Dr. Ralph H. Hruban
Dr. Günter Klöppel
Case 4 -
Intraductal oncocytic papillary neoplasm with carcinoma
Dr. N. Volkan Adsay
Wayne State University
74-year old male had an 8 cm cystic lesion that contained
nodular areas, located in the body of the pancreas.
Case 4 - Figure 1
This tumor is characterized by a papillary
proliferation involving the cystically dilated main and branch pancreatic ducts. The adjacent pancreatic
tissue is normal. Architecturally, the papillae are complex, arborizing, and are lined by
pseudostratified epithelium of 1-5 cell layers. Intraepithelial lumina formation is prominent. These
are microcystic spaces of 1-3 cell size, punctuating the epithelium without obvious polarization of cells
around them. Some contain mucin. Cytologically, the cells are cuboidal, and have round nuclei with
prominent, eccentric nucleoli. The cytoplasm is abundant, acidophilic and finely granular. Despite the
monotony of the cells and their low nucleocytoplasmic ratio (due to the abundance of cytoplasm),
architectural complexity and cytologic features are quite atypical.
"Intraductal oncocytic papillary neoplasm with carcinoma
in-situ. No invasive carcinoma is identified".
Oncocytes and mitochondrion-rich cells are not usually
present in the normal pancreas. They may be detected occasionally in the ductal epithelium as part of a
metaplastic process in chronic pancreatitis. Oncocytic change is also relatively uncommon in pancreatic
neoplasms, detected most often in solid pseudopapillary tumors and pancreatic endocrine neoplasms.
Before the recognition of "intraductal oncocytic papillary neoplasms", only a handful of examples of true
(?) oncocytic tumors (i.e., oncocytoma or oncocytic carcinoma) had been reported in the pancreas, mostly
as individual case reports.
Intraductal oncocytic papillary neoplasms (IOPNs) is a relatively recently described group. Grossly,
these tumors exhibit cystic dilatation of the ducts, many of which contain large, tan and friable nodular
proliferations. The tumors are relatively large (mean size: 5.2 cm) at the time of diagnosis.
Histologically, IOPN is characterized by intraductal growth of papillary tumor, and is frequently
associated with mucin production as well as multilocular cystic transformation of the ductal system. The
papillae of IOPNs exhibit a "pancreaticobiliary (PB)" pattern, which is characterized by exuberant,
arborizing papillae lined by 1-5 cell layers of cuboidal cells. The nuclei in IOPNs contain single,
prominent and eccentric nucleoli. One distinctive feature that appears to be relatively specific for
these tumors is the presence of "intraepithelial lumina" which are round, punched-out spaces within the
epithelium that often give the proliferation a cribriform architecture, similar to that seen in oncocytic
schneiderian papillary tumors of the sinonasal tract. These intraepithelial lumina often contain mucin.
In most cases, the degree of cytoarchitectural atypia, the exuberance of the papillae, and the
presence of mitoses in the intraductal proliferation qualify for the diagnosis of carcinoma even in the
absence of invasion. In our experience, the cases of IOPN were associated with invasive carcinoma in 5
of 17 cases; however, the invasion was usually limited in extent and displayed a nested or glandular
oncocytic pattern that is distinctly different from the other types of invasive carcinoma in the
pancreas. In some cases, the intraductal papillae fuse, forming large solid areas replacing the
papillary architecture, to an extent that they can be mistaken for nodules of invasive carcinoma. These
areas can be distinguished from invasive oncocytic carcinoma, by their large size, round appearance and
IOPNs exhibit the common characteristic features of pancreatic tumors with ductal differentiation.
They produce mucin, which is frequently detectable at the macroscopic level, as well as histochemically
with PAS and mucicarmine stains, and immunohistochemically by CEA and B72.3. Scattered neuroendocrine
cells are not uncommon, and in rare cases focal acinar differentiation can be demonstrated
immunohistochemically by staining for trypsin and lipases, and ultrastructurally by the presence of
zymogen granules. To confirm the oncocytic nature of these cells, PTAH and novelli stains or the
immunohistochemical marker 111-3 may be useful. Electron microscopy is also helpful in demonstrating the
abundance of mitochondria and paucity of other organelles. In most cases, morphologic findings on
H&E are adequate to arrive at the diagnosis.
The main differential diagnosis of IOPN is with the other cystic, papillary and mucinous tumors of the
pancreas, especially intraductal papillary mucinous neoplasms and mucinous cystic neoplasms. IOPNs share
so many aspects with IPMNs that they are also regarded as a distinct subset of IPMNs, rather than a
separate entity. The main distinguishing feature of this "subset" is the microscopic appearance of the
papillae including their arborizing architecture (rather than villous pattern seen in many IPMNs), the
oncocytic nature of the cells and the presence of distinctive intraepithelial lumina. In addition, IOPNs
lack diffuse MUC2/CDX2 expression that characterizes the intestinal subset of IPMNs. Moreover, in
contrast with ordinary IPMNs, mesothelin and heppar expression is significantly more common in IOPNs than
IPMNs. Most interestingly, mutation in k-ras oncogene which is present in 70%
of IPMNs appears to be very uncommon, if present at all, in IOPNs. In other organs such as the kidney,
oncocytic versions of tumors have different biology and genetic alterations, which suggests that whatever
leads to accumulation of mitochondria may also influence the biology and behavior of the tumor.
Mucinous cystic neoplasms (MCNs) are also cystic neoplasia composed of mucinous cells and may have
florid papilla formation. MCNs are seen typically in perimenopausal females (mean age = 48; >95%
females), they occur predominantly in the tail of the organ, and most importantly, ovarian-type stroma is
specific for this tumor type. Oncocytic cytology is seldom seen in MCNs.
IOPNs also need to be differentiated from other oncocytic tumors of the pancreas. Most oncocytic
tumors in the pancreas represent oncocytic change in solid pseudopapillary or islet cell tumors.
Although the follow-up in the reported cases is rather limited, the clinical course of these tumors
also seem to be relatively more favorable than usual ductal adenocarcinoma for which they have been
mistaken. It is difficult to determine whether the favorable outcome of oncocytic tumors in other organs
such as the kidney will also apply to IOPNs, and that they will prove to be biologically more benign than
their non-oncocytic relatives, i.e. IPMNs.
- Adsay NV , Adair CF, Heffess CS, and Klimstra DS. Intraductal oncocytic papillary neoplasms of the pancreas, American Journal of Surgical Pathology 20 (8), 980-94, 1996.
- 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, Luttges J, Maitra A, Offerhaus GJ, Shimizu M, Yonezawa S. An Illustrated Consensus On The Classification Of Pancreatic Intraepithelial Neoplasia And Intraductal Papillary Mucinous Neoplasms. American Journal of Surgical Pathology 28(8):977-87, 2004.
- Tanaka M, Chari S, Adsay NV,Fernandez-del Castillo C, Falconi M, Shimizu M, Yamaguchi K, Yamao K, Matsuno S. . International Guideline For Management Of Intraductal Papillary-Mucinous Neoplasms And Mucinous Cystic Neoplasms. A Consensus Of The Working Group Of The International Association Of Pancreatology. Pancreatology 2005 Nov 29;6(1-2):17-32.