Case 5 -
Mimickers of Pancreatic Cancer
Ralph H. Hruban
Johns Hopkins Medical Institutions
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This 60-year old man presented with the recent onset of jaundice. Abdominal imaging revealed a poorly defined mass in the head of his pancreas. A pancreatoduodenectomy was performed.
Lymphoplasmacytic Sclerosing Pancreatitis
1. Mimickers of Pancreatic Cancer:
A number of non-neoplastic conditions form a mass in the pancreas and mimic pancreatic
cancer (Table 1)
It should therefore not be surprising that 5-10% of Whipple resections
(pancreatoduodenectomies) performed for a clinical diagnosis of a malignancy are found to have benign
non-neoplastic disease on pathological examination
Chronic pancreatitis is the most
common of the non-neoplastic mimickers of pancreatic cancer listed in Table 1.
Table 1 - Mimickers of Pancreatic Cancer
|Chronic Pancreatitis ||Inflammatory injury characterized by loss of parenchyma and scarring|
|Reactive Fibroinflammatory Pseudotumor ||Composed of a mixture of non-neoplastic inflammatory cells and fibroblasts|
|Paraduodenal Pancreatitis ||Also known as "Groove Pancreatitis," occurs in the duodenal wall area near the minor ampulla|
|Granulomatous Inflammation ||Particularly tuberculosis and sarcoidosis|
|Nodular Lymphoid Hyperplasia ||Mass forming aggregates of non-neoplastic lymphoid tissue|
|Heterotopic Spleen ||Usually involves the tail of the pancreas|
|Lipomatous Pseudohypertrophy ||Significant replacement of the exocrine elements by adipose tissue|
|Hamartoma ||A benign mass-forming overgrowth of disorganized mature parenchymal elements native to the pancreas|
Case 5 - Slide 1
Case 5 - Figure 4 - Progressively higher magnification views of a representative pancreatic duct
Case 5 - Figure 5 - Intermediate and high-magnification views of the pancreatic mass
Case 5 - Figure 6 - Intermediate and high-magnification views of the pancreatic mass
Case 5 - Figure 7 - Intermediate and high-magnification views of blood vessels adjacent to the pancreatic mass
Case 5 - Figure 8 - Intermediate and high-magnification views of blood vessels adjacent to the pancreatic mass
2. Chronic Pancreatitis vs. Pancreatic Cancer:
Chronic pancreatitistops the list for the differential diagnosis of
pancreatic cancer . Chronic pancreatitis can be clinically, grossly and microscopically
confused with pancreatic cancer, and yet the prognosis and treatment of these two diseases couldn't be
Clinically, age less than 40 years favors the diagnosis of chronic pancreatitis . Chronic
pancreatitis diffusely scars the gland and usually does not form a discrete mass. By contrast,
pancreatic cancer is more likely in patients over the age of 50, and it usually forms a mass. Carcinomas
of the head of the pancreas often cause dramatic focal stenosis of the bile duct, while chronic
pancreatitis, if it does narrow the duct, will do so more diffusely.
The microscopic pattern of growth is the single most helpful finding in distinguishing between chronic
pancreatitis and pancreatic cancer . The most useful histologic features in establishing the
diagnosis of infiltrating adenocarcinoma include: 1) the pattern of growth.
Benign glands have a structured lobular growth pattern, while infiltrating carcinomas grow haphazardly.
2) Glands and muscular blood vessels normally do not run together in the pancreas. Therefore, the
finding of a gland immediately adjacent to a muscular vessel without intervening
stroma or acini
is suggestive of an invasive carcinoma .
3) Perineural and vascular invasion, while virtually diagnostic features, are often
not present in smaller biopsies. 4) Non-neoplastic glands usually form complete lumina, while the glands
of infiltrating adenocarcinoma frequently have incomplete lumina. Single
cells infiltrating into stroma represent the extreme of this. 5) The nuclei in non-neoplastic glands do
not vary in size significantly. Therefore, the finding that the area of one nucleus is ≥4 times
larger than the area of another nucleus within a single gland, is highly suggestive of a carcinoma. This
has been called the four to one rule. 6) Huge,
irregular nucleoli one quarter to one third the diameter of the nucleus also suggest the diagnosis
of carcinoma. 7) Necrotic glandular debris, when present can be a clue to
the diagnosis. 8) Although mitoses can be seen in benign processes, the presence of numerous or abnormal mitotic figures, should suggest the diagnosis of carcinoma.
When these criteria are rigorously applied, frozen section evaluation of the pancreas can have false
positive and false negative rates of less than 2%, particularly when frozen sections are interpreted in
collaboration with the surgeon
Immunohistochemical labeling is usually not needed, but can supplement the histologic diagnosis. Most
reactive glands do not express carcinoembryonic antigen (CEA) and they will all show intact labeling for
the dpc4 protein. By contrast, most pancreatic cancers will express CEA and 55% will show complete loss
of dpc4 expression .
Table 2 - Features Useful in Establishing a Diagnosis of Infiltrating Adenocarcinoma
Lymphoplasmacytic sclerosing pancreatitis (also known as autoimmune pancreatitis) can produce a mass
lesion in the pancreas and it can even cause narrowing of the intrapancreatic segment of the bile duct.
As a result, lymphoplasmacytic sclerosing pancreatitis is the form of chronic pancreatitis that most
closely mimics pancreatic cancer .
- Haphazard growth pattern
- Glands adjacent to muscular vessels
- Perineural invasion
- Intravascular invasion
- 4 to 1 rule
- Incomplete lumina
- Huge irregular nucleoli
- Mitoses, particularly atypical mitoses
- Glandular necrotic debris
- Immunolabeling for CEA, loss of dpc4 expression
3. Autoimmune (Lymphoplasmacytic Sclerosing) Pancreatitis:
Lymphoplasmacytic sclerosing pancreatitis is a distinctive form of chronic pancreatitis characterized
by an intense mixed inflammatory cell infiltrate centered around the pancreatic ducts . The
inflammatory cell infiltrate is composed of a mixture of lymphocytes and plasma cells, with scattered
eosinophils and some neutrophils, and the infiltrate is associated with loss of acinar parenchyma, a
periductal fibrosis and obliterative venulitis . Patients typically lack the risk factors for
conventional chronic pancreatitis such as alcoholism and cholelithiasis.
Lymphoplasmacytic sclerosing pancreatitis occurs more commonly in men than women (male to female ratio
of 2 to 1), and the mean age at diagnosis is close to 60 years (range 19-87)
significant fraction of the patients have a history of an autoimmune disease such as Sjögrens syndrome,
sclerosing cholangitis, chronic idiopathic inflammatory bowel disease, retroperitoneal fibrosis and
Common clinical presentations include jaundice, weight loss and abdominal pain
Computerized tomography will reveal diffusely enlarged pancreatic parenchyma without a discrete
The common bile duct may be thickened. Features of alcoholic pancreatitis, such
as pancreatolithiasis and pseudocysts are usually absent . Serum IgG4 levels are elevated
above 135 mg/dl in the majority of cases
Autoantibodies to carbonic anhydrase II,
lactoferin, rheumatoid factor and to nuclear antigens may also be present
Lymphoplasmacytic sclerosing pancreatitis involves the head of the gland more frequently than the
tail. The affected portions of the gland are enlarged and the sharp distinction among lobules is
lost . Microscopically, as noted earlier, lymphoplasmacytic sclerosing pancreatitis
characterized by an intense mixed lymphoplasmacytic infiltrate centered on the pancreatic ducts and a
venulitis. Elastin stains can be used to highlight the venulitis. As in any form of chronic
pancreatitis, the inflammation is associated with loss of acinar parenchyma and fibrosis. The fibrosis
in lymphoplasmacytic sclerosing pancreatitis is distinctive in that it tends to form periductal bands,
and in some cases the fibrinoinflammatory infiltrate can expand producing a reactive fibroinflammatory
The inflammatory infiltrate may also involve the common bile duct and in some
cases even the gallbladder
Immunohistochemical labeling can be used to demonstrate that the majority of the
lymphocytes are T-cells (CD4+ and CD8+), and in most cases >10 IgG4 expressing plasma cells per high
This latter feature is helpful diagnostically, and, as discussed in the
next section, has been used to suggest that lymphoplasmacytic sclerosing pancreatitis is part of a
broader class of IgG4-related systemic sclerosing diseases
labeling for ALK-1 can be used to differentiate between an inflammatory myofibroblastic tumor (which
should express ALK-1) and a reactive fibroinflammatory pseudotumor associated with lymphoplasmacytic
Most cases of lymphoplasmacytic sclerosing pancreatitis are treated surgically because the
disease clinically closely mimics pancreatic cancer . Surgical resection can be curative, but
the pathology is important to recognize because lymphoplasmacytic sclerosing pancreatitis may recur in
the remnant pancreas or in the biliary tree . Lymphoplasmacytic sclerosing pancreatitis
often responds to steroid treatment, suggesting that patients with elevated serum IgG4 level and a
diffusely enlarged pancreas without a discrete mass may benefit from a trial of steroid therapy rather
than going directly to surgery. Those patients who respond would be spared surgery. Caution should,
however, be exerted in following this course as some patients with pancreatic cancer have elevated serum
IgG4 levels, and we have observed a patient with synchronous lymphoplasmacytic sclerosing pancreatitis
and pancreatic cancer .
4. IgG4-related systemic sclerosing diseases:
A growing body of evidence suggests that lymphoplasmacytic sclerosing pancreatitis is one of a number
of IgG4-related systemic autoimmune/sclerosing diseases (Table 3)
by the name, these diseases are all characterized by an intense lymphoplasmacytic cell infiltrate rich in
IgG4 positive plasma cells with exuberant fibrosis. Many of these diseases respond to steroid therapy,
particularly in the early active phase of inflammation before significant fibrosis has developed.
Further studies may better define the etiology and pathobiology of these diseases.
Table 3 - IgG4-related systemic autoimmune/sclerosing diseases
|Lymphoplasmacytic sclerosing pancreatitis|
|Idiopathic retroperitoneal fibrosis (Ormand disease)|
|Chronic sclerosing sialadenitis (Küttner tumor)|
|Sclerosing lymphoplasmacytic tubulointerstitial nephritis|
|Plasma cell granuloma of the lung|
|Reactive fibroinflammatory pseudotumor|
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