Christophe Laurent

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.)

Hepatocellular adenoma management and phenotypic classification: The Bordeaux experience

We took advantage of the reported genotype/phenotype classification to analyze our surgical series of hepatocellular adenoma (HCA). The series without specific known etiologies included 128 cases (116 women). The number of nodules varies from single, <5, and ≥5 in 78, 38, and 12 cases, respectively. The resection was complete in 95 cases. We identified 46 HNF1α‐inactivated HCAs (44 women), 63 inflammatory HCAs (IHCA, 53 women) of which nine were also β‐catenin–activated, and seven β‐catenin–activated HCAs (all women); six additional cases had no known phenotypic marker and six others could not be phenotypically analyzed. Twenty‐three of 128 HCAs showed bleeding. No differences were observed in solitary or multiple tumors in terms of hemorrhagic manifestations between groups. In contrast, differences were observed between the two main groups. Steatosis (tumor), microadenomas (resected specimen), and additional benign nodules were more frequently observed in HNF1α‐inactivated HCAs (P < 0.01) than in IHCAs. Body mass index > 25, peliosis (tumor), and steatosis in background liver were more frequent in IHCA (P < 0.01). After complete resection, new HCAs in the centimetric range were more frequently found during follow‐up (>1 year) in HNF1α‐inactivated HCA. After incomplete resection (HCA left in nonresected liver), the majority of HCA remained stable in the two main groups and even sometimes regressed. Six patients of 128 developed hepatocellular carcinoma (HCC) (all were β‐catenin–activated, whether inflammatory or not). Conclusion: There were noticeable clinical differences between HNF1α–inactivated HCA and IHCA; there was no increased risk of bleeding or HCC related to the number of HCAs; β‐catenin–activated HCAs are at higher risk of HCC. As a consequence, we believe that management of HCA needs to be adapted to the phenotype of these tumors. (HEPATOLOGY 2009.)

Sphincter-Saving Resection for All Rectal Carcinomas: The End of the 2-cm Distal Rule

Objective:To assess oncologic outcome of patients treated by conservative radical surgery for tumors below 5 cm from the anal verge. Summary Background Data:Standard surgical treatment of low rectal cancer below 5 cm from the anal verge is abdominoperineal resection. Methods:From 1990 to 2003, patients with a nonfixed rectal carcinoma at 4.5 cm or less from the anal verge and without external sphincter infiltration underwent conservative surgery. Surgery included total mesorectal excision with intersphincteric resection, that is, removal of the internal sphincter, to achieve adequate distal margin. Patients with T3 disease or internal sphincter infiltration received preoperative radiotherapy. Results:Ninety-two patients with a tumor at 3 (range 1.5–4.5) cm from the anal verge underwent conservative surgery. There was no mortality and morbidity was 27%. The rate of complete microscopic resection (R0) was 89%, with 98% negative distal margin and 89% negative circumferential margin. In 58 patients with a follow-up of more than 24 months, the rate of local recurrence was 2% and the 5-year overall and disease-free survival were 81% and 70%, respectively. Conclusions:The technique of intersphincteric resection permits us to achieve conservative surgery in patients with a tumor close to or in the anal canal without compromising local control and survival. Tumor distance from the anal verge is no longer a limit for sphincter-saving resection.

High frequency of telomerase reverse-transcriptase promoter somatic mutations in hepatocellular carcinoma and preneoplastic lesions

Somatic mutations activating telomerase reverse-trancriptase promoter were recently identified in several tumour types. Here we identify frequent similar mutations in human hepatocellular carcinomas (59%), cirrhotic preneoplastic macronodules (25%) and hepatocellular adenomas with malignant transformation in hepatocellular carcinomas (44%). In hepatocellular tumours, telomerase reverse-transcripase- and CTNNB1-activating mutations are significantly associated. Moreover, preliminary data suggest that telomerase reverse-trancriptase promoter mutations can increase the expression of telomerase transcript. In conclusion, telomerase reverse-trancriptase promoter mutation is the earliest recurrent genetic event identified in cirrhotic preneoplastic lesions so far and is also the most frequent genetic alteration in hepatocellular carcinomas, arising from both the cirrhotic or non-cirrhotic liver.

Laparoscopic Versus Open Surgery for Rectal Cancer: Long-term Oncologic Results

Objective:The goal was to assess long-term oncologic outcome after laparoscopic versus open surgery for rectal cancer and to evaluate the impact of conversion. Summary Background Data:Laparoscopic resection of rectal cancer is technically feasible, but there are no data to evaluate the long-term outcome between laparoscopic and open approach. Moreover, the long-term impact of conversion is not known. Methods:Between 1994 and 2006, patients treated by open (1994–1999) and laparoscopic (2000–2006) curative resection for rectal cancer were included in a retrospective comparative study. Patients with fixed tumors or metastatic disease were excluded. Those with T3–T4 or N+ disease received long course preoperative radiotherapy. Surgical technique and follow-up were standardized. Survival were analyzed by Kaplan Meier method and compared with the Log Rank test. Results:Some 471 patients had rectal excision for invasive rectal carcinoma: 238 were treated by laparoscopy and 233 by open procedure. Postoperative mortality (0.8% vs. 2.6%; P = 0.17), morbidity (22.7% vs. 20.2%; P = 0.51), and quality of surgery (92.0% vs. 94.8% R0 resection; P = 0.22) were similar in the 2 groups. At 5 years, there was no difference of local recurrence (3.9% vs. 5.5%; P = 0.371) and cancer-free survival (82% vs. 79%; P = 0.52) between laparoscopic and open surgery. Multivariate analysis confirmed that type of surgery did not influence cancer outcome. Conversion (36/238, 15%) had no negative impact on postoperative mortality, local recurrence, and survival. Conclusions:The efficacy of laparoscopic surgery in a team specialized in rectal excision for cancer (open and laparoscopic surgery) is suggested with similar long-term local control and cancer-free survival than open surgery. Moreover, conversion had no negative impact on survival.

Volumetric HIFU ablation under 3D guidance of rapid MRI thermometry.

A volumetric sonication method is proposed that produces volume ablations by steering the focal point along a predetermined trajectory consisting of multiple concentric outward-moving circles. This method was tested in vivo on pig thigh muscle (32 ablations in nine animals). Trajectory diameters were 4, 12, and 16 mm with sonication duration depending on the trajectory size and ranging from 20 to 73 s. Despite the larger trajectories requiring more energy to reach necrosis within the desired volume, the ablated volume per unit applied energy increased with trajectory size, indicating improved treatment efficiency for larger trajectories. The higher amounts of energy required for the larger trajectories also increased the risk of off-focus heating, especially along the beam axis in the near field. To avoid related adverse effects, rapid volumetric multiplane MR thermometry was introduced for simultaneous monitoring of the temperature and thermal dose evolution along the beam axis and in the near field, as well as in the target region with a total coverage of six slices acquired every 3 s. An excellent correlation was observed between the thermal dose and both the nonperfused (R=0.929 for the diameter and R=0.964 for the length) and oedematous (R=0.913 for the diameter and R=0.939 for the length) volumes as seen in contrast-enhanced T1-weighted difference images and T2-weighted postsonication images, respectively. Histology confirmed the presence of a homogeneous necrosis inside the heated volumes. These results show that volumetric high-intensity focused ultrasound (HIFU) sonication allows for efficiently creating large thermal lesions while reducing treatment duration and also that the rapid multiplane MR thermometry improves the safety of the therapeutic procedure by monitoring temperature evolution both inside as well as outside the targeted volume.

Hepatocellular adenomas: Magnetic resonance imaging features as a function of molecular pathological classification

Hepatocellular adenomas (HCAs) are a group of benign tumors forming three molecular pathological subgroups: (1) hepatocyte nuclear factor 1α (HNF‐1α)–inactivated, (2) β‐catenin–activated, and (3) inflammatory. Some HCAs present both β‐catenin activation and inflammation. We analyzed magnetic resonance imaging (MRI) data for correlations between features on imaging and pathological classification of HCAs. We included 50 cases for which pathology specimens were classified into three groups based on immunohistochemical staining. Two characteristic MRI profiles were identified corresponding to HNF‐1α–inactivated and inflammatory HCAs. Fifteen HCAs were HNF‐1α–inactivated. The corresponding lesions showed (1) diffuse signal dropout on T1‐weighted chemical shift sequence due to steatosis, (2) isosignal or slight hypersignal on T2‐weighted (T2W) images, and (3) moderate enhancement in the arterial phase, with no persistent enhancement in the portal venous and delayed phases. For the diagnosis of HNF‐1α–inactivated HCA, the positive predictive value of homogeneous signal dropout on chemical shift images was 100%, the negative predictive value was 94.7%, the sensitivity was 86.7%, and the specificity was 100%. Twenty‐three HCAs were inflammatory and showed (1) an absence or only focal signal dropout on chemical shift sequence; (2) marked hypersignal on T2W sequences, with a stronger signal in the outer part of the lesions, correlating with sinusoidal dilatation areas; and (3) strong arterial enhancement, with persistent enhancement in the portal venous and delayed phases. Marked hypersignal on T2W sequences associated with delayed persistent enhancement had a positive predictive value of 88.5%, a negative predictive value of 84%, a sensitivity of 85.2%, and a specificity of 87.5% for the diagnosis of inflammatory HCA. Conclusion: HNF‐1α–mutated HCAs and inflammatory HCAs were associated with specific MRI patterns related to diffuse fat repartition and sinusoidal dilatation, respectively. (HEPATOLOGY 2008.)

Comparison of Functional Results and Quality of Life Between Intersphincteric Resection and Conventional Coloanal Anastomosis for Low Rectal Cancer

PURPOSE:The technique of intersphincteric resection permits sphincter preservation with good oncologic results in very low rectal cancer. This study aimed to investigate functional results and quality of life after intersphincteric resection compared with conventional coloanal anastomoses.METHODS:From 1990 to 2000, 170 patients underwent total mesorectal excision with coloanal anastomosis for low rectal tumors. Questionnaires were obtained from 77 patients alive without colostomy: 37 had a conventional coloanal anastomosis and 40 had intersphincteric resection. Both groups were similar according to age, gender, anastomotic stenosis, colonic pouch, anastomotic leakage, preoperative radiotherapy, and follow-up (median, 56 months). Assessment included one functional and two quality-of-life questionnaires: the SF-36 Health Status and the Fecal Incontinence Quality of Life score.RESULTS:There was no difference in stool frequency, fragmentation, urgency, dyschesia, and alimentary restriction between patients with and without intersphincteric resection. Patients with intersphincteric resection had significantly worse continence (Wexner score, 10.8 vs. 6.9; P < 0.001) and needed more antidiarrheal drugs (60 vs. 35 percent; P = 0.04) than those without. Compared with conventional coloanal anastomoses, quality of life was altered by intersphincteric resection for the subscale embarrassment (P < 0.01) in the Fecal Incontinence Quality of Life score, whereas no difference of quality of life was observed with SF-36.CONCLUSIONS:Compared with conventional coloanal anastomoses, patients with intersphincteric resection have a higher risk of fecal incontinence and a slightly altered quality of life.

Intersphincteric resection with excision of internal anal sphincter for conservative treatment of very low rectal cancer

PURPOSE: Standard surgical treatment for low rectal cancer situated below 5 cm from the anal verge or at less than 1 cm from the anal ring is abdominoperineal resection. This is because of the necessity both to achieve a sufficient distal margin and to preserve the whole of the anal sphincter. The aim of this study was to evaluate morbidity, oncologic, and functional results of intersphincteric resection with excision of the internal anal sphincter and low coloanal anastomosis for carcinomas of the anorectal junction. METHODS: From January 1990 to December 1996, 16 patients were studied prospectively. All patients had an infiltrating adenocarcinoma (5 T2 and 11 T3), located between 2.5 and 4.5 (mean, 3.6) cm from the anal verge. Rectal resection with a minimum distal margin of 2 (mean, 2.4) cm was performed in all cases; six patients underwent partial resection of the internal sphincter, and ten patients had a subtotal resection. A colonic J-pouch was associated with coloanal anastomoses in eight cases. Twelve patients had preoperative radiotherapy, 3 with concomitant chemotherapy; 5 patients had postoperative chemotherapy. RESULTS: There was no post-operative mortality. Morbidity occurred in four patients, of whom two underwent permanent colostomy after pelvic hemorrhage or anovaginal fistula. After a median follow-up of 44 (range, 11–92) months, no local recurrence was observed, and two patients died of distal metastases. The five-year actuarial survival rate was 75 percent. Continence was normal in one-half of patients and was altered in the other patients who suffered from occasional minor leaks. The median resting pressure was lower after subtotal than after partial resection of the internal sphincter (40vs. 70 cm H2O;P=0.02), but functional results were similar in the two groups. CONCLUSION: These preliminary results suggest that intersphincteric resection can be an alternative to abdominoperineal resection for selected rectal tumors situated at the anorectal junction, without compromising chance of cure. Functional results and continence were not altered by subtotal resection of the internal anal sphincter.

Lymph nodes after preoperative chemoradiotherapy for rectal carcinoma: number, status, and impact on survival.

The number and status of lymph nodes examined is crucial for tumor staging. Impact of preoperative chemoradiotherapy on lymph nodes status and survival is still controversial in rectal carcinoma. The aim of this study was (i) to define the impact of preoperative chemoradiotherapy on the number of both retrieved and positive lymph nodes in rectal cancer specimen, (ii) to evaluate the influence of the number of lymph nodes retrieved on survival in patients treated by preoperative chemoradiotherapy. From 1994 to 2004, 495 patients underwent rectal excision for cancer, of which 332 received long course preoperative radiotherapy. Surgery and pathologic assessment were standardized. Multivariate analysis evaluated the influence of clinical and pathologic variables on the number of both retrieved and positive lymph nodes. Kaplan-Meier method and log-rank test assessed the relation between survival and the number of lymph nodes retrieved in patients treated by preoperative chemoradiotherapy. Compared with surgery alone, preoperative chemoradiotherapy decreased both the mean number of lymph nodes retrieved (17 vs. 13; P<0.001) and the mean number of positive lymph nodes (2.3 vs. 1.2; P=0.001). Multivariate analysis confirmed the independent impact of preoperative chemoradiotherapy on retrieved and positive lymph nodes. In patients treated by preoperative chemoradiotherapy, the 5-year overall (71%) and disease-free (60%) survival was not associated with the number of lymph nodes retrieved. Although long course preoperative chemoradiotherapy decreases by 24%, the mean number of lymph nodes retrieved and by 48% the mean number of positive lymph nodes, survival was not influenced by the number of lymph nodes retrieved in irradiated rectal specimen.