—  SPECIALTY CONFERENCE  —

Surgical Pathology

Case 5 - Mimickers of Pancreatic Cancer

Ralph H. Hruban
Johns Hopkins Medical Institutions
Baltimore, MD





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Clinical Summary:
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.

Diagnosis:
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) [1, 2]. 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 [1, 3]. 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
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Case 5 - Figure 1 - Low-power view of the pancreatic mass
Case 5 - Figure 2 - Progressively higher magnification views of a representative pancreatic duct
Case 5 - Figure 3 - Progressively higher magnification views of a representative pancreatic duct

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

Case 5 - Figure 9 - Another pancreatic duct
Case 5 - Figure 10 - High-power view of the pancreatic mass


2. Chronic Pancreatitis vs. Pancreatic Cancer:
Chronic pancreatitistops the list for the differential diagnosis of pancreatic cancer [4]. 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 further apart.

Clinically, age less than 40 years favors the diagnosis of chronic pancreatitis [2]. 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 [2]. 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 [5]. 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 [2, 6, 7, 8].

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 [2].
Table 2 - Features Useful in Establishing a Diagnosis of Infiltrating Adenocarcinoma

  1. Haphazard growth pattern

  2. Glands adjacent to muscular vessels

  3. Perineural invasion

  4. Intravascular invasion

  5. 4 to 1 rule

  6. Incomplete lumina

  7. Huge irregular nucleoli

  8. Mitoses, particularly atypical mitoses

  9. Glandular necrotic debris

  10. Immunolabeling for CEA, loss of dpc4 expression
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 [3].

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 [2]. 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 [9]. 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) [3, 10]. A 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 thyroiditis [11, 12, 13].

Common clinical presentations include jaundice, weight loss and abdominal pain [9, 13]. Computerized tomography will reveal diffusely enlarged pancreatic parenchyma without a discrete mass [10, 14]. The common bile duct may be thickened. Features of alcoholic pancreatitis, such as pancreatolithiasis and pseudocysts are usually absent [12]. Serum IgG4 levels are elevated above 135 mg/dl in the majority of cases [9, 12]. Autoantibodies to carbonic anhydrase II, lactoferin, rheumatoid factor and to nuclear antigens may also be present [12, 13].

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 [9]. 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 pseudotumor [2, 9]. The inflammatory infiltrate may also involve the common bile duct and in some cases even the gallbladder [15, 16].

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 power field [9, 12, 13]. 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 [11, 15, 16, 17]. Immunohistochemical 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 sclerosing pancreatitis.

Most cases of lymphoplasmacytic sclerosing pancreatitis are treated surgically because the disease clinically closely mimics pancreatic cancer [3]. 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 [10]. 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 [18].

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) [11, 15, 16, 17, 19, 20, 21]. As suggested 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
Sclerosing cholangitis
Idiopathic retroperitoneal fibrosis (Ormand disease)
Chronic sclerosing sialadenitis (Küttner tumor)
Sclerosing lymphoplasmacytic tubulointerstitial nephritis
Plasma cell granuloma of the lung
Reactive fibroinflammatory pseudotumor


References
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  2. Hruban, R. H., Klimstra, D. S., and Pitman, M. B. Atlas of tumor pathology. Tumors of the pancreas, Fourth Series ed.Washington, DC: Armed Forces Institute of Pathology, 2006.

  3. Abraham, S. C., Wilentz, R. E., Yeo, C. J., Sohn, T. A., Cameron, J. L., Boitnott, J. K., and Hruban, R. H. Pancreaticoduodenectomy (Whipple resections) in patients without malignancy: are they all 'chronic pancreatitis'? Am J Surg Pathol, 27: 110-120, 2003.

  4. Adsay, N. V., Bandyopadhyay, S., Basturk, O., Othman, M., Cheng, J. D., Klöppel, G., and Klimstra, D. S. Chronic pancreatitis or pancreatic ductal adenocarcinoma? Semin Diagn Pathol, 21: 268-276, 2004.

  5. Sharma, S. and Green, K. B. The pancreatic duct and its arteriovenous relationship: an underutilized aid in the diagnosis and distinction of pancreatic adenocarcinoma from pancreatic intraepithelial neoplasia. A study of 126 pancreatectomy specimens. Am J Surg Pathol, 28: 613-620, 2004.

  6. Cioc, A. M., Ellison, E. C., Proca, D. M., Lucas, J. G., and Frankel, W. L. Frozen section diagnosis of pancreatic lesions. Arch Pathol Lab Med, 126: 1169-1173, 2002.

  7. Hyland, C., Kheir, S. M., and Kashlan, M. B. Frozen section diagnosis of pancreatic carcinoma: a prospective study of 64 biopsies. Am J Surg Pathol, 5: 179-191, 1981.

  8. Weiland, L. H. Frozen section diagnosis in tumors of the pancreas. Semin Diagn Pathol, 1: 54-58, 1984.

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  10. Hardacre, J. M., Iacobuzio-Donahue, C. A., Sohn, T. A., Abraham, S. C., Yeo, C. J., Lillemoe, K. D., Choti, M. A., Campbell, K. A., Schulick, R. D., Hruban, R. H., Cameron, J. L., and Leach, S. D. Results of pancreaticoduodenectomy for lymphoplasmacytic sclerosing pancreatitis. Ann Surg, 237: 853-859, 2003.

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  13. Zhang, L., Notohara, K., Levy, M. J., Chari, S. T., and Smyrk, T. C. IgG4-positive plasma cell infiltration in the diagnosis of autoimmune pancreatitis. Mod.Pathol., 20: 23-28, 2007.

  14. Kawamoto, S., Siegelman, S. S., Hruban, R. H., and Fishman, E. K. Lymphoplasmacytic sclerosing pancreatitis with obstructive jaundice: CT and pathology features. AJR Am J Roentgenol., 183: 915-921, 2004.

  15. Abraham, S. C., Cruz-Correa, M., Argani, P., Furth, E. E., Hruban, R. H., and Boitnott, J. K. Lymphoplasmacytic chronic cholecystitis and biliary tract disease in patients with lymphoplasmacytic sclerosing pancreatitis. Am J Surg Pathol, 27: 441-451, 2003.

  16. Kamisawa, T., Tu, Y., Nakajima, H., Egawa, N., Tsuruta, K., Okamoto, A., and Horiguchi, S. Sclerosing cholecystitis associated with autoimmune pancreatitis. World J.Gastroenterol., 12: 3736-3739, 2006.

  17. Neild, G. H., Rodriguez-Justo, M., Wall, C., and Connolly, J. O. Hyper-IgG4 disease: report and characterisation of a new disease. BMC.Med., 4: 23, 2006.

  18. Kamisawa, T., Chen, P. Y., Tu, Y., Nakajima, H., Egawa, N., Tsuruta, K., Okamoto, A., and Hishima, T. Pancreatic cancer with a high serum IgG4 concentration. World J.Gastroenterol., 12: 6225-6228, 2006.

  19. Watson, S. J., Jenkins, D. A., and Bellamy, C. O. Nephropathy in IgG4-related Systemic Disease. Am.J.Surg.Pathol., 30: 1472-1477, 2006.

  20. Kitagawa, S., Zen, Y., Harada, K., Sasaki, M., Sato, Y., Minato, H., Watanabe, K., Kurumaya, H., Katayanagi, K., Masuda, S., Niwa, H., Tsuneyama, K., Saito, K., Haratake, J., Takagawa, K., and Nakanuma, Y. Abundant IgG4-positive plasma cell infiltration characterizes chronic sclerosing sialadenitis (Kuttner's tumor). Am.J.Surg.Pathol., 29: 783-791, 2005.

  21. Zen, Y., Harada, K., Sasaki, M., Sato, Y., Tsuneyama, K., Haratake, J., Kurumaya, H., Katayanagi, K., Masuda, S., Niwa, H., Morimoto, H., Miwa, A., Uchiyama, A., Portmann, B. C., and Nakanuma, Y. IgG4-related sclerosing cholangitis with and without hepatic inflammatory pseudotumor, and sclerosing pancreatitis-associated sclerosing cholangitis: do they belong to a spectrum of sclerosing pancreatitis? Am.J.Surg.Pathol., 28: 1193-1203, 2004.