgG4-positive plasma cells leads to periductal fibrosis. Eventually, atrophy of the parenchymal acini occurs along with extensive sclerosis, leading to loss of lobular structure.
The International Association of Pancreatology released the International consensus diagnostic criteria for autoimmune pancreatitis in 2011. These criteria are based upon five cardinal features of type 1 pancreatitis
Imaging findings
Radiologically, IgG4-related pancreatitis can be mistaken for various other conditions such as pancreatic adenocarcinoma, lymphoma, acute pancreatitis or chronic pancreatitis. Thus, it is essential for a radiologist to have a thorough understanding of the pattern of presentation on cross-sectional imaging to facilitate in making an early and correct diagnosis, directing the physician towards appropriate management and avoiding unnecessary invasive procedures.
Morphology of Type 1 and Type 2 AIP are radiologically indistinguishable. Autoimmune pancreatitis can present as a diffuse enlargement, a more focal enlargement or a multifocal enlargement.
Ultrasonography findings
The affected regions of the pancreas with AIP typically appear hypoechoic on ultrasonography.
CT imaging findings
Contrast-enhanced CT (CECT) is an essential imaging modality in the evaluation of IgG4-related pancreatitis. It demonstrates classical features of AIP such as diffuse or focal enlargement of the pancreas.
Diffuse form
- • Characterized by a smooth, sausage-like enlargement of the pancreas with loss of normal pancreatic lobulations.
- • The affected area is hypoattenuating relative to the normal parenchyma as seen on CT.
- • A more specific finding is the presence of a peripancreatic capsule surrounding the pancreas that tends to be hypoattenuating and is referred to as a ‘halo’. This ‘halo’ represents a combination of fibrotic tissue, fluid and phlegmon. This is an important differentiating feature between IgG4-related AIP and pancreatic adenocarcinoma.
- • Preservation of peripancreatic fat planes without vascular enhancement
- • Narrowing of peripancreatic veins may be present.
- • Regional lymph node enlargement may be present but is not considered a specific feature.
- • AIP is not known to be associated with peripancreatic collections, pancreatic pseudocysts or retroperitoneal fluid. An absence of these features suggests a diagnosis of AIP over acute or chronic forms of pancreatitis.
Focal form
- • In the focal form, AIP may present as a well-defined focal mass-like lesion
- • The mass-like lesion leads to irregular narrowing of the pancreatic duct, CBD involvement and pancreatic tail retraction.
- • Absence of upstream dilatation of pancreatic duct, even in the presence of duct narrowing. This feature can help radiologists differentiate between AIP and pancreatic carcinoma.
- • Enhancement of the main pancreatic duct, known as ‘Enhanced duct sign’, is a more specific feature of focal form of AIP. It occurs due to periductal fibrosis.
Postcontrast
- • Early phase – decreased enhancement within the involved area relative to normal pancreatic parenchyma.
- • Delayed phases – moderate and persistent enhancement.
- • Delayed phase images are a useful discriminator of AIP and pancreatic carcinoma. Pancreatic carcinoma generally shows higher delayed phase attenuation values.
- • A typical pattern of homogenous enhancement is seen in AIP. This is a useful tool in discriminating AIP from pancreatic carcinoma, as pancreatic carcinoma may demonstrate a ring-like enhancement, if at all.
- • Another feature that highly favours the diagnosis towards AIP is the delayed enhancement of a peripancreatic capsule
- • Delayed phase images are a useful discriminator of AIP and pancreatic carcinoma. Pancreatic carcinoma generally shows higher delayed phase attenuation values.
MR imaging findings
Magnetic Resonance Imaging (MRI) of AIP shows the same gross morphological features as on CT. MRI can demonstrate diffuse or focal enlargement of the pancreas along with loss of normal pancreatic lobulations. Regions that are affected by AIP show a hypointense T1 and hyperintense T2 signal. The hypoattenuated peripancreatic capsule (halo) shows a hypointense signal on both T1 and T2 sequences.
Dynamic contrast-enhanced MRI demonstrates nonenhancement in the early phases and enhancement in the delayed phases. The peripancreatic capsule (halo) shows a delayed enhancement. Therefore, DCE-MRI shows a similar pattern of enhancement as seen on CECT.
- • Because of a better contrast resolution, T2-weighted sequences on MRI are a more useful tool than CT in delineating the pancreatic duct.
- • Irregular or segmental narrowing of the main pancreatic duct without associated upstream dilation of the pancreatic duct is the imaging feature favouring AIP. This can be demonstrated by ERCP and MRCP
- • Secretin-enhanced MRCP improves duct distension. It is an extremely useful tool in the evaluation of AIP.
- • ‘Duct penetrating sign’ (mass penetrated by an unobstructed pancreatic duct) is a highly specific finding of benign strictures, which are a common associated finding in patients with autoimmune pancreatitis. However, this sign is not appreciated in pancreatic carcinoma.
- • ‘Ice pick sign’ (smooth, tapered narrowing of the upstream pancreatic duct just distal to the pancreatic lesion) is a common finding in patients with AIP. This can be used to discriminate AIP with pancreatic cancer, as pancreatic cancer tends to produce an abrupt obstruction of the pancreatic duct due to its origin in the ductal epithelium and typically produces an early obstruction. Whereas in AIP, the duct gets extrinsically compressed due to inflammation and periductal fibrosis.
Diffusion-weighted imaging
- • Diffusion-weighted imaging (DWI) along with the corresponding apparent diffusion coefficient (ADC) can be used in the evaluation of AIP.
- • Both autoimmune pancreatitis and pancreatic cancer show an increased signal on high b-value sequences along with corresponding low ADC values.
- • Kamisawa T et al. revealed that autoimmune pancreatitis shows high b-value DWI signal in a more linear morphology in comparison to pancreatic adenocarcinoma.
- • Although both autoimmune pancreatitis and pancreatic adenocarcinoma show low ADC values relative to normal pancreatic parenchyma, AIP demonstrates lower ADC values compared to pancreatic adenocarcinoma.
PET/CT imaging findings
Fluorodeoxyglucose PET/CT (FDG PET/CT) imaging is also a promising tool in the evaluation of IgG4-related AIP.
- • Multiple studies have concluded multifocal increased FDG uptake to be a sensitive indicator in evaluating AIP. However, it is not specific to AIP. Typical chronic pancreatitis does not show FDG uptake. However, pancreatic carcinomas and AIP both tend to demonstrate FDG avidity. The pattern of FDG uptake can be a useful tool in differentiating between AIP and pancreatic carcinomas. AIP tends to show a more diffuse, elongated and heterogenous pattern of uptake, whereas pancreatic carcinoma tends to show a more nodular and focal pattern of uptake.
- • Measurement of standardized uptake value (SUV) between the pancreas and liver can also be a helpful differentiating factor between AIP and pancreatic carcinoma. A recent study from 2017 demonstrated a lower maximum standardized uptake value (SUVmax) in the affected regions of AIP when compared to pancreatic carcinomas.
- • The presence of extrapancreatic sites of disease is one of the strongest indicators for considering a diagnosis of AIP over pancreatic carcinoma. FDG PET/CT scan is an imaging modality that can be used to demonstrate the extrapancreatic sites of disease.
Imaging findings in response to corticosteroid therapy
IgG4-related AIP shows an excellent response to corticosteroid therapy with resolution of features observed both clinically and radiologically. Improvement in the imaging findings can be seen within 2 weeks of employing corticosteroid therapy. However, it may take up to 4–6 weeks to observe marked improvement in pancreatic morphology and function.
The 2011 the International consensus diagnostic criteria for autoimmune pancreatitis recommends repeat imaging after a 2-week trial of corticosteroid treatment for a new diagnosis of AIP.
The cardinal features of response to treatment with corticosteroids on CT and MRI include the following:
The response to therapy, however, depends upon the stage of the disease. For example, an IgG-4 related AIP that is limited to features of early phase inflammation such as diffuse parenchymal swelling and a peripancreatic capsule or ‘halo’ will show a better response to steroid therapy, whereas IgG4-related AIP that has progressed to the late fibrotic phase of the disease with features such as focal mass like lesion or ductal strictures will generally show a poor response to steroid therapy. Therefore, evaluation of the stage of disease can be a helpful predictor of response to steroid therapy.
FDG PET/CT imaging can also be a useful tool in monitoring the response to steroid therapy in AIP. Abnormal radiotracer uptake exhibited by FDG PET scan in AIP tends to disappear along with a reduction in maximum SUV (SUVmax) with appropriate treatment by corticosteroids.
IgG4-related sclerosing cholangitis
Sclerosing Cholangitis (SC) can be defined as a condition characterized by progressive stenosis and destruction of the bile ducts because of diffuse inflammation and fibrosis. SC can be divided into three main subtypes: (i) Primary Sclerosing Cholangitis (PSC), (ii) Secondary Sclerosing Cholangitis and (iii) IgG4-Related Sclerosing Cholangitis (IgG4-SC). PSC is usually of unknown aetiology, whereas secondary SC occurs secondary to some underlying pathology such as iatrogenic biliary strictures, bacterial cholangitis, choledocholithiasis, etc. Earlier, SC was categorized broadly into primary and secondary cholangitis. IgG4-related sclerosing cholangitis (IgG4-SC) is a more recently established aetiology and clinical phenotype in the spectrum of IgG4-related disease.
IgG4-SC is a distinct phenotype of sclerosing cholangitis that is recognized as the biliary tract manifestation in the systemic spectrum of IgG4-related disease and is often found in association with autoimmune pancreatitis (AIP). AIP and IgG4-SC are the predominant manifestations of IgG4-related disease. IgG4-SC is characterized by a dense infiltration by IgG4-positive plasma cells and lymphocytes, fibroinflammatory lesions and obliterative phlebitis in the wall of the bile duct. The ability of IgG4-SC to mimic other inflammatory and neoplastic disorders such as primary sclerosing cholangitis (PSC), cholangiocarcinoma and pancreatic adenocarcinoma poses a challenge to physicians and radiologists in providing an accurate diagnosis and appropriate management. IgG4-SC, like AIP, shows an excellent response to steroid therapy in its early inflammatory phase. However, a delay in treatment may cause the disease to progress to a more severe late fibrotic phase leading to organ failure and mortality.
IgG4-SC has a poorly understood aetiology and is often found coexisting with other autoimmune disorders. However, studies have associated IGG4-SC with ‘blue-collar work’ leading to history of chronic occupational exposure. de Buy Wenninger LJM et al. in their study revealed a link between IgG4-SC and a history of occupational exposure (especially ‘blue collar’ work) in 60%–80% of patients in United Kingdom and Dutch subjects. Culver et al. reported a clinical history of allergy or atopy in 40%–60% of patients, associated with elevated Immunoglobulin E (IgE) levels and peripheral eosinophilia.
Incidence
- • Kanno et al. found the overall estimated prevalence of patients who have both IgG4-related AIP and SC to be 1.8 per 100,000 population and an estimated annual incidence of patients with both AIP and IgG4-SC to be 0.5 per 100,000 population.
- • A 2015 nationwide survey in Japan also revealed that 87% of all IgG4-SC cases had both AIP and IgG4-SC.
- • From this collective data, an overall prevalence and annual incidence of IgG4-SC was estimated to be 2.1 and 0.63 per 100,000 population, respectively, in Japan.
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