c-MYC amplification and c-myc protein expression in pancreatic acinar cell carcinomas. New insights into the molecular signature of these rare cancers.

The molecular alterations of pancreatic acinar cell carcinomas (ACCs) and mixed acinar-neuroendocrine carcinomas (MANECs) are not completely understood, and the possible role of c-MYC amplification in tumor development, progression, and prognosis is not known. We have investigated c-MYC gene amplification in a series of 35 ACCs and 4 MANECs to evaluate its frequency and a possible prognostic role. Gene amplification was investigated using interphasic fluorescence in situ hybridization analysis simultaneously hybridizing c-MYC and the centromere of chromosome 8 probes. Protein expression was immunohistochemically investigated using a specific monoclonal anti-c-myc antibody. Twenty cases had clones with different polysomies of chromosome 8 in absence of c-MYC amplification, and 5 cases had one amplified clone and other clones with chromosome 8 polysomy, while the remaining 14 cases were diploid for chromosome 8 and lacked c-MYC amplification. All MANECs showed c-MYC amplification and/or polysomy which were observed in 54% pure ACCs. Six cases (15.3%) showed nuclear immunoreactivity for c-myc, but only 4/39 cases showed simultaneous c-MYC amplification/polysomy and nuclear protein expression. c-myc immunoreactivity as well as c-MYC amplification and/or chromosome 8 polysomy was not statistically associated with prognosis. Our study demonstrates that a subset of ACCs shows c-MYC alterations including gene amplification and chromosome 8 polysomy. Although they are not associated with a different prognostic signature, the fact that these alterations are present in all MANECs suggests a role in the acinar-neuroendocrine differentiation possibly involved in the pathogenesis of MANECs.

TP53 alterations in pancreatic acinar cell carcinoma: new insights into the molecular pathology of this rare cancer.

The molecular alterations of pancreatic acinar cell carcinomas (ACCs) are poorly understood and have been reported as being different from those in ductal adenocarcinomas. Loss of TP53 gene function in the pathogenesis of ACCs is controversial since contradictory findings have been published. A comprehensive analysis of the different possible genetic and epigenetic mechanisms leading to TP53 alteration in ACC has never been reported and hence the role of TP53 in the pathogenesis and/or progression of ACC remains unclear. We investigated TP53 alterations in 54 tumor samples from 44 patients, including primary and metastatic ACC, using sequencing analysis, methylation-specific multiplex ligation probe amplification, fluorescence in situ hybridization, and immunohistochemistry. TP53 mutations were found in 13 % of primary ACCs and in 31 % of metastases. Primary ACCs and metastases showed the same mutational profile, with the exception of one case, characterized by a wild-type sequence in the primary carcinoma and a mutation in the corresponding metastasis. FISH analysis revealed deletion of the TP53 region in 53 % of primary ACCs and in 50 % of metastases. Promoter hypermethylation was found in one case. The molecular alterations correlated well with the immunohistochemical findings. A statistically significant association was found between the combination of mutation of one allele and loss of the other allele of TP53 and worse survival.

Breast metastasis as the first clinical manifestation of ileal neuroendocrine tumor. A challenging diagnosis with relevant clinical implications.

Ileal neuroendocrine tumors are slow-growing grade 1 or, more rarely, grade 2 neuroendocrine tumors which, however, are frequently metastatic to regional lymph nodes and the liver. A few cases of ileal neuroendocrine tumors that are metastatic to the breast have also been reported in the medical literature. The knowledge of this uncommon clinical presentation is of great importance because it needs to be differentiated from primary breast carcinomas with neuroendocrine features, which represent completely different entities with a different therapeutic approach. The diagnosis of a breast metastasis from an ileal neuroendocrine tumor and its distinction from a well-differentiated primary neuroendocrine tumor of the breast is a challenging task for clinicians and pathologists. This workup is particularly difficult when the breast lesion is the first sign of malignancy. In the present paper, we describe the clinicopathological features of an ileal neuroendocrine tumor first presenting with a breast metastasis in a 50-year-old woman and we discuss the key diagnostic features for the differential diagnosis with primary well-differentiated neuroendocrine tumor of the breast. Moreover, we have reviewed the medical literature to give the reader a comprehensive overview on this topic.

APC alterations are frequently involved in the pathogenesis of acinar cell carcinoma of the pancreas, mainly through gene loss and promoter hypermethylation.

Genetic and epigenetic alterations involved in the pathogenesis of pancreatic acinar cell carcinomas (ACCs) are poorly characterized, including the frequency and role of gene-specific hypermethylation, chromosome aberrations, and copy number alterations (CNAs). A subset of ACCs is known to show alterations in the APC/ß-catenin pathway which includes mutations of APC gene. However, it is not known whether, in addition to mutation, loss of APC gene function can occur through alternative genetic and epigenetic mechanisms such as gene loss or promoter methylation. We investigated the global methylation profile of 34 tumor suppressor genes, CNAs of 52 chromosomal regions, and APC gene alterations (mutation, methylation, and loss) together with APC mRNA level in 45 ACCs and related peritumoral pancreatic tissues using methylation-specific multiplex ligation probe amplification (MS-MLPA), fluorescence in situ hybridization (FISH), mutation analysis, and reverse transcription-droplet digital PCR. ACCs did not show an extensive global gene hypermethylation profile. RASSF1 and APC were the only two genes frequently methylated. APC mutations were found in only 7 % of cases, while APC loss and methylation were more frequently observed (48 and 56 % of ACCs, respectively). APC mRNA low levels were found in 58 % of cases and correlated with CNAs. In conclusion, ACCs do not show extensive global gene hypermethylation. APC alterations are frequently involved in the pathogenesis of ACCs mainly through gene loss and promoter hypermethylation, along with reduction of APC mRNA levels.

Clinicopathologic study of 62 acinar cell carcinomas of the pancreas: insights into the morphology and immunophenotype and search for prognostic markers.

Acinar cell carcinoma (ACC) of the pancreas is a very rare tumor that has various morphologic features, which may give rise to diagnostic difficulties. Because of its rarity, many clinicopathologic characteristics remain to be further elucidated, and prognostic factors are yet to be well established. With the aim of better characterizing this carcinoma and searching for prognostic indicators, we collected 62 ACCs and investigated the following parameters: site, size, local infiltration, node and distant metastases, architectural pattern, nuclear atypia, presence of necrosis, lymphovascular and perineural invasion, proliferation, BCL10, trypsin, carboxyl ester lipase, amylase, lipase, PDX1, cytokeratin 19 (CK19), CK7, p53, and ß-catenin expression. Twelve cases showing >30% of endocrine cells were reclassified as mixed acinar-neuroendocrine carcinomas, whereas 1 tumor was reclassified as a mixed ductal-acinar carcinoma and was excluded from the statistical prognostic evaluations. BCL10 and trypsin were the most reliable immunohistochemical markers, whereas amylase and lipase were not. Surgery was statistically correlated with a better prognosis (P=0.0008). Among resected tumors there was no difference in survival between ACCs and mixed acinar-neuroendocrine carcinomas, and factors that significantly correlated with poor prognosis were size >6.5 cm (P=0.004), lymph node (P=0.0039) and distant (P=0.008) metastases, and UICC stage (P=0.009). Stage was the only independent prognostic factor at multivariable analysis, and the best prognostic discrimination was observed on grouping together stages I and II and grouping together stages III and IV, suggesting a simplification of the UICC staging for such cancers. In addition, vascular and perineural invasion and CK19 and p53 expression showed a trend for poor prognosis, not reaching statistical significance.

Sinusoidal obstruction syndrome compromises liver regeneration in patients undergoing two-stage hepatectomy with portal vein embolization.

PURPOSE: Several factors have been reported to affect liver regeneration after portal vein embolization (PVE); however, the effect of sinusoidal obstruction syndrome (SOS) has not been evaluated. Therefore, we assessed the effect of SOS on liver regeneration after PVE in patients with multiple bilobar colorectal liver metastases scheduled to undergo two-stage hepatectomy (TSH) combined with PVE. METHODS: The subjects of this study were 78 patients prospectively scheduled to undergo TSH between December 1996 and August 2009. Archived formalin-fixed, paraffin-embedded nontumoral tissue samples were collected from the 1st- and 2nd-stage hepatectomies in 42 and 45 patients, respectively, and SOS and steatohepatitis were diagnosed pathologically. We analyzed the clinicopathological variables affecting liver regeneration after PVE. RESULTS: Sinusoidal obstruction syndrome was diagnosed in 11 (26.2%) and 20 patients (44.4%) at the time of the 1st- and 2nd-stage hepatectomy, respectively. Patients with SOS at the 1st-stage hepatectomy had a significantly lower hypertrophy ratio of the future remnant liver (FRL) after PVE than patients without SOS (16.8 ± 24.0 vs 55.6 ± 32.5; P < 0.001). Multivariate logistic regression analysis revealed that SOS was an independent factor predicting lower FRL hypertrophy after PVE (Δ% FRL <20: hazard ratio 31.7, 95% confidence interval 2.84-355.12; P = 0.005). The incidence of postoperative transient liver failure after the 2nd-stage hepatectomy in patients presenting with SOS was higher than that in those without SOS, but the difference did not reach significance (25.0% vs 4.0%; P = 0.052). Steatohepatitis was confirmed at the 1st- and 2nd-stage hepatectomy in 6 (14.3%) and 3 (6.7%) patients, respectively. CONCLUSION: Sinusoidal obstruction syndrome inhibits FRL hypertrophy after PVE and induces postoperative liver failure. Therefore, an alternative strategy is needed to perform TSH safely in the presence of SOS.

Histological and immediate postoperative outcome after preoperative cetuximab: case-matched control study.

BACKGROUND: The aim of this study was to analyze the effects of preoperative cetuximab (cetu) on nontumorous liver parenchyma and the clinical and biological outcomes after liver resection for colorectal liver metastases (CLM). METHODS: Between January 2005 and June 2009, 26 patients who received preoperative cetu were matched to a control group of 26 patients who did not receive cetu. They were matched on the basis of age, gender, body mass index, extent of hepatectomy, and type and number of cycles of neoadjuvant chemotherapy. RESULTS: Liver function tests, postoperative outcome, and histopathology of the resected liver were compared. There was no mortality. Postoperative morbidity and perioperative bleeding rates were similar in both groups. Serum aspartate aminotransferase and serum alanine aminotransferase were higher on postoperative day 5 in the control group (p = 0.02 and p = 0.04, respectively). In the cetu group, the postoperative peaks of γ-glutamyl transpeptidase and alkaline phosphatase were statistically higher than in the control group. Interestingly, pathological review of the nontumorous liver parenchyma revealed no significant difference between patients who received cetu and those treated without cetu with respect to prevalence of steatosis, steatohepatitis, sinusoidal obstructive syndrome, and fibrosis. CONCLUSIONS: The addition of cetu to the neoadjuvant chemotherapy regimens does not appear to increase the morbidity rate after hepatectomy for CLM, and also in cases of major hepatectomy. The pathological examination did not show additional injury to the nontumorous liver parenchyma.

The role of "fatty pancreas" and of BMI in the occurrence of pancreatic fistula after pancreaticoduodenectomy.

INTRODUCTION: Pancreatic fistula (PF) after pancreaticoduodenectomy (PD) is still a serious complication. We hypothesized that the amount of fatty tissue in the pancreatic parenchyma could be associated with the occurrence of PF after PD with pancreatogastrostomy. MATERIAL AND METHODS: From January 2004 to December 2006, 111 consecutive patients underwent PD with pancreatogastrostomy. The microscopic amount of fatty tissue in the pancreas was evaluated. RESULTS: The morbidity and mortality rates were 35.1% and 1.8%, respectively. PF occurred in 10.8% (n = 12). PF was of grade A in nine, grade B in two, and grade C in one patient. Univariate analysis showed that a body mass index (BMI) > 25 (P = 0.035), a soft pancreatic parenchyma (P = <0.003), a pancreatic duct size <3 mm (P = 0.015), and a fatty infiltration of the pancreas of more than 10% (P = 0.0003) were associated with the occurrence of PF. The advanced age (P = 0.049) and the BMI (P < 0.0001) were significantly associated with the presence of >10% of pancreatic fat. CONCLUSIONS: A pancreatic fatty infiltration of the pancreas over 10% constitutes a risk factor for PF after PD. Age and BMI are useful preoperative predictors of the percentage of pancreatic fat.

[Internal quality control of histological diagnosis in pathology. A nine-year experience]. / Le contrôle qualité interne du diagnostic histologique en anatomie et cytologie pathologiques. A propos d'un vécu de neuf années.

Internal quality control (IQC) is a necessary component of total quality management. We report our experience with an internal audit scheme focusing on the histological diagnosis. We outline other strategies of IQC and analyze the causes of errors and ways to prevent them. Some practical guidelines to initiate this type of procedure are presented. Our audit was designed to check the accuracy of diagnosis, the clarity and completeness of the report, the quality of the documents leading to the diagnosis, and the turn-around time. It consisted of a retrospective analysis of 4185 randomly selected cases (representing 2% of all cases), over nine years. The control took place once a week and was done by two pathologists working as a team. The mean time spent by each pathologist was 45 minutes per week. Errors were scored using a 3-level grading scheme depending on their potential harm or impact on patient care. The overall rate of errors was 1.1%, and 0.1% of errors were potentially harmful to the patients. A single case (0.02%), in which a cancer was missed, had a real impact on patient care. Retrospective analysis of randomly selected cases mirrors the overall activity of a surgical pathology department. Nevertheless, each lab has to develop its own strategy of IQC, based on its size, its functioning, and its objectives. Although it may be difficult to initiate quality assurance when medical time is already limited, it is a helpful procedure in a more and more demanding medical and societal context and a pragmatic step towards "culture of quality".

Sinusoidal injury increases morbidity after major hepatectomy in patients with colorectal liver metastases receiving preoperative chemotherapy.

OBJECTIVE: To investigate whether sinusoidal injury (SI) was associated with a worse outcome after hepatectomy in patients with colorectal liver metastases (CRLM). BACKGROUND: Correlation between SI and oxaliplatin-based chemotherapy (OBC) was recently shown in patients with CRLM. However, it has yet to be fully clarified whether SI affects liver functional reserve and outcome after hepatectomy. PATIENTS AND METHODS: Between 2003 and 2005, 90 patients with CRLM who underwent an elective hepatectomy after preoperative chemotherapies were included. Diagnosis of SI was established pathologically in the nontumoral liver parenchyma of the resected specimens, and perioperative data were assessed in these patients. RESULTS: OBC was significantly associated with a higher incidence of SI. Preoperative indocyanine green retention rate at 15 minutes (ICG-R15) and postoperative value of total-bilirubin were significantly higher, and hospital stay was significantly longer in patients presenting with SI. Multivariate analysis showed that female gender, administration of 6 cycles or more of OBC, abnormal value of preoperative aspartate aminotransferase >36 IU/L, or abnormal value of preoperative ICG-R15 (>10%) were preoperative factors significantly associated with SI. Among patients undergoing a major hepatectomy, SI was significantly associated with higher morbidity and longer hospital stay. CONCLUSION: The present study suggests that SI resulted in a poorer liver functional reserve and in a higher complication rate after major hepatectomy. Therefore, female patients who received 6 cycles or more of OBC, or presenting with abnormal preoperative aspartate aminotransferase and ICG-R15 values should be carefully selected before deciding to undertake a major hepatectomy.

Asymptomatic cardiac papillary fibroelastoma: diagnostic assessment and therapy.

Papillary fibroelastoma is a rare benign cardiac tumor with elevated risk for embolization. This report describes the case of a 65-year-old man, admitted for the occasional finding of a round, pedunculate mass adherent to the chordae of the anterior mitral valve leaflet, mimicking an endocarditic mass. Appropriate diagnostic evaluations lead to the suspect of a papillary fibroelastoma. Because of the elevated risk of thromboembolism, surgery was emergently performed with complete removal of the mass and preservation of the integrity of the mitral valve. Histologic evaluation confirmed the diagnosis. Papillary fibroelastoma should be always considered in the differential diagnosis of intracardiac masses.