Discussion
We present a patient with an AIP type 1 that underwent a Whipple procedure due to a high suspicion for PM, had a full recovery, and presented a year later with a true PM. The differential diagnosis included recurrence of AIP type 1 or a pancreatic tumor de novoin the remaining part of the pancreas. It should be noted that at this time point, both serum IgG4 levels and tumor marker CA-19-9 levels were normal and the elevation of CA-19-9 has been noted concurrently with the appearance of the liver metastases. Neither MRI nor PET-FDG could differentiate between the two possible diagnoses during the evaluation, and only repeated EUS with FNA revealed adenocarcinoma of the pancreas.
IgG4-RD is a rare systemic fibro-inflammatory disease. The disease affects mainly the pancreas, an entity known as autoimmune pancreatitis (AIP) type 1. Middle-aged males are more prone to IgG4-RD and AIP type 1 (1). One cohort study described a higher prevalence of IgG4-RD in plumbers and construction workers, suggesting that chronic exposure to occupational antigens such as pigments, oils, solvents and industrial dusts may be related to the underlying pathogenesis of the IgG4-RD in these patients (2). Most commonly, the clinical presentation is sub-acute. AIP type 1 presents as a painless jaundice (74% of cases) or as an abdominal pain (37% of cases). In 60-90% of the cases, AIP type 1 is accompanied by damage to other organs or by a malignancy, which may result in organ failure and increased morbidity and mortality. There are reports of combined IgG4-related sclerosing cholangitis (IgG4-SC) disease in 56% of patients with AIP type 1 (3,4). Rarely, an overlap of IgG4-RD and ANCA-associated vasculitis have been seen (5,6).
AIP type 1 and pancreatic malignancy (PM) have similar clinical and radiologic presentations (7,8). Therefore, in order to establish the appropriate treatment approach, it is essential to differentiate between both entities. According to the International Consensus Diagnostic Criteria (ICDC), IgG4-RD is confirmed by the combination of clinical presentation, biochemical laboratory tests, radiologic findings and IHC findings (9). In particular, the diagnosis of AIP type 1 is determined by the following: an appropriate clinical presentation which often includes obstructive jaundice; increased levels of IgG4 in serum (>1.35 g/L); and typical findings in radiologic imaging (CT or MRI), which include diffuse enlargement of the pancreas with multiple strictures, lack of upstream dilatation and late contrast enhancement. The histologic findings from pancreatic biopsy obtained by endoscopic ultrasound (EUS) consist of lympho-plasmacytic infiltrate (often associated with eosinophil infiltrate) (10,11), 10-50% IgG4+ plasma cells per high-power field, an IgG4/Ig4 cell ratio of more than 40%, fibrosis arranged in a storiform pattern and obliterative phlebitis. A favorable response to steroid treatment also supports the diagnosis (12-14).
The association of AIP type 1 and increased risk for PM is controversial, and data on this subject are limited. Nevertheless, several findings have been described regarding the appearance of malignancy in patients with AIP type 1.
Firstly, AIP type 1 has been associated with a high incidence rate of PM, especially within 1 year of AIP type 1 diagnosis (15-17). In addition, several studies showed a higher risk of predominant lung, gastric and prostate malignancies (18), and a general increased incidence rate for all type cancers compared with the general population (3,19). In contrast, different studies which included 95 and 116 patients with AIP type 1 showed no significant increase in the incidence rate of PM (20,21).
Secondly, several studies have described a coexistence between AIP type and PM (22). Thus, elevated serum levels of IgG4 has been reported in 14 patients with established diagnosis of PM, and in 2 of these patients, the levels were twice the upper limit of normal. In these patients, further IHC examination of the surgical pancreatic biopsy revealed IgG4 lympho-plasmacytic infiltrate (22).
Increased serum levels of IgG4 (70%-80% of cases) may possibly aid to distinguish between AIP type 1 and PM, although it is known that high serum levels of IgG4 are sensitive but not specific for IgG4-RD (23). A retrospective study tested different serological markers including IgG4, anti-plasminogen binding peptide (a-PBP) and anti-carbonic anhydrase-II (a-CA-II) in order to find new serological markers which would help to differentiate AIP type 1 from PM. This study concluded that IgG4 was the most useful marker in this regard (24). When differentiating between PM and AIP type 1, CA-19-9 elevation over 150 U/ml is associated with increased risk for PM, whereas levels of CA-19-9 that are less than 85 U/ml, combined with a high IgG4 serum level (over twice the upper limit of normal) support the diagnosis of AIP type 1 (22,25).
In conclusion, we present an interesting case of a patient with AIP type 1 who consequently developed metastatic PM in the remaining part of the pancreas after 1 year of disease remission. Physicians should be aware of the possibility of PM in a patient that was previously diagnosed with AIP type 1.