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WHO Classification of Tumours
Ductal adenocarcinoma
Pancreas


Histopathology

Histopathology
Most ductal adenocarcinomas are composed of well- to moderately developed glandular and duct-like structures, which infiltrate the pancreatic parenchyma, grow in a haphazard pattern, are associated with a desmoplastic stroma and produce sialo-type and sulfated acid mucins that stain with Alcian blue and periodic acid-Schiff (PAS). Poorly differentiated ductal adenocarcinomas form small, poorly formed glands composed of cells with pleomorphic nuclei, individual infiltrating cells, and solid cellular areas. They produce much less mucin than more differentiated carcinomas.

Well-differentiated carcinomas
These carcinomas are composed of haphazardly arranged infiltrating duct-like structures and medium-sized neoplastic glands. The contours of the duct-like structures may be angular or irregular, such irregular contours are especially pronounced in the “large-duct” variant

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Kosmahl M, Pauser U, Anlauf M, Klöppel G (2005)
Pancreatic ductal adenocarcinomas with cystic features: neither rare nor uniform.
Mod Pathol 18: 1157-64



. Perineural or vascular invasion are both highly diagnostic of an invasive cancer, and “ruptured” or “incomplete” ducts (which lack a portion of epithelium and instead are partially lined by cellular stromal tissue) are highly suggestive of an invasive cancer. Non-neoplastic ducts, as well as remnants of acini and individual islets of Langerhans, are typically interspersed among the neoplastic glands, and some neoplastic glands may even infiltrate into non-neoplastic islets of Langerhans. Only in exceptional cases do neuroendocrine cells constitute a second neoplastic cell component of ductal carcinomas.The neoplastic cells are cuboidal to columnar, and form a single cell layer, although papillary projections can be seen. The cytoplasm is usually eosinophilic, but a pale or even clear appearance may sometimes be prominent. The nuclei are round to oval and may be three to four times larger than non-neoplastic nuclei. Importantly, the size, shape, and location of the nuclei vary among cells within the individual neoplastic glands. The nuclear membranes are sharp and the distinct nucleoli are often large. Mitoses are not common.
At the time of diagnosis, virtually all carcinomas deeply infiltrate the surrounding pancreatic tissue and the adjacent peripancreatic adipose tissue. The infiltrating malignant glands are often found in abnormal locations, such as immediately adjacent to muscular blood vessels; a finding that may be diagnostically useful. They may also invade the common bile duct, the ampulla, and the duodenal mucosa, typically following pre-existing structures such as ducts, nerves and vessels. Cancerization of the pancreatic ducts, particularly the medium-sized interlobular ducts, is not uncommon, and may extend far beyond the main neoplastic mass

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Klöppel G, Lohse T, Bosslet K, Rückert K (1987)
Ductal adenocarcinoma of the head of the pancreas: incidence of tumor involvement beyond the Whipple resection line. Histological and immunocytochemical analysis of 37 total pancreatectomy specimens.
Pancreas 2: 170-5



. In these cases, the normal epithelium is replaced by atypical columnar cells that often form papillary projections without fibrovascular stalks. This change is usually accompanied by a ductocentric desmoplasia, and can be virtually indistinguishable from high-grade pancreatic intraepithelial neoplasia (PanIN-3). Perineural invasion is seen in almost all cases within the pancreas itself, and invasive carcinoma typically extends into the retroperitoneal fatty tissue behind the head of the pancreas and around the bile duct, where nerves are abundant. In the vast majority of cases, the neoplastic cells that invade the nerves show glandular differentiation. Benign ducts are rarely encountered in the vicinity of a nerve and a non-neoplastic glandular inclusion in a nerve is exceedingly uncommon, although non-neoplastic islet cells may involve nerves. Lymphatic invasion is another very common finding and is associated with lymph-node metastasis. Carcinoma may invade the wall of blood vessels (e.g. the portal vein), or the neoplastic cells may penetrate the lumen, causing thrombosis. In some cases, the neoplastic epithelium can entirely replace the endothelium and re-line the vessel, producing a vessel lined by well-differentiated epithelial cells; such structures can mimic pancreatic intraepithelial neoplasia (PanIN).
Neoplastic glands may also infiltrate the peripancreatic adipose tissue without following pre-existing structures. Typically these glands lie individually as naked glands within the fat, either directly abutting adipocytes or surrounded by inflammatory cells. If infiltrating neoplastic glands reach the mucosa of the distal common bile duct, the ampulla and/or the duodenum, the neoplastic cells may replace the normal epithelium, mimicking a primary neoplasm of the involved site.

Moderately differentiated carcinomas
These carcinomas are largely identical to well-differentiated adenocarcinomas in growth pattern and behaviour, except that they produce a mixture of medium-sized duct-like structures and small tubular glands of variable size and shape (some are incompletely formed, others create a cribriform pattern). Moderately differentiated carcinomas are also characterized by a greater variation in nuclear size, chromatin structure and prominence of nucleoli and more mitotic figures. The cytoplasm is usually slightly eosinophilic, but clear cells are occasionally abundant. Mucin production appears to be decreased. Foci of poor and irregular glandular formation are often found at the leading edge of the neoplasm, particularly where the carcinoma invades the peripancreatic tissue.

Poorly differentiated ductal adenocarcinomas
These neoplasms are composed of a mixture of densely packed, small irregular glands, solid sheets and nests, as well as individual cells. The desmoplastic response to the neoplasm can be minimal and foci of necrosis and haemorrhage may occur. The cells forming glands and solid cellular sheets show marked nuclear pleomorphism (occasionally with squamoid or spindle-cell differentiation), little or no mucin production, and brisk mitotic activity. Intraductal extension of the carcinoma is seen less often than in more differentiated carcinomas, while peri neural, lymphatic, and blood-vessel invasion are equally frequent. Many ductal adenocarcinomas obstruct the main pancreatic duct, causing upstream obstructive chronic pancreatitis. Complete obstruction usually results in the upstream duct becoming markedly dilated, the pancreatic parenchyma is atrophied, and there can be a marked clustering (“aggregation”) of the residual islets, which can mimic a neuroendocrine neoplasm. The intraductal calcifications that are typically seen in alcoholic chronic pancreatitis are generally absent

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Bosman FT, Carneiro F, Hruban RH, Theise ND (Eds.)
WHO Classification of Tumours of the Digestive System.
4th Edition
International Agency for Research on Cancer: Lyon 2010




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Cytopathology
Cytological diagnosis is most often obtained by fine-needle aspiration (FNA), increasingly performed endoscopically using EUS guidance

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Bardales RH, Stelow EB, Mallery S, Lai R, Stanley MW (2006)
Review of endoscopic ultrasound-guided fine-needle aspiration cytology.
Diagn Cytopathol 34: 140-75




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Turner BG, Cizginer S, Agarwal D, Yang J, Pitman MB, Brugge WR (2010)
Diagnosis of pancreatic neoplasia with EUS and FNA: a report of accuracy.
Gastrointest Endosc 71: 91-8



. Techniques of pancreatobiliary-duct brushing have improved
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Uchida N, Kamada H, Tsutsui K, Ono M, Aritomo Y, Masaki T, Kushida Y, Haba R, Nakatsu T, Kuriyama S (2007)
Utility of pancreatic duct brushing for diagnosis of pancreatic carcinoma.
J Gastroenterol 42: 657-62



, but brushing cytology has a lower sensitivity for malignancy than FNA, averaging 50% compared with 80% for EUS-FNA
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Bellizzi AM, Stelow EB (2009)
Pancreatic cytopathology: a practical approach and review.
Arch Pathol Lab Med 133: 388-404




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Turner BG, Cizginer S, Agarwal D, Yang J, Pitman MB, Brugge WR (2010)
Diagnosis of pancreatic neoplasia with EUS and FNA: a report of accuracy.
Gastrointest Endosc 71: 91-8



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The smear pattern of adenocarcinomas is one of scattered cellular glandular clusters admixed with single cells. This contrasts with the diffuse, uniform solid cellular smear pattern produced by the parenchymal-rich, stromal-poor neoplasms such as acinar cell carcinomas and well-differentiated neuroendocrine neoplasms

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Pitman MB, Deshpande V (2007)
Endoscopic ultrasound-guided fine needle aspiration cytology of the pancreas: a morphological and multimodal approach to the diagnosis of solid and cystic mass lesions.
Cytopathology 18: 331-47



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Moderately to poorly differentiated carcinomas have overt features of malignancy. Nuclei are enlarged, hyperchromatic and display irregular nuclear membranes; the cytoplasm ranges from scant and nonmucinous to abundant and mucinous

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Pitman MB, Deshpande V (2007)
Endoscopic ultrasound-guided fine needle aspiration cytology of the pancreas: a morphological and multimodal approach to the diagnosis of solid and cystic mass lesions.
Cytopathology 18: 331-47




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Robins DB, Katz RL, Evans DB, Atkinson EN, Green L (1995)
Fine needle aspiration of the pancreas. In quest of accuracy.
Acta Cytol 39: 1-10




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Ylagan LR, Edmundowicz S, Kasal K, Walsh D, Lu DW (2002)
Endoscopic ultrasound guided fine-needle aspiration cytology of pancreatic carcinoma: a 3-year experience and review of the literature.
Cancer 96: 362-9



. The recognition of well-differentiated adeno - carcinoma is more challenging as the aspirated neoplastic ductal cells must be distinguished from atypical but reactive ductal cells
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Deshpande V, Mino-Kenudson M, Brugge WR, Pitman MB, Fernandez-del Castillo C, Warshaw AL, Lauwers GY (2005)
Endoscopic ultrasound guided fine needle aspiration biopsy of autoimmune pancreatitis: diagnostic criteria and pitfalls.
Am J Surg Pathol 29: 1464-71




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Krishna NB, Mehra M, Reddy AV, Agarwal B (2009)
EUS/EUS-FNA for suspected pancreatic cancer: influence of chronic pancreatitis and clinical presentation with or without obstructive jaundice on performance characteristics.
Gastrointest Endosc 70: 70-9



, as well as from gastrointestinal contamination from the EUS biopsy procedure
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Nawgiri RS, Nagle JA, Wilbur DC, Pitman MB (2007)
Cytomorphology and B72.3 labeling of benign and malignant ductal epithelium in pancreatic lesions compared to gastrointestinal epithelium.
Diagn Cytopathol 35: 300-5



. Cytological criteria for well-differentiated adenocarcinoma include irregular spacing of cells in a cohesive group, anisonucleosis of 4 : 1 in a single group, parachromatin clearing and irregular nuclear membranes
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Lin F, Staerkel G (2003)
Cytologic criteria for well differentiated adenocarcinoma of the pancreas in fine-needle aspiration biopsy specimens.
Cancer 99: 44-50




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Pitman MB, Deshpande V (2007)
Endoscopic ultrasound-guided fine needle aspiration cytology of the pancreas: a morphological and multimodal approach to the diagnosis of solid and cystic mass lesions.
Cytopathology 18: 331-47




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Robins DB, Katz RL, Evans DB, Atkinson EN, Green L (1995)
Fine needle aspiration of the pancreas. In quest of accuracy.
Acta Cytol 39: 1-10



. Variants such as adenosquamous carcinoma, undifferentiated carcinoma and undifferentiated carcinoma with osteoclast-like giant cells can also be recognized by their unique cytological features
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Layfield LJ, Bentz J (2008)
Giant-cell containing neoplasms of the pancreas: an aspiration cytology study.
Diagn Cytopathol 36: 238-44




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Rahemtullah A, Misdraji J, Pitman MB (2003)
Adenosquamous carcinoma of the pancreas: cytologic features in 14 cases.
Cancer 99: 372-8



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Ultrastructure
Ductal adenocarcinoma cells are characterized by mucin granules in the apical cytoplasm, irregular microvilli on the luminal surface, and a more or less polarized arrangement of the differently sized nuclei

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Hruban RH, Pitman MB, and Klimstra DS
Tumors of the Pancreas. Armed Forces Institute of Pathology
Washington, DC 2007



. Loss of differentiation is characterized by loss of cell polarity, disappearance of a basal lamina, appearance of irregular luminal spaces, and loss of mucin granules.

Histological variants
The variants that appear to have distinct clinical or prognostic features include:
Adenosquamous carcinoma
Colloid carcinoma (Mucinous noncystic carcinoma/adenocarcinoma)
Hepatoid adenocarcinoma
Medullary carcinoma
Signet ring cell carcinoma
Poorly differentiated carcinoma
Carcinoma with osteoclast-like giant cells .
Histological types that are not considered among the variants are the ductal adenocarcinomas with a foamy gland pattern

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Adsay V, Logani S, Sarkar F, Crissman J, Vaitkevicius V (2000)
Foamy gland pattern of pancreatic ductal adenocarcinoma: a deceptively benign-appearing variant.
Am J Surg Pathol 24: 493-504



, with clear cell features
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Lüttges J, Vogel I, Menke M, Henne-Bruns D, Kremer B, Klöppel G (1998)
Clear cell carcinoma of the pancreas: an adenocarcinoma with ductal phenotype.
Histopathology 32: 444-8



and with large-duct features
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Chen J, Baithun SI (1985)
Morphological study of 391 cases of exocrine pancreatic tumours with special reference to the classification of exocrine pancreatic carcinoma.
J Pathol 146: 17-29




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Cubilla AL, Fitzgerald PJ (eds)
Tumours of the Exocrine Pancreas.
Armed Forces Institute of Pathology: Washington, DC 1984




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Kloppel G, Solcia E, Longnecker DS, Capella C, and Sobin LH (eds.)
Histological Typing of Tumours of the Exocrine Pancreas.
Springer-Verlag: Berlin 1996




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Kosmahl M, Pauser U, Anlauf M, Klöppel G (2005)
Pancreatic ductal adenocarcinomas with cystic features: neither rare nor uniform.
Mod Pathol 18: 1157-64



; these latter types have no prognostic significance and are typically found within ductal adenocarcinomas with otherwise conventional histological features.

Differential diagnosis
Chronic pancreatitis
The most significant differential diagnosis for conventional (tubular-type) pancreatic adenocarcinoma is chronic pancreatitis

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Adsay NV, Bandyopadhyay S, Basturk O, Othman M, Cheng JD, Klöppel G, Klimstra DS (2004)
Chronic pancreatitis or pancreatic ductal adenocarcinoma?
Semin Diagn Pathol 21: 268-76




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Krishna NB, Mehra M, Reddy AV, Agarwal B (2009)
EUS/EUS-FNA for suspected pancreatic cancer: influence of chronic pancreatitis and clinical presentation with or without obstructive jaundice on performance characteristics.
Gastrointest Endosc 70: 70-9



. From the gross perspective, chronic pancreatitis of alcoholic or obstructive etiology usually involves the pancreas more diffusely than carcinoma. The ducts may be dilated and lithiasis can occur. The texture of the gland is more rubbery than in carcinoma, which has a more gritty consistency.
Autoimmune pancreatitis is an exception to these rules, and it can both clinically and grossly mimic pancreatic cancer, often being grossly discrete and tumourlike, and ductal dilatation is not common. The characteristic microscopic features of autoimmune pancreatitis include dense inflammation with abundant plasma cells concentrated around pancreatic ducts, a cellular fibroinflammatory stroma with a storiform appearance, and obliterative venulitis, although these features maybe less obvious in biopsies than in resection specimens. Increased numbers of plasma cells expressing IgG4 (> 10–50 cells per high power field) is typical of autoimmune pancreatitis, as are elevations in serum IgG4

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Chari ST, Takahashi N, Levy MJ, Smyrk TC, Clain JE, Pearson RK, Petersen BT, Topazian MA, Vege SS (2009)
A diagnostic strategy to distinguish autoimmune pancreatitis from pancreatic cancer.
Clin Gastroenterol Hepatol 7: 1097-103




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Detlefsen S, Mohr Drewes A, Vyberg M, Klöppel G (2009)
Diagnosis of autoimmune pancreatitis by core needle biopsy: application of six microscopic criteria.
Virchows Arch 454: 531-9




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Morselli-Labate AM, Pezzilli R (2009)
Usefulness of serum IgG4 in the diagnosis and follow up of autoimmune pancreatitis: A systematic literature review and meta-analysis.
J Gastroenterol Hepatol 24: 15-36




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Raina A, Yadav D, Krasinskas AM, McGrath KM, Khalid A, Sanders M, Whitcomb DC, Slivka A (2009)
Evaluation and management of autoimmune pancreatitis: experience at a large US center.
Am J Gastroenterol 104: 2295-306




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Zhang L, Notohara K, Levy MJ, Chari ST, Smyrk TC (2007)
IgG4-positive plasma cell infiltration in the diagnosis of autoimmune pancreatitis.
Mod Pathol 20: 23-8



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The microscopic findings most helpful in distinguishing adenocarcinoma from reactive glands are the location and architecture of the glands, and the cytological features. The ductal system of the normal pancreas has a lobular architecture, and this lobular pattern is retained in chronic pancreatitis, with a central more dilated duct surrounded by a cluster of smaller ductules and atrophic acini. In contrast, carcinoma has a haphazard arrangement of glands, with loss of the normal lobularity. The abnormal presence of glands within the duodenal muscularis or submucosa, or immediately adjacent to a muscular vessel is highly suggestive of carcinoma

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Adsay VN, Bandyopadhyay S, Basturk O (2006)
Duct adjacent to a thick-walled medium-sized muscular vessel in the pancreas is often indicative of invasive adenocarcinoma.
Am J Surg Pathol 30: 1203-5




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Sharma S, Green KB (2004)
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: 613-20



. Profound atrophy of the pancreas can juxtapose benign glands and vessels
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Wachtel MS, Miller EJ (2005)
Focal changes of chronic pancreatitis and duct-arteriovenous relationships: avoiding a diagnostic pitfall.
Am J Surg Pathol 29: 1521-3



, but only in the most extreme cases of atrophic pancreatitis.
Perineural and intravascular invasion are almost diagnostic of carcinoma. It is exceptional to find benign glands within the perineurium

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Hruban RH, Pitman MB, and Klimstra DS
Tumors of the Pancreas. Armed Forces Institute of Pathology
Washington, DC 2007



, and true vascular invasion does not occur in benign conditions. Other helpful features are “naked glands in fat” – individual glands touching adipocytes without any intervening fibrotic stroma
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Adsay NV, Bandyopadhyay S, Basturk O, Othman M, Cheng JD, Klöppel G, Klimstra DS (2004)
Chronic pancreatitis or pancreatic ductal adenocarcinoma?
Semin Diagn Pathol 21: 268-76




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Klöppel G, Adsay NV (2009)
Chronic pancreatitis and the differential diagnosis versus pancreatic cancer.
Arch Pathol Lab Med 133: 382-7



– and glands with irregular contours, luminal necrosis, and incomplete glands lacking epithelium on one edge
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Klöppel G, Adsay NV (2009)
Chronic pancreatitis and the differential diagnosis versus pancreatic cancer.
Arch Pathol Lab Med 133: 382-7



. A nuclear size variation of 4 : 1 within a single duct is considered virtually diagnostic
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Hruban RH, Pitman MB, and Klimstra DS
Tumors of the Pancreas. Armed Forces Institute of Pathology
Washington, DC 2007



. Mitotic figures, especially if atypical, are also helpful, as are very prominent nucleoli. Other features that point to a malignant diagnosis are necrotic luminal debris and stromal desmoplasia (as opposed to the usually dense and hyalinized stroma of chronic pancreatitis).

Pancreatic intraepithelial neoplasia (PanIN)
The distinction between PanIN and invasive carcinoma is based on the shape and location of the glands. Distinguishing high-grade PanIN (PanIN-3) from invasive carcinoma on the basis of cytological appearance can be very difficult. Of note, it is very unusual to encounter PanIN-3 in the absence of invasive carcinoma, especially when there is a mass lesion in the pancreas.
Reactive glands and low-grade PanIN lesions do not express tumour-associated glycoproteins (CEA, B72.3, and CA125), p53, mesothelin, claudin 4, S100A4, or 14-3-3σ

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Agarwal B, Ludwig OJ, Collins BT, Cortese C (2008)
Immunostaining as an adjunct to cytology for diagnosis of pancreatic adenocarcinoma.
Clin Gastroenterol Hepatol 6: 1425-31




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Hassan R, Laszik ZG, Lerner M, Raffeld M, Postier R, Brackett D (2005)
Mesothelin is overexpressed in pancreaticobiliary adenocarcinomas but not in normal pancreas and chronic pancreatitis.
Am J Clin Pathol 124: 838-45




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Hornick JL, Lauwers GY, Odze RD (2005)
Immunohistochemistry can help distinguish metastatic pancreatic adenocarcinomas from bile duct adenomas and hamartomas of the liver.
Am J Surg Pathol 29: 381-9




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Hruban RH, Pitman MB, and Klimstra DS
Tumors of the Pancreas. Armed Forces Institute of Pathology
Washington, DC 2007




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Maitra A, Adsay NV, Argani P, Iacobuzio-Donahue C, De Marzo A, Cameron JL, Yeo CJ, Hruban RH (2003)
Multicomponent analysis of the pancreatic adenocarcinoma progression model using a pancreatic intraepithelial neoplasia tissue microarray.
Mod Pathol 16: 902-12



. Positive immunolabelling for any of these markers favours a diagnosis of carcinoma, although the sensitivity of these markers varies widely. Loss of immunoexpression of SMAD4 in the face of intact expression in normal cells also strongly supports a diagnosis of carcinoma
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Hornick JL, Lauwers GY, Odze RD (2005)
Immunohistochemistry can help distinguish metastatic pancreatic adenocarcinomas from bile duct adenomas and hamartomas of the liver.
Am J Surg Pathol 29: 381-9




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Hua Z, Zhang YC, Hu XM, Jia ZG (2003)
Loss of DPC4 expression and its correlation with clinicopathological parameters in pancreatic carcinoma.
World J Gastroenterol 9: 2764-7



, but is only found in about half of infiltrating ductal adenocarcinomas
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Tascilar M, Offerhaus GJ, Altink R, Argani P, Sohn TA, Yeo CJ, Cameron JL, Goggins M, Hruban RH, Wilentz RE (2001)
Immunohistochemical labeling for the Dpc4 gene product is a specific marker for adenocarcinoma in biopsy specimens of the pancreas and bile duct.
Am J Clin Pathol 116: 831-7



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Macroscopic precursor lesions
The macroscopic presence of a recognized precursor (intraductal papillary mucinous neoplasm [IPMN] or mucinous cystic neoplasm [MCN]) to infiltrating carcinoma increases the chances that a solid mass may be an infiltrating carcinoma. The distinction between infiltrating carcinoma and these mass-forming cystic neoplasms (MCN and IPMN) is generally not a problem if radiographic and clinical findings are integrated with the pathology. However, some infiltrating carcinomas form massively dilated invasive glands that can simulate a cystic neoplasm. This pattern has been designated the “largeduct type” of infiltrating carcinoma

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Hruban RH, Pitman MB, and Klimstra DS
Tumors of the Pancreas. Armed Forces Institute of Pathology
Washington, DC 2007



and is generally not associated with gross cyst formation. The cystic glands are irregular, do not communicate with the native ducts, have an associated desmoplastic stromal response, and lack the ”ovarianlike” subepithelial stroma of MCNs.

Neuroendocrine neoplasms
Paradoxically, poorly differentiated ductal adenocarcinomas can resemble welldifferentiated pancreatic neuroendocrine neolasms, especially neuroendocrine neolasms with nuclear pleomorphism

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Zee SY, Hochwald SN, Conlon KC, Brennan MF, Klimstra DS (2005)
Pleomorphic pancreatic endocrine neoplasms: a variant commonly confused with adenocarcinoma.
Am J Surg Pathol 29: 1194-200



. The sclerotic (rather than desmoplastic) nature of the stroma, nuclear features of neuroendocrine differentiation, organoid architectural patterns, and a lack of mitotic activity all suggest that a neuroendocrine neoplasm should be considered. Immunohistochemical labelling for chromogranin and synaptophysin help to establish this diagnosis. Non-neoplastic islets in chronic pancreatitis can also simulate carcinoma, as they can assume a pseudo-infiltrative appearance within fibrotic stroma once the acinar elements have completely atrophied
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Bartow SA, Mukai K, Rosai J (1981)
Pseudoneoplastic proliferation of endocrine cells in pancreatic fibrosis.
Cancer 47: 2627-33



. The nuclei remain bland, however, and immunohistochemistry is helpful in difficult cases.

Extrapancreatic metastatic adenocarcinoma
It is not uncommon to encounter a metastatic adenocarcinoma in an extrapancreatic location for which the pancreas appears to be a possible primary; however, there are no pancreas-specific immunohistochemical stains to prove pancreatic origin. A common immunophenotype for ductal adenocarcinomas of the pancreas is positive for keratins 7 and 19, CEA, B72.3; focally positive or negative for keratin 20, and negative for CDX2, TTF1, and hormone receptors. This labelling profile is shared by primary carcinomas of the upper gastrointestinal tract, biliary tree, gallbladder, and some pulmonary and mammary carcinomas. Immunolabelling for the SMAD4 protein can be helpful, as this is lost in 55% of invasive ductal adenocarcinomas of the pancreas, but only rarely in carcinomas arising outside of the pancreatobiliary tree.

Precursor lesions
The most common precursor lesions of pancreatic ductal adenocarcinoma are pancreatic intraepithelial neoplasia (PanIN) lesions. Less frequently, macroscopic (cystic) precursor lesions, including mucinous cystic neoplasms (MCNs) and intraductal papillary mucinous neoplasms (IPMNs) , may also progress to ductal adenocarcinoma.

Lobulocentric atrophy.
PanIN lesions are associated with lobulocentric atrophy in the immediately adjacent pancreatic parenchyma

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Brune K, Abe T, Canto M, O'Malley L, Klein AP, Maitra A, Volkan Adsay N, Fishman EK, Cameron JL, Yeo CJ, Kern SE, Goggins M, Hruban RH (2006)
Multifocal neoplastic precursor lesions associated with lobular atrophy of the pancreas in patients having a strong family history of pancreatic cancer.
Am J Surg Pathol 30: 1067-76




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Detlefsen S, Sipos B, Feyerabend B, Klöppel G (2005)
Pancreatic fibrosis associated with age and ductal papillary hyperplasia.
Virchows Arch 447: 800-5




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Shi C, Hong SM, Lim P, Kamiyama H, Khan M, Anders RA, Goggins M, Hruban RH, Eshleman JR (2009)
KRAS2 mutations in human pancreatic acinar-ductal metaplastic lesions are limited to those with PanIN: implications for the human pancreatic cancer cell of origin.
Mol Cancer Res 7: 230-6



. Although the exact pathogenesis of lobulocentric atrophy remains uncertain, these foci of atrophy are larger than the PanIN lesion itself. In patients that have a familial predisposition to pancreatic cancer, PanIN lesions, and the resulting lobulocentric atrophy, tend to be multifocal in the pancreatic parenchyma
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Brune K, Abe T, Canto M, O'Malley L, Klein AP, Maitra A, Volkan Adsay N, Fishman EK, Cameron JL, Yeo CJ, Kern SE, Goggins M, Hruban RH (2006)
Multifocal neoplastic precursor lesions associated with lobular atrophy of the pancreas in patients having a strong family history of pancreatic cancer.
Am J Surg Pathol 30: 1067-76



. It is possible to detect this distinctive change in imaging studies, such as EUS, suggesting a potential screening tool for identification of individuals with a higher risk of developing invasive carcinoma
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Canto MI, Goggins M, Hruban RH, Petersen GM, Giardiello FM, Yeo C, Fishman EK, Brune K, Axilbund J, Griffin C, Ali S, Richman J, Jagannath S, Kantsevoy SV, Kalloo AN (2006)
Screening for early pancreatic neoplasia in high-risk individuals: a prospective controlled study.
Clin Gastroenterol Hepatol 4: 766-81; quiz 665



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Diagnostic algorithms for tumours of the pancreas


Ductal adenocarcinoma, well-differentiated, showing intensive desmoplastic stromal reaction
Ductal adenocarcinoma, well-differentiated, showing intensive desmoplastic stromal reaction
Ductal adenocarcinoma, large-duct type
Ductal adenocarcinoma, large-duct type
Poorly differentiated ductal adenocarcinoma
Poorly differentiated ductal adenocarcinoma
Infiltrating ductal adenocarcinoma with perineural invasion
Infiltrating ductal adenocarcinoma with perineural invasion
Ductal adenocarcinoma with venous invasion, mimicking pancreatic intraepithelial neoplasia (PanIN)
Ductal adenocarcinoma with venous invasion, mimicking pancreatic intraepithelial neoplasia (PanIN)
Well-differentiated infiltrating ductal adenocarcinoma
Well-differentiated infiltrating ductal adenocarcinoma
Direct smear of ductal adenocarcinoma of the pancreas
Direct smear of ductal adenocarcinoma of the pancreas
Direct smear of well-differentiated ductal adenocarcinoma of the pancreas
Direct smear of well-differentiated ductal adenocarcinoma of the pancreas