Histopathologic Analysis of Pancreaticoduodenectomy Specimen

Introduction: Whipple’s Pancreaticoduodenectomy has increasingly been used as an appropriate resectional procedure for tumors of the periampullary region which are pancreatic, periampullary, ampullary and biliary tumors. Our aim was to study the distribution and histopathologic features of these tumors and to examine local trends of periampullary neoplasms resected with a PD. Methods: A descriptive study was conducted in the department of Pathology, Kathmandu Medical College Teaching Hospital from July 2013 to June 2016. Results: Thirty five patients underwent Whipple’s Pancreaticoduodenectomy procedure during a period of 36 months from July 2013 to June 2016. Malignant tumor was present in 31 (88.57%) cases where as four cases (11.43%) harboured benign lesions. Periampullary mixed carcinoma was the predominant tumor (34.28%) followed by periampullary duodenal (20%), ampullary (14.28%), pancreatic adenocarcinoma (11.42%) and distal cholangiocarcinoma (5.71%). There was no significant difference in tumor size among periampullary, ampullary, pancreatic and biliary carcinomas. Ampullary carcinomas were predominantly well differentiated (80%) where as the other tumors were mostly moderately differentiated. Lymphovascular and perineural invasion varied in different tumor types. Four pancreatic adenocarcinomas showed lymphovascular and perineural invasion. Adequate surgical margin clearance was achieved in most of the cases except in one case each of periampullary duodenal carcinoma and distal cholangiocarcinoma and two cases of pancreatic adenocarcinoma.. conclusions: Pancreaticoduodenectomy specimen requires thorough histopathological evaluation. Pathologists should also be aware of possibility of a benign diagnosis in PD specimens which have been resected presuming malignancy based on clinical judgement and radiological data. _______________________________________________________________________________________


INtRODUctION
Kausch is credited with the first successful resection of the duodenum and portion of pancreas (pancreaticoduodenectomy) which was later popularized by Whipple and now bears his name for the operation. 1,2dvances in surgical technique, perioperative care and concentration of surgery in large volume centres have significantly improved mortality and morbidity associated with the Whipple's procedure. 3,4Today Whipple's Pancreaticoduodenectomy has increasingly been used as a safe and appropriate resectional option for tumors of the periampullary region which are pancreatic, ampullary, biliary and duodenal tumors. 1,5e distribution of resected pancreatic, ampullary, biliary and duodenal carcinomas is variable in different studies which affects patient survival.A recent large study done by Chen et al. on 501 periampullary cancers found ampullary carcinomas represented the majority of cancers subjected to a pancreaticoduodenectomy while other literature show pancreatic cancer to be more frequent. 6,7Pathologic assessment of surgical specimens from PD needs special attention in order to accurately evaluate many factors that are prognostically important.10] The aim of this study was to examine the distribution and histopathologic features of pancreatic, ampullary, biliary and duodenal cancers resected by PD in a tertiary level hospital over a period of three years.

MEtHODs
A descriptive study was conducted in the department of Pathology, Kathmandu Medical College Teaching Hospital from July 2013 to June 2016.Pancreaticoduodenectomy specimens received in the department of Pathology for various clinical indications were included in the study.The specimens were fixed in 10% formalin, grossed and processed as per standard protocol.Location of the tumor, histolopathologic categorization, grading, lymphovascular and perineural invasion, margin status and lymph node status were assessed.TNM staging of the tumor was done based on AJCC TNM classification. 11Relevant clinical history and radiological findings were traced where applicable.Maximum tumor dimension, tumor differentiation, mean number of lymph node dissected, lymph node status, resected margin status, lymphovascular and perineural invasion among the different adenocarcinomas are demonstrated in Table 3.Most of the periampullary mixed and duodenal, pancreatic and distal cholangiocarcinomas were moderately differentiated whereas ampullary carcinomas were predominantly well differentiated (80%).There was no significant difference in tumor size among periampullary, ampullary, pancreatic and biliary carcinomas.Lymphovascular and perineural invasion varied in different tumor types.Surprisingly all four pancreatic adenocarcinomas showed lymphovascular and perineural invasion.The average number of lymph nodes dissected was twelve.

Thirty
The lymph node involvement by tumor varied in different tumor types.Lymph nodes were involved by tumor in all the four cases of Pancreatic adenocarcinoma (100%).Adequate surgical margin clearance was achieved in most of the cases except in one case of periampullary duodenal carcinoma and two cases of pancreatic adenocarcinoma.Pathologic staging of the malignant tumors is demonstrated in Table 4.

DIscUssION
Whipple pancreaticoduodenectomy is one of the most complex surgeries performed for the management of a variety of tumors involving the head of pancreas, ampulla of Vater, distal common bile duct or duodenum. 12lthough regarded as a life saving procedure, long term survival is largely dependent on the pathology within the resected specimen which emphasizes the need of meticulous evaluation of PD specimens. 1We tried to report PD specimen with utmost care as per the protocol given by College of American Pathologists (CAP). 13 our study periampullary carcinoma was the predominant cancer on Whipple PD specimen which is in contrast to other studies.5][16] We found ampullary carcinoma in only 5 cases (14.28%).This discrimination could be due to our strict adherence to the diagnostic criteria as proposed by Klimstra et al for the diagnosis of Ampullary carcinoma.According to them the tumor should be called as ampullary when the epicentre of the tumor is in the ampulla and there should be a pre invasive ampullary lesion.The tumor that grows circumferentially around the ampulla is called periampullary carcinoma. 17umors predominantly in the periampullary duodenum with no significant involvement of ampulla are classified as periampullary duodenal where as those involving both periampullary duodenum as well as ampulla are described as periampullary mixed.Periampullary mixed tumor can either be exophytic or ulcerated. 17We found eight of the periampullary mixed tumor presenting as exophytic mass (66.67%) whereas four of them were ulcerative (33.33%).
Western literature reveals pancreatic adenocarcinoma to be the commonest finding in PD specimens.In a review of 650 pancreaticoduodenectomies Yeo et al found 43% cases to be pancreatic adenocarcinoma. 1 We found only four cases of pancreatic adenocarcinoma and one case of Pancreatic neuroendocrine tumor which is lower compared to their studies.This finding should however be interpreted with caution due to the small number of cases that we studied and an extensive study of larger sample size would highlight the true incidence of pancreatic malignancy in our country.
Histopathologically ampullary/ periampullary carcinoma can be of intestinal type, pancreaticobiliary type, mixed type and undifferentiated type.Categorization is important because the prognosis of the intestinal type is better than pancreaticobiliary type. 17We found only one case of pancreaticobiliary carcinoma (4.1%) in contrast to studies done by Ibrahim et al and Howe et al who reported 6.7% and 27% respectively. 16,18hey reported most of the cases to be either well or moderately differentiated which is in agreement to our study.
Yeo et al performed a multivariate analysis of 443 patients with periampullary adenocarcinoma and reported four factors found to adversely affect survival: 1) tumor diameter ≥ 3 cm; 2) the presence of positive resection margins; 3) the finding of lymph node metastases in the resected specimen and 4) the presence of a poorly differentiated tumor.They also reported ampullary carcinomas to have the smallest tumor dimension with lower incidence of positive resection margins. 1 In our study we found the mean tumor diameter to be smallest in ampullary carcinoma (mean 2.2 cm).Moreover, 80% of these cases were well differentiated and resected margins were free of tumor in all cases.Positive resected margins were noted in two cases of pancreatic adenocarcinoma and one case each of periampullary duodenal and distal cholangiocarcinoma.Optimal histologic examination of a pancreaticoduodenectomy specimen should include analysis of a minimum of 12 lymph nodes. 11The average number of lymph nodes recovered in our study was 12 which demonstrates adequate nodal dissection practised in our institute.In only three cases, five or less number of lymph nodes were harvested.When lymph nodes involvement by malignant tumor is taken into consideration (including one neuroendocrine tumor), 17 cases (54.8%) showed lymph node metastasis which is significantly higher as compared to studies done by Ibrahim et al(10%) and Allema JH et al (40%). 18,19Furthermore fifteen cases were diagnosed to be in advanced stages (T3 or higher).This shows many of our patients are diagnosed in advanced stages with widespread lymph node metastasis.Hence precise assessment of signs and symptoms along with correlation with radiological/ other laboratory findings should be emphasized for early diagnosis of cancer.
In the large series of 1175 resected pancreatic cancers by Winter et al., the incidence of perineural invasion was 91% whereas vascular involvement was lower (53%). 20In our study, patients with pancreatic cancer had the highest incidence of lymphovascular invasion (100%) and perineural invasion (100%) which have been shown to be poor prognostic features.Pancreatic cancers also had a 50% incidence of microscopic margin involvement which was higher than that of ampullary, periampullary duodenal and periampullary mixed carcinoma.Chandrasegaram et al have reported clear margin in 46% of patients prior to 2010 and 67% of patients after 2010.They have concluded this change might be due to the improvement in their surgical technique. 5Margin status has been shown to relate to survival outcomes.Yeo et al. showed in their series of 201 patients that the five year survival in those with a negative margin was 26% (median survival 18 months) compared to those with a positive margin 8% (median survival 10 months). 21Whilst margin positivity appears to be critically important, not all margins may have a similar impact on patient survival.Delpero et al. reported that a positive Superior Mesenteric Artery (SMA) or Superior Mesenteric Vein (SMV) margin had a significant impact on progression-free survival, a positive posterior margin had no impact. 22In our study both of the pancreatic cancers had SMA margin involvement.
Two of the cases suspected of malignancy in our study turned out to be benign on histopathology.One of the cases suspected of Periampullary carcinoma was found to be periampullary adenomatous hyperplasia while another case thought to be a distal cholangiocarcinoma showed only non-specific inflammation.The diagnostic work-up for patients with presumed cancer is complex, costly and not always accurate.Studies have shown the incidence of benign histopathology on PD specimens could be as high as 13%. 23In a report from Mayo Clinic, Smith et al. reviewed 484 patients who underwent Whipple procedure for suspected periampullary malignancy and found chronic inflammatory disease on final pathologic assessment in 24 patients (5%). 24vanGulik et al. described 220 patients who underwent Whipple and reported 6% benign findings.They suggested that at least 5% of benign finding is expected when performing PD for a suspected malignant disease.Given the grim prognosis of the pancreatic cancer this should not stop surgeons from performing the procedure on patients with clinically suspected malignancy but with no other confirming data. 25Number of carcinoma mimics including adenomyoma of the ampulla, papillary hyperplasia, sclerosing papillitis, benign biliary and duodenal disease have been identified.Adenomatous hyperplasia of the ampulla is larger than 0.5 cm and contains complex glands, arranged in a lobular architecture surrounded by the lamina propria and muscle bundles.7][28] Two cases in which the final histopathologic diagnosis of serous cystadenoma and noninvasive mucinous cystic neoplasm with low grade dysplasia were made, preoperative radiological diagnosis suggested mucinous cystadenoma.Interestingly, in two cases of periampullary carcinoma, concomitant tubercular lymphadenitis was observed which highlights the impact of Tuberculosis in our community.cONcLUsIONs Pancreaticoduodenectomy specimen requires meticulous histopathologic evaluation for proper categorization of histologic type and other features which affect patient survival following PD.Possibility of a benign diagnosis remains in PD specimen which have been resected presuming malignancy based on clinical judgement and radiological data.

table 1 . Agewise distribution of patients undergoing Pancreaticoduodenectomy. Age (years) n (%)
).Most of the patients presented with history of jaundice.