Christian Partensky

Influence of the Interval Between Preoperative Radiation Therapy and Surgery on Downstaging and on the Rate of Sphincter-Sparing Surgery for Rectal Cancer: The Lyon R90-01 Randomized Trial

PURPOSE The optimal timing of surgery after preoperative radiotherapy in rectal cancer is unknown. The aim of this trial was to evaluate the role of the interval between preoperative radiotherapy and surgery. PATIENTS AND METHODS Patients with rectal carcinoma accessible to rectal digital examination, staged T2 to T3, NX, M0, were randomized before radiotherapy (39 Gy in 13 fractions) into two groups: in the short interval (SI) group, surgery had to be performed within 2 weeks after completion of radiation therapy, compared with 6 to 8 weeks in the long interval (LI) group. Between 1991 and 1995, 201 patients were enrolled onto the study. RESULTS A long interval between preoperative radiotherapy and surgery was associated with a significantly better clinical tumor response (53. 1% in the SI group v 71.7% in the LI group, P =.007) and pathologic downstaging (10.3% in the SI group v 26% in the LI group, P =.005). At a median follow-up of 33 months, there were no differences in morbidity, local relapse, and short-term survival between the two groups. Sphincter-preserving surgery was performed in 76% of cases in the LI group versus 68% in the SI group (P = 0.27). CONCLUSION A long interval between preoperative irradiation and surgery provides increased tumor downstaging with no detrimental effect on toxicity and early clinical results. When sphincter preservation is questionable, a long interval may increase the chance of a successful sphincter-saving surgery.

Genotype–phenotype correlation in hepatocellular adenoma: New classification and relationship with HCC

Hepatocellular adenomas are benign tumors that can be difficult to diagnose. To refine their classification, we performed a comprehensive analysis of their genetic, pathological, and clinical features. A multicentric series of 96 liver tumors with a firm or possible diagnosis of hepatocellular adenoma was reviewed by liver pathologists. In all cases, the genes coding for hepatocyte nuclear factor 1α (HNF1α) and β‐catenin were sequenced. No tumors were mutated in both HNF1α and β‐catenin enabling tumors to be classified into 3 groups, according to genotype. Tumors with HNF1α mutations formed the most important group of adenomas (44 cases). They were phenotypically characterized by marked steatosis (P < 10−4), lack of cytological abnormalities (P < 10−6), and no inflammatory infiltrates (P < 10−4). In contrast, the group of tumors defined by β‐catenin activation included 13 lesions with frequent cytological abnormalities and pseudo‐glandular formation (P < 10−5). The third group of tumors without mutation was divided into two subgroups based on the presence of inflammatory infiltrates. The subgroup of tumors consisting of 17 inflammatory lesions, resembled telangiectatic focal nodular hyperplasias, with frequent cytological abnormalities (P = 10−3), ductular reaction (P < 10−2), and dystrophic vessels (P = .02). In this classification, hepatocellular carcinoma associated with adenoma or borderline lesions between carcinoma and adenoma is found in 46% of the β‐catenin–mutated tumors whereas they are never observed in inflammatory lesions and are rarely found in HNF1α mutated tumors (P = .004). In conclusion, the molecular and pathological classification of hepatocellular adenomas permits the identification of strong genotype–phenotype correlations and suggests that adenomas with β‐catenin activation have a higher risk of malignant transformation. (HEPATOLOGY 2006;43:515–524.)

Cystadenomas and Cystadenocarcinomas of the Pancreas: A Multiinstitutional Retrospective Study of 398 Cases

OBJECTIVE To review the features of patients with benign and malignant cystadenomas of the pancreas, focusing on preoperative diagnostic accuracy and long-term outcome, especially for nonoperated serous cystadenomas and resected cystadenocarcinomas. SUMMARY BACKGROUND DATA Serous cystadenomas (SCAs) are benign tumors. Mucinous cystic neoplasms should be resected because of the risk of malignant progression. A correct preoperative diagnosis of tumor type is based on morphologic criteria. Despite the high quality of recent imaging procedures, the diagnosis frequently remains uncertain. Invasive investigations such as endosonography and diagnostic aspiration of cystic fluid may be helpful, but their assessment is limited to small series. The management of typical SCA may require resection or observation. Survival after pancreatic resection seems better for cystadenocarcinomas (MCACs) than for ductal adenocarcinomas of the pancreas. METHODS Three hundred ninety-eight cases of cystadenomas of the pancreas were collected between 1984 and 1996 in 73 institutions of the French Surgical Association. Clinical presentation, radiologic evaluation, and surgical procedures were analyzed for 144 operated SCAs, 150 mucinous cystadenomas (MCAs), and 78 MCACs. The outcome of 372 operated patients and 26 nonoperated patients with SCA was analyzed. RESULTS Cystadenomas represented 76% of all primary pancreatic cystic tumors (398/522). An asymptomatic tumor was discovered in 32% of patients with SCA, 26% of those with MCA, and 13% of those with MCAC. The tumor was located in the head or uncinate process of the pancreas in 38% of those with SCA, 27% of those with MCA, and 49% of those with MCAC. A communication between the cyst and pancreatic duct was discovered in 0.6% of those with SCA, 6% of those with MCA, and 10% of those with MCAC. The main investigations were ultrasonography and computed tomography (94% for SCA, MCA, and MCAC), endosonography (34%, 28%, and 22% for SCA, MCA, and MCAC respectively), endoscopic retrograde cholangiopancreatography (16%, 14%, 22%), and cyst fluid analysis (22%, 31%, 35%). An accurate preoperative diagnosis of tumor type was proposed for 20% of those with SCA (144 cases), 30% of those with MCA, and 29% of those with MCAC. An atypical unilocular macrocyst was observed in 10% of SCA cases. The most common misdiagnosis for mucinous cystic tumors was pseudocyst (9% of MCAs, 15% of MCACs). Intraoperative frozen sections (126 cases) allowed a diagnosis according to definitive histologic examination in 50% of those with SCA and MCA and 62% of those with MCAC. For management, 93% of patients underwent surgery. Nonoperated patients (7%) had exclusively typical SCA. A complete cyst excision was performed in 94% of benign cystadenomas, with an operative mortality rate of 2% for SCA and 1.4% for MCA. Resection was possible in 74% of cases of MCAC. Mean follow-up of 26 patients with nonresected SCAs was 38 months, and no patients required surgery. For resected MCACs, the actuarial 5-year survival rate was 63%. CONCLUSIONS Spiral computed tomography is the examination of choice for a correct prediction of tumor type. Endosonography may be useful to detect the morphologic criteria of small tumors. Diagnostic aspiration of the cyst allows differentiation of the macrocystic form of SCA (10% of cases) and the unilocular type of mucinous cystic neoplasm from a pseudocyst. Surgical resection should be performed for symptomatic SCAs, all mucinous cystic neoplasms, and cystic tumors that are not clearly defined. Conservative management is wholly justified for a well-documented SCA with no symptoms. An extensive resection is warranted for MCAC because the 5-year survival rate may exceed 60%.

Improved Sphincter Preservation in Low Rectal Cancer With High-Dose Preoperative Radiotherapy: The Lyon R96-02 Randomized Trial

PURPOSE The potential advantage of high-dose preoperative radiotherapy to increase tumor response and improve the chance of sphincter preservation for low rectal cancer remains controversial. The aim of this trial was to evaluate the role of escalating the dose of preoperative radiation to increase sphincter-saving procedures. PATIENTS AND METHODS Patients with rectal carcinoma located in the lower rectum, staged T2 or T3, Nx, or M0 with endorectal sonography, and not involving more than two-thirds circumference, were randomly assigned to one of two groups: preoperative external-beam radiotherapy (EBRT; 39 Gy in 13 fractions over 17 days) versus the same EBRT with boost (85 Gy in three fractions) using endocavitary contact x-ray. RESULTS Between 1996 and 2001, 88 patients were enrolled onto the study. A significant improvement was seen in favor of the contact x-ray boost for complete clinical response (24% v 2%) and for a complete or near-complete sterilization of the operative specimen (57% v 34%). A significant increase in sphincter preservation was observed in the boost group (76% v 44%; P =.004). At a median follow-up of 35 months, there was no difference in morbidity, local relapse, and 2-year overall survival. CONCLUSION A dose escalation with endocavitary irradiation provides increased tumor response and sphincter preservation with no detrimental effect on treatment toxicity and early clinical outcome.

Intraductal papillary and mucinous tumors of the pancreas: accuracy of preoperative computed tomography, endoscopic retrograde pancreatography and endoscopic ultrasonography, and long-term outcome in a large surgical series

BACKGROUND Few data are available on the accuracy of preoperative imaging or on long-term outcome after surgery for intraductal papillary and mucinous tumors of the pancreas. The aims of this study were to assess the following: (1) the accuracy of preoperative computed tomography, endoscopic retrograde pancreatography, and endoscopic ultrasonography for determination of tumor invasion and pancreatic extension as compared with surgical findings; (2) the long-term outcome after surgery. METHODS Forty-seven patients who underwent surgery between 1980 and 1995 for pathologically diagnosed intraductal papillary and mucinous tumors were included in this study. The findings of available computed tomography (n = 25), endoscopic retrograde pancreatography (n = 29), and endoscopic ultrasonography (n = 21) were reviewed by experienced clinicians blinded to pathologic diagnosis to assess tumor invasion and pancreatic extension. Pathologic specimens were reviewed by experienced pathologists. Postoperative follow-up data were analyzed. RESULTS Histologic features of invasive carcinoma were found in 43% of patients, severe dysplasia in 21%, and mild or moderate dysplasia in 36%. The overall accuracy of computed tomography, endoscopic retrograde pancreatography, and endoscopic ultrasonography in distinguishing between invasive and noninvasive tumors were, respectively, 76%, 79%, and 76%. The overall 3-year disease-free survival rate was 63%, but it was 21% among patients with invasive carcinoma at surgery (p < 0.001). CONCLUSIONS This study emphasizes the need for early surgical resection in patients with suspected intraductal papillary and mucinous tumors of the pancreas because of the high frequency of invasive carcinoma and the inadequacy of preoperative imaging for assessing malignancy.

Cystic endocrine tumors of the pancreas: clinical, radiologic, and histopathologic features in 13 cases.

Cystic endocrine tumors of the pancreas are rare and raise difficult clinical problems. Our aims were to reevaluate the diagnostic and therapeutic strategy and to assess their histopathologic characteristics. Thirteen cystic endocrine tumors diagnosed in 10 patients were included. Clinical, radiologic, and pathologic data were reviewed. There were 6 male and 4 female patients (median age, 46 yrs). Six patients had evidence of multiple endocrine neoplasia type 1 (MEN1) disease. Four had a functional endocrine syndrome. Ten tumors were visible on imaging studies. The most suggestive radiologic features were the existence of a peripheral hypervascular rim (10 cases) and images of cyst into cyst (two cases). On gross and histologic examinations, two distinct types were present. Macrocystic tumors (six cases) were unilocular and limited by a thick wall containing nests of tumor cells. Microcystic tumors (seven cases) were characterized by the presence of multiple cystic spaces directly lined by tumor cells. Surgical resection was performed in all cases. Three patients had lymph node metastases at the time of diagnosis. One patient is dead with metastatic dissemination. The others are alive without recurrence or metastasis. The diagnosis of endocrine tumor must be considered for any pancreatic cyst discovered in a patient with a history of MEN1 syndrome or with clinical features suggestive of this syndrome. Cystic pancreatic endocrine tumors must be treated by surgical resection because of their possible malignant evolution.

Low Microvessel Density Is an Unfavorable Histoprognostic Factor in Pancreatic Endocrine Tumors

BACKGROUND AND AIMS In many malignant tumors, intratumoral microvascular density (MVD) has been suggested to be a prognostic parameter. We aimed to provide a quantitative evaluation of intratumoral microvascular density in a large series of resected endocrine tumors of the pancreas and to evaluate the potential prognostic significance of this parameter. METHODS Eighty-two tumors from 77 patients have been studied. MVD was evaluated by 2 observers after CD34 immunostaining and correlated with the following parameters: WHO classification, hormonal profile, tumor size, vascular endothelial growth factor expression, occurrence of metastasis, duration of survival. RESULTS MVD ranged from 5 to 92 vessels/field. MVD was significantly higher in well-differentiated benign endocrine tumors than in tumors of uncertain behavior and in carcinomas. No close correlation was found between MVD and the hormonal profile. MVD was significantly higher in tumors characterized by the following histoprognostic parameters: size <2 cm, proliferation index <2%, no evidence of metastasis. No close correlation was observed between MVD and VEGF expression. Finally, a MVD <30 vessels/field was associated with the occurrence of metastasis in tumors <2 cm and/or with a proliferation index <2% and with a significantly shorter survival after surgery. CONCLUSIONS The quantitative analysis of microvessel density in pancreatic endocrine tumors may identify patients who, despite favorable conventional histoprognostic factors, are at risk of unfavorable evolution.

Central Pancreatectomy: Single-Center Experience of 50 Cases

Central pancreatectomy is a nonstandard operation for unusual lesions. This study reports a single-center experience of central pancreatectomy. Thirty-eight women and 12 men with a mean age of 49.4 years (range, 13.4-79.2 years) underwent central pancreatectomy from January 1987 to October 2005. Indications included 18 neuroendocrine tumors (11 nonfunctioning), 10 serous and 10 mucinous cystadenomas, 5 intraductal papillary mucinous neoplasms, 3 main pancreatic duct strictures, 2 solid cystic papillary tumors, 1 hydatid cyst, and 1 acinar cell carcinoma. The proximal pancreatic remnant was suture ligated. The distal pancreatic end was anastomosed to a Roux-en-Y jejunal loop (n = 6) or to the stomach (n = 44). Three patients had associated procedures, 1 each for metastatic liver cytoreduction (VIPoma), hydatid liver disease, and pancreatic resection for multifocal mucinous cystadenoma. The median operative time was 3 hours 21 minutes (range, 1 hour 50 minutes to 6 hours). The mean length of the resected pancreas was 45 mm (range, 20-80 mm) and the mean tumor size was 23 mm (5-60 mm). The perioperative mortality was nil. Complications included the following: 4 patients (8%) had pancreatic anastomotic leak, 5 patients (10%) had acute pancreatitis, 7 patients (14%) had intra-abdominal collection, and 3 patients (6%) had bleeding. Six patients (12%) required a reoperation during the postoperative period. Eight patients (16%) required endoscopic (1 with biliary endoscopic stent) or radiological (7 with percutaneous drainage) intervention. No patients developed de novo diabetes. On long-term follow-up, 2 patients with invasive intraductal papillary mucinous neoplasia had recurrence; one was treated successfully by completion pancreatectomy and the other died at 20 months. One patient with serous cystadenoma died at 16.8 years without recurrence. One patient with metastatic VIPoma had a liver transplant 9 years postoperatively and is alive. The median follow-up was 55 months (range, 2 months to 16.8 years). The actuarial 5-year patient and pancreatic remnant survival rates were 98% and 95%, respectively. In our series, central pancreatectomy led to effective preservation of both cephalic and distal pancreatic remnants without a significant increase in postoperative morbidity compared with conventional pancreatectomy.

Preoperative chemoradiation in potentially resectable pancreatic adenocarcinoma: feasibility, treatment effect evaluation and prognostic factors, analysis of the SFRO-FFCD 9704 trial and literature review

BACKGROUND We explored the feasibility and the histologic assessment of treatment effect of preoperative chemoradiation in patients presenting with resectable pancreatic adenocarcinoma. PATIENTS AND METHODS Treatment consisted of concurrent radiotherapy (50 Gy within 5 weeks) and chemotherapy with 5-fluorouracil (300 mg/m(2)/day, 5 days/week, weeks 1-5) and cisplatin (20 mg/m(2)/day, days 1-5 and 29-33), followed by surgical resection of the pancreatic tumor in patients without progression. RESULTS In all, 41 patients were enrolled; 38 (93%) received >or=47 Gy; 30 patients (73%) received >or=75% of the prescribed doses of chemotherapy. Among 40 assessable patients, 27 (67.5%; 95% confidence interval 50.9% to 81.4%) were successfully treated (entire dose of radiation, >or=75% of the chemotherapy dose, no grade 4 non-hematologic toxicity). In all, 26 patients (63%) underwent surgical resection with curative intent and 21 (80.7%) had R0 resection. A total of 13 of 26 specimens (50%) presented a major pathologic response (>or=80% of severely degenerative cancer cells), with one complete pathologic response. Operative mortality was 2.8%. The local recurrence and 2-year survival rates were 4% and 32%, respectively, for the 26 operated patients. CONCLUSIONS This proposed preoperative scheme is feasible, does not prevent successful surgery, and provides antitumoral effect associated with major histopathological response in 50% of patients and a high R0 resection rate.

Long-term survival (5-20 years) after pancreatectomy for pancreatic ductal adenocarcinoma: a series of 30 patients collected from 3 institutions.

Objectives: Long-term survival after pancreatectomy for pancreatic duct adenocarcinoma has been rarely reported. Factors influencing survival are still debated. The aim of the study is to report a French multicentric series of long-term survivors after pancreatectomy for pancreatic duct adenocarcinoma. Methods: Data of patients who survived >5 years (February 1983-January 2000) were analyzed. All operative specimens were reviewed. Patients with intraductal-papillary-mucinous-neoplasia, cystadenocarcinoma, acinous-adenocarcinoma, neuroendocrine, or mixed tumors were excluded. Results: Long-term survivors were 20 men and 10 women, with median age of 61 years. Twenty-five patients had pancreaticoduodenectomies (6 pylorus preserving pancreatoduodenectomy [PPPD]), 3 had total pancreaticoduodenectomies, and 2 had splenopancreatectomies. Three patients had portal vein resection, 1 had hepatic artery resection-reconstruction, and 1 had segmentectomy for liver metastasis. All resections were complete macroscopic and microscopic resection (R0). Median tumor size was 30 mm. Tumors were pT2 (n = 1), pT3 (n = 24), pT4 (n = 5), 12 N+, 1 M+. Twenty patients had adjuvant radiotherapy, and 18 had concomitant chemotherapy. Median survival was 7.3 years (range, 5.2-21 years). Nineteen patients are alive, 1 with recurrence and 18 with no evidence of disease (2 had more than 20 years of follow-up). Eleven patients died, 6 from recurrence. Conclusions: Pancreatic duct adenocarcinoma can be cured, and long-term survival after R0 curative surgery has become a reality. Long-term survivors did not fulfil the ideal prognostic criteria and even presented with advanced stage.