Case 4 -
Constitutinal Mismatch Repair Deficiency Syndrome (Also Known as "Mismatch Repair Cancer Syndrome" and "Childhood Cancer Syndrome").
Vikram Deshpande, Massachusetts General Hospital, Boston, MA
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79 year old man with recent onset of diarrhea and weight loss and eventual jaundice. CT scan demonstrated a 3x4 cm mass in the head with multiple cysts within the mass measuring up to 0.9 cm. An EUS guided fine needle aspiration biopsy showed low grade mucinous epithelium and the cyst fluid CEA measured 685 IU/ml. A Whipple resection and cholecystectomy was performed. 10 years prior to to this episode of jaundice this patient presented with a lesion on the scalp. A biopsy was performed at an outside hospital and a diagnosis of 'pseudolymphoma' was made.
Case 4 - Slide 1
Pathological/Microscopic Findings and any Immunohistochemical or Other Studies:
The pancreas shows
extreme atrophy of the pancreatic acinar epithelium and is replaced by fibrosis and inflammation. The
fibrosis is focally organized in a storiform pattern. The inflammation is predominantly
lymphoplasmacytic with a generous sprinkling of eosinophils. In addition multiple foci of obliterative
phlebitis are also present. This fibroinflammatory infiltrate involves the bile duct (not shown) causing
mild narrowing of the duct. This histological appearance is typical of type 1 autoimmune pancreatitis.
In addition the pancreas shows dilated cysts lined by atypical mucinous epithelium arranged in papillary
or micropapillary formation with budding of cellular tufts into the lumen. These features indicate
PanIN2-3 lesion. Some of these PanIN lesions were dilated and in areas aggregates of tiny microscopic
cysts were present. The gallbladder also shows transmural inflammation that is accompanied by fibrosis.
The infiltrate is remarkably similar to that seen in the pancreas. On immunohistochemsitry there were 80
IgG4 positive plasma cells per HPF and a IgG4 to IgG ratio of 70%.
1. Autoimmune pancreatitis type 1
2. Autoimmune pancreatitis type 2
3. Chronic pancreatitis - not otherwise specified with PanIN2-3
5. Intraductal papillary mucinous neoplasm with moderate to severe dysplasia and chronic pancreatitis
Autoimmune pancreatitis type 1 IgG4-related cholecystitis
The clinical history is suggestive of autoimmune pancreatitis. This is a disease of elderly males who
present with obstructive jaundice and weight loss. Unfortunately, this is also the typical presentation
of pancreatic ductal adenocarcinoma. Furthermore, pancreatic carcinoma is still far more common than
autoimmune pancreatitis and thus statistically a history such as provided here is far more likely to
represent a pancreatic carcinoma.
An elevated serum IgG4 (>140 mg/dL) level is generally suggestive of autoimmune pancreatitis.
However, neither pre-operative nor post-operative serum IgG4 was drawn in this case.
While the clinical history offers few clues to the diagnosis of autoimmune pancreatitis, radiological
evaluation (CT and Endoscopic ultrasound) is often extremely helpful. On CT scan the pancreas shows a
mass lesion involving the head of the pancreas. The presence of a 'halo' sign around the mass is highly
suggestive of autoimmune pancreatitis. An ERCP or pancreatogram will often reveal an irregularly
narrowed main pancreatic duct. Unfortunately, as this case shows, many cases of autoimmune pancreatitis
continue to be mistaken for pancreatic carcinoma and thus subjected to radical surgery (the treatment of
this disease is a short course of steroids, see below). The criteria for the diagnosis of autoimmune
pancreatitis have been codified (Pancreas. 2011 Apr;40(3):352-8).
History of Cutaneous Pseudolymphoma
A clue to the diagnosis of autoimmune pancreatitis in this case is the history of pseudolymphoma.
The type 1 variant of autoimmune pancreatitis is a systemic disease. While the disease may manifest
primarily in the pancreas (as in this case), there is invariably synchronous/and or metachronous
involvement of other organs, and virtually every organ has been involved. Cutaneous involvement,
although uncommon, has been reported and some examples of cutaneous 'pseudolymphoma' have been shown to
represent cutaneous IgG4-related disease. Although the slides from the skin biopsy could not be
reviewed, it is highly likely that the histology will reveal IgG4-related cutaneous disease.
The diagnosis of autoimmune pancreatitis rests on three histological features-
1. Dense lymphoplasmacytic infiltrate
2. Storiform -type fibrosis
3. Obliterative phlebitis
In addition, the diagnosis requires the presence of elevated numbers of IgG4 positive plasma cells.
The case shown herein showed all three histological features. The dense lymphoplasmacytic infiltrate
involves both the interlobular stroma and the lobules. The lymphocytes and plasma cells form a collar
around pancreatic ducts. However, the ducts do not appear to show significant damage. Storiform-type of
fibrosis is highly characteristic of type 1 autoimmune pancreatitis (and of IgG4-related disease, see
review of literature). The storiform pattern resembles the spokes of a cartwheel with spindle cells
radiating from a center. This pattern of fibrosis is similar to the pattern seen in soft tissue lesions
such as dematofibrosarcoma protruberans. The fibrosis is composed of plump fibroblasts and
myofibroblasts, and is infiltrated by lymphocytes, plasma cells and eosinophils. Eosinophils are readily
identified in cases of autoimmune pancreatitis and occasionally may dominate the lesion. Obliterative
phlebitis is another highly characteristic lesion seen in autoimmune pancreatitis and was easily found in
this case. The venous channels are obliterated by a dense lymphoplasmacytic infiltrate. Lymphocytes and
plasma cells are seen both within the wall of venous channels and within the lumen. Partially
obliterated veins with transmural inflammatory infiltrates are also consistent with the diagnosis of
autoimmune pancreatitis. Fully-obliterated veins may require elastin stains for identification.
However, medium sized venous channels are generally accompanied by arteries, which are less likely to be
affected by the inflammatory process (in most organs) and can therefore serve as a guidepost to detecting
obliterated venous structures. Obliterated venous channels without the requisite inflammation are not
considered evidence of autoimmune pancreatitis. Arteritis is occasionally observed in cases of
autoimmune pancreatitis, although this case did not reveal foci of arteritis. The arteritis of
autoimmune pancreatitis is characterized by a non-necrotizing lymphoplasmacytic infiltrate with or
without obliteration of the lumen, similar to obliterative phlebitis. Necrotizing forms of arteritis are
IgG4 and IgG stain
While the histological appearance is highly characteristic of autoimmune pancreatitis, type 1,
immunohistochemical confirmation of this diagnosis is required. This case shown here showed 80 IgG4
positive plasma cells per HPF and a IgG4 to IgG ratio of 70%. It is recommended that >10/HPF IgG4+
plasma cells on a biopsy and > 50 per HPF on a resection specimen are required for a positive
diagnosis of autoimmune pancreatitis. An IgG4 to IgG ratio of > 40% is typical of autoimmune
pancreatitis. A recently published consensus statement on IgG4-related disease has recommended counting
three x40 fields with the highest number of IgG4+ plasma cells and calculating the average number of
IgG4+ plasma cells within these fields. The same three fields should be counted for the purpose of
calculating the IgG4 to IgG ratio.
PanIN and cystic PanIN
The other dominant histologic finding in this case were cysts lined by mucinous epithelium. These
represent a cystic version of PanIN. Conventional PanIN lesions were also identified within this
pancreas. The atypia of the lining cells varied from mild to focally severe and thus all 3 grades of
PanIN were represented in this case.
The gallbladder in this case showed evidence of IgG4-related cholecystitis. IgG4-related
cholecystitis is characterized by transmural inflammation by a lymphoplasmacytic infiltrate, often
forming tumoral nodules (as seen in this case) and obliterative phlebitis. The histological features are
akin to those seen in autoimmune pancreatitis. In fact the histological findings are so characteristic,
that histological examination of the gallbladder may help establish a diagnosis of autoimmune
Chronic pancreatitis –not otherwise specified
By far the most common cause of chronic pancreatitis is long-term alcohol abuse. Other forms of
pancreatitis include long-standing obstruction of the pancreatic ducts, tropical pancreatitis, hereditary
pancreatitis, and pancreatitis associated with cystic fibrosis. Alcohol related pancreatitis is
characterized by dense acellular fibrosis, calcification, and dilated ducts filled with inspissated
proteinaceous material. Inflammation is generally mild and is composed predominantly of lymphocytes.
Eosinophils and plasma cells are generally absent, as is storiform pattern of fibrosis and obliterative
phlebitis. In our experience, some forms of chronic pancreatitis may show a periductal lymphoplasmacytic
infiltrate and these may mimic the type 2 variant of autoimmune pancreatitis (see below). An IgG4
immunostain generally will show few IgG4 + plasma cells, although occasional examples of chronic
pancreatitis do show clusters of IgG4 + plasma cells that might reach the suggested cut point for
autoimmune pancreatitis (50/HPF).
Type 2 autoimmune pancreatitis
This 'variant' continues to bear the same name as the type 1. However, many expert are of the opinion
that this disease is a distinct entity that is unrelated to type 1 autoimmune pancreatitis.
Histologically, while it shows a dense periductal inflammatory infiltrate, this variant frequently lacks
both storiform type fibrosis and obliterative phlebitis. Instead the hallmark of this variant of
'autoimmune pancreatitis' are neutrophilic abscesses within ducts – also referred to by Zamboni and his
co-workers as granulocytic epithelial lesions. A comparison of the two diseases is listed below (table 1
||Type 1 autoimmune pancreatitis
||Type 2 autoimmune pancreatitis
||Elderly, 60’s ||Middle age 40-50|
||Predominantly male ||M=F|
||Jaundice, weight loss, malaise ||Similar to type 1 but may have abdominal pain|
|Elevated serum IgG4
|Type 1 AIP ||Type 2 AIP|
|Periductal inflammation with one or more of these features ||Periductal inflammation with one or more of these features|
|Storiform fibrosis ||Ductal/lobular absesses|
|Obliterative phlebitis ||Ductal ulceration with neutrophils|
The presence of cystic PanIN lesions raises the specter of a neoplastic process including cystic PanIN
and intraductal papillary mucinous neoplasm. In fact, the radiologist and gastroenterologist felt that
this lesion represented an invasive ductal carcinoma arising in a intraductal papillary mucinous
neoplasm. This impression was also supported by the elevated CEA levels and the presence of mucinous
epithelium on the EUS guided fine needle aspiration biopsy.
Distinction of cystic PanIN from IPMN is frequently arbitrary. The relatively small size of the cysts
(<1.0 cm) and the lack of papillary formation support the the diagnosis of PanIN. All 3 grades were
represented, and the micropapillary pattern suggested that foci of grade 3 PanIN were also present. The
presence of widespread PanIN lesions suggests that this patient may have an elevated risk of pancreatic
carcinoma. See discussion below for a commentary on the risk of malignancy in autoimmune pancreatitis.
In spite of the overwhelming inflammation, the ductal epithelium does not show significant atypia and
malignancy is seldom a diagnostic issue. There was no evidence of invasive carcinoma in this pancreas.
Lastly, although it is not unreasonable to consider a diagnosis of lymphoma in this case, the
polymorphic lymphoid infiltrate and the classic features of autoimmune pancreatitis in this specimen
makes this diagnosis unlikely.
Review of Literature, Conlusions and References
Autoimmune Pancreatitis and the Concept of IgG4 related Disease
Autoimmune pancreatitis would have remained an obscure disease, of interest to only a handful of
individuals interested in the pancreas. However, the discovery that this is a systemic disease elevates
this from an unknown disease to one that is of interest to physicians of virtually every subspecialty.
It is now widely accepted that autoimmune pancreatitis is a smaller component of a wider disease concept,
now termed IgG4-related disease. Over the last decade we've realized that the pancreas is only one
manifestation of this disease and that the majority of cases of IgG4-related disease occur outside the
pancreas, and are generally not associated with clinically evident pancreatic disease.
IgG4-related disease is a newly recognized fibroinflammatory condition characterized by tumefactive
lesions, a dense lymphoplasmacytic infiltrate rich in IgG4-positive plasma cells, storiform fibrosis,
and, often but not always,
elevated serum IgG4 concentrations. IgG4-related disease has been described in virtually every organ
system: the biliary tree, gallbladder, salivary glands, periorbital tissues, kidneys, lungs, lymph
nodes, meninges, aorta, breast, prostate, thyroid, pericardium, and skin (table 3). Many medical
conditions that have long been viewed as conditions confined to single organs are part of the spectrum of
IgG4-related disease. Patients with diagnosis such as Mikulicz's syndrome, Küttner's tumor, and Riedel's
thyroiditis — names embedded in the medical literature for more than a century in some cases —also belong
to the IgG4-RD spectrum.
IgG4 is a unique antibody in both structure and function. This molecule accounts for less than 5% of
the total IgG in healthy persons and is the least abundant IgG subclass. The IgG4 molecule shows a
relatively weak association between its heavy chains. The heavy chains thus dissociate and recombine
randomly with other heavy chains, such that asymmetric antibodies with two different antigen combining
sites are formed. The resulting bispecific (functionally monovalent) IgG4 molecules are unable to
cross-link antigens, thereby losing the ability to form immune complexes.
Histopathology of IgG4 related disease
Histopathological analysis of biopsy specimens remains the cornerstone in the diagnosis of IgG4-
related disease. Elevated concentrations of IgG4 in4 tissue and serum are helpful in diagnosing IgG4-
related disease, but neither one is a specific diagnostic marker. Correlation with specific
histopathological findings is essential, regardless of the serum IgG4 concentration, the number of IgG4-
positive plasma cells in tissue, or the ratio of IgG4 to IgG in tissue. Misdiagnoses of IgG4-related
disease are increasingly common because of excessive emphasis on moderate elevations of serum IgG4
concentration and overreliance on the finding of IgG4-positive plasma cells in tissue. The key
morphologic features of IgG4-related disease are identical to those seen in the type 1 variant of
autoimmune pancreatitis: a dense lymphoplasmacytic infiltrate that is organized in a storiform pattern,
obliterating phlebitis, and a mild-to-moderate eosinophil infiltrate.
Table 3: Organs involved by IgG4-related disease
|Organ ||Clinical Presentations|
|Orbits and peri-orbital tissues ||Tumefactive lesions of the orbit or peri-orbital tissues, including orbital pseudotumor; dacryoadenitis; dacrocystitis; orbital myositis; Bilateral disease is common.|
|Ears, nose, and sinuses ||Allergic phenomena are common in IgG4-RD (e.g. allergic)|
Eosinophilic angiocentric fibrosis
|Salivary glands ||Submandibular and/or parotid gland enlargement (isolated bilateral submandibular gland involvement more common).|
|Meninges ||Predilection for the dura rather than the leptomeninges. Tendency to form mass lesions.|
|Lymph nodes ||Either generalized lymphadenopathy or localized disease adjacent to a specific affected organ.|
|Thyroid gland ||Riedel’s thyroiditis|
Fibrosing variant of Hashimoto’s thyroiditis
|Lungs ||Four main clinical syndromes: inflammatory pseudotumor, central airway disease, localized or diffuse interstitial pneumonia, and pleuritis.|
|Aorta ||Lymphoplasmacytic aortitis of thoracic or abdominal aorta; aortic dissection; periaortitis and periarteritis; and inflammatory abdominal aneurysm.|
|Retroperitoneum ||Retroperitoneal fibrosis|
|Kidneys ||The typical renal syndrome is tubulointerstitial nephritis. |
Many patients have asymptomatic tumoral lesions, typically multiple and bilateral
|Pancreas ||Type 1 autoimmune pancreatitis. Type 2 autoimmune pancreatitis does not belong to the IgG4-related disease spectrum|
|Biliary tree ||Sclerosing cholangitis mimics primary sclerosing cholangitis|
|Liver ||Inflammatory mass forming ‘pseudotumor’|
|Other ||Gallbladder (lymphoplasmacytic sclerosing cholecystitis)|
Malignancy in autoimmune pancreatitis
Chronic pancreatitis is an independent risk factor for adenocarcinoma of the pancreas. Recent reports
have described the development of synchronous and metachronous pancreatic adenocarcinomas in patients
with autoimmune pancreatitis. These cases of autoimmune pancreatitis with synchronous or metachronous
pancreatic malignancy are listed below (table 4):
|Case ||Age/Sex ||Subtype of AIP ||IgG4 ||Radiological evidence for AIP ||Synchronous Metachronous ||Histology|
|Witkiewicz, 2008 ||80/M ||Type 1 ||Tissue >50/HPF ||None ||Synchronous ||Poorly differentiated|
|Inoue, 2006 ||62/M ||No biopsy ||Serum X2 normal ||Diffuse narrowing of MPD ||Synchronous ||Adenocarcinoma (Cytology)|
|Ghazale, 2007 ||77/M ||Type 1 ||Tissue >30/HPF ||None ||Metachronous (5 years) ||Adenocarcinoma|
|Fukui, 2008 ||80 ||Unknown ||None ||MPD irregular narrowing ||Metachronous (3 years) ||Adenocarcinoma (cytology)|
|Deshpande, ||73/M ||Type 1 ||Not performed ||None ||Metachronous (10) ||Adenosquamous|
|Motosugi, 2009 ||59/M ||Type 1 ||Tissue > 50/HPF ||Pancreatic body and tail swollen, capsule-like hypodense rim ||Synchronous ||Adenocarcinoma|
Numbers in parenthesis indicate duration between the diagnosis of AIP and pancreatic adenocarcinoma.
MPD=main pancreatic duct
In a retrospective study (unpublished data) our group has identified grade 2 PanIN lesions in 25% of
cases with autoimmune pancreatitis. We've identified of 2 cases of metachronous pancreatic carcinoma in
our cohort of autoimmune pancreatitis. This data while far from conclusive does raise the possibility
that patients with autoimmune pancreatitis may be associated with an elevated risk of malignancy. In
this particular patient, a discussion on the risk of malignancy may well be an academic one. However,
when faced with a recurrent mass in the pancreas in an individual with autoimmune pancreatitis, it is
worth considering the possibility of malignancy as well as recurrent autoimmune pancreatitis, the latter
obviously being the more common of the two possibilities.
Treatment for autoimmune pancreatitis and IgG4-RD
Glucocorticoids are typically the first line of therapy. The response in the pancreas is generally
swift with shrinking of the pancreas and resolution of obstructive jaundice. In cases where the
pancreatic carcinoma cannot be distinguished from autoimmune pancreatitis, a trial with steroids may be
For patients with recurrent or refractory disease, B-cell depletion with rituximab appears to be a
useful approach. Swift clinical responses have been observed, with a striking targeting of the serum
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of IgG4-Related Disease: Lessons from ten consecutive patients