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Abstract and Case Presentation
Abstract
Background: Intraductal papillary mucinous neoplasm (IPMN) of the pancreas is less common than classic invasive ductal adenocarcinoma of the pancreas but is being diagnosed with greater frequency since its clinicopathologic features are now clearly defined. Often multifocal in its existence along the pancreatic duct, IPMN is associated with a significant risk for recurrence and warrants vigilant surveillance, even after a margin-negative resection.
Methods: The authors present a case highlighting important features in the diagnosis, workup, and management of IPMN. They also review existing literature highlighting epidemiology, findings of molecular studies, and current treatment recommendations.
Results: Physicians and patients must carefully weigh the risks and benefits associated with treatment options. Limited resection in a patient with a high likelihood of multifocal disease preserves pancreatic parenchyma and reduces the risk of developing pancreatic endocrine and exocrine insufficiency. Though the risk of developing invasive cancer in the remnant is small, the prognosis is worse if it does develop. Conversely, total pancreatectomy eliminates the risk of future malignancy but involves life-long insulin and exogenous pancreatic enzyme dependence and significant associated morbidity.
Conclusions: Decision making for effective treatment of IPMN is complex and requires attention to detail by an interdisciplinary team with experience in the diagnosis and management of these tumors. Treatment must be individualized based on patient life expectancy in terms of remaining years and overall quality. Molecular profiling of these lesions may allow for more precise tailoring of treatment in the future.
Case Presentation
Dr Malafa: A 67-year-old white woman with a history of hyperlipidemia was taking pravastatin in an effort to improve this condition. She developed a mild elevation of her transaminases aspartate aminotransferase and alanine aminotransferase. An abdominal ultrasound revealed fatty infiltration of the liver and mild dilatation of the common bile duct to 9 mm and of the pancreatic duct to 5 mm. This study was followed by a computed tomography (CT) scan of the abdomen that confirmed the presence of biliary and pancreatic ductal dilatation and also showed a 2.3-cm cystic mass in the body of the pancreas. At this point, the differential diagnosis was broad ( Table 1 ). She then underwent endoscopic retrograde cholangiopancreatography (ERCP). Dr Klapman, please review the findings.
Dr Klapman: Cystic, bulbous dilatation of the main pancreatic duct and its side branches was seen on completion of the pancreatogram (Fig 1). However, filling the pancreatic ductal system with contrast was difficult secondary to resistance. No discrete strictures were seen, but the duct had an irregular appearance and was filled with linear filling defects. Brushings of the duct were performed, but cytology was unrevealing.
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Figure 1.
Areas of cystic dilatation (arrows) of the pancreatic ductal system seen at ERCP.
Dr Malafa: The patient remained symptom-free and was referred to our institute for further evaluation. Her past medical history was significant for hyperlipidemia, hypertension, and osteoarthritis. She had previously undergone total abdominal hysterectomy for benign disease and had no history of cholecystectomy or cholelithiasis. She had a 25-pack-year history of smoking but had quit 25 years prior to evaluation. She consumed two to three alcoholic beverages daily and had done so for many years. Family history was significant for coronary artery disease in her father and leukemia in a brother. Physical examination was unremarkable. Repeat serum liver function studies including transaminases were all within normal reference ranges for the hospital laboratory. It was recommended that the patient undergo endoscopic ultrasound (EUS) of the pancreatic mass for visual assessment and potential biopsy.
Dr Klapman: A multiloculated 2.7 × 2.0-cm cystic mass was present at the junction of the body and tail of the pancreas, communicating directly with a dilated (5.9 mm) main pancreatic duct. A 7-mm cystic mass was noted in the head of the pancreas but appeared to be a simple cyst. Fine-needle aspiration (FNA) was performed of both lesions (Fig 2).
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Figure 2.
EUS revealing cystic lesions in the pancreas. (A) Multi-lobulated 2.7-cm cystic mass at the junction of the body and tail of the pancreas. Communication with the main pancreatic duct, though present, is not visualized. Note the thick appearance of the septa, a characteristic frequently noted in cystic mucinous neoplasms of the pancreas. (B) A 7-mm head lesion with characteristics of a simple cyst.
Dr Malafa: Dr Centeno, please describe the FNA findings.
Dr Centeno: We obtained 1 mL of reddish fluid from the head lesion. The specimen was interpreted as negative for malignancy with only a few epithelial cells noted other than blood. A 10-mL specimen of light pink fluid with interspersed white mucoid strands was obtained from the body lesion. Benign cyst-lining cells with minimal atypia, rare histiocytes and lymphocytes, and mucinous fluid were seen. I did not detect malignant cells. A mucicarmine stain was positive. These results are compatible with a neoplastic mucinous cyst (Fig 3). In addition, serum and fluid from the body lesion were submitted for measurement of carcinoembryonic antigen (CEA) tumor marker levels and amylase levels ( Table 2 ).
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Figure 3.
FNA of cystic mass in the body of the pancreas. (A) Higher power demonstrates degenerated epithelial cells and histiocytes that are characteristically found in the mucin from the neoplastic cysts (Papanicolaou, × 40). (B) The mucicarmine stain confirms the presence of a uniform layer of thick background mucin (mucicarmine, × 40).
Dr Malafa: A follow-up CT was performed. Did this demonstrate any changes?
Dr Choi: The CT (Fig 4) showed a 3.1 × 4.1-cm complex cystic mass abutting the splenic artery and vein at the junction of the body and tail of the pancreas. Obvious septations were present within the mass. Although the pancreatic duct was dilated throughout the gland, it was most pronounced adjacent to the mass in the body of the gland. In the tail, the ductal dilatation was associated with significant glandular atrophy. No cystic lesion was seen in the head of the gland.
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Figure 4.
Triple-phase CT. (A) Arterial phase CT demonstrates subtle septations (yellow arrow) within a cystic body mass. Note abutment of the splenic artery (red arrow). (B) Venous phase CT demonstrating relationship of the mass to the splenic vein (blue arrow).
Dr Malafa: The patient's case was discussed at the weekly meeting of the Institutional Multidisciplinary Gastrointestinal Tumor Board. Though no malignant cells were found on cytology, the presence of mucin in the fluid coupled with the mass´s appearance on EUS and CT suggested the presence of a mucin-producing cystic neoplasm. The consensus opinion of the Tumor Board was that the patient should undergo surgical exploration for potential resection. Based on the intimate involvement of the mass with the splenic vessels, it was believed that splenic preservation would be unlikely. This was explained to the patient,who was agreeable with the treatment plan. Secondary to the high likelihood of splenectomy, the patient received preoperative vaccination against Streptococcus pneumoniae, Haemophilus influenzae, and Neisseria meningitidis.
After standard surgical exploration was performed to rule out unexpected peritoneal or other metastatic disease, attention was turned fully to the pancreas. Intraoperative ultrasound of the gland was performed revealing the complex cystic mass in the body as well as ductal dilatation throughout. I found no other discrete cystic or solid masses. Based on these findings, I proceeded with distal pancreatectomy and splenectomy. Intraoperative assessment of the resection specimen was performed.
Dr Centeno: The presence of a cystic neoplasm was confirmed on gross examination (Fig 5). Frozen section examination of the pancreatic resection margin was negative for intraductal papillary mucinous neoplasm (IPMN) with high-grade dysplasia and also for invasive carcinoma.
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Figure 5.
Resection specimen. (A) Photograph of the resection specimen. The splenic artery is to the left (blue arrow). The top cystic-appearing structure is the main pancreatic duct (yellow arrow), which is surrounded by fibrosis. A papillary excrescence (red arrow) extrudes into the lumen. The bottom cyst is a dilated side branch (green arrow). The surrounding parenchyma has lost the yellow, lobulated appearance of normal pancreas and instead has a white, glistening, smooth-cut surface, as seen with fibrosis. (B) The main pancreatic duct is dilated. The normal lining epithelium is replaced by a papillary proliferation of mucin-containing epithelial cells (hematoxylin-eosin, × 4). (C) Tall, columnar cells with cytoplasmic mucin line the fibrovascular cores forming the papillae (hematoxylin-eosin, × 20). (D) The lining epithelium shows enlarged hyperchromatic nuclei. Small papillary tufts fall into the lumen. The nuclei of these cells are angulated. These features are typical of IPMNs with high-grade dysplasia (hematoxylin-eosin, × 40). (E) This duct demonstrates an abrupt transition from the normal duct lining to columnar mucinous epithelium, which occurs frequently (hematoxylin-eosin, × 40).
Dr Malafa: The patient had an uneventful hospital stay and was discharged home on postoperative day 7. Dr Centeno, please describe the findings of final pathology review.
Dr Centeno: The patient's tumor was a main branch-type IPMN with highgrade dysplasia (Fig 5). It was the intestinal type of IPMN and was composed of multiple cysts measuring 0.8 cm to 1.5 cm in diameter. The cysts were filled with clear,mucinous material, and grossly they had smooth walls. The pancreatic duct wall was lined by a papillary excrescence and was markedly dilated up to 1.3 cm. Prominent chronic pancreatitis was present in the surrounding pancreatic tissue secondary to obstructed ducts. Evaluation of the pancreatic resection margin revealed the presence of IPMN with low-grade dysplasia but no evidence of in situ or invasive cancer. Two lymph nodes were found, but they did not contain metastatic disease.
Dr Malafa: The pathology findings were discussed in detail with the patient. Since her pancreatic parenchymal margin was free of in situ and invasive cancer, I told the patient that no further surgery was immediately indicated. However, I cautioned her that close follow-up with repeat imaging would be essential secondary to the possibility of recurrent disease. She developed insulin-dependent diabetes mellitus during the course of the year but was able to keep her blood sugar under control. I requested that she return for repeat EUS after an otherwise uneventful and symptom-free year at home.
Dr Klapman: The study revealed an irregularly shaped, anechoic 9-mm lesion in the head of the pancreas that communicated directly with the pancreatic ductal system. About 1 mL of reddish fluid was aspirated resulting in complete collapse of the lesion.
Dr Centeno: Cytologic analysis revealed benign pancreatic acinar cells, benign glandular cells, degenerated cells, and scant background mucin most compatible with duodenal contaminant. No malignant or neoplastic cells were detected. An aliquot of the fluid was submitted for k-ras mutational analysis and loss of heterozygosity (LOH) analysis using the PathFinder TG technology (RedPath Integrated Pathology Inc, Pittsburgh, Pennsylvania).
Dr Choi: Subsequent CT showed no evidence of a mass lesion in the residual pancreas. Ductal dilatation was again noted, although it was of a lesser degree compared with the patient's first scans.
Dr Malafa: Secondary to the patient's history of IPMN with in situ carcinoma, and now with a recurrent cystic lesion in the remaining gland, I was concerned about the possible presence of a new or residual pancreatic cancer. How can mutational analysis of cyst fluid assist us in decision making?
Dr Centeno: The assay looks at a panel of molecular parameters including DNA amount and quality, as well as k-ras-2 oncogene point mutation and allelic imbalance (LOH) mutations of a broad panel of associated tumor suppressor genes in pancreatic neoplasia. A prospective study involving its use in 31 patients who eventually underwent surgical resection has been published. The authors reported that molecular analysis was statistically superior to conventional diagnosis based on cytology and cyst fluid levels of CEA. They stated that k-ras mutation followed by allelic loss was predictive of a malignant cyst with a sensitivity of 91% and a specificity of 93% and that molecular determination of the temporal sequence of k-ras-2 oncogene point mutation acquisition in relationship to other acquired LOH mutations was a powerful indicator of cystic disease etiology and biological aggressiveness. However, it must be stressed that these diagnostic methods remain investigational.
In this case, the assay revealed an elevated amount of good-quality DNA in the cyst fluid with a profile supporting the presence of a neoplastic mucinous cyst. To enhance the accuracy of decision making, mutational analysis of the original resection specimen was also performed to allow comparative mutational profiling. Genotyping of the resected tumor revealed a similar mutational profile, and it was believed that the cystic mass present in the pancreatic head likely represented an IPMN with the potential to harbor malignancy.
Dr Malafa: With these findings suggesting either a redevelopment or extension of IPMN along the pancreatic duct, I had a frank discussion with the patient. The consensus opinion of our tumor board was that the potential benefit from completion pancreatectomy outweighed the morbidity from pancreatic endocrine and exocrine insufficiency. The challenges of potentially brittle diabetes were discussed in detail with the patient, as were the risks of repeat surgery. Despite these factors, she agreed that the resection of a potential cancer outweighed the inherent risks and is now awaiting surgery.
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