Pancreatic cancer, once invasive, is almost uniformly fatal. In order to alleviate the dismal prognosis associated with this disease, it is imperative that pancreatic cancer be recognized and treated prior to invasion. Understanding the morphology and biology of precursor lesions of invasive pancreatic cancer has therefore become an issue of paramount importance. In the last decade, significant progress has been in the recognition and appropriate classification of these precursor lesions, and the current review will focus on our state-of-the-art knowledge on this topic. Mucinous cystic neoplasms (MCNs), intraductal papillary mucinous neoplasms (IPMNs), and pancreatic intraepithelial neoplasia (PanIN) encompass the three known morphologically distinct precursors to invasive pancreatic cancer. In addition to discussion of the "classic" precursor entities, this review will also address some of the recent diagnostic controversies for these lesions, in particular features that distinguish IPMNs from PanIN lesions. Finally, the potential clinical impact of recognizing these precursor lesions in the context of early detection of pancreatic cancer will be discussed.

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Precursors to Invasive Pancreatic Cancer

Precursors to Pancreatic Cancer

Objective:Although branch duct intraductal papillary mucinous neoplasms (BD-IPMNs) are slow-growing tumors with a favorable prognosis, the synchronous occurrence of pancreatic ductal adenocarcinomas (PDAs) in patients with BD-IPMNs has been reported. This study was aimed to elucidate the development

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Pancreatic ductal adenocarcinomas in long-term follow-up patients with branch duct intraductal papillary mucinous neoplasms.

BACKGROUND

Multiple lesions of intraductal papillary-mucinous tumor of the pancreas (IPMT) in the same pancreas often are encountered. To elucidate field (multicentric) cancerization and clonality of IPMT, clonal analyses of IPMT and its precursor lesion of ductal hyperplasia were performed. K-ras codon 12 mutations and X-chromosome inactivation of human androgen receptor gene (HUMARA) were investigated.



METHODS

Paraffin embedded tissue samples from the pancreata of 37 patients who underwent resection for IPMTs were microdissected manually or by laser capture microdissection. Multiple samples from each surgical specimen were microdissected representing each IPMT and discrete ductal hyperplasias. DNA was extracted, and K-ras codon 12 mutations were examined by two-step polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). The mutations were analyzed by direct DNA sequence. The HUMARA locus was digested with or without HpaII and HhaI prior to amplification. The HUMARA assay was conducted by fluorescence-labeled PCR-RFLP and was analyzed with specialized software.



RESULTS

All 37 pancreata had at least two lesions of ductal hyperplasia, and 23 of 37 pancreata (62%) had K-ras codon 12 mutations in these precursor lesions. Of 23 pancreata with mutated K-ras hyperplasia, 15 (65%) had multiple, distinct mutations in different lesions of hyperplasia in the same pancreas, suggesting a field defect. Thirty-two of 37 IPMTs (86%) had K-ras codon 12 mutations. Among these, 16 IPMTs (50%) had multiple, distinct mutations at K-ras codon 12. The HUMARA assay showed that 12 of 15 IPMTs were informative, and 9 were considered polyclonal and/or oligoclonal origin in origin. With the combined results of multiple K-ras mutation detection and the HUMARA assay, 12 of 15 IPMTs from female patients (80%) were considered polyclonal and/or oligoclonal in origin.



CONCLUSIONS

The current results suggest that multiple, distinct K-ras mutations of different ductal hyperplasias in a given pancreas are due to a field (multicentric) cancerization effect in IPMTs. Thus, most of IPMTs are polyclonal and/or oligoclonal in origin, i.e., IPMTs may originate from multiple (molecularly distinct) precursor lesions. Cancer 2001;92:1807–17. © 2001 American Cancer Society.

Clonality and field cancerization in intraductal papillary-mucinous tumors of the pancreas

/pdf/precursors-to-invasive-pancreatic-cancer-y5pb5ap3om.pdf

Precursors to invasive pancreatic cancer

Mucin-producing tumors (MPTs) of the pancreas are increasingly being recognized. To evaluate the appropriate surgical treatment and predict the prognosis of MPTs, we performed a retrospective clinicopathological study in 51 patients, 27 with benign tumors and 24 with borderline/malignant tumors. Three of the malignant tumors showed stromal invasion and lymph node metastasis on histological examination. Of the 24 patients with borderline/malignant tumors, 2 died of MPTs and 4 died of other diseases. At the last follow-up, 35 patients were alive and well. The 5-year postoperative survival rate was 90% for patients with benign tumors, and 78% of these with borderline/malignant tumors. Five of the patients with borderline/malignant tumors had multicentric tumors. Three of these patients underwent resection of the rest of the pancreas, 5, 6, and 8 years, respectively, after the first operation. Extended radical resection is required for malignant MPT with invasion of the pancreatic stroma. We prefer to perform pancreatogastrostomy or Imanaga's procedure to allow examination of the body and tail of the pancreas by endoscopic retrograde pancreatography after resection of the pancreatic head. Careful follow-up for a long period may be the most prudent approach for detecting multiple MPTs in the residual pancreas after surgical treatment.

Mucin-producing tumors of the pancreas: clinicopathological features, surgical treatment, and outcome

Background/Purpose
Total pancreatectomy (TP) is rarely performed to treat invasive ductal carcinoma of the pancreas, due to the associated markedly impaired quality of life and poor prognosis after the resection Intraductal papillary-mucinous neoplasm (IPMN) of the pancreas is characterized by extensive intraductal spread and a favorable outcome even when presenting at an invasive stage We herein reappraise the role of pylorus-preserving total pancreatectomy (PPTP) as a viable alternative pancreatic resection modality for borderline and malignant IPMN

http://amcor.asahikawa-med.ac.jp/modules/xoonips/download.php?id=17520201

Pylorus-preserving total pancreatectomy for an intraductal papillary-mucinous neoplasm of the pancreas

A 72-year-old woman with multilocular liver cysts was admitted. This lesions seemed to be an alveolar hydatid disease. Two methods of Western blotting were used for serologic diagnosis. One method recognizes antigens of crude extracts of Echinococcus multilocularis (EM). The other method recognizes a purified antigen (Em18) of EM. Her serum only reacted with the former method and never reacted with Em18 antigen. Eighteen months after first admission, she had an operation. The resected specimen was diagnosed with simple cysts. Western blotting using Em18 antigen could greatly facilitate the differential diagnosis of simple liver cyst and alveolar hydatid disease.

A case of liver cystis wlud Em18-WB was useful for differential diagnosis

We report a case of mucinous carcinoma of Vater's ampulla with a unique extension along only the main pancreatic duct (MPD) and microinvasion to the pancreas. A 52-year-old man was referred to our hospital for the evaluation and treatment of acute pancreatitis. Abdominal computed tomography (CT) demonstrated swelling in the head of the pancreas with a mass in the duodenum. Hypotonic duodenography and endoscopic examination revealed a well-defined mass, measuring about 25 mm in size, in Vater's ampulla. A biopsy specimen of the tumor showed moderately differentiated adenocarcinoma. A pylorus-preserving pancreaticoduodenectomy with a regional lymphadenectomy was performed, under a preoperative diagnosis of adenocarcinoma of Vater's ampulla with direct invasion into the head of the pancreas. The resected specimen of the duodenum confirmed the presence of the mass, which measured 22 x 15 mm in size, in Vater's ampulla. Microscopically, the tumor consisted of two components: moderately differentiated adenocarcinoma in the peripheral region of the tumor Vater's papilla and mucinous carcinoma in the central region of the tumor. The mucinous carcinoma component uniquely extended along only the MPD with microinvasion to the pancreas. Immunohistochemically, both the moderately differentiated adenocarcinoma and the mucinous carcinoma were positive for cytokeratin 20 (CK20) and negative for cytokeratin 7 (CK7) which is the pattern of intestinal-type carcinoma of Vater's ampulla. We concluded that the original site of this tumor may have been the duodenal epithelium of Vater's ampulla originally moderately differentiated adenocarcinoma-which subsequently changed to mucinous carcinoma that extended along only the MPD with microinvasion to the pancreas.

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Mitsuhiro Obara

Papers

Mucin-producing tumors of the pancreas: clinicopathological features, surgical treatment, and outcome

Pylorus-preserving total pancreatectomy for an intraductal papillary-mucinous neoplasm of the pancreas

A case of liver cystis wlud Em18-WB was useful for differential diagnosis

Mucinous carcinoma of Vater's ampulla with a unique extension along the main pancreatic duct.

A case of multilocular mesothelial cyst arisen from the inguinal canal