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WHO Classification of Tumours
Intraductal papillary mucinous carcinoma (IPMN) with an associated invasive carcinoma
Pancreas


Histopathology

IPMNs are characterized by the intraductal proliferation of columnar mucin-producing cells. The intraductal nature of these neoplasms can be appreciated by their involvement of the branching duct system. IPMNs lack the “ovarian-type” hypercellular periductal stroma that characterizes mucinous cystic neoplasms (MCNs)
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Tanaka M, Chari S, Adsay V, Fernandez-del Castillo C, Falconi M, Shimizu M, Yamaguchi K, Yamao K, Matsuno S, (2006)
International consensus guidelines for management of intraductal papillary mucinous neoplasms and mucinous cystic neoplasms of the pancreas.
Pancreatology 6: 17-32



. Architecturally, the epithelium of IPMNs can be flat or form papillae with fibrovascular cores. The papillae range from microscopic folds of neoplastic epithelium to grossly visible finger-like projections that measure up to several centimetres. The papillae may be simple and villouslike, or complex and branching. The lesion can be focal (localized), multifocal (in up to 40% of cases
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Pelaez-Luna M, Chari ST, Smyrk TC, Takahashi N, Clain JE, Levy MJ, Pearson RK, Petersen BT, Topazian MD, Vege SS, Kendrick M, Farnell MB (2007)
Do consensus indications for resection in branch duct intraductal papillary mucinous neoplasm predict malignancy? A study of 147 patients.
Am J Gastroenterol 102: 1759-64



), or diffuse. In general, the leading edges of IPMNs tend to be relatively ill-defined, and IPMNs often extend microscopically beyond the grossly visible mass lesion. The neoplastic epithelium can extend into the smaller pancreatic ducts, mimicking pancreatic intraepithelial neoplasia. The neoplastic epithelium can show a variety of directions of differentiation
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Adsay NV, Merati K, Basturk O, Iacobuzio-Donahue C, Levi E, Cheng JD, Sarkar FH, Hruban RH, Klimstra DS (2004)
Pathologically and biologically distinct types of epithelium in intraductal papillary mucinous neoplasms: delineation of an "intestinal" pathway of carcinogenesis in the pancreas.
Am J Surg Pathol 28: 839-48




Click to access Pubmed
Ban S, Naitoh Y, Mino-Kenudson M, Sakurai T, Kuroda M, Koyama I, Lauwers GY, Shimizu M (2006)
Intraductal papillary mucinous neoplasm (IPMN) of the pancreas: its histopathologic difference between 2 major types.
Am J Surg Pathol 30: 1561-9




Click to access Pubmed
Furukawa T, Klöppel G, Volkan Adsay N, Albores-Saavedra J, Fukushima N, Horii A, Hruban RH, Kato Y, Klimstra DS, Longnecker DS, Lüttges J, Offerhaus GJ, Shimizu M, Sunamura M, Suriawinata A, Takaori K, Yonezawa S (2005)
Classification of types of intraductal papillary-mucinous neoplasm of the pancreas: a consensus study.
Virchows Arch 447: 794-9



. On the basis of the predominant architectural and cell differentiation pattern, IPMNs can be subclassified into four types: gastric, intestinal, pancreatobiliary and oncocytic
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Adsay NV, Adair CF, Heffess CS, Klimstra DS (1996)
Intraductal oncocytic papillary neoplasms of the pancreas.
Am J Surg Pathol 20: 980-94




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Adsay NV, Merati K, Basturk O, Iacobuzio-Donahue C, Levi E, Cheng JD, Sarkar FH, Hruban RH, Klimstra DS (2004)
Pathologically and biologically distinct types of epithelium in intraductal papillary mucinous neoplasms: delineation of an "intestinal" pathway of carcinogenesis in the pancreas.
Am J Surg Pathol 28: 839-48




Click to access Pubmed
Ban S, Naitoh Y, Mino-Kenudson M, Sakurai T, Kuroda M, Koyama I, Lauwers GY, Shimizu M (2006)
Intraductal papillary mucinous neoplasm (IPMN) of the pancreas: its histopathologic difference between 2 major types.
Am J Surg Pathol 30: 1561-9



[[562]]
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Furukawa T, Klöppel G, Volkan Adsay N, Albores-Saavedra J, Fukushima N, Horii A, Hruban RH, Kato Y, Klimstra DS, Longnecker DS, Lüttges J, Offerhaus GJ, Shimizu M, Sunamura M, Suriawinata A, Takaori K, Yonezawa S (2005)
Classification of types of intraductal papillary-mucinous neoplasm of the pancreas: a consensus study.
Virchows Arch 447: 794-9




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



.

Gastric-type IPMN
The gastric type is characteristically found in the branch-duct IPMNs. The epithelium lining gastric IPMNs is composed of innocuous, tall columnar cells with basally oriented nuclei and abundant pale mucinous cytoplasm, reminiscent of gastric foveolar epithelium. The peripheral portions of the lesion often form pyloric- like glands

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Ban S, Naitoh Y, Mino-Kenudson M, Sakurai T, Kuroda M, Koyama I, Lauwers GY, Shimizu M (2006)
Intraductal papillary mucinous neoplasm (IPMN) of the pancreas: its histopathologic difference between 2 major types.
Am J Surg Pathol 30: 1561-9



. This latter finding may be prominent in some cases and has been designated as “pyloric gland adenoma” by some authors
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Albores-Saavedra J, Sheahan K, O'Riain C, Shukla D (2004)
Intraductal tubular adenoma, pyloric type, of the pancreas: additional observations on a new type of pancreatic neoplasm.
Am J Surg Pathol 28: 233-8




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Chetty R, Serra S (2009)
Intraductal tubular adenoma (pyloric gland-type) of the pancreas: a reappraisal and possible relationship with gastric-type intraductal papillary mucinous neoplasm.
Histopathology 55: 270-6




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Nakayama Y, Inoue H, Hamada Y, Takeshita M, Iwasaki H, Maeshiro K, Iwanaga S, Tani H, Ryu S, Yasunami Y, Ikeda S (2005)
Intraductal tubular adenoma of the pancreas, pyloric gland type: a clinicopathologic and immunohistochemical study of 6 cases.
Am J Surg Pathol 29: 607-16



. Generally, the gastric-type IPMN proves to have only low- or intermediate-grade dysplasia. Scattered goblet cells can be seen.

Intestinal-type IPMN
This type is characterized by main-duct involvement, the formation of tall papillae lined by columnar cells with pseudostratified, cigar-shaped nuclei, and basophilic cytoplasm with variable amount of apical mucin. The overall picture is highly reminiscent of colonic villous adenomas

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Adsay NV, Merati K, Basturk O, Iacobuzio-Donahue C, Levi E, Cheng JD, Sarkar FH, Hruban RH, Klimstra DS (2004)
Pathologically and biologically distinct types of epithelium in intraductal papillary mucinous neoplasms: delineation of an "intestinal" pathway of carcinogenesis in the pancreas.
Am J Surg Pathol 28: 839-48



. Some examples are composed predominantly of goblet-like cells with micropapillary features
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Furukawa T, Klöppel G, Volkan Adsay N, Albores-Saavedra J, Fukushima N, Horii A, Hruban RH, Kato Y, Klimstra DS, Longnecker DS, Lüttges J, Offerhaus GJ, Shimizu M, Sunamura M, Suriawinata A, Takaori K, Yonezawa S (2005)
Classification of types of intraductal papillary-mucinous neoplasm of the pancreas: a consensus study.
Virchows Arch 447: 794-9



. The epithelial cells in intestinal-type IPMNs usually have intermediate- or high-grade dysplasia.

Pancreatobiliary-type IPMN
The pancreatobiliary type of IPMN

Click to access Pubmed
Adsay NV, Merati K, Basturk O, Iacobuzio-Donahue C, Levi E, Cheng JD, Sarkar FH, Hruban RH, Klimstra DS (2004)
Pathologically and biologically distinct types of epithelium in intraductal papillary mucinous neoplasms: delineation of an "intestinal" pathway of carcinogenesis in the pancreas.
Am J Surg Pathol 28: 839-48



occurs less frequently than the others, and is less well-characterized. Pancreatobiliary- type IPMNs typically involve the main pancreatic duct, and form thin, branching papillae with high-grade dysplasia. The neoplastic cells are cuboidal, with round, hyperchromatic nuclei, prominent nucleoli, moderately amphophilic cytoplasm, and have a less mucinous appearance. Some cases have overlapping features with intraductal oncocytic papillary neoplasms, and some with intraductal tubulopapillary neoplasms.

Oncocytic-type IPMN
The oncocytic type of IPMN usually has complex and arborizing papillae with delicate stroma. The papillae are lined by two to five layers of cuboidal to columnar cells with abundant eosinophilic granular cytoplasm. The nuclei are round, large, and fairly uniform and typically contain single, prominent, eccentrically located nucleoli. Goblet cells may be interspersed among the oncocytic cells. The neoplastic cells often form intraepithelial lumina, which are spaces about one quarter the size of the cells, but which merge to form multicell-sized punched-out spaces within the epithelium. In some cases, these intraepithelial lumina produce a cribriform pattern, and in others the epithelium of adjacent papillae may fuse, producing a solid growth pattern punctuated by small vessels. The intraductal nature of oncocytic-type IPMNs with extensive solid areas may be difficult to recognize. Most oncocytic-type IPMNs have sufficient cytoarchitectural atypia to be calssified as having high-grade dysplasia. Several directions of differentiation can be seen in an individual IPMN. In particular, the gastric type of epithelium can be seen in the less papillary regions of all IPMNs

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Adsay NV, Merati K, Basturk O, Iacobuzio-Donahue C, Levi E, Cheng JD, Sarkar FH, Hruban RH, Klimstra DS (2004)
Pathologically and biologically distinct types of epithelium in intraductal papillary mucinous neoplasms: delineation of an "intestinal" pathway of carcinogenesis in the pancreas.
Am J Surg Pathol 28: 839-48



. In fact, some authors believe that the pancreatobiliary type of IPMNs is a highgrade transformation of the gastric type
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Ban S, Naitoh Y, Mino-Kenudson M, Sakurai T, Kuroda M, Koyama I, Lauwers GY, Shimizu M (2006)
Intraductal papillary mucinous neoplasm (IPMN) of the pancreas: its histopathologic difference between 2 major types.
Am J Surg Pathol 30: 1561-9



. However, it is uncommon to find both intestinal and pancreatobiliary epithelium within the same IPMN
Click to access Pubmed
Furukawa T, Klöppel G, Volkan Adsay N, Albores-Saavedra J, Fukushima N, Horii A, Hruban RH, Kato Y, Klimstra DS, Longnecker DS, Lüttges J, Offerhaus GJ, Shimizu M, Sunamura M, Suriawinata A, Takaori K, Yonezawa S (2005)
Classification of types of intraductal papillary-mucinous neoplasm of the pancreas: a consensus study.
Virchows Arch 447: 794-9




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



.

Degree of dysplasia
Noninvasive IPMNs are classified as having low-grade, intermediate-grade, or high-grade dysplasia on the basis of the highest degree of architectural and cytological atypia (dysplasia) identified

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



.
> IPMNs with low-grade dysplasia are characterized by a single layer of well-polarized cells, small and uniform nuclei with only mild pleomorphism, and rare mitoses.
> IPMNs with intermediategrade dysplasia have nuclear stratification, crowding, and loss of polarity. The nuclei are enlarged and moderately hyperchromatic. The papillae maintain identifiable stromal cores.
> IPMN with high grade dysplasia are characterized by severe architectural and cytological atypia, with the formation of irregular branching papillae and sometimes cribriform growth. The epithelial cells lack polarity, and the nuclei are stratified, hyperchromatic, and pleomorphic. Mitoses are frequently found, and can even be found near the luminal surface.

Cytopathology
On cytological preparations, the findings for IPMNs and MCNs are nearly identical, and the generic cytological diagnosis of “mucinous cyst” is often used to refer to cytological findings consistent with either of these neoplasms. Cyst fluid aspirated from an IPMN can contain highly variable amounts of extracellular mucin and neoplastic epithelium

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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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Emerson RE, Randolph ML, Cramer HM (2006)
Endoscopic ultrasound-guided fine-needle aspiration cytology diagnosis of intraductal papillary mucinous neoplasm of the pancreas is highly predictive of pancreatic neoplasia.
Diagn Cytopathol 34: 457-62




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Frossard JL, Amouyal P, Amouyal G, Palazzo L, Amaris J, Soldan M, Giostra E, Spahr L, Hadengue A, Fabre M (2003)
Performance of endosonography-guided fine needle aspiration and biopsy in the diagnosis of pancreatic cystic lesions.
Am J Gastroenterol 98: 1516-24




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Layfield LJ, Cramer H (2005)
Primary sclerosing cholangitis as a cause of false positive bile duct brushing cytology: report of two cases.
Diagn Cytopathol 32: 119-24




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Michaels PJ, Brachtel EF, Bounds BC, Brugge WR, Pitman MB (2006)
Intraductal papillary mucinous neoplasm of the pancreas: cytologic features predict histologic grade.
Cancer 108: 163-73




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Pitman MB, Michaels PJ, Deshpande V, Brugge WR, Bounds BC (2008)
Cytological and cyst fluid analysis of small (< or =3 cm) branch duct intraductal papillary mucinous neoplasms adds value to patient management decisions.
Pancreatology 8: 277-84




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Recine M, Kaw M, Evans DB, Krishnamurthy S (2004)
Fine-needle aspiration cytology of mucinous tumors of the pancreas.
Cancer 102: 92-9




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Solé M, Iglesias C, Fernández-Esparrach G, Colomo L, Pellisé M, Ginés A (2005)
Fine-needle aspiration cytology of intraductal papillary mucinous tumors of the pancreas.
Cancer 105: 298-303




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Stelow EB, Shami VM, Abbott TE, Kahaleh M, Adams RB, Bauer TW, Debol SM, Abraham JM, Mallery S, Policarpio-Nicolas ML (2008)
The use of fine needle aspiration cytology for the distinction of pancreatic mucinous neoplasia.
Am J Clin Pathol 129: 67-74



. In many cases, the aspirate is composed only of mucinous material, without a cellular component. Thus, if gastrointestinal contamination can be ruled out, the presence of mucin may be the only manifestation that the lesion is in fact a “mucinous cyst.” In such cases, the imaging findings, stains for mucin, and elevated levels of CEA in the cyst fluid
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Hirono S, Tani M, Kawai M, Ina S, Nishioka R, Miyazawa M, Fujita Y, Uchiyama K, Yamaue H (2009)
Treatment strategy for intraductal papillary mucinous neoplasm of the pancreas based on malignant predictive factors.
Arch Surg 144: 345-9; discussion 349-50



, with or without elevated levels of exocrine enzymes, may be needed to verify the diagnosis of IPMN. As IPMNs connect with the duct system, it has been suggested that cytology of the pancreatic juice may also be useful
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Hibi Y, Fukushima N, Tsuchida A, Sofuni A, Itoi T, Moriyasu F, Mukai K, Aoki T (2007)
Pancreatic juice cytology and subclassification of intraductal papillary mucinous neoplasms of the pancreas.
Pancreas 34: 197-204



. Owing to sampling phenomena, cytology tends to underestimate the highest histological grade of dysplasia
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Basturk O, Coban I, Adsay NV (2009)
Pancreatic cysts: pathologic classification, differential diagnosis, and clinical implications.
Arch Pathol Lab Med 133: 423-38




Click to access Pubmed
Michaels PJ, Brachtel EF, Bounds BC, Brugge WR, Pitman MB (2006)
Intraductal papillary mucinous neoplasm of the pancreas: cytologic features predict histologic grade.
Cancer 108: 163-73




Click to access Pubmed
Pitman MB, Michaels PJ, Deshpande V, Brugge WR, Bounds BC (2008)
Cytological and cyst fluid analysis of small (< or =3 cm) branch duct intraductal papillary mucinous neoplasms adds value to patient management decisions.
Pancreatology 8: 277-84



. The oncocytic nature of IPMNs with oncocytic differentiation is reflected in the cytoplasm of the aspirated cells. The presence of small clusters of atypical epithelial cells with irregular nuclei and a high nucleus-to-cytoplasm ratio, with or without visible cytoplasmic mucin, correlates with an increased risk of malignancy, even when these clusters are very few in number
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Michaels PJ, Brachtel EF, Bounds BC, Brugge WR, Pitman MB (2006)
Intraductal papillary mucinous neoplasm of the pancreas: cytologic features predict histologic grade.
Cancer 108: 163-73




Click to access Pubmed
Pitman MB, Michaels PJ, Deshpande V, Brugge WR, Bounds BC (2008)
Cytological and cyst fluid analysis of small (< or =3 cm) branch duct intraductal papillary mucinous neoplasms adds value to patient management decisions.
Pancreatology 8: 277-84




Click to access Pubmed
Shen J, Brugge WR, Dimaio CJ, Pitman MB (2009)
Molecular analysis of pancreatic cyst fluid: a comparative analysis with current practice of diagnosis.
Cancer 117: 217-27



. A diagnosis of malignancy is rendered with sufficient quality and quantity of an atypical epithelial component, generally composed of crowded groups of cells with parachromatin clearing, irregular nuclear membranes and nucleoli
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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




Click to access Pubmed
Michaels PJ, Brachtel EF, Bounds BC, Brugge WR, Pitman MB (2006)
Intraductal papillary mucinous neoplasm of the pancreas: cytologic features predict histologic grade.
Cancer 108: 163-73




Click to access Pubmed
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



. Whether the malignant cells represent high-grade dysplasia or invasive carcinoma is often difficult to determine. The association of such cells with abundant acute inflammation or necrosis suggests an associated invasive carcinoma
Click to access Pubmed
Michaels PJ, Brachtel EF, Bounds BC, Brugge WR, Pitman MB (2006)
Intraductal papillary mucinous neoplasm of the pancreas: cytologic features predict histologic grade.
Cancer 108: 163-73



.

Ultrastructure
IPMN has no specific ultrastructural features

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Morohoshi T, Kanda M, Asanuma K, Klöppel G (1989)
Intraductal papillary neoplasms of the pancreas. A clinicopathologic study of six patients.
Cancer 64: 1329-35



. The neoplastic cells lie on a basement membrane and have numerous microvilli on the apical surface, a number of mitochondria, a well-developed rough endoplasmic reticulum and Golgi apparatus. Mucin droplets of variable size and electron density are present
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Morohoshi T, Kanda M, Asanuma K, Klöppel G (1989)
Intraductal papillary neoplasms of the pancreas. A clinicopathologic study of six patients.
Cancer 64: 1329-35



. Oncocytic-type IPMNs contain numerous mitochondria that exclude other organelles.

Differential diagnosis
The differential diagnosis for larger IPMNs includes other macrocystic (oligocystic) lesions, in particular, mucinous cystic neoplasms (MCNs) and macrocystic serous cystadenomas

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Basturk O, Coban I, Adsay NV (2009)
Pancreatic cysts: pathologic classification, differential diagnosis, and clinical implications.
Arch Pathol Lab Med 133: 423-38



. The differential for small IPMNs primarily includes pancreatic intraepithelial neoplasia (PanIN) and retention cysts
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Adsay NV, Merati K, Andea A, Sarkar F, Hruban RH, Wilentz RE, Goggins M, Iocobuzio-Donahue C, Longnecker DS, Klimstra DS (2002)
The dichotomy in the preinvasive neoplasia to invasive carcinoma sequence in the pancreas: differential expression of MUC1 and MUC2 supports the existence of two separate pathways of carcinogenesis.
Mod Pathol 15: 1087-95




Click to access Pubmed
Hruban RH, Takaori K, Klimstra DS, Adsay NV, Albores-Saavedra J, Biankin AV, Biankin SA, Compton C, Fukushima N, Furukawa T, Goggins M, Kato Y, Kloppel G, Longnecker DS, Lüttges J, Maitra A, Offerhaus GJ, Shimizu M, Yonezawa S (2004)
An illustrated consensus on the classification of pancreatic intraepithelial neoplasia and intraductal papillary mucinous neoplasms.
Am J Surg Pathol 28: 977-87



.

Mucinous cystic neoplasia (MCN)
MCNs can closely mimic branchduct type IPMNs

Click to access Pubmed
Basturk O, Coban I, Adsay NV (2009)
Pancreatic cysts: pathologic classification, differential diagnosis, and clinical implications.
Arch Pathol Lab Med 133: 423-38




Click to access Pubmed
Tanaka M, Chari S, Adsay V, Fernandez-del Castillo C, Falconi M, Shimizu M, Yamaguchi K, Yamao K, Matsuno S, (2006)
International consensus guidelines for management of intraductal papillary mucinous neoplasms and mucinous cystic neoplasms of the pancreas.
Pancreatology 6: 17-32



. MCNs typically occur in women with a median age in the fifth decade of life, and almost all MCNs are located in the tail or body of the pancreas. The vast majority of MCNs do not communicate with the pancreatic duct system. MCNs contain a cellular “ovariantype” stroma that expresses hormone receptors by immunohistochemistry. In contrast, IPMNs occur in men slightly more often than women, in a slightly older age group, involving the head of the gland more frequently than the tail, always communicating with the duct system, and do not have ovarian-type stroma.

Macrocystic serous cystadenomas.
Macro (oligocystic) serous cystic neoplasms

Click to access Pubmed
Basturk O, Coban I, Adsay NV (2009)
Pancreatic cysts: pathologic classification, differential diagnosis, and clinical implications.
Arch Pathol Lab Med 133: 423-38



form larger and less defined cysts than the more common microcystic serous cystic neoplasms; they may thus resemble branch-duct IPMNs. However, the epithelial cells of macrocystic serous cystic neoplasms are cuboidal and have glycogen-rich clear cytoplasm, with no mucin and no significant nuclear atypia.

Pancreatic intraepithelial neoplasia (PanIN)
PanINs should be distinguished from small IPMNs. Most PanINs are < 0.5 cm in greatest ductal diameter, whereas IPMNs are defined to be grossly detectable cystic lesions that typically measure ≥ 1.0 cm

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Hruban RH, Takaori K, Klimstra DS, Adsay NV, Albores-Saavedra J, Biankin AV, Biankin SA, Compton C, Fukushima N, Furukawa T, Goggins M, Kato Y, Kloppel G, Longnecker DS, Lüttges J, Maitra A, Offerhaus GJ, Shimizu M, Yonezawa S (2004)
An illustrated consensus on the classification of pancreatic intraepithelial neoplasia and intraductal papillary mucinous neoplasms.
Am J Surg Pathol 28: 977-87



. Lesions measuring 0.5–1.0 cm with mucinous epithelium are intermediate-grade lesions. PanINs tend to have short stubby papillae, while IPMNs often have long finger-like papillae. The presence of abundant luminal mucin and the expression of MUC2 suggests a diagnosis of IPMN
Click to access Pubmed
Adsay NV, Merati K, Andea A, Sarkar F, Hruban RH, Wilentz RE, Goggins M, Iocobuzio-Donahue C, Longnecker DS, Klimstra DS (2002)
The dichotomy in the preinvasive neoplasia to invasive carcinoma sequence in the pancreas: differential expression of MUC1 and MUC2 supports the existence of two separate pathways of carcinogenesis.
Mod Pathol 15: 1087-95




Click to access Pubmed
Hruban RH, Takaori K, Klimstra DS, Adsay NV, Albores-Saavedra J, Biankin AV, Biankin SA, Compton C, Fukushima N, Furukawa T, Goggins M, Kato Y, Kloppel G, Longnecker DS, Lüttges J, Maitra A, Offerhaus GJ, Shimizu M, Yonezawa S (2004)
An illustrated consensus on the classification of pancreatic intraepithelial neoplasia and intraductal papillary mucinous neoplasms.
Am J Surg Pathol 28: 977-87



. However, there is histological overlap, and the distinction between these two lesions can be nearly impossible in cases measuring between 0.5 and 1.0 cm.

Retention cysts
These are usually unilocular and are lined by a flat single layer of ductal epithelium without nuclear atypia. Mucinous cytoplasm is typically lacking, although retention cysts can be focally involved by PanIN

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Kosmahl M, Egawa N, Schröder S, Carneiro F, Lüttges J, Klöppel G (2002)
Mucinous nonneoplastic cyst of the pancreas: a novel nonneoplastic cystic change?
Mod Pathol 15: 154-8



. ITPN. ITPNs may resemble IPMNs of the pancreatobiliary type
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Königsrainer I, Glatzle J, Klöppel G, Königsrainer A, Wehrmann M (2008)
Intraductal and cystic tubulopapillary adenocarcinoma of the pancreas--a possible variant of intraductal tubular carcinoma.
Pancreas 36: 92-5




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Tajiri T, Tate G, Kunimura T, Inoue K, Mitsuya T, Yoshiba M, Morohosh T (2004)
Histologic and immunohistochemical comparison of intraductal tubular carcinoma, intraductal papillary-mucinous carcinoma, and ductal adenocarcinoma of the pancreas.
Pancreas 29: 116-22




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Yamaguchi H, Shimizu M, Ban S, Koyama I, Hatori T, Fujita I, Yamamoto M, Kawamura S, Kobayashi M, Ishida K, Morikawa T, Motoi F, Unno M, Kanno A, Satoh K, Shimosegawa T, Orikasa H, Watanabe T, Nishimura K, Ebihara Y, Koike N, Furukawa T (2009)
Intraductal tubulopapillary neoplasms of the pancreas distinct from pancreatic intraepithelial neoplasia and intraductal papillary mucinous neoplasms.
Am J Surg Pathol 33: 1164-72



. IPMNs are distinguished by more complex papillary architecture, fewer tubular structures, and evident intracellular mucin. The similarities between pancreatobiliary variant of IPMN and intraductal tubulopapillary neoplasms include expression of MUC6
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Basturk O, Khayyata S, Klimstra DS, Hruban RH, Zamboni G, Coban I, Adsay NV (2010)
Preferential expression of MUC6 in oncocytic and pancreatobiliary types of intraductal papillary neoplasms highlights a pyloropancreatic pathway, distinct from the intestinal pathway, in pancreatic carcinogenesis.
Am J Surg Pathol 34: 364-70



.

Acinar cell carcinoma
Some acinar cell carcinomas have a prominent intraductal pattern of growth and contain papilla, and can resemble IPMNs

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Basturk O, Zamboni G, Klimstra DS, Capelli P, Andea A, Kamel NS, Adsay NV (2007)
Intraductal and papillary variants of acinar cell carcinomas: a new addition to the challenging differential diagnosis of intraductal neoplasms.
Am J Surg Pathol 31: 363-70



. The cells of these carcinomas contain abundant apical, acidophilic zymogen granules, and immunolabelling reveals the expression of pancreatic exocrine enzymes
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Basturk O, Zamboni G, Klimstra DS, Capelli P, Andea A, Kamel NS, Adsay NV (2007)
Intraductal and papillary variants of acinar cell carcinomas: a new addition to the challenging differential diagnosis of intraductal neoplasms.
Am J Surg Pathol 31: 363-70




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Toll AD, Mitchell D, Yeo CJ, Hruban RH, Witkiewicz AK (2009)
Acinar Cell Carcinoma With a Prominent Intraductal Growth Pattern: Case Report With Review of the Literature.
Int J Surg Pathol :



.

Oncocytic variants
The differential diagnosis of rare solid examples of oncocytictype IPMN include occasional oncocytic variants of pancreatic neoplasms, such as oncocytic neuroendocrine neoplasms, and rare oncocytic solid-pseudopapillary neoplasms; however, careful sampling allows for the recognition of the characteristic features of the respective entities in each case.

Pseudoinvasion
The distinction between an invasive carcinoma arising in association with an IPMN and pseudoinvasion is critically important. In particular, benign mucin spillage into the stroma that presumably occurs owing to rupture of involved distended duct can mimic an invasive colloid carcinoma. Mucin spillage is characterized by stromal dissection by acellular mucin and is usually associated with a brisk inflammatory reaction. In contrast, the stromal mucin of invasive carcinoma contains neoplastic cells and is usually not associated with intense inflammation; however, any mucin in the stroma should be evaluated carefully as being suspicious for invasion. Similarly, IPMN extending along branch ducts or tributary ductules may create the impression of early invasion. The lobular architecture, smooth contours of the units, and morphological similarity to the larger lesion are the main features that help distinguish this pattern of growth from invasive carcinoma

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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



.

Diagnostic algorithms for tumours of the pancreas


Intestinal-type IPMN with associated invasive colloid carcinoma
Intestinal-type IPMN with associated invasive colloid carcinoma
High-grade dysplasia (top left) adjacent to the invasive colloid carcinoma (bottom right)
High-grade dysplasia (top left) adjacent to the invasive colloid carcinoma (bottom right)