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Pancreatic cancers nearly always arise from the ductal epithelium and are therefore adenocarcinomas. Thus, other rarer variants of pancreatic carcinoma are covered elsewhere in this site. To date, there are no effective screening tests for this cancer. Patients usually present with increasing abdominal pain and unexplained weight loss. Painless jaundice may be present in 10-20% of patients. Most tumors arise in the head of the pancreas and this directly impinges or invades the common bile duct and main pancreatic duct. This may lead to stenosis or complete blockage of the bile duct which leads to jaundice.

Uncommon But Important Clinical Presentations of Pancreatic Cancer:
Migratory thrombophlebitis
Diabetes mellitus

By the time the patient is exhibiting symptoms, it has often spread beyond the pancreas. One year survival is less than 20% following diagnosis, regardless of treatment. The pathologist is often called upon to perform intraoperative frozen sections on the margins of the tumor as well as regional lymph nodes to determine whether the tumor has spread.


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Gross Appearance and Clinical Variants  
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SYNONYMS Duct cell adenocarcinoma
Duct cell carcinoma
Pancreatic adenocarcinoma of the ductal type
Exocrine pancreatic carcinoma

85-90% of all pancreatic tumors

8-12/100,000 males worlwide
4.5-7/100,000 females worldwide

5th leading cause of death in the United States

AGE RANGE-MEDIAN 60-80 years (80% of cases)
Diet Nitrosoamine derivatives
Black race  
Advancing age  
Jewish religion  


Previous partial gastrectomy  
Chronic pancreatitis Small but significantly increased risk
Hereditary pancreatitis Increased incidence up to 6%
Familial cases Rare
Peutz-Jeghers syndrome  
Hereditary polyposis  
Colorectal cancer  
Familial breast cancer  
Familial atypical multiple mole-melanoma  


Gene expression alterations in the non-neoplastic parenchyma adjacent to infiltrating pancreatic ductal adenocarcinoma.

Fukushima N, Koopmann J, Sato N, Prasad N, Carvalho R, Leach SD, Hruban RH, Goggins M.

1Department of Pathology, The Johns Hopkins Medical Institutions, Baltimore, MD, USA.

Mod Pathol. 2005 Jun;18(6):779-87. Abstract quote  

The non-neoplastic pancreatic parenchyma adjacent to infiltrating ductal adenocarcinoma demonstrates inflammation, fibrosis, acinar cell loss and small duct-like metaplasia of acinar cells. Similar morphologic changes are also observed in the setting of chronic pancreatitis. In addition, peritumoral acini have been shown to have alterations in gene expression even in the absence of morphological changes.

To better understand the pancreatic acinar responses to infiltrating pancreatic ductal adenocarcinoma, we characterized gene expression patterns of pancreatic acinar tissue adjacent to infiltrating pancreatic ductal adenocarcinomas and compared them to gene expression patterns of acinar tissue affected by chronic pancreatitis as well as to those of normal pancreatic acini. Fresh-frozen pancreatic acinar tissue was microdissected from nine patients (three with pancreatic cancer, three with chronic pancreatitis, three with normal pancreata) using laser capture microdissection, and extracted RNA from each microdissection was subjected to two rounds of linear amplification and hybridized to oligonucleotide microarrays. Gene expression patterns were confirmed using quantitative RT-PCR and/or immunohistochemistry. A total of 20 genes was found to be overexpressed in peritumoral acinar tissue compared to normal acinar tissue and to acini affected by chronic pancreatitis. These 20 genes included pancreatitis-associated protein (HIP/PAP), a gene known to be overexpressed in acini adjacent to infiltrating pancreatic cancer, and the gene cartilage glycoprotein-39 (HC gp-39 or TKL-40). Serum HC gp-39 protein levels were significantly higher in patients with pancreatic cancer and in those with chronic pancreatitis than in controls without pancreatic disease. There was no significant difference in the levels of serum HC gp-39 in patients with pancreatic cancer and those with chronic pancreatitis.

Our results demonstrate some of the molecular alterations in acinar cells that occur in response to adjacent infiltrating pancreatic ductal adenocarcinoma and reveal that such alterations can provide a rich source of markers of pancreatic cancer.
Expression of novel markers of pancreatic ductal adenocarcinoma in pancreatic nonductal neoplasms: additional evidence of different genetic pathways.

Cao D, Maitra A, Saavedra JA, Klimstra DS, Adsay NV, Hruban RH.

1Department of Pathology, The Johns Hopkins Medical Institutions, Baltimore, MD, USA.
Mod Pathol. 2005 Jun;18(6):752-61. Abstract quote  

Solid pseudopapillary tumor, pancreatoblastoma, undifferentiated carcinoma with osteoclastic-like giant cells, and acinar cell carcinomas are rare pancreatic nonductal neoplasms. Compared to the significant advances in our understanding of the pathogenesis of pancreatic ductal adenocarcinomas in the last decades, the molecular mechanisms underlying pancreatic nonductal neoplasms are poorly understood.

In order to elucidate their molecular pathogenesis, we constructed tissue microarrays to study the expression of some novel pancreatic ductal adenocarcinoma-associated tumor markers in these nonductal pancreatic neoplasms.

We analyzed nine markers including tumor suppressor gene (14-3-3 sigma), proliferation marker (topoisomerase II alpha), epithelial markers (prostate stem cell antigen, mesothelin and cytokeratin 19), stromal markers (fascin, hsp47 and fibronectin), and gamma-synuclein whose function is not delineated. In addition, we included tumor suppressor gene DPC4 and oncogene Beta-catenin to further confirm their expression in pancreatic nonductal tumors.

Our results showed that in contrast to pancreatic ductal adenocarcinomas that show loss of Dpc4 protein in 55% of cases, loss of Dpc4 expression is absent in pancreatic nonductal neoplasms. Expression of 14-3-3 sigma is frequently seen in both pancreatic nonductal neoplasms (25-100%) and ductal adenocarcinomas (89%). Aberrant nuclear expression of beta-catenin is common in pancreatic nonductal neoplasms, specifically in solid pseudopapillary tumors (88%) and pancreatoblastomas (100%) but is rarely seen in pancreatic ductal adenocarcinomas (<5%). Expression of topoisomerase II alpha is not seen in solid pseudopapillary tumors and undifferentiated carcinomas with osteoclastic-like giant cells but is focally seen in pancreatoblastomas (50%) and acinar cell carcinomas (85%). Expression of PSCA and mesothelin was observed in pancreatic nonductal neoplasms but their expression was seen less frequently (0-50%) and weaker than that in pancreatic ductal adenocarcinomas (60-100%). CK19, a marker of pancreatic ductal adenocarcinomas, is not expressed in pancreatic nonductal neoplasms. Expression of gamma-synuclein as well as stromal markers (fascin, hsp47 and fibronectin) is frequently seen in both.

Our findings indicate pancreatic nonductal neoplasms have distinctive patterns of protein expression relative to pancreatic ductal adenocarcinomas and suggest that pancreatic nonductal neoplasms have different genetic pathways from the more common pancreatic ductal adenocarcinomas.

Tumor-suppressive pathways in pancreatic carcinoma.

Rozenblum E, Schutte M, Goggins M, Hahn SA, Panzer S, Zahurak M, Goodman SN, Sohn TA, Hruban RH, Yeo CJ, Kern SE.

Department of Pathology, The Johns Hopkins Medical Institutions, Baltimore, Maryland 21205-2196, USA.

Cancer Res 1997 May 1;57(9):1731-4 Abstract quote

During tumorigenesis, positive selection is exerted upon those tumor cells that alter rate-limiting regulatory pathways. A corollary of this principle is that mutation of one gene abrogates the need for alteration of another gene in the same pathway and also that the coexistence in a single tumor of mutations in different genes implies their involvement in distinct tumor-suppressive pathways.

We studied 42 pancreatic adenocarcinomas for genetic alterations in the K-ras oncogene and the p16, p53, and DPC4 tumor suppressor genes. All of them had the K-ras gene mutated. Thirty-eight % of the tumors had four altered genes, another 38% had three altered genes, 15% had two altered genes, and 8% of the tumors had one altered gene. Interestingly, we noted a high concordance of DPC4 and p16 inactivations (P = 0.007), suggesting that the genetic inactivation of p16 increases the selective advantage of subsequent mutation in DPC4. No statistically significant association was identified between the alteration of these cancer genes and pathological or clinical parameters.

This type of multigenic analysis in human tumors may serve to substantiate experimental tumor models and thus increase our understanding of the truly physiologically relevant tumor-suppressive pathways that are abrogated during human tumorigenesis.


c-MYC activation in primary and metastatic ductal adenocarcinoma of the pancreas: incidence, mechanisms, and clinical significance.

Schleger C, Verbeke C, Hildenbrand R, Zentgraf H, Bleyl U.

Institute of Pathology, Universitatsklinikum Mannheim, Germany.

Mod Pathol 2002 Apr;15(4):462-9 Abstract quote

Amplification and overexpression of c-MYC is a common event in various neoplasias. Recently, comparative genomic hybridization (CGH) of primary pancreatic adenocarcinomas revealed a distinct high-level amplification of 8q23-qter, suggesting that c-MYC located on 8q24 may be a candidate oncogene.

To evaluate the biological significance and prognostic value of c-MYC activation in pancreatic carcinoma, we performed interphase fluorescence in situ hybridization (FISH) and immunohistochemistry on a series of 69 primary pancreatic adenocarcinomas, 19 corresponding lymph node metastases, and 5 pancreatic intraductal lesions. Dual color FISH using a probe for c-MYC (8q24) and a centromeric probe for chromosome 8 revealed amplification of c-MYC in 32.3% and 29.4% of primary and metastatic tumors, respectively. Immunostaining identified c-MYC protein overexpression in 43.5% of primaries and 31.6% of metastases. Low concordance between positive FISH and immunostaining (13.4%) suggests multiple independent regulatory pathways of c-MYC activation. Statistical evaluation revealed significant correlation (alpha = 0.033) between c-MYC protein overexpression and histopathological tumor grade but absence of correlation with tumor stage or lymph node status. Analysis of pancreatic intraductal lesions showed c-MYC amplification and protein overexpression in two of five cases in which invasive carcinoma exhibited identical aberrations.

We conclude that deregulation of c-MYC protein is common in pancreatic cancer and that it may be involved in early neoplastic development and progression rather than in locoregional spread of invasive cancer.


Fas and fas ligand expression in pancreatic adenocarcinoma.

Pernick NL, Sarkar FH, Tabaczka P, Kotcher G, Frank J, Adsay NV.

Pancreas 2002 Oct;25(3):E36-41 Abstract quote

INTRODUCTION Fas and Fas ligand (FasL) mediate apoptosis of tumor cells in immune surveillance, and expression of FasL by tumors may mediate their counterattack on cytotoxic lymphocytes. Both proteins are expressed in most if not all pancreatic carcinoma cell lines, but their study in primary human tumors has been limited.AIM We performed Fas and FasL immunohistochemical staining on 81 primary pancreaticobiliary or ampullary ductal adenocarcinomas of patients in our institutional database to determine the extent and strength of staining.

METHODOLOGY The expression of Fas and FasL was compared with regard to clinicopathologic variables, K- mutations, and immunoexpression of HER2, p21, p27, and p53.

RESULTS AND CONCLUSION Fas was expressed in 19% of patients with strong or intermediate intensity but with variable percentages of tumor cell staining. FasL was expressed in 49% of patients, usually with diffuse expression but variable intensity. Fas expression was more common in women than men, as women had 93% of Fas-positive tumors but only 55% of Fas-negative tumors ( = 0.007), and was associated with strong HER2 expression (67% of Fas-positive versus 18% of Fas-negative patients; = 0.04). Fas expression tended to be less common in blacks (4% had Fas-positive tumors) than whites (22% had Fas-positive tumors; = 0.052). FasL expression tended to be associated with stage 4 disease at diagnosis (24% versus 0%; = 0.07). Neither Fas expression nor FasL expression was associated with survival, a circumstance suggesting that their role, if any, in contributing to the aggressiveness of these tumors is complex.

K-RAS High frequency

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.

Adsay NV, Merati K, Andea A, Sarkar F, Hruban RH, Wilentz RE, Goggins M, Iocobuzio-Donahue C, Longnecker DS, Klimstra DS.

Departments of Pathology, Karmanos Cancer Institute (NVA, KM, AA, FS) and Wayne State University, Detroit, Michigan.

Mod Pathol 2002 Oct;15(10):1087-95 Abstract quote

Emerging evidence suggests a dichotomy in the dysplasia-CIS-invasive carcinoma sequence in the pancreas. Pancreatic intraepithelial neoplasms (PanINs; small, incidental duct lesions) progress to invasive ductal adenocarcinomas (5-y survival of <15%), whereas intraductal papillary mucinous neoplasms (large, intraductal tumors with ductal dilatation) are often associated with colloid carcinoma (5-y survival of >55%).

We explored the relationship of these lesions by examining the expression of MUC1 and MUC2, glycoproteins reportedly reflecting "aggressive" and "indolent" phenotypes in pancreas cancer, respectively. Immunohistochemical labeling with MUC1 (clone Ma695) and MUC2 (clone Ccp58) antibodies was performed on PanINs (n = 43), intraductal papillary mucinous neoplasms (n = 74), ductal adenocarcinomas (n = 136), and colloid carcinomas (n = 15). Fifty-four percent of the intraductal papillary mucinous neoplasms expressed MUC2, whereas none of the PanINs did. In contrast, PanINs, especially higher grade lesions, were often positive for MUC1 (61% of PanIN 3), whereas the expression of this glycoprotein was infrequent in intraductal papillary mucinous neoplasms (20%). This dichotomy was further accentuated in the invasive carcinomas with which these two preinvasive pathways are respectively associated: all colloid carcinomas were MUC2+ (100%) and MUC1- (0%), whereas the labeling pattern was the reverse for ductal adenocarcinomas: 63% were MUC1+ and only 1% were MUC2+.

These results support a dichotomy in the dysplasia-CIS sequence in the pancreas. Because these two pathways often lead to different types of invasive carcinomas, this is an invaluable model for the study of carcinogenesis. The findings here also support the previous impression that MUC2 (the mucin associated with gel formation) is a marker of the "indolent" pathway (intraductal papillary mucinous neoplasm and colloid carcinoma), whereas MUC1 (the glycoprotein known to have an inhibitory role in cell-cell and cell-stroma interactions as well as in immunoresistance of tumor cells) is a marker of the "aggressive" pathway (PanIN to ductal adenocarcinoma).


Radiologic Endoscopic ultrasound and abdominal CT scan with or without a percutaneous fine-needle biopsy
Serologic markers

No definitive screening test-both CEA and CA19-9 have been used:
CEA>3 ng/ml
CA19-9 >37 U/ml

Sensitivity varies from 55-95%

Expression Patterns of Protein Kinase C Isoenzymes Are Characteristically Modulated in Chronic Pancreatitis and Pancreatic Cancer

James D. Evans, MD, FRCS
Philip A. Cornford, FRCS
Andrew Dodson
John P. Neoptolemos, MA, MD, FRCS
Christopher S. Foster, MD, PhD, DSc, FRCPath

Am J Clin Pathol 2003;119:392-402 Abstract quote

We immunohistochemically identified protein kinase C (PKC) isoenzymes and the receptor for activated C-kinase (RACK-1) in normal, chronically inflamed, and malignant pancreas specimens. Expression patterns were specific and consistent for each microanatomic structure. In chronic pancreatitis, the expression patterns by epithelial cells were indistinguishable from those in normal pancreas.

In the stroma, there was a gain of PKC-delta (P < .05) and loss of PKC-mu (P < .0001). Expression in pancreatic duct carcinomas, compared with control normal minor ductular epithelial cells, revealed relative loss of PKC-epsilon (P < .0001), PKC-iota (P = .005), and PKC-theta (P < .0001) but no gain in any isoenzyme. Compared with control normal major duct epithelial cells, the principal differences were a relative loss in PKC-gamma (P < .05) and a relative gain in PKC-beta (P < .05), PKC-iota (P < .05), and PKC-zeta (P < .005). The stroma adjacent to ductal carcinomas was characterized by prominent expression of PKC-mu and a gain in PKC-delta (P < .0001) and PKC-zeta (P > .005). Ampullary carcinomas revealed a relative gain of PKC-iota (P < .05) and RACK-1 (P < .05). In the adjacent stroma was enhanced expression of PKC-delta (P < .005) and PKC-gamma (P < .001) and loss of PKC-mu (P < .05).

Specific changes in isoenzyme expression in stroma of chronic pancreatitis and in epithelial cells and stroma of ductal and ampullary pancreatic adenocarcinomas reflect specific modulation of intracellular signaling pathways that control critical homeostatic mechanisms.

Immunohistochemical Validation of a Novel Epithelial and a Novel Stromal Marker of Pancreatic Ductal Adenocarcinoma Identified by Global Expression Microarrays
Sea Urchin Fascin Homolog and Heat Shock Protein 47

Anirban Maitra, MD, etal.

Am J Clin Pathol 2002;118:52-59 Abstract quote

We extended the results of a previous microarray analysis by immunohistochemical validation of differential protein expression in a series of 57 surgically resected infiltrating ductal pancreatic adenocarcinomas.

Two representative genes were examined: sea urchin fascin homolog (overexpressed in both cell lines and primary tumors) and heat shock protein 47 (HSP47; overexpressed in primary tumors only). Protein expression also was evaluated in the precursor lesions of pancreatic cancer, pancreatic intraepithelial neoplasia (PanIN), and normal ductal epithelium. Fascin expression was seen in the neoplastic cells of 54 (95%) of 57 ductal adeno-carcinomas but not in 49 (94%) of 52 adjacent nonneoplastic epithelium.

In the multistep pathogenesis of ductal adenocarcinomas, fascin expression seemed to be a late event, usually present in PanINs 2 and 3. HSP47 expression was almost universal and most intense in the ductal adenocarcinoma–associated stromal desmoplasia (57/57), although 37 cases (65%) also expressed HSP47 in the neoplastic epithelium. HSP47 expression was absent in the majority of nonneoplastic pancreata (46 [88%]). Fascin and HSP47 are novel tumor markers with potential diagnostic and therapeutic implications for pancreatic carcinoma. These results establish the usefulness of global expression platforms to identify novel tumor markers.


Classic Firm mass with ill-defined margins
Yellow to white cut surface
2.5-3.5 cm
5-7 cm
5-7 cm
Location Percentage
Multifocal tumors 15-40% of cases
High-Grade Neuroendocrine Carcinoma of the Ampulla of Vater: A Clinicopathologic and Immunohistochemical Analysis of 14 Cases.

Nassar H, Albores-Saavedra J, Klimstra DS.

From *Memorial Sloan-Kettering Cancer Center, New York, NY; and daggerLSU Health Sciences Center, Shreveport, LA.
Am J Surg Pathol. 2005 May;29(5):588-594. Abstract quote  

We describe the clinical and pathologic features of 14 cases of high-grade neuroendocrine carcinoma (HGNEC) of the ampulla of Vater classified according to WHO classification of lung tumors into small cell carcinoma (SCC, 6 cases) and large cell neuroendocrine carcinoma (LCNEC, 8 cases) types.

The immunohistochemical findings were compared with those of 13 cases of primary poorly differentiated ampullary adenocarcinomas (PDACA) lacking neuroendocrine morphology. The mean age of 10 males and 4 females was 70 years. The mean tumor size was 2.5 cm. Ten of 13 patients had lymph node metastases (mean, 2.3 nodes involved). Documented sites of distant metastases included brain and liver. Overall, 64% of patients with ampullary HGNEC died of disease (mean follow-up, 14.5 months). Four patients had no evidence of disease after resection (mean, 20 months). Half of the tumors were associated with adenomas of the adjacent mucosa, 2 with high-grade dysplasia. Two HGNECs were combined with a conventional adenocarcinoma and another with a squamous cell carcinoma component. By immunohistochemistry, the HGNECs were positive for cytokeratins (AE1/AE3, 100%; Cam5.2, 67%; CK7, 87%; CK20, 38%), similar to the pattern found in PDACAs. p27 expression was lost in 1 case of HGNEC and in all PDACAs. Retinoblastoma (Rb) protein expression was lost in 60% of HGNECs and in none of the PDACA cases.

In conclusion, HGNECs of the ampulla are rare (2%-3% of ampullary tumors in our material). The clinical course parallels that of their pulmonary counterparts and appears to be worse than that of locally advanced ampullary adenocarcinomas. The association with adenoma and or conventional adenocarcinoma components may suggest a common pathway in the initial carcinogenesis of these two types of tumors. Loss of Rb expression, a characteristic finding in pulmonary SCCs, is present in almost half of ampullary HGNECs. In contrast, p27 expression is lost in PDACAs and retained in most HGNECs. Thus, there are differences in the molecular phenotypes of these two types of ampullary carcinoma, supporting the distinction of poorly differentiated carcinomas with a neuroendocrine phenotype from those without.



Most are well to moderately differentiated adenocarcinomas which elicit a desmoplastic stromal host response

Often incomplete glandular lumina

Perineural invasion may be prominent

Multifocal Neoplastic Precursor Lesions Associated With Lobular Atrophy of the Pancreas in Patients Having a Strong Family History of Pancreatic Cancer.

Departments of *Pathology daggerMedicine double daggerOncology section signArt as Applied to Medicine musical sharpRadiology **Surgery, and parallelThe Institute for Genomic Medicine, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins Medical Institutions, Baltimore, MD paragraph signDepartment of Pathology, Karmanos Cancer Center, Wayne State University, Detroit, MI.


Am J Surg Pathol. 2006 Sep;30(9):1067-1076 Abstract quote

We screened 116 patients with a strong family history of pancreatic cancer using a combination of endoscopic ultrasound and computed tomography. Ten of these patients underwent surgical resection at our institution, providing an opportunity to define the morphology of pancreatic precursor lesions in patients with a strong family history of pancreatic cancer.

Eight of the 10 pancreata were available and these were entirely submitted for histologic examination. The number of pancreatic intraepithelial neoplasia (PanIN) lesions and intraductal papillary mucinous neoplasms (IPMNs) were compared with age-matched controls. Parenchymal changes were defined. Selected precursor neoplasms from 6 pancreata were microdissected and analyzed for KRAS gene mutations. PanINs were significantly more common in the 8 cases (mean of 10.7% of the duct profiles, range 1.0% to 27.3%) than in the controls (mean 1.9%, range 0% to 9.2%, P<0.01). Different KRAS gene mutations were identified in separately microdissected precursor lesions in 2 of 6 cases. IPMNs were identified in 4 of the 8 cases, including 2 pancreata each having 2 distinct IPMNs. Both the IPMNs and the PanINs, even the low-grade PanIN-1 lesions, were associated with lobular parenchymal atrophy. Some individuals with a strong family history of pancreatic cancer develop multifocal, noninvasive epithelial precursor lesions of the pancreas. PanINs and IPMNs produce obstructive lobular atrophy, and this atrophy is likely the source of the chronic pancreatitis-like changes seen in these patients.

The multifocal nature of familial pancreatic neoplasia suggests that surveillance of these patients is warranted after partial pancreatectomy.
Pancreas head carcinoma: frequency of invasion to soft tissue adherent to the superior mesenteric artery.

Noto M, Miwa K, Kitagawa H, Kayahara M, Takamura H, Shimizu K, Ohta T.

From the Department of Gastroenterologic Surgery, Division of Cancer Medicine, Graduate School of Medical Science, Kanazawa University, Kanazawa, Japan.
Am J Surg Pathol. 2005 Aug;29(8):1056-61. Abstract quote  

Despite radical extension of surgical procedures, the cure rate of pancreatic head carcinoma patients still remains low. A cause of this concerns unsuccessful locoregional control, which may originate from a positive surgical margin near the superior mesenteric artery (SMA). However, no studies have examined invasion of pancreatic carcinoma around the SMA.

En bloc resection of the head of the pancreas and the superior mesenteric vessels was performed on 6 patients who had pancreatic head carcinoma invading the superior mesenteric vein. The specimens were cut perpendicular to the SMA and consecutive serial sections were made. The slices were stained with hematoxylin and eosin or immunohistochemistry for cytokeratin 19 to easily detect carcinoma tissue under a microscope. Nodal metastasis around the SMAs was found in all of the cases.

There were no characteristics of the arrangement of the metastatic nodes along the SMA. Lymphatic emboli were often observed close to the metastatic nodes. Neural invasions were detected around the tumors in every case and were continuously connected with the extrapancreatic nerve plexus. The nerve plexus covering the SMA were involved in 4 cases. Involvement was observed mainly behind the SMA, reaching as far as the left side of the SMA in 3 cases.

The invasion extended further upwards along the right side of SMA for the celiac nerve plexus. The lymphatics and the nerve plexus in the area around the SMA were frequently involved by pancreatic head carcinoma. This involvement would have been left behind unless the SMA was resected.
Pancreas head carcinoma: frequency of invasion to soft tissue adherent to the superior mesenteric artery.

Noto M, Miwa K, Kitagawa H, Kayahara M, Takamura H, Shimizu K, Ohta T.

From the Department of Gastroenterologic Surgery, Division of Cancer Medicine, Graduate School of Medical Science, Kanazawa University, Kanazawa, Japan.
Am J Surg Pathol. 2005 Aug;29(8):1056-61. Abstract quote  

Despite radical extension of surgical procedures, the cure rate of pancreatic head carcinoma patients still remains low. A cause of this concerns unsuccessful locoregional control, which may originate from a positive surgical margin near the superior mesenteric artery (SMA). However, no studies have examined invasion of pancreatic carcinoma around the SMA.

En bloc resection of the head of the pancreas and the superior mesenteric vessels was performed on 6 patients who had pancreatic head carcinoma invading the superior mesenteric vein. The specimens were cut perpendicular to the SMA and consecutive serial sections were made. The slices were stained with hematoxylin and eosin or immunohistochemistry for cytokeratin 19 to easily detect carcinoma tissue under a microscope. Nodal metastasis around the SMAs was found in all of the cases.

There were no characteristics of the arrangement of the metastatic nodes along the SMA. Lymphatic emboli were often observed close to the metastatic nodes. Neural invasions were detected around the tumors in every case and were continuously connected with the extrapancreatic nerve plexus. The nerve plexus covering the SMA were involved in 4 cases. Involvement was observed mainly behind the SMA, reaching as far as the left side of the SMA in 3 cases.

The invasion extended further upwards along the right side of SMA for the celiac nerve plexus. The lymphatics and the nerve plexus in the area around the SMA were frequently involved by pancreatic head carcinoma. This involvement would have been left behind unless the SMA was resected.

Mixed acinar-endocrine carcinoma arising in the ampulla of Vater.

Moncur JT, Lacy BE, Longnecker DS.

Department of Pathology, Walter Reed Army Medical Center, Washington, DC; the Department of Digestive Diseases, Johns Hopkins Bayview Medical Center, Baltimore, MD, and the Department of Pathology, Dartmouth Hitchcock Medical Center, Lebanon, NH.

Hum Pathol 2002 Apr;33(4):449-51 Abstract quote

We present a case of mixed acinar-endocrine carcinoma arising in the periampullary region of the duodenum. The patient was a 78-year-old male with a periampullary mass diagnosed during upper endoscopy.

On gross dissection, the mass was 2.3 cm in diameter, noncystic, and confined to the duodenal submucosa. Microscopically, the tumor formed nests that were positive for amylase, trypsin (weakly), and synaptophysin (diffusely). Ultrastructurally, the tumor had 2 populations of granules with mean diameters of 175 nm and 540 nm, consistent with endocrine and zymogen granules, respectively. These studies were consistent with a mixed acinar-endocrine carcinoma that arose in the duodenum. A review of the literature revealed 1 report of an acinar cell carcinoma arising in jejunal pancreatic heterotopia.

The present article is the first reported case of an acinar cell carcinoma arising in the periampullary region of the duodenum, possibly in a focus of pancreatic heterotopia.

ADENOSQUAMOUS (Mucoepidermoid carcinoma, adenoacanthoma)  
Adenosquamous Carcinoma Of The Pancreas: A Clinicopathologic Series Of 25 Cases David E. Kardon, etal.

Mod Pathol 2001;14:443-451 Abstract quote

Background: Adenosquamous carcinoma is a rare aggressive subtype of pancreatic adenocarcinoma. We describe the clinical, pathologic, and molecular characteristics of 25 of these lesions, the largest series to date.

Methods: Twenty-five cases of adenosquamous carcinoma of the pancreas diagnosed between 1961 and 1994 were retrieved from the files of the Endocrine Registry of the Armed Forces Institute of Pathology. Histologic features were reviewed, histochemical, immunohistochemical, and molecular (k-ras) studies were performed, and patient follow-up was obtained.

Results: The patients included 17 men and eight women, aged 28 to 82 years (mean, 65.4 y). The patients usually experienced weight loss (n = 17) or painless jaundice (n = 11), while also presenting with other abdominal symptoms. The tumors affected the head most frequently (n = 17), followed by the tail (n = 9) or body (n = 4). Five cases involved more than one anatomic region of the pancreas. Microscopically, all tumors demonstrated dual differentiation toward adenocarcinoma and squamous cell carcinoma. All cases tested were immunoreactive with keratin (AE1:AE3 and CK1), whereas other keratin markers were variably expressed: CK5/6 (88%), CK7 (68%), Cam5.2 (41%), and CK20(26%). CA-19–9 (84%) and CEA (74%) were positive in the majority of the cases. K-ras oncogene mutations were identified in seven of 13 cases. All patients died from their disease an average of 5.8 months after diagnosis (range, 1 to 33 months).

Conclusions: Adenosquamous carcinoma of the pancreas represents a distinct clinical and pathologic entity, demonstrating the expected immunoprofile and k-ras oncogene mutation of a ductal origin, with a worse prognosis than ductal adenocarcinoma.


Colloid (Mucinous Noncystic) Carcinoma of the Pancreas N.

Volkan Adsay, M.D.; Christopher Pierson, M.D.; Fazlul Sarkar, Ph.D.; Judith Abrams, Ph.D.; Donald Weaver, M.D.; Kevin C. Conlon, M.D.; Murray F. Brennan, M.D.; David S. Klimstra, M.D.

From the Departments of Pathology (N.V.A., C.P., F.S.), Surgery (D.W.), and Biostatistics (J.A.) of the Karmanos Cancer Institute, Harper Hospital, Detroit Medical Center, Wayne State University School of Medicine, Detroit, Michigan, U.S.A.; and the Departments of Pathology (D.S.K.) and Surgery (K.C.C., M.F.B.) of Memorial Sloan-Kettering Cancer Center, New York, NY, U.S.A.

Am J Surg Pathol 2001;25:26-42 Abstract quote

In the past, colloid (mucinous noncystic) carcinoma (CC) of the pancreas had been included under the category of ordinary ductal adenocarcinoma, a tumor with a dismal prognosis, or was frequently misdiagnosed as mucinous cystadenocarcinoma. The clinicopathologic features of CC have not yet been well characterized, because most cases on record have been parts of studies on either mucinous cystic neoplasms (MCN) or intraductal papillary mucinous neoplasms (IPMN), with which colloid carcinomas are frequently associated.

To determine the clinicopathologic characteristics of CC, 17 pancreatic tumors composed predominantly (>80%) of CC (defined as nodular extracellular mucin lakes with scanty malignant epithelial cells) and in which the invasive carcinoma measured larger than 1 cm were studied. Ten of these were originally classified as mucinous ductal adenocarcinoma and four as mucinous cystadenocarcinoma.

The mean age of the patients was 61 years; 9 were men and 8 were women. The mean size of the CC was 5.3 cm (range, 1.2–16 cm). In more than half of the patients, CC represented the invasive component of an IPMN (in nine cases) or MCN (in one case). The tumors were composed of well-defined pools of mucin with sparse malignant cells in various patterns of distribution. Signet-ring cells floating in the mucin (but not as individual cells infiltrating stroma, a characteristic finding of signet-ring cell adenocarcinomas) were commonly identified and were prominent in five cases. Perineurial invasion was noted in six cases and regional lymph node metastases in eight. Mutation in codon 12 of the k-ras gene was detected in only 4 of 12 cases studied and p53 mutation in 2 of 9. Immunohistochemical and histochemical mucin stains suggested luminalization of the basal aspects of the cells.

Five-year survival was 57%. At an overall mean follow up of 57 months, 10 patients were alive with no evidence of disease (median, 79 mos), including four with lymph node metastasis, three others with perineurial invasion, and another with vascular invasion. Four patients died of disease (18, 18, 25, and 26 mos), and three died of thromboembolism (with persistent disease) at 2, 5, 10 months. All seven patients who died with or of tumor had undergone incisional biopsy of the tumor either before the operation or intraoperatively, whereas none of the patients who were alive had incisional biopsy. When compared with 82 cases of resectable ordinary ductal adenocarcinoma on whom follow-up and staging information was complete, it was found that the patients with CC present with larger tumors (p = 0.03) but lower stage (p = 0.01). The prognosis of CC is significantly better: 2-year and 5-year survival are 70% versus 28% and 57% versus 12%, respectively (p = 0.001). In conclusion, pancreatic CC may occur with or without an identifiable IPMN and MCN component, and should be distinguished from mucinous cystadenocarcinoma, ordinary ductal adenocarcinoma, and signet-ring cell adenocarcinoma. CC of the pancreas is associated with a significantly better prognosis than ordinary ductal adenocarcinoma. In addition to its distinctive morphologic and clinical characteristics, CC of the pancreas also appears to have a low incidence of mutation in codon 12 of the k-ras gene.

In cases with a clinical suspicion of colloid carcinoma, the possibility that an incisional biopsy may contribute to thromboembolic complications or even dissemination of the tumor may need to be considered. The luminalization of the basal aspects of the tumor cells may be the cause of stromal mucin accumulation that characterizes colloid carcinoma and may act as a containing factor.

Almost All Infiltrating Colloid Carcinomas of the Pancreas and Periampullary Region Arise From In Situ Papillary Neoplasms A Study of 39 Cases

Gregory Seidel, M.D. ; Marianna Zahurak, M.S. ; Christine Iacobuzio-Donahue, M.D. , Ph.D. ; Taylor A. Sohn, M.D. ; N. Volkan Adsay, M.D. ; Charles J. Yeo, M.D. ; Keith D. Lillemoe, M.D. ; John L. Cameron, M.D. ; Ralph H. Hruban, M.D. ; Robb E. Wilentz, M.D.

From the Departments of Pathology (G.S., C.I.-D., R.H.H., R.E.W.), Oncology (M.Z., C.J.Y., R.H.H.), and Surgery (T.A.S., C.J.Y., K.D.L., J.L.C.), Johns Hopkins Medical Institutions, Baltimore, Maryland; and the Department of Pathology (N.V.A.), Karmanos Cancer Institute-Wayne State University, Detroit, Michigan, U.S.A

Am J Surg Pathol 2002;26:56-63 Abstract quote

Colloid carcinomas of organs such as the breast, colon, and prostate have been well characterized. However, up until now there have been only a few studies of colloid carcinomas of the pancreas and periampullary region, and the number of colloid carcinomas in these studies has been limited.

A search of our files revealed 39 resections for pancreatic and periampullary carcinomas with colloid differentiation. All neoplasms were extensively sampled. “Carcinomas with colloid differentiation” were defined as tumors associated with abundant extracellular mucin containing free-floating mucinous epithelial cells. Cases with >50% colloid differentiation were classified as “colloid carcinomas,” whereas those with less were termed “carcinomas with focal colloid features.” Cases with no colloid differentiation at all were designated “carcinomas without colloid differentiation.”

Of the 39 carcinomas, 31 were colloid carcinomas, and eight were carcinomas with focal colloid features. Twenty-seven were centered in the pancreas, seven were in the duodenum, and five were in the ampulla of Vater. Remarkably, 38 of the 39 carcinomas (97%) arose in association with an intraductal papillary mucinous neoplasm or a tubular/tubulovillous adenoma. Of the patients with colloid carcinomas, the 2-and 5-year actuarial survival rates were 69% and 29%, respectively. There was no significant difference in survival rates between patients with colloid carcinomas and patients with adenocarcinomas without colloid differentiation, whether or not the latter arose in association with intraductal papillary mucinous neoplasms or tubular/tubulovillous adenomas.

In a multivariate model colloid differentiation was not an independent predictor of patient survival, while other factors such as tumor location, perineural invasion, vascular invasion, and margin status after resection independently influenced patient survival. Most colloid carcinomas of the pancreas and periampullary region arise in association with a well-defined in situ papillary neoplasm.

The diagnosis of a pancreatic or periampullary colloid carcinoma should encourage the pathologist to search for an associated low-grade in situ component. In addition, colloid carcinomas of the pancreas and periampullary region do not necessarily have a better prognosis than carcinomas without colloid differentiation. Instead, other factors such as tumor location, perineural invasion, vascular invasion, and margin status after resection are far more important.

Pancreatic ductal adenocarcinomas with cystic features: neither rare nor uniform.

Kosmahl M, Pauser U, Anlauf M, Kloppel G.

1Department of Pathology, University of Kiel, Germany.

Mod Pathol. 2005 Sep;18(9):1157-64. Abstract quote  

Cystic tumors of the pancreas are uncommon but important because of their diverse pathology and biology. Their wide spectrum also includes cystic variants of otherwise solid tumors, such as cystic endocrine tumors, cystic acinar cell carcinomas and ductal adenocarcinomas with cystic changes.

In this study, we screened pancreatic ductal adenocarcinomas and their variants for macrocystic changes and determined the nature of the cysts (neoplastic vs non-neoplastic). Of 483 tumors 38 (8%) had cystic features. The largest group consisted of 24 pancreatic ductal adenocarcinomas showing a large-gland pattern with small cysts whose diameter varied between 0.5 and 1.8 cm. The epithelial lining of these cysts was generally positive for CEA (83%) and/or MUC1 (71%) and MUC5AC (74%). p53 was positive in 57% of the cases. The second group of cystic tumors (8/483) showed degenerative cystic cavities with diameters ranging between 1 and 6 cm. This group consisted of poorly differentiated pancreatic ductal adenocarcinomas, undifferentiated carcinomas with or without osteoclast-like giant cells and one adenosquamous carcinoma. In the third group of cystic tumors there were four pancreatic ductal adenocarcinomas containing tumor-related retention cysts. Their epithelial cells were positive for MUC5AC, but negative for CEA, MUC1 and p53. The fourth group consisted of two pancreatic ductal adenocarcinomas showing closely attached pseudocysts caused by tumor-associated pancreatitis.

The results indicate that a considerable number of pancreatic ductal adenocarcinomas and their variants display cystic features and must therefore be considered in the differential diagnosis of cystic neoplasms of the pancreas. Moreover, not all of the cystic structures we observed were neoplastic in nature. They may also represent non-neoplastic changes, such as retention cysts and inflammatory pseudocysts.
The Cytology of Pancreatic Foamy Gland Adenocarcinoma

Edward B. Stelow, MD, etal.
Am J Clin Pathol 2004;121:893-897 Abstract quote

All cell block specimens from pancreatic fine-needle aspirations (FNAs) obtained between January 1, 2002, and June 30, 2003, were reviewed for foamy gland adenocarcinoma (FGA). All smears from these cases were reviewed for cytologic features, including those previously noted in conventional pancreatic adenocarcinoma.

Fifty-two cell block specimens showed adenocarcinoma. Of these, 12 (23%) showed histologic features of FGA. This pattern predominated in 6 cases and was present focally in 6 cases. Although there were relatively low nuclear/cytoplasmic (N/C) ratios, other features of adenocarcinoma were present universally, including loss of cohesiveness, nuclear overlap or loss of "honeycomb" architecture, anisonucleosis (>4 to 1), irregular nuclear contours, prominent nucleoli, and atypical chromatin. Background necrosis was present in 8 cases. Distinct cell borders were present in 9 cases, and foamy cytoplasm was present in all cases.

Pancreatic FGA is a recently described histologic pattern of pancreatic adenocarcinoma. It is not uncommon, and we identified the pattern, at least focally, in 23% of our FNA cell blocks. Although cytologic samples show low N/C ratios, most cytologic features of conventional pancreatic adenocarcinoma are present, and the diagnosis presents little additional difficulty.

Foamy Gland Pattern of Pancreatic Ductal Adenocarcinoma A Deceptively Benign-Appearing Variant

Volkan Adsay, M.D.; Sanjay Logani, M.D.; Fazlul Sarkar, Ph.D.; John Crissman, M.D.; Vainitus Vaitkevicius, M.D.

From The Departments of Pathology and Internal Medicine (V.V.), The Karmanos Cancer Institute, Harper Hospital, Detroit Medical Center, Wayne State University, Detroit, Michigan, U.S.A.

Am J Surg Pathol 2000;24:493-504 Abstract quote

Pathologic diagnosis of pancreatic adenocarcinoma is frequently a challenge, particularly in small biopsies, frozen sections, and in metastatic foci. Here we report a deceptively benign-appearing and morphologically distinctive pattern of ductal adenocarcinoma with prominent microvesicular cytoplasm, giving the cells a foamy appearance similar to that described in the prostate (Am J Surg Pathol 1996;20:419). This variant, which we refer to as foamy gland pattern (FGP), was frequently misdiagnosed in frozen sections or biopsies and its pathologic stage underestimated in surgical specimens.

Histologically, the diagnostic features were: (1) white and crisply foamy, ``microvesicular'' cytoplasm; (2) often basally located and compressed, hyperchromatic nuclei reminiscent of endocervical glands (and so-called ``adenoma malignum'') or gastric foveolar glands; (3) irregular nuclear contours forming wrinkled (raisinoid) nuclei in some areas; and (4) a distinctive chromophilic condensation of the cytoplasmic material in the luminal aspect of the cells forming a brush border-like zone (BLZ).

Histochemically, this BLZ was positive for mucicarmine, alcian blue, and high iron diamine, but not PAS. The remainder of the cytoplasm was negative for all these stains. In contrast, benign mucinous ducts, which constitute the major differential diagnosis, had more homogeneous acidophilic cytoplasm, lacked BLZ, and showed cytoplasmic staining with PAS.

Immunohistochemically, the tumor cells were diffusely and strongly positive for CEA and cytokeratin 8 whereas B72.3 staining was focal and weak. MUC1 staining was largely confined to the BLZ. MUC2 was negative. P53 staining was detected in 16 of the 20 cases studied and was strong and diffuse in five. K-ras mutation was detected in 6 of 8 cases studied.

The clinical findings in the 20 patients in this study (4 pure and 16 mixed with usual ductal carcinoma) did not appear to differ significantly from those of ordinary ductal adenocarcinoma of the pancreas. Eleven patients were men and nine were women; the mean age was 62 years and the mean tumor size was 4.4 cm.

Follow-up information was available in 17 patients of whom 7 were alive at an average follow up of 23 months (range, 7–104 mos), and 10 were dead of disease at a median follow up of 15 months (range, 4–42 mos). The median survival of the four patients with pure FGP was 18 months. The median survival did not appear to be significantly longer than that of the patients with resectable ordinary ductal adenocarcinoma in the authors' experience (109 patients, median survival of 12 mos, p = 0.48).

In conclusion, foamy gland pattern of invasive pancreatic ductal carcinoma is morphologically distinctive and is prone to misdiagnosis as a benign process. The pathologic stage is often underestimated as a result of the lack of its recognition and misinterpretation as mucinous ducts. Careful attention to its microscopic features is adequate for accurate diagnosis. Histochemical and immunohistochemical stains are useful in confirming the diagnosis of malignancy in challenging cases.


Invasive micropapillary carcinomas of the ampullo-pancreatobiliary region and their association with tumor-infiltrating neutrophils.

Khayyata S, Basturk O, Adsay NV.

1Department of Pathology, The Karmanos Cancer Institute and Harper University Hospital, Wayne State University, Detroit, MI, USA.

Mod Pathol. 2005 Nov;18(11):1504-11. Abstract quote  

Invasive micropapillary carcinoma, originally described as a distinctive type of invasive carcinoma in the breast, is being increasingly recognized as a separate entity in many other organs; however, it has not yet been documented in the pancreas or periampullary region. In this study, 313 pancreatic and 73 periampullary carcinomas were reviewed to investigate the micropapillary pattern in this location. Eight periampullary and eight pancreatic cases (4%) were composed at least focally (>20%) of invasive micropapillary carcinoma.

The patients were 10 males and six females, mean age 69 years. The mean tumor size was 3.2 cm. Lymph node metastasis was detected in 11/15 cases. The median survival was 8 months (all were resected). Invasive micropapillary carcinoma was characterized by small, closely packed micropapillary clusters (without fibrovascular cores) lying within clefts. The cells had moderate degree of nuclear atypia. In nine cases, there was abundant inflammation composed of neutrophils concentrating around the tumor cells, both intraepithelial ('cannibalism') and stromal. Molecules implicated in abnormalities of tumor cell-stroma adhesion, galectin-3 and E-cadherin were expressed in the cytoplasm of 11/11 and 9/11 cases, respectively. Reversal of cell polarity was observed by MUC 1 in all 11 cases tested, which showed labeling in the stroma-facing surfaces of the micropapillary clusters, also confirming that the clefts are not merely a processing artifact, but indeed a true biologic alteration.

In conclusion, invasive micropapillary carcinoma constitutes 4% of carcinomas in the pancreatic/periampullary region and is commonly associated with abundant neutrophilic infiltrates. Invasive miropapillary carcinoma appears to be more common in periampullary than in pancreatic invasive micropapillary carcinoma would qualify as poorly differentiated both based on pattern and the median survival (8 months).
The Prevalence of Pancreatic Intraepithelial Neoplasia in Pancreata With Uncommon Types of Primary Neoplasms.

Stelow EB, Adams RB, Moskaluk CA.

From the Departments of *Pathology and daggerSurgery, University of Virginia, Charlottesville, VA.

Am J Surg Pathol. 2006 Jan;30(1):36-41. Abstract quote  

Pancreatic ductal adenocarcinoma is thought to develop through a series of genetic events through its purported precursor lesion, pancreatic intraepithelial neoplasia (PanIN). Little, however, is known regarding the role of possible precursor lesions in the development of other primary neoplasms of the pancreas.

This study investigated the prevalence of PanIN, as defined by recent consensus statements, in pancreata with uncommon types of primary neoplasms. All pancreata resected at the University of Virginia from June 1, 1991 to March 1, 2005 for neoplasia not diagnosed as conventional ductal adenocarcinoma were reviewed and classified according to the World Health Organization's classification schema for tumors of the exocrine and endocrine pancreas. All slides from these cases were then assessed for PanIN, which was classified according to the criteria of the most recent consensus statement. Three acinar cell carcinomas (ACCs), 18 mucinous cystic neoplasms (MCNs), 24 pancreatic endocrine tumors (PETs), 12 serous cystadenomas (SCs), and 3 solid-pseudopapillary tumors (SPTs) were identified. PanIN was identified in the pancreata of 3 of 3 ACCs, 17 of 18 MCNs, 16 of 24 PETs, 10 of 12 SCs, and 2 of 3 SPTs. The degree of PanIN was noted to trend with patient age.

Although the high prevalence of PanIN in pancreata concomitantly harboring certain uncommon neoplasms of the pancreas could signify its role as a precursor lesion for those neoplasms, its high prevalence throughout our series may simply be the result of a coincidental, prevalent finding seen in all pancreata, especially with aging. Because of the ubiquitous nature of PanIN, it should not be used histologically to assist in the diagnosis and subclassification of pancreatic neoplasia.
An Illustrated Consensus on the Classification of Pancreatic Intraepithelial Neoplasia and Intraductal Papillary Mucinous Neoplasms.

Hruban RH, etal.
Am J Surg Pathol. 2004 Aug;28(8):977-987. Abstract quote

Invasive pancreatic ductal adenocarcinoma is an almost uniformly fatal disease. Several distinct noninvasive precursor lesions can give rise to invasive adenocarcinoma of the pancreas, and the prevention, detection, and treatment of these noninvasive lesions offers the potential to cure early pancreatic cancers.

Noninvasive precursors of invasive ductal adenocarcinoma of the pancreas include pancreatic intraepithelial neoplasias (PanINs), intraductal papillary mucinous neoplasms (IPMNs), and mucinous cystic neoplasms. Diagnostic criteria, including a distinct ovarian-type stroma, and a consistent nomenclature are well established for mucinous cystic neoplasms. By contrast, consistent nomenclatures and diagnostic criteria have been more difficult to establish for PanINs and IPMNs. Because both PanINs and IPMNs consist of intraductal neoplastic proliferations of columnar, mucin-containing cells with a variable degree of papilla formation, the distinction between these two classes of precursor lesions remains problematic. Thus, considerable ambiguities still exist in the classification of noninvasive neoplasms in the pancreatic ducts.

A meeting of international experts on precursor lesions of pancreatic cancer was held at The Johns Hopkins Hospital from August 18 to 19, 2003. The purpose of this meeting was to define an international acceptable set of diagnostic criteria for PanINs and IPMNs and to address a number of ambiguities that exist in the previously reported classification systems for these neoplasms.

We present a consensus classification of the precursor lesions in the pancreatic ducts, PanINs and IPMNs.

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.

Sharma S, Green KB.

Department of Pathology, Emory University Hospital, Atlanta, GA.
Am J Surg Pathol. 2004 May;28(5):613-20. Abstract quote  

Pancreatic intraepithelial neoplasia (PanIN) may be difficult to differentiate from isolated glands of pancreatic adenocarcinoma.

We studied the normal relationship between the pancreatic ducts and the pancreatic muscular blood vessels in 126 pancreata, 64 of which were removed for pancreatic adenocarcinoma and 62 for other diagnoses. We also examined the effects that atrophy and PanIN have on this relationship.

In normal pancreatic parenchyma and in mild to moderate atrophy, blood vessels are guideposts of the interlobular space. The pancreatic acinar parenchyma ensheathes the pancreatic ductal system and separates it from the muscular pancreatic vasculature. Since these blood vessels do not accompany the pancreatic ducts, the presence of a well-differentiated duct-like structure, which may resemble PanIN, located adjacent to a pancreatic blood vessel should be a clue to the infiltrative and hence malignant nature of that gland. Ducts showing PanIN appear to resist atrophy. Since lobular outlines and vascular landmarks are ultimately lost in severe atrophy, they cannot be relied on to aid in the distinction between PanIN and invasive carcinoma.

However, it is unusual to see PanIN1 in such severe atrophy (2%), and although the normal vascular landmarks are no longer there to aid in the interpretation, the presence of well-differentiated duct-like structures resembling PanIN1 in this background should be viewed with suspicion for well-differentiated adenocarcinoma.

p16 Inactivation in pancreatic intraepithelial neoplasias (PanINs) arising in patients with chronic pancreatitis.

Rosty C, Geradts J, Sato N, Wilentz RE, Roberts H, Sohn T, Cameron JL, Yeo CJ, Hruban RH, Goggins M.

Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, Maryland 21205, USA.

Am J Surg Pathol. 2003 Dec;27(12):1495-501. Abstract quote  

Patients with long-standing chronic pancreatitis are thought to be at increased risk of developing pancreatic ductal adenocarcinoma, but the mechanism for this increased risk is unknown. Since increasing evidence supports the notion that infiltrating pancreatic ductal adenocarcinomas arise from pancreatic intraepithelial lesions (PanINs), we sought to determine if patients with chronic pancreatitis harbor PanINs with alterations in tumor suppressor genes that are associated with infiltrating pancreatic ductal adenocarcinoma.

We identified 122 patients with a diagnosis of chronic pancreatitis and 29 patients with a well-differentiated pancreatic endocrine tumor that underwent pancreatic surgery at the Johns Hopkins Hospital from 1985 to 1999. PanINs from each resection specimen were identified, graded, counted, and correlated with smoking and alcohol history. The expression patterns of p16 and Smad4 were determined in a subset of PanINs by immunohistochemistry, and the pattern of labeling compared with that seen in PanINs associated with infiltrating adenocarcinoma of the pancreas as identified in prior studies, and to PanINs associated with pancreatic endocrine tumor.

Duct lesions were present in 80 of the 122 pancreata with chronic pancreatitis (66%). Of 405 duct lesions identified in the chronic pancreatitis group, 7.6% were reactive changes, 65.5% were PanIN-1A, 18% were PanIN-1B, 7.4% were PanIN-2, and 1.5% were PanIN-3. Within the pancreatic endocrine tumor group, 22 PanINs were identified: 15 PanIN-1A, 4 PanIN-1B, and 3 PanIN-2. There were significantly fewer high-grade PanINs in the pancreata with chronic pancreatitis than in pancreata with pancreatic adenocarcinoma (P < 0.0001). Within the chronic pancreatitis group, the 80 patients with PanINs were significantly older than the 42 patients without PanINs (mean age 57.0 +/- 14.1 years vs. 50.9 +/- 14.7 years, P = 0.01). Smoking history was not associated with PanIN prevalence or grade, but patients who reported a history of excessive alcohol consumption had fewer PanINs (25 of 44 harbored PanINs, 57%) than those who did not (54 of 74, 73%, P = 0.07). In the chronic pancreatitis group, 0% of PanIN-1A, 11% of the PanIN-1B, 16% of the PanIN-2, and 40% of the PanIN-3 lesions showed loss of p16 expression, whereas all of the PanINs from patients with an pancreatic endocrine tumor retained p16 expression. All of the PanINs analyzed from patients with chronic pancreatitis retained normal Smad4 expression.

We conclude that a significant minority of PanINs arising in patients with chronic pancreatitis show loss of p16 expression. This alteration, common to pancreatic cancer-associated PanINs, may contribute to the predisposition of patients with chronic pancreatitis to develop pancreatic ductal adenocarcinoma.

Clinicopathological correlates of pancreatic intraepithelial neoplasia: a comparative analysis of 82 cases with and 152 cases without pancreatic ductal adenocarcinoma.

Andea A, Sarkar F, Adsay VN.

Department of Pathology, Harper Hospital,Wayne State University School of Medicine, Detroit, Michigan 48201, USA.

Mod Pathol. 2003 Oct;16(10):996-1006. Abstract quote  

Pancreatic intraepithelial neoplasia is often associated with pancreatic ductal adenocarcinoma and is presumed to be its precursor. It has been difficult to determine the frequency of these lesions because until recently, there was no consensus regarding the terminology and criteria for their grading. Here we compare the frequency and clinical correlates of pancreatic intraepithelial neoplasia in pancreata involved by ductal adenocarcinoma and in benign ones, using the criteria put forward recently.

We evaluated pancreatectomy specimens from 82 patients with ductal adenocarcinoma and 152 patients who underwent pancreatectomy for reasons other than primary malignancy (trauma, pancreatitis, and metastatic tumor to pancreas) for the presence, grade, and number of foci of pancreatic intraepithelial neoplasia. Cases were graded by the highest grade of pancreatic intraepithelial neoplasia focus identified. An average of 5.3 sections of pancreas was available for evaluation (range, 1-28 sections). Overall, the frequency of pancreatic intraepithelial neoplasia lesions in ductal adenocarcinoma patients, including Grade 1A (mucinous duct lesions), was 82%, which was significantly higher than the one in benign pancreata -54%, P <.001. There was a progressive increase from normal pancreata to pancreatitis and to ductal adenocarcinoma in the frequency of overall pancreatic intraepithelial neoplasia lesions (16%, 60%, and 82%, respectively) and Grade 3 pancreatic intraepithelial neoplasia (0%, 4%, and 40%, respectively). In most instances, in any given case of higher-grade pancreatic intraepithelial neoplasia lesion, there were also several foci of lower grade lesions.

The frequency of higher-grade pancreatic intraepithelial neoplasia lesions (2 and 3) in pancreata resected for ductal adenocarcinoma was 59%, significantly higher than in those without primary carcinoma (17%). This progressive increase in frequency of pancreatic intraepithelial neoplasia from incidental pancreatectomies (presumed to have a nonpathologic pancreas) to pancreatitis (considered a risk factor for carcinoma) and to ductal adenocarcinoma constitutes an indirect support for the precancerous role attributed to pancreatic intraepithelial neoplasia lesions.

The relatively high absolute occurrence of pancreatic intraepithelial neoplasia Grade 1A (mucinous duct lesions) in benign conditions (43%) suggests that this group represents a combination of neoplastic and non-neoplastic lesions.

Pancreatic Intraepithelial Neoplasia A New Nomenclature and Classification System for Pancreatic Duct Lesions

Ralph H. Hruban, etal.

Am J Surg Pathol 2001;25:579-586 Abstract quote

Proliferative epithelial lesions in the smaller caliber pancreatic ducts and ductules have been the subject of numerous morphologic, clinical, and genetic studies; however, a standard nomenclature and diagnostic criteria for classifying these lesion have not been established.

To evaluate the uniformity of existing systems for grading duct lesions in the pancreas, 35 microscopic slides with 35 representative duct lesions were sent to eight expert pathologists from the United States, Canada, and Europe. Kappa values for interobserver agreement could not be calculated initially because more than 70 different diagnostic terms were used by the eight pathologists. In several cases, the diagnoses rendered for a single duct lesion ranged from ``hyperplasia,'' to ``metaplasia,'' to ``dysplasia,'' to ``carcinoma in situ.'' This review therefore demonstrated the need for a standard nomenclature and classification system.

Subsequently, during a working group meeting, the pathologists agreed to adopt a single standard system. The terminology pancreatic intraepithelial neoplasia (or PanIN) was selected, and diagnostic criteria for each grade of PanIN were established (http://pathology.jhu.edu/pancreas_panin). This new system was then evaluated by having the eight pathologists rereview the original 35 cases. Only seven different diagnoses were rendered, and kappa values of 0.43, 0.14, and 0.42 were obtained for PanINs 1, 2, and 3 respectively. Cases assigned other diagnoses (e.g., squamous metaplasia) collectively had a kappa value of 0.41. These results show both the potential of the classification system, and also the difficulty of classifying these lesions even with a consistent nomenclature. However, even when there is lack of consensus, having a restricted set of descriptions and terms allows a better understanding of the reasons for disagreement.

It is suggested that we adopt and apply this system uniformly, with continued study of its reliability and use, and possibly further refinement. The acceptance of a standard classification system will facilitate the study of pancreatic duct lesions, and will lead ultimately to a better understanding of their biologic importance.

Pancreatic intraepithelial neoplasia and infiltrating adenocarcinoma: Analysis of progression and recurrence by DPC4 immunohistochemical labeling

Denis M. McCarthy, MD, Daniel J. Brat, MD, Robb E. Wilentz, MD, Charles J. Yeo, MD, John L. Cameron, MD, Scott E. Kern, MD, and Ralph H. Hruban, MD

Hum Pathol 2001;32:638-642 Abstract quote

Pancreatic intraepithelial neoplasia (PanIN) is thought to be a precursor lesion of infiltrating pancreatic ductal adenocarcinoma (IPA). DPC4 is a tumor-suppressor gene on chromosome 18q21.1 and is inactivated in approximately 55% of IPAs. Recently, immunohistochemical labeling using a monoclonal antibody to the Dpc4 protein has been shown to mirror DPC4 genetic status in invasive adenocarcinomas of the pancreas.

In the present study, we examined the role of Dpc4 loss in neoplastic progression and recurrence. Two cases in which a PanIN clinically progressed to an invasive adenocarcinoma and a third of a patient with IPA of the head of the pancreas who later developed invasive adenocarcinoma in the tail of the pancreas were studied using Dpc4 immunolabeling. The first patient underwent pancreatic resection, which revealed PanIN-3 that lacked Dpc4 expression, and the patient developed an invasive pancreatic ductal carcinoma 10 years later that shared this loss of expression. The second patient had a pancreaticoduodenectomy for recurrent pancreatitis, and the resected pancreas contained PanIN-3 with intact Dpc4 expression. Seventeen months later, the patient developed an invasive adenocarcinoma of the distal pancreas that also had intact Dpc4 expression. In the third case, the patient underwent pancreaticoduodenectomy for an invasive ductal adenocarcinoma with negative margins. This carcinoma lacked Dpc4 expression. Three years later, resection of the pancreatic tail showed a second invasive adenocarcinoma. The cancer in the tail of the gland showed intact Dpc4 expression, suggesting it represented a second primary tumor, not a recurrence.

We conclude that Dpc4 expression in PanIN can be predictive of Dpc4 expression in the subsequent invasive ductal adenocarcinoma. Additionally, Dpc4 expression can be used to differentiate recurrent or persistent adenocarcinoma from a second primary adenocarcinoma.

Direct correlation between proliferative activity and dysplasia in pancreatic intraepithelial neoplasia (PanIN): additional evidence for a recently proposed model of progression.

Klein WM, Hruban RH, Klein-Szanto AJ, Wilentz RE.

Department of Pathology, The Johns Hopkins Medical Institutions, Baltimore, Maryland 21205, USA.

Mod Pathol 2002 Apr;15(4):441-7 Abstract quote

A growing body of morphological, clinical, and genetic observations suggests a progression model for pancreatic ductal adenocarcinoma.

In this model, pancreatic ducts progress through a series of architectural and cytological changes that define degrees of pancreatic intraepithelial neoplasia (PanIN). Expressed in dividing cells, Ki-67 has been extensively used as a proliferation marker. Its expression in different grades of PanIN has not been well studied. A total of 76 PanINs from 41 patients were histologically graded according to recently established criteria. These PanINs were then immunolabeled with a monoclonal antibody against Ki-67 (Mib-1). Normal ducts and invasive ductal adenocarcinomas were also labeled with the antibody. In 15 normal ducts, only 0.41% of the epithelial cells expressed Ki-67. Ki-67-labeling indices in the increasing grades of PanIN were as follows: PanIN-1A, 0.69%; PanIN-1B, 2.33%; PanIN-2, 14.08%; and PanIN-3, 22.01%. Fifteen invasive ductal adenonocarcinomas showed an average labeling index of 36.99%.

The difference in Ki-67 labeling among these groups was statistically significant (P <.0005, Kruskal-Wallis test). This pattern of proliferation provides additional evidence supporting the recently proposed pancreatic progression model. It also correlates well with known molecular changes, such as activating point mutations in the K-ras oncogene and the loss of DPC4 and p16 gene expression. Ki-67 staining may be useful as an adjunct in the diagnosis of precancerous lesions in the pancreas and may provide a reliable way to identify lesions at high risk for the subsequent development of infiltrating carcinoma.


Carcinosarcoma of the pancreas.

Darvishian F, Sullivan J, Teichberg S, Basham K.

Departments of Pathology (Drs Darvishian, Teichberg, and Basham) and Surgery (Dr Sullivan), North Shore University Hospital, Manhasset, NY.

Arch Pathol Lab Med 2002 Sep;126(9):1114-7 Abstract quote

We report the case of a 74-year-old white man with a mass in the head of the pancreas, which was found incidentally on computerized tomographic scan during a workup for deep vein thrombosis. Endoscopy with pancreatic duct brushings yielded a diagnosis of adenocarcinoma. A pancreaticoduodenectomy followed, with complete resection of the tumor.

Pathologic examination showed 2 distinct components. One component was a conventional infiltrating pancreatic ductal adenocarcinoma, and the other component was high-grade sarcoma with features of malignant fibrous histiocytoma.

To our knowledge, this carcinosarcoma is the seventh reported case of a primary pancreatic neoplasm with mixed carcinomatous and sarcomatous elements.

UNDIFFERENTIATED CARCINOMA (Anaplastic, giant cell, pleomorphic large cell, sarcomatoid)

Ann Diagn Pathol 2001;5:129-140

35 cases from AFIP
10F, 25M
Age range 34-85 years
Mean 62.5 years
Symptoms lasted average of 13.2 weeks
Mean size 9.2 cm, usually head or tail

Tumors widely infiltrative and composed of large pleomorphic cells or spindle cells with tumor phagocytosis and necrosis
IPOX had epithelial markers in 78% of tumors
K-ras mutations in 8/12 cases tested

29/35 DOD average 5.2 months
3 died with no evidence of disease
3 pts. alive after average 94 months, one with residual disease

No statistically significant difference between pts. with and without K-ras mutations


Immunohistochemical Staining in the Diagnosis of Pancreatobiliary and Ampulla of Vater Adenocarcinoma: Application of CDX2, CK17, MUC1, and MUC2.

Chu PG, Schwarz RE, Lau SK, Yen Y, Weiss LM.

From the *Division of Pathology and double daggerMedical Oncology, City of Hope National Medical Center, Duarte, CA; and daggerDepartment of Surgery, UMDNJ, Robert Wood Johnson University Hospital, New Brunswick, NJ.
Am J Surg Pathol. 2005 Mar;29(3):359-367. Abstract quote  

Pancreatobiliary and ampulla of Vater adenocarcinomas frequently metastasize to regional lymph nodes, liver, or lung and are difficult to diagnose because they lack specific immunohistochemical markers.

We studied the expression of cytokeratin 7 (CK7), cytokeratin 17 (CK17), cytokeratin 20 (CK20), CDX2, mucin 1 (MUC1), mucin 2 (MUC2), and mucin 5AC (MUC5AC) in 46 cases of pancreatic ductal carcinoma, 18 ampulla of Vater adenocarcinomas, and 24 intrahepatic cholangiocarcinomas. The expression of MUC1 and CK17 was restricted to pancreatic ductal carcinoma (41 of 46, 89%; 38 of 46, 83%, respectively), the ampullary carcinoma of pancreatobiliary origin (6 of 6, 100%; 5 of 6, 83%, respectively), and intrahepatic cholangiocarcinoma (20 of 24, 83%; 17 of 24, 71%, respectively). More than 50% of cases of pancreatobiliary adenocarcinomas showed diffuse cytoplasmic CK17 positivity. In contrast, less than 5% cases (8 of 184) of extra-pancreatobiliary nonmucinous adenocarcinomas expressed CK17, and only 3 of them showed diffuse CK17 positivity. The expression of MUC2 and CDX2 was restricted to the intestinal, mucinous, and signet-ring cell-type adenocarcinomas of duodenal papillary origin (9 of 11, 82%; 11 of 11, 100%, respectively). MUC2 was rarely expressed in pancreatic ductal carcinoma (1 of 46, 2%) and was negative in the ampullary carcinoma of pancreatobiliary origin and in intrahepatic cholangiocarcinoma. A heterogeneous CDX2 staining pattern was seen in 1 of 6 cases of the ampullary carcinoma of pancreatobiliary origin (17%), 5 of 24 intrahepatic cholangiocarcinomas (21%), and 10 of 46 (22%) pancreatic ductal carcinomas.

In contrast, all 11 cases of the intestinal, mucinous, and signet-ring cell-type adenocarcinomas of duodenal papillary origin showed homogeneous CDX2 nuclear positivity.

We concluded that CK17 is a useful marker in separating pancreatobiliary adenocarcinomas from extra-pancreatobiliary nonmucinous adenocarcinomas, including adenocarcinomas from the colon, breast, gynecologic organs, stomach, lung, prostate, thyroid, kidney, and adrenal gland, and malignant mesothelioma. MUC1+/CK17+ can be used as positive markers for pancreatic ductal carcinomas, the ampullary carcinoma of pancreatobiliary origin, and cholangiocarcinomas with positive predictive values of 76%, 83%, and 58%, respectively. MUC2+/CDX2+ can be used as positive markers for the intestinal-type adenocarcinoma of duodenal papillary origin with a positive predictive value of 82%.

Analysis of novel tumor markers in pancreatic and biliary carcinomas using tissue microarrays.

Swierczynski SL, Maitra A, Abraham SC, Iacobuzio-Donahue CA, Ashfaq R, Cameron JL, Schulick RD, Yeo CJ, Rahman A, Hinkle DA, Hruban RH, Argani P.
Hum Pathol 2004;35:356-366 Abstract quote

Using global gene expression analyses, multiple novel tumor markers overexpressed in infiltrating ductal adenocarcinomas of the pancreas have recently been identified. However, the expression of these markers in morphologically similar adenocarcinomas of the biliary tree has not been investigated.

The purpose of the present study was 3-fold. First, we used 8 markers that have been shown to be overexpressed in whole tissue sections of pancreatic adenocarcinomas to validate tissue microarrays (TMAs) created from a series of pancreatic adenocarcinomas (n = 68). The labeling patterns of 6 epithelial markers (fascin, mucin 4, 14-3-3sigma, prostate stem cell antigen, topoisomerase IIalpha, and cdc2/p34) were concordant with previously published studies on whole tissue sections, yet required far fewer slides and reagents. Mesothelin, an epithelial marker, and heat shock protein 47, a marker of peritumoral desmoplasia, showed lower levels of expression in the TMAs when compared with whole tissue sections. Second, we examined the previously unknown expression of the same 8 novel tumor proteins in cancers of the biliary tree by using TMAs created from a series of intrahepatic cholangiocarcinomas, gallbladder adenocarcinomas, and adenocarcinomas of the distal common bile duct (n = 38). Each of the 8 markers was overexpressed in the biliary cancers, ranging from 14% demonstrating at least focal labeling with prostate stem cell antigen to 100% labeling with cdc2/p34. Most of the markers showed lower frequencies of expression in the biliary tract carcinomas in comparison to the pancreatic adenocarcinomas. In addition, expression patterns varied with location in the biliary system (intrahepatic versus gallbladder versus distal common bile duct). These differences were statistically significant (P < 0.05) for mesothelin, mucin 4, and heat shock protein 47. Finally, the expression of selected markers in neoplastic progression of gallbladder cancer was examined. Two markers, fascin and mesothelin, showed up-regulation of expression with transition from carcinoma in situ to invasive adenocarcinoma, implicating a role for these markers in neoplastic progression.

The results of this study indicate that TMA technology provides valid and cost-effective means to screen large numbers of novel tumor markers, even in tumors such as pancreatic and biliary adenocarcinomas that characteristically have abundant desmoplastic stroma. In addition, novel tumor markers of pancreatic adenocarcinomas show similar, yet not identical, expression patterns in biliary carcinomas.

Therefore, these markers are potentially useful in developing diagnostic tests and treatment paradigms for tumors involving the biliary system.
K-ras, p53, and DPC4 (MAD4) Alterations in Fine-Needle Aspirates of the Pancreas
A Molecular Panel Correlates With and Supplements Cytologic Diagnosis

Tjarda van Heek, MD
Anne E. Rader, MD
G. Johan A. Offerhaus, MD
Denis M. McCarthy, MD
Michael Goggins, MD
Ralph H. Hruban, MD
Robb E. Wilentz, MD

Am J Clin Pathol 2002;117:755-765 Abstract quote

Between January 1997 and February 2000, 101 fine-needle pancreatic aspirates were obtained. After a cytologic diagnosis was made, possible molecular alterations were determined on the 94 aspirates with adequate tissue using a molecular panel (K-ras, p53, and DPC4 [MAD4] genes).

The 94 aspirates were categorized as follows: diagnostic of adenocarcinoma, 48 (51%); atypical (suggestive of, but not diagnostic of, adenocarcinoma), 19 (20%); negative for adenocarcinoma, 25 (27%); diagnostic of a neoplasm other than adenocarcinoma, 2 (2%). Clinical follow-up revealed that 3 patients (12%) with negative cytologic diagnoses and 12 patients (63%) with atypical cytologic diagnoses had adenocarcinoma. Of 63 with a final diagnosis of adenocarcinoma, 42 (67%) had an alteration in at least 1 of the genes analyzed. In contrast, only 2 (6%) of 31 patients without adenocarcinoma had an alteration in 1 gene on the panel. Overall, the molecular analyses supported the diagnosis of adenocarcinoma in 6 (32%) of 19 aspirates originally diagnosed as atypical by cytology alone.

A molecular panel that includes the K-ras, p53, and DPC4 (MAD4) genes correlates with and can supplement traditional cytologic diagnosis of pancreatic fine-needle aspirates.
CEA Usually labels neoplastic ducts but is negative within normal glands
CA19-9 80% of cases

Cytokeratins 7, 17, and 20 Reactivity in Pancreatic and Ampulla of Vater Adenocarcinomas Percentage of Positivity and Distribution Is Affected by the Cut-Point Threshold

Neal S. Goldstein and Deepa Bassi

Am J Clin Pathol 2001;115:695-702 Abstract quote

We studied reactivity of cytokeratins (CK) 7, 17, and 20 in 64 pancreaticobiliary adenocarcinomas to examine the effect of different cut-point thresholds on "positive" results, compare ampulla of Vater and pancreas adenocarcinomas, and provide additional experience with CK17 reactivity.

Almost all neoplasms had extensive CK7 reactivity. The number of CK20-positive cases decreased from 29 (45%; any stained cells) to 19 (30%; >25% staining) to 14 (22%; >50% staining) with an increasing threshold of reactive cells. Similar shifts in the distribution of CK7 and CK20 reactivity occurred when different thresholds of reactivity were used for a positive result. There were no differences in CK7 or CK20 reactivity in pancreas only, ampulla only, and neoplasms involving both sites. Of 64 adenocarcinomas, 29 (45%) had no or single-cell CK17 reactivity, and 19 (30%) had reactivity in more than 50% of neoplastic cells.

Ampulla of Vater and pancreas adenocarcinomas have similar CK immunophenotypes that cannot assist in distinguishing ampullary from pancreatic neoplasms on endoscopically procured tissue. CK17 staining occurs in approximately 50% of pancreaticobiliary adenocarcinomas and is usually patchy. Single antibody staining results, especially CK7 and CK20 coordinate reactivity, are influenced by the reactivity threshold used.

Claudin 4 Protein Expression in Primary and Metastatic Pancreatic Cancer Support for Use as a Therapeutic Target

Lynette S. Nichols, MD, Raheela Ashfaq, MD, and Christine A. Iacobuzio-Donahue, MD, PhD
Am J Clin Pathol 2004;121:226-230 Abstract quote

We performed a comprehensive immunohistochemical evaluation of claudin 4 protein expression in paraffin-embedded tissue samples from 72 patients with primary infiltrating pancreatic cancer, 38 patients with metastatic pancreatic cancer, and a panel of normal control tissue samples from various organs. In 11 samples of primary infiltrating pancreatic cancer, foci of pancreatic intraepithelial neoplasia (PanIN) were present and also were analyzed for claudin 4 protein expression.

Intense positive claudin 4 immunolabeling was noted within virtually all primary (71/72 [99%]) and metastatic (49/49 [100%]) pancreatic cancer tissue samples analyzed and in 10 of 11 samples of PanIN. In all cases, immunolabeling was noted in a membranous distribution. Claudin 4 protein also was detectable in normal breast, prostate, bladder, and gastrointestinal mucosa, although expression was substantially less intense than that seen in pancreatic cancer tissue samples.

Our findings support the use of claudin 4 as a target for novel therapeutics or radioimaging of infiltrating pancreatic cancer. Furthermore, the finding of claudin 4 overexpression within pancreatic intraepithelial neoplasia, the precursor lesion of pancreatic cancer, suggests a potential benefit of imaging claudin 4 before the development of an invasive carcinoma.
Cyclooxygenase 2 Expression in Pancreatic Adenocarcinoma and Pancreatic Intraepithelial Neoplasia
An Immunohistochemical Analysis With Automated Cellular Imaging

Anirban Maitra, MD
Raheela Ashfaq, MD
Carla R. Gunn
Ayman Rahman|
Charles J. Yeo, MD
Taylor A. Sohn, MD
John L. Cameron, MD
Ralph H. Hruban, MD
Robb E. Wilentz, MD

Am J Clin Pathol 2002;118:194-201 Abstract quote

We immunohistochemically examined material from 36 pancreata (adenocarcinomas, 30 lesions; pancreatic intraepithelial neoplasia [PanIN], 65; normal pancreatic ducts, 30) for cyclooxygenase 2 (COX-2) with an automated platform. We analyzed 7 to 10 discrete foci and generated an average percentage of positive cells and average staining intensity for each lesion.

These 2 values were then multiplied to create an overall "HistoScore" for each lesion. COX-2 demonstrated considerable heterogeneity of expression between and within cases. The overall average percentage of positive cells in adenocarcinomas was 47.3%; in PanINs, 36.3%; and in normal ducts, 19.2%. COX-2 was expressed in more than 20% of cells in 23 adenocarcinomas (77%), 42 PanINs (65%), and 12 normal ducts (40%). The overall average HistoScore for adenocarcinomas was 6.1; for PanINs, 5.4; and for normal ducts, 3.5. Significant differences in COX-2 expression were demonstrable in adenocarcinomas vs normal ducts, PanINs vs normal ducts, and PanIN 2/3 vs PanIN 1a/1b.

In general, the pattern of COX-2 expression increased from normal to PanIN to adenocarcinoma. The up-regulation of COX-2 in a subset of noninvasive precursor lesions makes it a potential target for chemoprevention with selective COX-2 inhibitors.

A Subset of Pancreatic Adenocarcinomas Demonstrates Coamplification of Topoisomerase IIa and HER2/neu
Use of Immunolabeling and Multicolor FISH for Potential Patient Screening and Treatment

Donna E. Hansel, MD, PhD, etal
Am J Clin Pathol 2005;123:28-35 Abstract quote

We sought to identify the frequency of amplification of the topoisomerase IIa gene (TOP2A) in pancreatic cancer and determine the usefulness of TOP2A immunolabeling in screening for TOP2A and human epidermal growth factor receptor (HER)2/neu amplification.

We examined 55 pancreatic adeno-carcinoma specimens for TOP2A immunolabeling and identified TOP2A protein expression in all specimens with a nuclear labeling index (NLI; positive nuclei/total nuclei × 100) of 5% to 80%. Normal pancreatic ductal epithelium, proposed to give rise to pancreatic adenocarcinoma, did not demonstrate detectable TOP2A expression. In a subset of specimens selected for fluorescence in situ hybridization analysis of TOP2A and HER2/neu amplification using a recently developed multicolor probe, 7 of 8 lesions with an NLI of 25% or more demonstrated TOP2A amplification, in contrast with 2 of 14 lesions with a TOP2A NLI of less than 25%. In 8 of 9 TOP2A-amplified cases, coamplifi-cation of HER2/neu was present, suggesting a potential relationship between TOP2A and HER2/neu in pancreatic adenocarcinoma.

We propose that TOP2A immunolabeling be used in conjunction with a newly developed multicolor probe to screen patients with pancreatic adenocarcinoma to determine the best potential therapeutic modalities, such as TOP2A inhibitors, trastuzumab, or both.
KOC (K Homology Domain Containing Protein Overexpressed in Cancer): A Novel Molecular Marker That Distinguishes Between Benign and Malignant Lesions of the Pancreas.

Yantiss RK, Woda BA, Fanger GR, Kalos M, Whalen GF, Tada H, Andersen DK, Rock KL, Dresser K.

From the Departments of *Pathology and double daggerSurgery, UMass Memorial Health Care, Worcester, MA; and the daggerDepartment of Tumor Antigen Discovery, Corixa Corporation, Seattle, WA.
Am J Surg Pathol. 2005 Feb;29(2):188-195. Abstract quote  

KOC (K homology domain containing protein overexpressed in cancer) is a novel oncofetal RNA-binding protein highly expressed in pancreatic carcinomas. Recently, Corixa Corporation developed a monoclonal antibody specific for KOC that can be used with standard immunohistochemical techniques.

The purposes of this study were 1) to assess KOC mRNA expression in pancreatic carcinoma, 2) to determine the pattern of KOC immunoexpression among benign, borderline, and malignant pancreatic epithelial lesions, and 3) to evaluate the utility of the KOC antibody in distinguishing between these entities. mRNA was isolated from fresh pancreatic tissues (19 carcinomas, 2 normal pancreas, 1 chronic pancreatitis) and amplified using standard RT-PCR techniques. Fifteen of 19 (79%) carcinomas overexpressed KOC mRNA relative to non-neoplastic tissue samples and expression increased progressively with tumor stage: the mean copy number of KOC mRNA transcripts was 1.5, 11.1, 31, and 28 for stage I, II, III, and IV carcinomas, respectively, compared with 0.9 and 1 for normal pancreatic tissue and chronic pancreatitis, respectively.

Immunostains using the KOC antibody were performed on 50 surgical resection specimens (38 invasive adenocarcinomas, 3 intraductal papillary-mucinous neoplasms, 2 mucinous cystic neoplasms, 7 chronic pancreatitis). KOC staining was present in 37 of 38 (97%) carcinomas: the staining reaction was moderate or strong in 36 of 38 (94%) and present in >50% of the tumor cells in 35 of 38 (92%) cases. Severe dysplasia of the ductal epithelium, present in 19 foci of intraductal papillary mucinous carcinoma, mucinous cystadenocarcinoma, and grade 3 pancreatic intraepithelial neoplasia (PanIN3) showed strong or moderate staining in 15 (79%) cases, whereas foci of mild and moderate dysplasia (intraductal papillary-mucinous neoplasms and mucinous cystic neoplasms with adenoma and/or moderate dysplasia, PanIN1, and PanIN2) were uniformly negative for this marker in 25 and 22 cases, respectively.

In the normal pancreas, weak background staining of acini was present in 12 of 50 (24%) cases but was easily distinguishable from the type of staining identified in neoplastic epithelium, and benign ducts and ductules were negative in all cases. Four of 38 (11%) foci of chronic pancreatitis, present in the 7 resections performed for chronic pancreatitis as well as 31 foci of peritumoral chronic pancreatitis, showed weak staining in <10% of the ductules.

We conclude that KOC is a sensitive and specific marker for carcinomas and high-grade dysplastic lesions of the pancreatic ductal epithelium. Therefore, immunostains directed against KOC may be of diagnostic utility in the evaluation of pancreatic lesions, particularly when biopsy material is limited.
Mesothelin Is Overexpressed in Pancreaticobiliary Adenocarcinomas but Not in Normal Pancreas and Chronic Pancreatitis

Raffit Hassan, MD, etal.
Am J Clin Pathol 2005;124:838-845
Abstract quote

Mesothelin, a cell surface glycoprotein present on normal mesothelial cells, has been reported to be expressed in pancreatic adenocarcinomas.

We conducted this study to fully characterize mesothelin expression in surgically resected, formalin-fixed, paraffin-embedded tissue specimens of 18 pancreatic adenocarcinomas, 9 adenocarcinomas of the ampulla of Vater, 12 adenocarcinomas of the common bile duct, and 17 cases of chronic pancreatitis. Mesothelin immunostaining was performed using the antimesothelin monoclonal antibody 5B2. All 18 cases (100%) of pancreatic adenocarcinomas showed mesothelin expression, as did 8 (89%) of 9 cases of ampullar adenocarcinoma and all 12 cases (100%) of common bile duct adenocarcinoma. In all cases of pancreaticobiliary adenocarcinoma, the adjacent normal pancreas did not stain for mesothelin. Of 17 specimens of chronic pancreatitis, 16 were negative for mesothelin expression, and 1 case showed weak mesothelin staining of fewer than 5% of normal pancreatic ducts.

Our results demonstrated mesothelin expression in the majority of pancreaticobiliary adenocarcinomas and no expression in normal pancreatic tissues and in chronic pancreatitis.

The Immunohistochemical Mucin Expression Pattern Distinguishes Different Types of Intraductal Papillary Mucinous Neoplasms of the Pancreas and Determines Their Relationship to Mucinous Noncystic Carcinoma and Ductal Adenocarcinoma

Jutta Lüttges, M.D.; Giuseppe Zamboni, M.D.; Daniel Longnecker, M.D.; Günter Klöppel, M.D.

From the Department of Pathology (J.L., G.K.), University of Kiel, Germany; the Department of Pathological Anatomy (G.Z.), University of Verona, Italy; and the Department of Pathology (D.L.), Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire, U.S.A.

Am J Surg Pathol 2001;25:942-948 Abstract quote

Intraductal papillary-mucinous neoplasms of the pancreas seem to comprise various types, whose relationship to ductal adenocarcinoma and mucinous noncystic carcinoma is unclear.

We analyzed the mucin immunophenotype and the DPC4/SMAD4 expression in intraductal papillary-mucinous neoplasms, ductal carcinomas, and mucinous noncystic carcinomas to define features that may help to distinguish between different types of intraductal papillary-mucinous neoplasms and to establish their relationship to other neoplasms of the exocrine pancreas.

A series of 51 intraductal papillary-mucinous neoplasms, three mucinous noncystic carcinomas (two with an intraductal component), and 35 ductal adenocarcinomas were screened immunohistochemically for their expression of MUC1, MUC2, MUC5, and DPC4/SMAD4. All intraductal papillary-mucinous neoplasms and mucinous noncystic carcinomas were positive for MUC5. Thirty-two intraductal papillary-mucinous neoplasms and three mucinous noncystic carcinomas abundantly expressed MUC2 but no (or only little) MUC1. The remaining intraductal papillary-mucinous neoplasms showed either mainly MUC1 expression or focal MUC1 and MUC2 expression. All ductal carcinomas but one were MUC2 negative and MUC1 and MUC5 positive. DPC4 was not expressed in two intraductal papillary-mucinous neoplasms that showed a tubular invasion pattern. Twelve of 23 ductal adenocarcinomas were DPC4 positive.

Intraductal papillary-mucinous neoplasms can be divided into at least three different mucin immunophenotypes. The first and largest group of intraductal papillary-mucinous neoplasms and mucinous noncystic carcinomas is MUC1 negative and MUC2 positive and probably forms one tumor entity. The second group seems to be related to ductal carcinoma because of its MUC1 positivity in the absence or very weak MUC2 staining. The third group shows focal MUC1/MUC2 expression and is characterized by oncocytic histology.

MUC4 Expression Increases Progressively in Pancreatic Intraepithelial Neoplasia

Michael J. Swartz,1 Surinder K. Batra, PhD,4 Grish C. Varshney, PhD,4 Michael A. Hollingsworth, PhD,4 Charles J. Yeo, MD,2,3 John L. Cameron, MD,3 Robb E. Wilentz, MD,1 Ralph H. Hruban, MD,1,2 and Pedram Argani, MD

Am J Clin Pathol 2002;117:792-796 Abstract quote

Pancreatic adenocarcinoma is believed to develop from histologically identifiable intraductal lesions known as pancreatic intraepithelial neoplasias (PanINs) that undergo a series of architectural, cytologic, and genetic changes, a progression model similar to the adenoma-carcinoma sequence in the colon. The apomucin MUC4 has been implicated in invasive pancreatic adenocarcinoma. MUC4 expression is not detectable at the RNA level in normal pancreas but is detectable at high levels in invasive pancreatic adenocarcinoma.

We documented the pattern of expression of MUC4 in PanINs by studying a series of 71 PanIN lesions immunohistochemically using a new monoclonal antibody to MUC4. Five (17%) of 30 PanIN-1 lesions, 10 (36%) of 28 PanIN-2 lesions, 11 (85%) of 13 PanIN-3 lesions, and 25 (89%) of 28 invasive adenocarcinomas labeled with the MUC4 antibody used in the study. In addition, a few nonneoplastic lesions labeled with the MUC4 antibody, including reactive ducts in chronic pancreatitis, atrophic ducts filled with inspissated secretions, and ducts showing squamous metaplasia.

Our data help establish the patterns of MUC4 expression in neoplastic precursors in the pancreas and add further support to the progression model for pancreatic adenocarcinoma.


WT1 Is an Integral Component of an Antibody Panel to Distinguish Pancreaticobiliary and Some Ovarian Epithelial Neoplasms

Neal S. Goldstein, MD, Deepa Bassi, MD, and Alison Uzieblo, MD

Am J Clin Pathol 2001;116:246-252 Abstract quote

We investigated whether a panel of antibodies including WT1 could separate pancreaticobiliary and ovarian carcinomas by staining 64 pancreaticobiliary adenocarcinomas, 41 ovarian serous carcinomas, and 12 primary ovarian mucinous neoplasms with WT1, cytokeratin (CK) 17, CK20, carcinoembryonic antigen (CEA), and CA-125. Moderate or strong intensity reactivity in more than 25% of cells was a positive result.

Of the ovarian serous carcinomas, 38 (93%) were WT1 reactive and 22 (54%) WT1 positive, 9 (22%) had CK20 reactivity, and 3 (7%) were CK20 positive in fewer than 50% of cells. All were CK17 or CEA nonreactive. Of the ovarian mucinous neoplasms, all were WT1 and CK17 nonreactive and 11 (92%) were CEA reactive, 8 (67%) CEA positive, 10 (83%) CK20 reactive, and 6 (50%) CK20 positive. Of the pancreaticobiliary adenocarcinomas, 19 (30%) were CK20 positive, 27 (42%) CK17 positive, and 52 (81%) CEA positive. All were WT1 nonreactive.

A panel including WT1, CK17, CK20, and CEA is useful to distinguish pancreaticobiliary and ovarian serous carcinomas. Extensive CK17 reactivity is supportive of a pancreaticobiliary adenocarcinoma when the differential diagnosis includes ovarian mucinous neoplasm. None of the antibodies positively identified ovarian mucinous neoplasms.


Choriocarcinoma involving the pancreas as first manifestation of a metastatic regressing mixed testicular germ cell tumor.

Wang L, Pitman MB, Castillo CF, Dal Cin P, Oliva E.

1Department of Pathology, Harvard Medical School, Boston, MA, USA.

Mod Pathol. 2004 Dec;17(12):1573-80. Abstract quote

We describe an unusual case of metastatic choriocarcinoma of the pancreas arising from a regressing testicular mixed germ cell tumor that clinically mimicked a primary pancreatic tumor. A 54-year-old male presented with a 2-month history of progressive upper abdominal pain, weight loss, and jaundice. He also had a history of recurrent epididymitis associated with the presence of a right testicular mass shown to be cystic by ultrasound and stable for at least 10 years. A computed tomography scan showed an isolated 6 cm mass in the head of the pancreas. A pancreaticoduodenectomy was performed.

Upon histological examination, the pancreatic tumor showed extensive hemorrhage and necrosis. In the viable area, the tumor was composed of an intimate mixture of mononuclear cytotrophoblast cells and multinucleated syncytiotrophoblasts with vascular invasion. These characteristic features led to the correct diagnosis on frozen section. The cytology of the tumor was nonspecific and suggested undifferentiated carcinoma of the pancreas. The trophoblastic origin of the tumor cells was confirmed by immunohistochemistry staining.

The testicular mass showed a regressed mixed germ cell tumor of predominantly seminoma with focal teratoma but without a choriocarcinoma component. In conclusion, we present a rare and unusual case of a regressing testicular mixed germ cell tumor that presented as a primary pancreatic tumor. Cytological features of the pancreatic mass were not specific and raised the possibility of a primary undifferentiated carcinoma of the pancreas.

Characteristic histological features of choriocarcinoma led to the correct diagnosis on frozen section. Subsequent resection of the testicular mass confirmed the presence of a cystic and scarring (regressing) mixed germ cell tumor but without evidence of choriocarcinoma.
CYSTIC TUMORS Acinar cystadenocarcinoma
Intraductal Oncocytic Papillary Neoplasm
Lymphoepithelial cyst
Mucinous cystic neoplasm
Serous cystadenoma

Genetic Analysis of Invasive Carcinoma Arising in Intraductal Oncocytic Papillary Neoplasm of the Pancreas

Shetal A. Patel; Reid Adams, M.D.; Meryl Goldstein, M.D., Ph.D.; Christopher A. Moskaluk, M.D., Ph.D.

Am J Surg Pathol 2002; 26(8):1071-1077 Abstract quote

A case of intraductal oncocytic papillary neoplasm of the pancreas, with the rare progression to invasive carcinoma, is described.

The intraductal oncocytic papillary neoplasm component had the features typical of this entity, with stratified layers of oncocytic cuboidal tumor cells growing in papillary and pseudopapillary arrangements within dilated pancreatic ducts. The invasive carcinoma formed a discrete fleshy tumor with well-circumscribed borders. The invasive carcinoma grew in solid lobules, subdivided by fine fibrovascular septae into predominantly organoid and trabecular growth patterns. Molecular analysis showed no loss of heterozygosity for microsatellite markers at the tumor suppressor loci of TP53, CDKN2A (p16/INK4A), and MADH4 (Smad4/DPC4) in the invasive carcinoma, although loss of heterozygosity was detected at one CDKN2A marker in the intraductal component. DNA sequencing of polymerase chain reaction amplification products of exons 1 and 2 of the CDKN2A gene showed no mutation in either tumor component. TP53 immunohistochemistry showed no increased levels of staining, consistent with the presence of wild-type gene product. Polymerase chain reaction and DNA sequencing showed no mutation of codons 12 and 13 of the KRAS proto-oncogene.

These results suggest that intraductal oncocytic papillary neoplasm is a neoplasm with genetic changes that are distinct from typical pancreatic adenocarcinoma. The lack of mutation in these genes may be an explanation for the typically indolent clinical behavior of intraductal oncocytic papillary neoplasms.

Lymphoepithelial cysts of the pancreas: a report of 12 cases and a review of the literature.

Adsay NV, Hasteh F, Cheng JD, Bejarano PA, Lauwers GY, Batts KP, Kloppel G, Klimstra DS.

Departments of Pathology, Karmanos Cancer Institute (NVA, FH) and Wayne State University School of Medicine, Detroit, Michigan.


Mod Pathol 2002 May;15(5):492-501 Abstract quote

Lymphoepithelial cyst (LEC) of the pancreas is a rare lesion of undetermined pathogenesis that had been documented almost exclusively in males. The literature on this entity is limited to reports of single or small numbers of cases.

Here is presented a clinicopathologic analysis of 12 patients with LEC, 4 of whom were female. The mean age of the patients was 56 years. Four patients presented with abdominal pain and nausea, but in two patients, the cysts were detected incidentally. Only one patient had a history of chronic pancreatitis, and another had a family member with pancreatic cancer. In one patient, a clinical diagnosis of pseudocyst was rendered, and the remaining patients were clinically thought to have cystic neoplasms.

None of the patients had any identifiable immunosuppression, HIV positivity, autoimmune disorder (such as Sjogren syndrome) or lymphoma. Seven cysts were located in the head of the pancreas, and 5 were in the tail. The mean size was 4.8 cm (range, 1.2-17 cm). Five LECs were multilocular, three were unilocular; in others, the number of loculi was not recorded. All were "macrocystic" lesions. Two patients had two separate lesions, both in the tail of the pancreas. Histologically, all cases were characterized by cysts, some containing keratin, and lined by mature stratified squamous epithelium surrounded by dense lymphoid tissue, often with prominent follicles. In some areas, the lining epithelium had more cuboidal, flattened, or transitional appearance. Mucinous goblet-like cells were seen in one case. Acute inflammation was not seen. Four cases contained solid lymphoepithelial islands, a feature not previously described in LECs. No squamous metaplasia was identified in the uninvolved pancreatic tissue and no epithelial elements were identified in peripancreatic lymph nodes.

In summary, LEC of the pancreas is a rare but distinctive lesion that may be seen in the tail of the organ where most cystic pancreatic neoplasms are encountered. In contrast to the impression from the literature, LECs may also develop in females and, therefore, should be considered in the clinical differential diagnosis of mucinous cystic neoplasms that affect a similar age group. LECs are not associated with the clinical syndromes that are seen with their analogues in the salivary glands.

Unilocular Acinar Cell Cystadenoma of the Pancreas
An Unusual Acinar Cell Tumor

Denis Chatelain, MD
François Paye, MD
Najat Mourra, MD
Jean-Yves Scoazec, MD, PhD
Marielle Baudrimont, MD
Rolland Parc, MD, PhD
Jean-François Flejou, MD, PhD

Am J Clin Pathol 2002;118:211-214 Abstract quote

We report an unusual case of acinar cell cystadenoma of the pancreas in a 52-year-old man treated for pulmonary adenocarcinoma.

The lesion, located in the body of the pancreas, was revealed incidentally by abdominal computed tomography during follow-up for a pulmonary neoplasm. A left pancreatectomy was performed. The unilocular cystic lesion measured 5 cm and was lined by a single layer of columnar acinar cells with eosinophilic granular cytoplasm, faintly stained by periodic acid–Schiff. Immunohistochemical analysis showed the lining cells were positive for cytokeratin and trypsin, and electronic microscopy showed that they contained zymogen granules.
Acinar cell tumors of the pancreas are rare and include acinar cell carcinomas, acinar cell cystadenocarcinomas, and acinar cell adenomas.

We report a case of cystic acinar cell tumor of the pancreas with benign gross and histologic features that could be added to the list of cystic neoplasms of the pancreas as acinar cell cystadenoma.


Acinar cystadenoma of the pancreas: A previously undescribed tumor.

Albores-Saavedra J.

Division of Anatomic Pathology, The University of Texas Southwestern Medical Center, Dallas, TX.

Ann Diagn Pathol 2002 Apr;6(2):113-5 Abstract quote

A 58-year-old diabetic woman died as a result of an acute myocardial infarction caused by coronary atherosclerosis and thrombosis. A 9 cm multiloculated cystic lesion was found incidentally in the body and tail of the pancreas.

The microcysts and locules were lined by one or two layers of normal-appearing acinar cells. In some locules there were clusters of acinar structures containing eosinophilic material. The cuboidal cells lining the locules had morphologic and immunohistochemical features of acinar cells.

The lesion was interpreted as an acinar cystadenoma, the benign counterpart of the well-established acinar cystadenocarcinoma of the pancreas. Acinar cystadenoma should be included in the differential diagnosis of cystic tumors of the pancreas.

Acinar cell cystadenoma of the pancreas: a new entity?

Zamboni G, Terris B, Scarpa A, Kosmahl M, Capelli P, Klimstra DS, Lam PW, Kloppel G.

Department of Pathology, University of Verona, Italy.

Am J Surg Pathol 2002 Jun;26(6):698-704 Abstract quote

This report describes a newly observed cystic lesion of the pancreas showing acinar cell differentiation. The patients affected by this lesion included seven women and three men (age range 16-66 years). In six patients, all of whom were female and all but one of whom suffered from abdominal pain, the cystic lesions (diameters, 4-15 cm) were detected by imaging techniques and subsequently removed. In four patients the cystic lesions were incidental findings.

Eight lesions occurred as unifocal, unilocular or multilocular cysts in the head (n = 6) or tail (n = 2) of the pancreas. One lesion was bifocal (head and tail) and another involved the entire pancreas.

The cysts were only rarely connected with the pancreatic duct system, but with acinar structures. Their lining cells expressed pancreatic enzymes and lacked any cellular atypia or proliferative activity (Ki67 index <1%). For a follow-up period of 6-84 months all patients remained alive and well.

Although a nonneoplastic nature cannot be fully excluded, we propose that this lesion, composed of well-differentiated acinar cells, may represent the benign counterpart of the well-recognized acinar cystadenocarcinoma. We therefore suggest the term acinar cell cystadenoma.

Intraductal Tubular Adenoma of the Pancreas, Pyloric Gland Type: A Clinicopathologic and Immunohistochemical Study of 6 Cases.

Nakayama Y, Inoue H, Hamada Y, Takeshita M, Iwasaki H, Maeshiro K, Iwanaga SI, Tani H, Ryu S, Yasunami Y, Ikeda S.

From the *Department of Pathology and the daggerFirst Department of Surgery, School of Medicine, Fukuoka University, Fukuoka, Japan.

Am J Surg Pathol. 2005 May;29(5):607-616. Abstract quote  

ABSTRACT:: The intraductal tubular adenoma (ITA), pyloric gland type, of the pancreas is an uncommon benign tumor, akin to the pyloric gland type adenoma of the gallbladder.

We report 6 cases of ITA of the pancreas: 3 male and 3 female aged 50 to 79 years (mean, 63.5 years; median, 65 years); all were examined clinicopathologically. Four patients showed no symptoms, but appetite loss and/or general fatigue presented in two. Grossly, all tumors formed a localized polypoid mass protruding into the lumen of the dilated pancreatic duct. Five of the six tumors were found within the main duct, and the other arose within the branch duct of the pancreas.

Microscopically, the tumors were composed of closely packed tubular glands resembling pyloric type glands. They were lined by columnar or cuboidal epithelial cells with foci of mild to moderate dysplastic change. In 2 cases, the adjacent pancreas showed foci of intraductal papillary-mucinous adenoma. Histochemically, the tumors largely showed neutral mucin with a lesser amount of acidic mucin made up mainly of sialomucin. Endocrine cells were found in five tumors. Immunohistochemically, all tumors were labeled with M-GGMC-1 and MUC6, whereas MUC1 and MUC2 stains were negative. Pepsinogen II was positive in 5 tumors; thus, the results displayed a pattern of differentiation similar to those of ordinary gastric pyloric or metaplastic pyloric glands. DPC4 expression was maintained in all tumors and p53-positive nuclei were hardly encountered.

All patients are alive with no evidence of disease 3 to 10.5 years after surgical resection.

Intraductal Tubular Adenoma, Pyloric Type, of the Pancreas: Additional Observations on a New Type of Pancreatic Neoplasm

Albores-Saavedra, Jorge MD*; Sheahan, Kieran MB†; O'Riain, Ciaran MB†; Shukla, Deepti MD*

From the *Department of Pathology, LSU Health Sciences Center School of Medicine, Shreveport, LA; and the †Department of Histopathology, St. Vincent's University Hospital, Elm Park, Dublin Ireland

Am Surg Pathol: Volume 28(2) February 2004 pp 233-238 Abstract quote

Three cases of a distinctive intraductal tubular adenoma, pyloric type, of the main pancreatic duct are reported. The patients, two women and a man, whose ages ranged from 63 to 70 years, complained of abdominal pain attributed to chronic pancreatitis in two patients. The patient with the largest tumor also had symptoms of gastric outlet obstruction. The tumors, two of which arose in the head and one in the tail of the pancreas, led to occlusion and cystic dilatation of the main pancreatic duct.

Two adenomas were sessile and one was attached to the wall of the pancreatic duct by a thin fibrous stalk. Microscopically, they were composed of lobules of closely packed tubular glands similar to pyloric glands. In one tumor, nearly all glands were lined by columnar mucin-secreting cells with abundant clear cytoplasm and basally oriented nuclei. In addition to pyloric glands, two adenomas contained glands lined by cells with little or no mucin as well as by pink oncocytic cells. Focal intestinal differentiation was identified in one tumor. Both intracellular and extracellular mucin was detected with the mucicarmine, periodic acid-Schiff, and alcian blue stains. All three adenomas were CK7 positive and CK20 negative. Focal carcinoembryonic antigen linear reactivity along the apical cytoplasm was seen in many cells, but few cells expressed cytoplasmic carcinoembryonic antigen. All three adenomas showed low proliferative activity as measured by the MIB-1 labeling index.

The three adenomas were p53 negative and showed loss of DPC4 expression. No endocrine cells were identified in any of the tumors. All patients are alive and symptom free from 4 months to 5 years following surgical treatment.


1 Well differentiated duct-like glands Intensive <5 Little pleomorphism
Polar arrangement
2 Moderately differentiated duct-like and tubular glands Irregular 6-10 Moderate pleomophism
3 Poorly differentiated glands Abortive >10 Marked pleomorphism
A Proposal for a New and More Practical Grading Scheme for Pancreatic Ductal Adenocarcinoma.

Adsay NV, Basturk O, Bonnett M, Kilinc N, Andea AA, Feng J, Che M, Aulicino MR, Levi E, Cheng JD.

From the *Department of Pathology, Karmanos Cancer Institute and Harper University Hospital, Wayne State University, Detroit, MI; daggerDepartment of Pathology, Huron Valley-Sinai Hospital, MI; double daggerDepartment of Pathology, John Dingell VA Medical Center, Detroit, MI; and section signDepartment of Pathology, Providence Hospital, Southfield, MI.

Am J Surg Pathol. 2005 Jun;29(6):724-733. Abstract quote  

There is no uniformly applied grading system for pancreatic ductal adenocarcinoma (DA). The scheme advocated by the WHO is essentially that of Kloppel et al, and is based on the "highest grade" focus. Although it is precise with good prognostic value, it is unfortunately not widely applied, largely because of the lack of recognition and partly because of its complex nature (interpretation of multiple parameters). Furthermore, it is fundamentally different from the one used in Japan, which evaluates the overall pattern.

To establish a more widely applicable, practical, and clinically relevant grading system, a scheme similar to Gleason's scoring system was developed and tested on 112 cases of resected pancreatic DA and was compared with the WHO system. In the grading system devised, patterns (P) of infiltration were classified as follows: P1, well-defined glands with easily discernible contours; P2, fused or poorly formed glands with ill-defined contours; P3, nonglandular patterns. A score was then obtained by the summation of the predominant and the secondary patterns. Scores </=3 (at least some well-formed glands and no nonglandular pattern) was graded as G1, 4 as G2, and >/=5 (at least some nonglandular patterns and no well-formed glandular pattern) as G3. Seventy-three percent of the cases displayed mixed patterns, with disparate patterns (P1 with P3) in 13%, confirming the high degree of heterogeneity of DA. There was a significant correlation between grade and survival, better than the correlation between survival and either the major or minor patterns evaluated separately. The median survival for G1, G2, and G3 were 22, 14, and 8 months; 1-year survival 68%, 44%, and 33%; 2-year was 67%, 11%, and 0%; and 3-year was 23%, 4%, and 0%, respectively (P = 0.0019). In a multivariate analysis, correlating survival with grade, tumor size, and lymph node status, the grade was the strongest independent predictor of survival. Odds ratio of dying of disease were 3.56 (P < 0.0001) in G3 versus G1, 1.79 (P = 0.058) in G2 versus G1, and 1.98 (P = 0.03) in G3 versus G2. Compared with this, the same odds ratio were 1.17 (P = 0.01) in tumors >2 cm versus </=2 cm and 1.78 (P = 0.01) in cases with positive versus negative lymph nodes.

The WHO grading scheme was not found to have as good a correlation with survival in this study, with WHO grade 2 showing a better survival than 1. The reproducibility of both the proposed grading system and that of WHO were found to be moderately good (with kappa values of 0.43 and 0.44, respectively), when 32 slides of DA were graded by four independent observers.

The grading scheme for pancreatobiliary adenocarcinoma proposed here is highly applicable because it is practical and readily adoptable. It reflects biologic characteristics of ductal carcinoma (prominent tubule formation and tumor heterogeneity). Most importantly, it is clinically relevant with good prognostic value. Lastly, it is also applicable for use in research, by utilizing "patterns," even in small specimens like microarrays or biopsies.


Clincial stage most important

Grade of the tumor-Poorly differentiated tumors have worse prognosis

Tumors of the body or tail are more advanced
>3cm poorer prognosis

Tumor directly invades the peripancreatic retroperitoneal fatty tissue, nerves, and blood vessels and lymphatics

Carcinomas of the head directly invade wall of duodenum
Carcinomas of the body and tail invade the stomach, spleen, peritoneum, colon, and left adrenal gland

Lymph nodes
Superior head and posterior pancreaticoduodenal groups commonly involved
Liver and peritoneum most common

2 Year survival is 28%
5 Year survival is 3.5-12%

Most die of tumor recurrence within 1-2 years
Mean survival time in untreated patients is 3 months
Mean survival time after radical resection is 10-20 months

Cytologic grade independently predicts survival of patients with pancreatic adenocarcinoma.

Eltoum IA, Eloubeidi MA, Chhieng DC, Tamhane A, Crowe R, Jhala D, St John KD, Wilcox CM, Siegal GP, Vickers S, Jhala NC.

Department of Pathology, Division of Anatomic Pathology, University of Alabama at Birmingham, AL, USA.

Am J Clin Pathol. 2005 Nov;124(5):697-707. Abstract quote  

Our objectives were to devise a cytologic grading system and determine whether it would predict survival of patients with solid-type pancreatic adenocarcinoma.

We evaluated 116 consecutive patients from July 2000 to November 2002; they were followed up until September 2003. We scored the following features on rapid Romanowsky-stained endoscopic ultrasound-guided fine-needle aspiration smears: cell group architecture, single cells, nuclear grade, mucus, bizarre cells, and necrosis. A cytologic grade (low vs high) was assigned. The Kaplan-Meier estimate of 6-month survival was 76% (SE, 7%) for patients with low-grade tumors vs 50% (SE, 6%) for patients with high-grade carcinoma. The median survival for patients with low-grade vs high-grade tumors was 1 year vs 6 months, respectively (chi2 = 4.45; P = .035).

Cox proportional hazards regression showed tumor stage, cancer-specific treatment, and cytologic grade to be independent predictors of survival (P = .001). No other factors (age, mass location, placement of stent, presence of concomitant chronic pancreatitis, race, sex) predicted survival.

We devised a grading system that independently predicted survival in patients with pancreatic adenocarcinoma.
Assessment of HER-2 Status in Pancreatic Adenocarcinoma: Correlation of Immunohistochemistry, Quantitative Real-Time RT-PCR, and FISH With Aneuploidy and Survival.

Saxby AJ, Nielsen A, Scarlett CJ, Clarkson A, Morey A, Gill A, Smith RC.

From the *University of Sydney, Department of Surgery, Royal North Shore Hospital; daggerDepartment of Anatomical Pathology, Royal North Shore Hospital; and double daggerDepartment of Anatomical Pathology, St. Vincents Hospital, Sydney, Australia.

Am J Surg Pathol. 2005 Sep;29(9):1125-1134. Abstract quote  

HER-2 is a transmembrane growth factor receptor recognized in overexpression as an independent adverse prognostic factor in several cancers. This study measured HER-2 overexpression in pancreatic adenocarcinoma at the genetic, transcriptional, and translational level. Expression was gauged with regard to stage, grade, and survival.

Pancreatic adenocarcinoma samples (n = 30) were analyzed with immunohistochemical labeling for HER-2 protein, Quantitative real-time reverse transcriptase polymerase chain reaction (Q-RT-PCR) measurement of HER-2 mRNA and fluorescence in situ hybridization (FISH) analysis of HER-2 gene expression. HER-2 expression in benign pancreatic lesions (n = 10) provided a control. Five (17%) of the pancreatic adenocarcinomas scored maximal 3+ immunohistochemistry (IHC) labeling, seven (23%) had significantly increased expression of HER-2 mRNA, while only one (3%) exhibited low level HER-2 gene amplification. Ten (33%) tumors demonstrated aneuploidy.

In general, concordance between methodologies was poor, but the best agreement was seen between FISH aneuploidy status and Q-RT-PCR mRNA overexpression (80% agreement), followed by IHC and Q-RT-PCR (73% agreement). The least agreement was seen between IHC and FISH aneuploidy status (67% agreement). Tumor stage was positively associated with HER-2 mRNA and protein expression, but tumor grade and other patient characteristics did not reach statistical significance. A poor survival outcome was demonstrated with positive HER-2 status in all three measures of overexpression (Kaplan-Meier log-rank score; P < 0.01 [IHC], P = 0.05 [Q-RT-PCR], P = 0.02 [FISH]).

Discordance in expression at the nuclear, cytoplasmic, and cell surface levels highlights the limitations of immunohistochemical evaluation alone and stresses the need for further evaluation of response to anti-HER-2 targeted therapies in tumors displaying overexpression in gene copy, mRNA, and receptor protein.

Prognostic implications of routine, immunohistochemical, and molecular staging in resectable pancreatic adenocarcinoma.

Niedergethmann M, Rexin M, Hildenbrand R, Knob S, Sturm JW, Richter A, Post S.


Am J Surg Pathol 2002 Dec;26(12):1578-87 Abstract quote

Cure for ductal adenocarcinoma of the pancreas is restricted to resectable tumors, but survival after surgery is still poor. Despite apparently curative resection, these cancers rapidly recur. Thus, the present pathologic examination should be enriched by sensitive methods to detect minimal residual disease.

In a prospective setting we studied the frequency of minimal residual disease after curative resection by routine histopathology, immunohistology, and polymerase chain reaction (PCR) for mutated K-ras. Furthermore, the prognostic implication of detecting of MRD was determined. Prospectively, tumor tissue and corresponding paraaortic lymph nodes were obtained from 78 patients, who underwent surgery for pancreatic head tumors between 1999 and 2001. Sixty-nine of 78 cases were diagnosed for ductal adenocarcinoma (study group), whereas nine cases were diagnosed for benign pancreatic tumors (control group). Paraaortic lymph nodes were examined in step sections by routine histopathology (hematoxylin and eosin) and immunohistology using a pan-cytokeratin antibody. DNA of the primary tumor and corresponding paraaortic lymph nodes were analyzed by PCR-based assays with respect to mutated K-ras in codon 12.

The recurrence-free survival and overall survival were correlated with the results of the latter methods. In 3 of 69 patients tumor cells were detected in paraaortic lymph nodes by routine histopathology and in 5 of 69 patients by immunohistology. K-ras mutations were detected in 42 of 69 ductal adenocarcinomas (61%), whereas 12 (17%) were positive in paraaortic lymph nodes. All of the latter patients had recurrence after surgery and a significant poorer survival than those without mutated K-ras.

Furthermore, paraaortic lymph nodes diagnosed for K-ras mutation were independent prognostic markers in multivariate analysis. In the control group K-ras mutations were detected in one adenoma of Vater's papilla but not in paraaortic lymph nodes. Tumor cell DNA can be detected more sensitively by the described PCR method than with hematoxylin and eosin or immunohistologic staining, leading to a higher sensitivity for detection of micrometastases.

The described PCR method clearly determines subgroups of patients after curative resection with early recurrence and poor survival and could therefore enrich the pathologic examination.


Surgical resection is treatment of choice but only 10-20% of cases are candidates

Chemotherapy leads to 10% response
Radiotherapy usually ineffective


Phase II study of gemcitabine in combination with cisplatin in patients with locally advanced and/or metastatic pancreatic cancer.

Brodowicz T, Wolfram RM, Kostler WJ, Tomek S, Vaclavik I, Steger GG, Teleky B, Fugger R, Jakesz R, Zielinski CC.

Department of Surgery, University Hospital, Vienna, Austria.

Anticancer Drugs 2000 Sep;11(8):623-8 Abstract quote

The present phase II trial was performed to assess the efficacy and toxicity of polychemotherapy with gemcitabine and cisplatin in patients with locally advanced or metastatic carcinoma of the pancreas.

Sixteen patients received six courses of an i.v. cytotoxic regimen consisting of gemcitabine (1000 mg/m2, days 1, 8 and 15) and cisplatin (35 mg/m2, days 1, 8 and 15) administered in 28-day intervals. Complete remission (CR) occurred in one patient (6%), partial remission (PR) in four patients (25%) and stable disease in seven patients (44%), whereas four patients (25%) developed progressive disease resulting in an overall response rate of 31%. Mean duration of responses (CR+PR) was 3.6 (range 0.7-8.5) months and mean time to progression was 7.4 (range 3.8-12.6) months. After a mean observation period of 11.5 months the overall survival was 9.6 months with 12 patients (75%) still being alive, which compares favorably with historical data of the administration of gemcitabine alone. The performance status improved in three (19%) and stabilized in eight (50%) out of 16 patients for 4 weeks or longer. Treatment-associated toxicity included alopecia of WHO grade III in all cases, leukopenia of WHO grades I and II in 10 patients (63%), grade III in five patients (31%), and thrombocytopenia grades I and II in four patients (25%), and grades III and IV in 10 patients (63%).

We conclude that the administered dosage and schedule of gemcitabine and cisplatin in patients with locally advanced or metastatic cancer of the pancreas constitutes an active cytotoxic regimen associated with moderate toxicity.


Treatment of locally unresectable carcinoma of the pancreas: comparison of combined-modality therapy (chemotherapy plus radiotherapy) to chemotherapy alone.

Gastrointestinal Tumor Study Group.

J Natl Cancer Inst 1988 Jul 20;80(10):751-5 Abstract quote

Randomized trials of the Gastrointestinal Tumor Study Group have previously demonstrated enhanced survival of patients with locally unresectable pancreatic cancer treated with 5-fluorouracil in combination with radiation therapy compared with that of patients treated with radiation therapy alone.

The present study compared the survival of patients treated with multidrug chemotherapy [streptozocin, mitomycin, and 5-fluorouracil (SMF)] versus radiation combined with 5-fluorouracil followed by the same three-drug SMF combination.

In 43 patients randomly allocated between these two arms, an improved median survival for the combined-modality therapy (42 weeks) compared with chemotherapy alone (32 weeks) was demonstrated.

Overall survival following this combined-modality treatment program (41% at 1 year) was significantly superior to that following SMF chemotherapy alone (19% at 1 year), by a two-tailed log rank test (P less than .02).

Serial studies of the Gastrointestinal Tumor Study Group with patients with locally unresectable pancreatic adenocarcinoma have shown that combined-modality therapy is superior to either optimal radiotherapy or chemotherapy alone.

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Commonly Used Terms



Whipple procedure-A radical surgical technique which removes the portion of the tumorous pancreas, a portion of the adjacent small intestine, regional lymph nodes, spleen, gallbladder, and portion of the stomach. There are many variations of this procedure depending upon the location of the primary tumor.

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