Prognostic performance of microscopic size measurements in small invasive carcinomas arising in intraductal papillary mucinous neoplasms of the pancreas.

AIMS: Small invasive carcinomas arising in intraductal papillary mucinous neoplasms (IPMNs) of the pancreas can present as multiple, small foci. In such cases, there is no clear optimal measurement method for determining the invasive size for tumour staging and prognostication. METHODS: In all, 117 small invasive IPMNs (size of largest invasive component ≤2 cm) from seven institutions (2000-2016) were reviewed, and all individual foci of invasive carcinoma were measured. T stages (AJCC 8th edition) based on the largest single focus size (LS), average size of all foci (AS), and total sum of all foci (TS) were examined in association with clinicopathologic parameters and patient outcomes. RESULTS: The cohort comprised IPMNs with invasive tubular-type (n = 82, 70%) and colloid-type (n = 35, 30%) carcinomas. The mean LS, AS, and TS were 0.86, 0.71, and 1.32 cm, respectively. Based on the LS, AS, and TS, respectively, 48, 65, and 39 cases were classified as pT1a; 22, 18, and 11 cases as pT1b; and 47, 34, and 50 cases as pT1c. Higher pT stages based on all measurements were significantly associated with small vessel, large vessel, and perineural invasion (P < 0.05). LS-, AS-, and TS-based pT stages were not significantly associated with recurrence-free survival (RFS) or overall survival (OS) by univariate or multivariate analyses. However, among tubular-type carcinomas, higher LS-, AS-, and TS-based pT stages trended with lower RFS (based on 1-, 3-, and 5-year survival rates). All microscopic measurement methods were most predictive of RFS and OS using a 1.5-cm cutoff, with LS significantly associated with both RFS and OS by univariate and multivariate analysis. CONCLUSIONS: For invasive tubular-type carcinomas arising in IPMN, microscopic size-based AJCC pT stages were not significant predictors of patient outcomes. However, for LS, a size threshold of 1.5 cm was optimal for stratifying both RFS and OS. The AJCC 8th ed. may not be applicable for stratifying small invasive IPMNs with colloid-type histology that generally portend a more favourable prognosis.

Membrane-bound MMP-14 protease-activatable adeno-associated viral vectors for gene delivery to pancreatic tumors.

Adeno-associated virus' (AAV) relatively simple structure makes it accommodating for engineering into controllable delivery platforms. Cancer, such as pancreatic ductal adenocarcinoma (PDAC), are often characterized by upregulation of membrane-bound proteins, such as MMP-14, that propagate survival integrin signaling. In order to target tumors, we have engineered an MMP-14 protease-activatable AAV vector that responds to both membrane-bound and extracellularly active MMPs. This "provector" was generated by inserting a tetra-aspartic acid inactivating motif flanked by the MMP-14 cleavage sequence IPESLRAG into the capsid subunits. The MMP-14 provector shows lower background transduction than previously developed provectors, leading to a 9.5-fold increase in transduction ability. In a murine model of PDAC, the MMP-14 provector shows increased delivery to an allograft tumor. This proof-of-concept study illustrates the possibilities of membrane-bound protease-activatable gene therapies to target tumors.

Molecular Evidence for Monoclonal Skip Progression in Main Duct Intraductal Papillary Mucinous Neoplasms of the Pancreas.

OBJECTIVE: To clarify clonality of distinct multisegmental main duct (MD)-intraductal papillary mucinous neoplasms (IPMNs) using microarray analysis. BACKGROUND: IPMNs represent a pancreatic ductal cell field defect, which causes multiple occurrences of lesions. In addtion, it has been speculated that MD-IPMNs display features of monoclonal skip progression. METHODS: Total RNA was extracted from fresh-frozen tissue samples of metachronous MD-IPMNs and nonneoplastic pancreas tissue from the same pancreas from two individuals, and whole human genome microarray analysis was performed. Formalin-fixed paraffin-embedded tissue specimens from 28 distinct IPMNs were then collected from 12 patients, genomic DNA was extracted, and GNAS/KRAS mutational status was investigated. Immunohistochemical analysis was performed to validate the expression pattern of the indicated proteins. RESULTS: Microarray analysis revealed that metachronous MD-IPMNs from the same individual displayed pair-wise correlation coefficients of 0.9523 and 0.9512. In contrast, MD-IPMNs of the same histological grade from different individuals displayed coefficients of 0.8092 and 0.8211. Scatter plot analysis revealed that metachronous MD-IPMNs from the same individual displayed a closer linear relationship. Furthermore, heat map and hierarchical cluster analyses revealed that metachronous MD-IPMNs from the same individual were classified in the same branch, and the gene expression patterns were similar. The GNAS/KRAS mutational statuses of distinct MD-IPMNs were consistent with each other. Immunohistochemical assessment of five specific proteins demonstrated that the same expression pattern between two lesions was observed in 95% of the samples. CONCLUSIONS: These findings using molecular analyses indicate that MD-IPMNs might display features of monoclonal skip progression.

GNAS and KRAS mutational analyses of intraductal papillary neoplasms of the pancreas and bile duct developing in the same individual: A case report.

Intraductal papillary mucinous neoplasm (IPMN) of the pancreas and intraductal papillary neoplasm of the bile duct (IPNB) are considered as counterparts of each other, and it is suggested that these two entities have similar molecular alteration pathways. However, the occurrence of IPMN of the pancreas and IPNB in the same patient is rare. We report a surgical case of a 69-year-old woman who developed invasive IPMN of the pancreas and underwent pancreatectomy, 6 months after hepatic resection of invasive IPNB. Molecular analysis revealed GNAS/KRAS mutation in both invasive IPMN of the pancreas and IPNB. This is believed to be the first case report investigating GNAS/KRAS mutational status in both IPMN of the pancreas and IPNB developing in the same patient, and these two entities may show similar molecular alternations.

Conversion surgery for initially unresectable locally advanced pancreatic ductal adenocarcinoma after chemotherapy followed by carbon-ion radiotherapy: a case report.

BACKGROUND: Recent advances in chemotherapy and chemoradiotherapy have enabled conversion surgery (CS) to be performed for selected patients with initially unresectable locally advanced (LA) pancreatic ductal adenocarcinoma (PDAC). Many studies indicate CS might extend the survival of patients with initially unresectable LA PDAC. However, several clinical questions concerning CS remain, such as the optimal preoperative treatment. Carbon-ion radiotherapy (CIRT) is a unique radiotherapy that offers higher biological effectiveness than conventional radiotherapy. Here, we report a long-term survival case with initially unresectable LA PDAC who underwent CS after chemotherapy followed by CIRT. CASE PRESENTATION: The patient was a 72-year-old Japanese woman with unresectable LA pancreatic head cancer with tumor contact to the superior mesenteric artery (SMA). She underwent four courses of chemotherapy (gemcitabine plus nanoparticle albumin-bound paclitaxel). However, the lesion did not shrink and tumor contact with the SMA did not improve after chemotherapy. Because the probability of achieving curative resection was judged to be low, she underwent radical dose CIRT, and chemotherapy was continued. She complained of vomiting 2 months after CIRT. Although imaging studies showed no tumor growth or metastasis, a duodenal obstruction which was speculated to be an adverse effect of CIRT was observed. She could not eat solid food and a trans-nasal feeding tube was inserted. Therapeutic intervention was required to enable enteral nutrition. We proposed several treatment options. She chose resection with the expectation of an anti-tumor effect of chemotherapy and CIRT rather than course observation with tube feeding or bypass surgery. Therefore, subtotal-stomach-preserving pancreatoduodenectomy with portal vein resection was performed as CS. Pathological examination of the resected specimen revealed an R0 resection with a histological response of Evans grade IIA. Postoperatively, she recovered uneventfully. Adjuvant chemotherapy with tegafur/gimeracil/oteracil (S1) was administrated. At the time of this report, 5 years have passed since the initial consultation and she has experienced no tumor recurrence. CONCLUSIONS: The present case suggests that multidisciplinary treatment consisting of a combination of recent chemotherapy and CIRT may be beneficial for unresectable LA PDAC. However, further studies are required to assess the true efficacy of this treatment strategy.

Mixed neuroendocrine-non-neuroendocrine neoplasm of the ampulla of Vater: a case report.

BACKGROUND: Mixed neuroendocrine-non-neuroendocrine neoplasms of the ampulla of Vater are rare and heterogenous, making it difficult to achieve a definitive preoperative diagnosis. Herein, we describe a patient in whom a provisional diagnosis of mixed neuroendocrine-non-neuroendocrine neoplasm of the ampulla of Vater was made preoperatively. CASE PRESENTATION: Computed tomography revealed an enhancing periampullary tumor in a 69-year-old man with obstructive jaundice. Subsequent duodenoscopy revealed an ulcerated lesion in the swollen ampulla of Vater, from which six biopsies were collected. Pathological examination revealed adenocarcinoma in five of them. The remaining one was a neuroendocrine neoplasm according to immunohistochemical analysis. With a provisional diagnosis of mixed neuroendocrine-non-neuroendocrine neoplasm of the ampulla of Vater, the patient underwent subtotal stomach-preserving pancreaticoduodenectomy with modified Child's reconstruction and was discharged without complications. Pathological examination revealed both adenocarcinoma and neuroendocrine carcinomas, each accounting for ≥ 30% of the tumor, resulting in a definitive diagnosis of mixed neuroendocrine-non-neuroendocrine neoplasm of the ampulla of Vater. Lymph node metastases with neuroendocrine components were also observed. Adjuvant chemotherapy was not administered because of the patient's renal dysfunction. Liver and lymph node metastases were detected 2 months after surgery, the neuroendocrine component being considered responsible for that relapse. The patient underwent platinum-based chemotherapy at 50% dosage, which initially resulted in significant tumor shrinkage; however, he died 6 months after surgery. CONCLUSIONS: While these tumors' heterogeneity make definitive preoperative diagnosis of mixed neuroendocrine-non-neuroendocrine neoplasm of the ampulla of Vater difficult, the possibility of this disease can be considered by careful examination. Further study is needed to establish the optimal diagnostic criteria and treatment strategy.

Preoperative frailty as a predictive factor for postoperative complications in patients with pancreatic cancer.

Frailty is considered one of the most important indicators of a patient's general condition. However, only a few studies have investigated the association between preoperative frailty and postoperative complications in pancreatic cancer. Therefore, this study aimed to examine this association in patients with pancreatic cancer. We retrospectively reviewed 52 consecutive patients who underwent pancreatectomy for pancreatic cancer between July 2019 and March 2021. Patients were classified into two groups according to the presence of postoperative complications. Their characteristics and clinical parameters, including physical function, were analyzed. Patients with postoperative complications had a higher prevalence of frailty (58.8% vs 14.3%, p = 0.003) and a shorter 6-min walk distance (380 m vs 436 m, p = 0.020) than those without postoperative complications. Logistic regression analysis identified preoperative frailty as the only independent risk factor for complications after pancreatectomy (p = 0.002). Preoperative frailty is associated with postoperative complications of pancreatectomy. Since preoperative frailty can be easily evaluated, it is a useful predictor of postoperative complications after pancreatectomy.

Pyogenic liver abscesses concomitant with advanced gastric cancer: a case report.

It has been reported that gastric cancer rarely causes pyogenic liver abscesses because of its mucosal acid barrier. Herein, we describe a rare case of pyogenic liver abscesses concomitant with advanced gastric cancer. A 61-year-old man was transferred to our hospital with persistent nausea and fever. Computed tomography showed a lobulated lesion in the caudate lobe of the liver, slightly rim-enhanced lesions in the right lobe, enhanced mass on the lesser curvature of the upper gastric body, and enlarged regional lymph nodes. Subsequent upper gastrointestinal endoscopy revealed a type 3 tumor on the lesser curvature of the upper gastric body; pathological examination of a biopsy showed adenocarcinoma. After treatment with antibiotics, the lesion in the caudate lobe decreased in size and the enhanced lesions in the right lobe resolved. The patient underwent curative gastrectomy; the pathological diagnosis was gastric cancer, T4aN3aM0 stage IIIB, according to the Japanese classification of gastric carcinoma (Third English edition). The patient was discharged without complications and underwent adjuvant chemotherapy. Gastric cancer can cause pyogenic liver abscesses. Although differentiating between liver abscesses and hepatic metastases can be difficult, multidisciplinary and appropriate treatment strategies are needed.

Recurrent intraductal papillary mucinous neoplasms of the pancreas mimicking ampullary cancer.

Although several studies have reported that some patients developed metachronous/recurrent intraductal papillary mucinous neoplasms (IPMNs) after partial pancreatectomy, recurrence of IPMN mimicking ampullary cancer is extremely rare. We report the case of a 62-year-old man who developed recurrent IPMN mimicking ampullary cancer. Every 3-6 months, the patient had received surveillance with computed tomography after distal pancreatectomy for IPMN, high-grade, pancreatobiliary type. However, a villous tumor at the major duodenal papilla was found incidentally by upper gastrointestinal endoscopy 2 years and 3 months after initial surgery, and the biopsy result was adenocarcinoma. Endoscopic ultrasonography showed a tumor at the periampullary lesion; however, the origin of the tumor could not be determined definitively. Remnant total pancreatectomy was performed, and the histological diagnosis revealed IPMN, high-grade, pancreatobiliary type. Some patients develop recurrent IPMN mimicking ampullary cancer; thus, careful surveillance for periampullary lesions as well as remnant pancreas should be performed.

Asymptomatic malignant melanoma of the gallbladder with multiple brain metastases diagnosed with endoscopic ultrasound-guided fine-needle aspiration cytology.

Malignant melanoma of the gallbladder (MMG) is extremely rare and its early stage diagnosis is difficult. Most reports of MMG describe metastatic tumors. We herein report a rare case of presumed primary MMG diagnosed by endoscopic ultrasonography-guided fine-needle aspiration (EUS-FNA) cytology without surgical resection. A 72-year-old Japanese male was diagnosed with multiple brain metastases. Fluorodeoxyglucose (FDG) positron emission tomography showed an abnormal uptake of FDG at the gallbladder; enhanced CT and MRI also showed an enhanced gallbladder lesion, which indicated a malignancy. We performed endoscopic naso-gallbladder drainage. However, cytological examination of the drained bile showed no evidence of malignancy. Finally, EUS-FNA was performed to confirm the histological diagnosis; cytopathological assessment, including immunohistochemical analysis, showed a cluster of small to large-sized cells with nuclear pleomorphism and melanin pigment, which was compatible with malignant melanoma. The patient subsequently underwent chemotherapy; however, he died 2 months after diagnosis. In patients with gallbladder tumors, MMG should be suspected even in patients with no history of malignant melanoma or any cutaneous lesions. EUS-FNA is safe and useful to confirm histological diagnoses and to determine optimal treatment strategies.

Laparoscopic treatment of intestinal obstruction due to a vitelline vascular remnant and simultaneous appendicitis: a case report.

BACKGROUND: The presence of a vitelline vascular remnant is rare, and definitive preoperative diagnosis is difficult. We herein describe a case of intestinal obstruction caused by a vitelline vascular remnant with mild chronic appendicitis successfully diagnosed and treated with laparoscopic surgery. CASE PRESENTATION: A 14-year-old male was admitted to our hospital with sudden-onset right lower abdominal pain and vomiting. A blood test on admission revealed slight leukocytosis. Computed tomography scan showed that the appendiceal wall was enhanced and thickened. Although the ileum was slightly dilated and ascites was present at the recto-vesical pouch, these were thought to be inflammatory changes secondary to appendicitis. Laparoscopic surgery was performed using three trocars. Strangulated small bowel obstruction caused by a band connecting the right medial umbilical fold to the ileal mesentery was found intraoperatively. After reduction, neither ischemic change of the small intestine nor Meckel's diverticulum was detected. The appendix was slightly inflamed, and serous ascites was present at the recto-vesical pouch; therefore, appendectomy was also performed. The patient was discharged on postoperative day 4 without complications. Pathological examination revealed that the band consisted of blood vessels, and it was diagnosed as a vitelline vascular remnant. The appendix included fecal stones and showed chronic inflammatory change histologically; the patient was thus diagnosed with chronic appendicitis. CONCLUSIONS: Definitive preoperative diagnosis of a vitelline vascular remnant, especially with coexisting appendicitis, might be difficult. Laparoscopic surgery might be useful for patients who demonstrate unusual symptoms because it allows for simultaneous diagnosis and treatment.

Surveillance of patients with intraductal papillary mucinous neoplasm with and without pancreatectomy with special reference to the incidence of concomitant pancreatic ductal adenocarcinoma.

BACKGROUND: The presence of an intraductal papillary mucinous neoplasm is important in the detection of concomitant pancreatic ductal adenocarcinoma. The aim of this study was to elucidate the incidence and timing of development of concomitant pancreatic ductal adenocarcinoma in patients with and without pancreatectomy for intraductal papillary mucinous neoplasm. METHODS: We reviewed retrospectively the surveillance data for 22 patients who underwent pancreatectomy for pancreatic ductal adenocarcinoma concomitant with intraductal papillary mucinous neoplasm (pancreatic ductal adenocarcinoma-resection group), 180 who underwent pancreatectomy for intraductal papillary mucinous neoplasm (intraductal papillary mucinous neoplasm-resection group), and 263 whose intraductal papillary mucinous neoplasms were left untreated (nonresection group). The incidence and timing of the development of a concomitant pancreatic ductal adenocarcinoma during the surveillance of patients with and without partial pancreatectomy for intraductal papillary mucinous neoplasm were investigated using the Kaplan-Meier method. RESULTS: During a median surveillance period of 40 months (range 6-262 months), 5 patients in the pancreatic ductal adenocarcinoma-resection group, 6 in the intraductal papillary mucinous neoplasm-resection group, and 8 in the nonresection group developed concomitant pancreatic ductal adenocarcinoma. The estimated 5-year (17%) and 10-year (56%) cumulative incidences of secondary pancreatic ductal adenocarcinoma in the pancreatic ductal adenocarcinoma-resection group were significantly greater than those in the other two groups (P < .01). Conversely, the difference in the estimated cumulative incidence of concomitant pancreatic ductal adenocarcinoma between the intraductal papillary mucinous neoplasm-resection and nonresection groups was not significant (5-year, 5.0% vs 2.2%; 10-year, 5.0% vs 8.7%; P = .87). CONCLUSION: Long-term (≥5-year) surveillance in patients with intraductal papillary mucinous neoplasm is necessary and important because of the potential for development of concomitant pancreatic ductal adenocarcinoma. Those with a history of resection of concomitant pancreatic ductal adenocarcinoma at the time of the initial operation are at quite high risk for the development of secondary pancreatic ductal adenocarcinoma.

Comparison of guidelines for intraductal papillary mucinous neoplasm: What is the next step beyond the current guidelines?

Management of intraductal papillary mucinous neoplasm is controversial, and several guidelines have aimed to establish an adequate strategy for surgical resection and surveillance. We compared various intraductal papillary mucinous neoplasm guidelines and considered new matters that are pivotal for improved treatment of intraductal papillary mucinous neoplasm. We identified and compared 11 published guidelines, three of which were major guidelines that mainly referred to the diagnosis and treatment of intraductal papillary mucinous neoplasm (International Association of Pancreatology 2012 guidelines, European Study Group on Cystic Tumours of the Pancreas 2013 guidelines, and American Gastroenterological Association 2015 guidelines). The main concerns of these three guidelines were indication for surgery and follow up of non-resected lesions. Among the differences between the three guidelines, the period of surveillance recommended was the most controversial matter. Meanwhile, several nomograms have been proposed to improve the diagnosis of intraductal papillary mucinous neoplasm from the level of experts' experiences to that of rational systems. We discuss the adequate strategy of surveillance for intraductal papillary mucinous neoplasm with and without pancreatectomy and nomograms aiming to predict the risk of malignancy in patients with intraductal papillary mucinous neoplasm.

Elevated bile amylase level without pancreaticobiliary maljunction is a risk factor for gallbladder carcinoma.

BACKGROUND: Elevated bile amylase level in patients with pancreaticobiliary maljunction (PBM) or high confluence of pancreaticobiliary ducts (HCPBD) is well known as a risk factor for gallbladder carcinoma (GBC) development. However, the effects of occult pancreaticobiliary reflux (OPR), a condition characterized by high bile amylase level in the presence of an anatomically normal pancreaticobiliary junction, on GBC development remain unclear. The aim of this study was to assess the relationship between OPR and GBC. METHODS: Clinicopathological data of 52 patients who were preoperatively diagnosed with gallbladder (GB) tumor (22 malignant, 30 benign) were retrospectively reviewed. All of the patients underwent preoperative endoscopic retrograde cholangiopancreatography to evaluate pancreaticobiliary junction morphology and bile amylase level. The relationship between the histological diagnosis of GB lesions, and pancreaticobiliary junction morphology and bile amylase level were investigated. RESULTS: Pancreaticobiliary maljunction, HCPBD, and normal pancreaticobiliary junction (NPJ) were identified in 12, nine, and 31 patients, respectively. The rates of GBC in patients with PBM, HCPBD, and NPJ were 58% (7/12), 67% (6/9), and 29% (9/31), respectively. Of the 31 patients with NPJ, 22 had OPR and nine of these had GBC. None of the patients with NPJ and normal bile amylase level had GBC. Additionally, among patients with NPJ, bile amylase level was significantly higher in patients with GBC than in patients with benign tumors. CONCLUSIONS: Occult pancreaticobiliary reflux, like PBM and HCPBD, is a risk factor for GBC development.

Expression of Bcl-2 19-kDa interacting protein 3 predicts prognosis after ampullary carcinoma resection.

BACKGROUND: An adequate management strategy for ampullary carcinoma (AC), a rare neoplasm, has yet to be determined. The aim of this study was to identify specific molecular markers allowing for the adequate management of AC. METHODS: The clinicopathological data of 41 patients who underwent curative resection of AC were reviewed retrospectively. The expression of thymidylate synthase (TS) and Bcl-2 19-kDa interacting protein 3 (BNIP3), two sensitive markers for S-1 and gemcitabine, respectively, was evaluated immunohistochemically. The relationship between the expression levels of these markers and the clinicopathological data were then investigated. RESULTS: The 5-year overall survival rate in the study population was 62%. In univariate and multivariate analyses, lymph node metastasis, neural invasion, lymphatic invasion, and the high-level BNIP3 expression were significant predictive factors for a poor postoperative prognosis. Neither TS nor BNIP3 expression were able to predict survival or the disease recurrence rate in patients who received postoperative adjuvant chemotherapy for AC. CONCLUSIONS: BNIP3 expression may serve as a prognostic marker for patients with AC, but neither TS nor BNIP3 contributes to the selection criteria for adjuvant chemotherapy for AC, at least with respect to current drug regimens.

Different Hormonal Expression Patterns Between Primary Pancreatic Neuroendocrine Tumors and Metastatic Sites.

OBJECTIVES: Pancreatic neuroendocrine tumors (PNETs) are known to have heterogeneity in terms of their ability to produce multiple hormones. The aim of this study was to evaluate the heterogeneity of PNETs from the viewpoint of hormonal expression. METHODS: The expressions of 4 representative hormones, gastrin, insulin, glucagon, and somatostatin, in both primary and metastatic lesions, were analyzed by immunohistochemical staining in 20 patients with metastatic PNETs (6 gastrinomas, 1 insulinoma, 1 glucagonoma, and 12 nonfunctioning PNETs [NF-PNETs]). Metastatic sites included lymph nodes in all 20 patients and liver metastasis in 7 patients (2 gastrinomas and 5 NF-PNETs). RESULTS: There were 6 PNETs with multiple hormone secretion (30%), and positive expression of 1 or more hormones was found in 9 of 12 patients whose primary tumors were diagnosed as NF-PNETs. The positive concordance rate of the hormonal expression pattern between primary tumors and metastatic lymph nodes and between primary tumors and hepatic metastasis were 50% and 11%, respectively. Three patients had metastatic lesions with positive hormonal expression, whereas their primary tumors were negative. CONCLUSIONS: Hormonal expressions are often different between the primary tumors and metastatic sites of PNETs.

Distinction of Invasive Carcinoma Derived From Intraductal Papillary Mucinous Neoplasms From Concomitant Ductal Adenocarcinoma of the Pancreas Using Molecular Biomarkers.

OBJECTIVES: To clarify the usefulness of molecular biomarkers for distinguishing invasive carcinoma derived from intraductal papillary mucinous neoplasms (IPMNs [Inv-IPMN]) from concomitant pancreatic ductal adenocarcinoma (PDAC). METHODS: Data from 19 patients with resected concomitant PDAC were retrospectively reviewed. KRAS/GNAS mutations and immunohistochemical (IHC) expression of p53 and p16/CDKN2A were assessed in both IPMN and distinct PDAC. As controls, KRAS/GNAS mutations and IHC labeling were assessed between invasive and noninvasive components in 1 lesion of 22 independent patients. RESULTS: KRAS/GNAS mutation status of invasive and noninvasive components in Inv-IPMN was consistent in 18 (86%) of 21 patients. Conversely, mutational patterns in IPMN and distinct PDAC in the same pancreas differed from each other in 17 (89%) of 19. There were 10 (53%) and 8 (42%) of 19 patients who showed the same p53 and p16/CDKN2A staining between concomitant PDAC and distinct IPMN. In the Inv-IPMN cohort, 19 (86%) of 22 patients showed the same IHC expression pattern between the noninvasive and invasive components. CONCLUSIONS: It may be possible to distinguish Inv-IPMN from concomitant PDAC by assessing these molecular biomarkers. More precise distinction of Inv-IPMN and concomitant PDAC will lead to adequate recognition of the natural history of IPMNs and hence optimal management.

Advanced composite of large cell neuroendocrine carcinoma and squamous cell carcinoma: a case report of uterine cervical cancer in a virgin woman.

Large cell neuroendocrine carcinoma (LCNEC) of the uterine cervix is very rare and aggressive. The prognosis is very poor despite multimodal treatment. We report a virgin woman with FIGO stage 4b LCNEC of uterine cervix coexisting with squamous cell carcinoma. An early thirties virgin woman presented with 2-month history of abdominal pain. A chest X-ray showed multiple lung metastatic tumors. A vaginal smear showed malignant cells, and a biopsy specimen had features of LCNEC. The tumor showed trabecular patterns. Tumor cells possessed a moderate amount of cytoplasm, prominent nucleoli, and large nuclei. The tumor cells are stained positive for synaptophysin, chromogranin A, and neuron specific enolase (NSE). The invasive tumor cells in connection with cervical squamous epithelium were focally positive for 34bE12. We made a diagnosis of composite LCNEC and nonkeratinizing squamous cell carcinoma. High-risk HPV test was negative with hybridized captured method 2.