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.