18.4.6Diagnostic Criteria

The principle differential diagnosis remains pancreatic carcinoma, although AIP also shows overlapping features with other forms of chronic pancreatitis. AIP is significantly less common than pancreatic carcinoma. The low pretest probability of AIP and the significant overlap with pancreatic cancer invariably makes this a diagnostic challenge. In an attempt to facilitate the diagnosis of AIP, a plethora of diagnostic criteria have been proposed, the majority of which have been developed in Japan [49–52]. These algorithms rely on imaging, elevated serum IgG4, supportive biopsy findings and the presence of extrapancreatic disease. In addition, a clinical and radiological response to glucocorticoids is a component of some diagnostic algorithms, although the Japanese algorithms caution against using this parameter [39].

18.5The Concept of IgG4-RD

18.5.1Introduction

In 2000, Kamisawa and coworkers identified patients of AIP with extrapancreatic disease and proposed the concept of a systemic disease [53]. Over the next few years, it became apparent that the extrapancreatic forms of the disease can occur in the absence of pancreatic disease, and this realization transformed a relatively exotic pancreatic disease into a systemic disease that could be encountered by virtually every medical and surgical subspecialty. The pancreatic manifestation of this disease, type 1 AIP, now constitutes only a minority of IgG4-RD patients seen at the Massachusetts General Hospital. The two features that unify these apparently disparate diseases are elevated serum/tissue levels of IgG4 and characteristic histopathologic features [35, 54–56]. IgG4-RD joins that list of systemic diseases that are unified by histopathologic features, the prototype being sarcoidosis.

18.5.2Nomenclature

The lack of a uniformly accepted name has been one of the factors that has stymied progress in this field. The following terms have been used commonly to describe this disease: IgG4-related autoimmune disease, IgG4-related sclerosing disease, systemic IgG4-related plasmacytic syndrome (SIPS), and IgG4+ positive multiorgan lymphoproliferative syndrome (MOLPS), IgG4-related systemic disease [39]. A study group in Japan proposed the term IgG4-RD, and we use this term to designate this multiorgan condition [57]. However, it must be acknowledged that the precise role played by IgG4 in this disorder is poorly understood. The term “IgG4related” conveys our fundamental lack of understanding of this disease.

by IgG4-related disease

Liver Bile duct

Gallbladder Gastrointestinal tract Salivary and lacrimal glands Kidney

Retroperitoneum and mesentery Lung

Thyroid

Aorta

Orbit Mediastinum Prostate Breast Pituitary gland Meningitis Lymph nodes Skin

18.5.3Clinical Manifestations

IgG4-RD involves virtually every organ in the body (Table 18.3). In the majority of cases, the disease manifests as a tumefactive lesion that has the potential to mimic a malignancy. Such is the case with involvement of the submandibular, parotid, and lacrimal glands (Fig. 18.3) [54, 58, 59]. Similar tumefactive lesions have been recognized in the meninges, lung, liver, retroperitoneum, kidney, breast, prostate, and other organs [60–63]. In fact, a significant proportion of cases previously classified as inflammatory pseudotumors belong to the IgG4-RD spectrum. A variety of disorders previously viewed as unrelated are now classified under the rubric of IgG4-RD, including Mikulicz’s disease, Küttner tumor, and Riedel’s thyroiditis (Table 18.2) [58, 64]. Patients with IgG4-RD often have multiorgan disease features, but the full extent of organ involvement may be either not present or not obvious at one particular time. A significant number of cases previously classified as “multifocal fibrosclerosis” actually represent IgG4-RD [65].

However, the spectrum of IgG4-RD also includes conditions that do not form tumefactive lesions. The prototypical example of this class is IgG4-related cholangitis [54, 66]. This disease mimics primary sclerosing cholangitis (PSC) but unlike PSC, IgG4-related cholangitis is a glucocorticoid-responsive disorder. IgG4-related aortitis, defined by lymphoplasmacytic infiltrates within the thoracic or abdominal aorta, generally presents with aneurysm or dissection rather than a tumefactive lesion (Fig. 18.4) [67].

b

lymphocytes and plasma cells surrounding ducts tends to be present when the disease involves glands such as the pancreas or submandibular glands, but the lymphoplasmacytic infiltrate is also scattered throughout the tissue [36]. Eosinophils are often present and may be numerous [35].

The lymphoplasmacytic infiltrate and eosinophils are associated with fibrosis that generally occurs in a storiform pattern. In contrast, inflammatory pathology unrelated to IgG4-RD typically shows a “pattern-less” fibrosis [56]. Obliterative phlebitis is seen in most cases [69]. Granulomatous inflammation, necrosis, or fibrinoid necrosis of vessels argue strongly against the diagnosis of IgG4-RD. Neutrophils, particularly neutrophilic microabscesses are distinctly uncommon in IgG4-RD.

Positive staining for IgG4-bearing plasma cells can clinch the diagnosis in the appropriate clinical setting, but it is also essential that the IgG4-staining plasma cells be accompanied by histopathologic findings that are consistent with this diagnosis [56] (Fig. 18.5a, b). There remains no consensus on the minimum requirements for