Intraductal Neoplasm Research Articles

A novel morphologic-molecular recurrence predictive model refines traditional prognostic tools for invasive breast carcinoma.

Histologic grade, TNM stage, and Nottingham Prognostic Index are traditional prognostic tools for breast cancer. "IHC-molecular" classification of breast cancer can also identify patients at different recurrence risks and provides insight into cancer therapy. However, cancers in each group are heterogeneous. A model based on the comprehensive analysis of morphologic features and molecular subtype was constructed to predict recurrence and refine these traditional prognostic tools. Morphologic features including histologic grade, fibrotic focus, extensive intraductal component, lymphocytic infiltrate, lymphovascular invasion, tumor necrosis, tumor margin and TNM stage, and molecular subtypes approximated by immunohistochemistry were analyzed in 633 patients with invasive breast carcinoma (excluding those with HER2 targeted therapy). Significant independent predictors for recurrence included: high histologic grade (p = 0.004), presence of lymphovascular invasion (p = 0.004), fibrotic focus (p = 0.020), mild lymphocytic infiltrate (p = 0.013), high TNM stage (p < 0.001), and HER2-overexpressing (p = 0.004) and basal-like (p < 0.001) molecular subtypes. A morphologic-molecular recurrence predictive model based on these features was useful in recurrence prediction, independent of treatment modalities, and was able to refine the traditional prognostic tools of histologic grade, TNM stage, and Nottingham prognostic index, particularly for intermediate-risk groups, and to refine the luminal group molecular subtypes. Such findings were reproducible with a validation cohort. TNM stage, histologic grade, lymphovascular invasion, fibrotic focus, mild lymphocytic infiltrate, HER2-overexpressing and basal-like molecular subtypes were important independent recurrence risk factors for breast cancer. This morphologic-molecular model was robust in recurrence prediction and refined recurrence risk stratified by the traditional prognostic parameters, independent of treatment modalities.

18F-FDG Uptake in Intraductal Tubulopapillary Neoplasm of the Pancreas

We report a 74-year-old man with intraductal tubulopapillary neoplasm (ITPN), a rare primary intraductal neoplasm of the pancreas. Focal intense uptake of 18F-FDG was seen on the initial PET, corresponding to a pancreatic mass. Although the patient had no treatment, the uptake was mild to moderate on a second PET performed about 1 month later. The tumor was resected, with the final diagnosis of ITPN with an associated invasive carcinoma. Clinicians should be aware that decreased uptake of FDG during the follow-up period without treatment can occur even in malignant tumors.

Evaluation of Factors Associated with Pain Experienced during Mammary Ductoscopy

Background: The aim of this study was to evaluate patient characteristics and findings after mammary ductoscopy in an effort to reduce the pain experienced during the procedure. Patients and Methods: We evaluated outpatients in whom mammary ductoscopy was performed under local or intraductal anesthesia without preference, and their clinical characteristics and findings were recorded. Average and maximum pain scores were determined after the examination for statistical analysis. Results: The overall average pain score was 3.74 ± 1.353, and the maximum pain score was 6.40 ± 1.681. The type of anesthesia, total operation time, nipple retraction, and discharge status significantly correlated with the pain score. Intraductal anesthesia lowered the average pain score by 0.60, whereas a total procedure time greater than 12 min increased the average pain score by 0.956. The pain score decreased if patients had nipple retraction, and intraductal anesthesia proved suitable for patients with normal nipples. Conclusion: Intraductal anesthesia is suitable for most patients, and ductoscopy should not exceed 12 min to minimize the pain. Nipple retraction does not significantly increase pain, but local anesthesia should be used in patients with retracted nipples. Patient age, breastfeeding history, menstrual stage, and presence of intraductal tumors were not associated with the level of pain experienced.

Differentiation of Branch Duct Intraductal Papillary Mucinous Neoplasms From Serous Cystadenomas of the Pancreas Using Contrast‐Enhanced Sonography

The purpose of this study was to determine whether contrast-enhanced sonography can improve the ability to differentiate branch duct intraductal mucinous neoplasms from serous cystadenomas of the pancreas compared to conventional (unenhanced) sonography alone. Between March 2008 and May 2012, there were 20 patients with branch duct intraductal mucinous neoplasms and 25 with serous cystadenomas in our institute, for whom preoperative conventional and contrast-enhanced sonographic results were available. The final diagnosis was obtained by histopathology. Various conventional and contrast-enhanced sonographic characteristics were retrospectively evaluated by 2 radiologists in consensus. A receiver operating characteristic curve analysis was used to evaluate the diagnostic value of conventional and contrast-enhanced sonography for discriminating between the two entities. Three conventional sonographic characteristics (microcysts, cysts with internal echoes, and main pancreatic duct dilatation) and 2 contrast-enhanced sonographic characteristics (communication between the lesion and main pancreatic duct and enhancement of mural nodules) significantly improved the ability to differentiate branch duct intraductal mucinous neoplasms from serous cystadenomas. The area under the receiver operating characteristic curve increased from 0.691 with conventional sonography to 0.859 with combined contrast-enhanced and conventional ultrasonography (P = .043). In this series of patients, the addition of contrast-enhanced sonography to conventional sonography improved the ability to differentiate branch duct intraductal mucinous neoplasms from serous cystadenomas.

Molecular Genetics of Pancreatic Neoplasms and Their Morphologic Correlates

To summarize the most clinically and biologically relevant advances in molecular/genetic characteristics of various pancreatic neoplasms, with morphologic correlation. Whole-exome sequencing of numerous benign and malignant pancreatic tumors, along with the plethora of highly sensitive molecular studies now available for analyzing these tumors, provide mounting evidence to support the long-held belief that cancer is essentially a genetic disease. These genetic discoveries have not only helped to confirm the age-old, morphology-based classifications of pancreatic neoplasia but have shed new light on their mechanisms. Many of these molecular discoveries are currently being used in preoperative diagnosis. Mutations in KRAS, P16/CDKN2A, TP53, and SMAD4/DPC4 are commonly seen in ductal neoplasia but not in nonductal tumors; ductal adenocarcinomas with SMAD4/DPC4 loss are associated with widespread metastasis and poor prognosis. GNAS and RNF43 mutations have been discovered in most intraductal pancreatic mucinous neoplasms, providing critical molecular fingerprints for their diagnosis. Mutation in DAXX/ATRX is only seen in pancreatic neuroendocrine tumors, making it a useful potential marker in distinguishing these tumors from mimics. When combined with morphologic observations, molecular studies will increase our understanding of the pathogenesis and morphomolecular signatures associated with specific neoplasms and provide new horizons for precision medicine and targeted therapies.

Case report: intraductal tubulopapillary neoplasm of the pancreas with unique clear cell phenotype

Intraductal tubulopapillary neoplasms of the pancreas are very rare tumors characterized by intraductal tubulopapillary growth, ductal differentiation, scant intracellular mucin production and cellular dysplasia. Here, we report the first case of an intraductal tubulopapillary neoplasm of the pancreas with clear cell morphology. The tumor was detected during the diagnostic work-up of acute pancreatitis in a 43- year old female. Histological examination revealed a tumor with the typical architecture of an intraductal tubulopapillary neoplasm of the pancreas with tumor cells showing abundant clear cytoplasm and Di-PAS negativity. Immunohistochemistry revealed positivity for Pan-CK, CK7, CK8/18, MUC1, MUC6, carbonic anhydrase IX, CD10, EMA, β-catenin and e-cadherin. Sanger sequencing did not detect mutations for β-catenin, BRAF, KRAS, PIK3CA and GNAS. Altogether, histology, immunohistochemical expression profile (MUC1+, MUC6+, MUC2-, MUC5AC-, thrypsin-, chymotrypsin-, CDX2-) and sequencing results led to the diagnosis of intraductal tubulopapillary neoplasm. However, the neoplasm consisted of cells showing abundant clear cytoplasm, a morphological pattern not being described so far in the current classification of pancreatic intraductal neoplasms. Potential differential diagnosis and the molecular basis of clear cell morphology are discussed. In conclusion, we consider this tumor as intraductal tubulopapillary neoplasm of the pancreas with unique clear cell phenotype. After surgery and without adjuvant therapy, the patient’s clinical course has been uneventful for over two years now.Virtual slidesThe virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1051828790117127

Acute Obstructive Cholangitis Complicated by Tumor Migration after Transarterial Chemoembolization: A Case Report and Literature Review

Intraductal tumor invasion of hepatocellular carcinoma (HCC) is considered rare. Transarterial chemoembolization (TACE) is effective for tumor thrombus of HCC in the bile duct. However, a few cases of obstructive jaundice caused by migration of a tumor fragment after TACE have recently been reported. The aim of this study was to identify factors that affect tumor migration after TACE. At this writing, a review of the medical literature disclosed seven reported cases of biliary obstruction caused by migration of a necrotic tumor cast after TACE. We, herein, report on an additional case of acute obstructive cholangitis complicated by migration of a necrotic tumor cast after TACE for intrabile duct invasion of HCC, in a 71-year-old man. The tumor cast in the common bile duct was removed successfully using a basket during ERCP and was pathologically confirmed to be a completely necrotic fragment of HCC. The patient's symptoms showed dramatic improvement. In summary, physicians should be aware of acute obstructive cholangitis complicated by tumor migration in a patient undergoing TACE. We suggest that an intrabile duct invasion would be a major predisposing factor of tumor migration after TACE and drainage procedures such as ERCP or percutaneous transbiliary drainage could be effective treatment modalities in these patients.

原発病巣の同定が困難であった胆管腫瘍栓を伴った肝細胞癌の1例

原発病巣の同定が困難であった胆管腫瘍栓を伴った肝細胞癌の1例

Endoscopic papillectomy: Indications, techniques, and results

Endoscopic papillectomy (EP) is currently accepted as a viable alternative therapy to surgery in sporadic ampullary adenoma and has been reported to have high success and low recurrence rates. At present, the indications for EP are not yet fully established. The accepted criteria for EP include size (up to 5 cm), no evidence of intraductal growth, and no evidence of malignancy on endoscopic findings (ulceration, friability, and spontaneous bleeding). Endoscopic ultrasound (EUS) is the imaging modality of choice for local T staging in ampullary neoplasms. Data reported in the literature have revealed that linear EUS is superior to helical computed tomography in the preoperative assessment of tumor size, detection of regional nodal metastases and detection of major vascular invasion. Endoscopic ampullectomy is performed using a standard duodenoscope in a similar manner to snare polypectomy of a mucosal lesion. There is no standardization of the equipment or technique and broad EP methods are described. Endoscopic ampullectomy is considered a ''high-risk'' procedure due to complications. Complications of endoscopic papillectomy can be classified as early (pancreatitis, bleeding, perforation, and cholangitis) and late (papillary stenosis) complications. The appropriate use of stenting after ampullectomy may prevent post-procedural pancreatitis and papillary stenosis. Tumor recurrence of benign lesions occurs in up to 20% of patients and depends on tumor size, final histology, presence of intraductal tumor, coexisting familial adenomatous polyposis (FAP), and the expertise of the endoscopist. Recurrent lesions are usually benign and most can be retreated endoscopically.

A case report of anaplastic carcinoma of the pancreas with remarkable intraductal tumor growth into the main pancreatic duct

We herein report a case of anaplastic carcinoma of the pancreas with remarkable intraductal tumor growth into the main pancreatic duct. A 76-year-old male was referred to our hospital for treatment of a pancreatic tumor. Preoperative examinations revealed a poorly defined tumor in the main pancreatic duct in the body of the pancreas, accompanied with severe dilatation of the main pancreatic duct, which was diagnosed as an intraductal papillary-mucinous neoplasm. We performed distal pancreatectomy and splenectomy. The pathological examination revealed that the tumor consisted of a mixture of anaplastic carcinoma (giant cell type) and adenocarcinoma in the pancreas. There was a papillary projecting tumor composed of anaplastic carcinoma in the dilated main pancreatic duct. The patient is now receiving chemotherapy because liver metastasis was detected 12 mo after surgery. In this case, we could observe a remarkable intraductal tumor growth into the main pancreatic duct. We also discuss the pathogenesis and characteristics of this rare tumor with specific tumor growth.

In situ proteomic analysis by MALDI imaging identifies ubiquitin and thymosin-β4 as markers of malignant intraductal pancreatic mucinous neoplasms

PurposeIntraductal pancreatic mucinous neoplasms (IPMN) are precancerous cystic lesions. The aim was to investigate the in situ IPMN proteome using MALDI (Matrix-Assisted Laser Desorption/Ionisation) imaging and to characterize biomarkers associated with the grade of dysplasia. Experimental designFrozen human Branch duct -IPMN sections were selected according to dysplasia and proteomic analyses were performed by MALDI imaging to obtain mass spectra distribution. The most discriminating peaks were identified using tissue extraction and nanoLC-ESI-MS/MS. Identified peaks were validated in independent series of IPMN by immunochemistry on surgical specimens (tissue-microarrays (TMA), n = 45) and endoscopic ultrasound fine-needle aspiration (EUS FNA) samples (n = 25). ResultsBD-IPMN samples with low (n = 10) and high (n = 10) grades of dysplasia were analyzed. Differential spectra of proteins were found in the two groups with significantly different intensities (n = 15). The two peaks (intense in high grade IPMN) (m/z 8565 and 4747) were characterized as the monomeric ubiquitin (Mascot score = 319.22) and an acetylated fragment of thymosin-β4 (2–42) (Omssa score = 1.37 E−9). Validation on TMA and EUS FNA samples confirmed that ubiquitin was overexpressed in high grade dysplasia (p = 0.04 and p = 0.0004). Thymosin-β4 expression was confirmed on TMA by immunohistochemistry on high grade IPMN (p = 0.011). ConclusionUbiquitin and thymosin-β4 are overexpressed in IPMN with high grade dysplasia. Positive immunochemical staining on EUS-FNA material is a major argument in support of preventive resection.

Ultrasonography-Guided Breast-Conserving Surgery Is Superior to Palpation-Guided Surgery for Palpable Breast Cancer

IntroductionThe aim of this study was to determine the efficacy of ultrasonography (US)–guided excision of palpable breast cancer and to compare it with the standard palpation-guided breast-conserving surgery (BCS). MethodsFor this purpose, 335 women with palpable breast cancer who underwent BCS were retrospectively studied. The positive surgical margins and re-excision rates were investigated. ResultsOf the total cohort, 137 patients were treated with palpation-guided BCS and 198 underwent US-guided tumor excision. The tumor and patient characteristics were similar in both groups. Patient age, postmenopausal status, tumor size, histological grade, intraductal tumor component, lobular histology, and palpation-guided tumor excision were associated with increased risk of positive margins. The shave margins were re-excised at the time of original operation more often by palpation-guided localization (28.5%) than by the US-guided procedure (11.1%) (P < .0001). A surgeon was able to correctly identify the “problematic” margin in 81.1% of cases via intraoperative US and in only 17.9% via palpation (P < .0001). The re-excision rate during a second operation was significantly reduced by US-guided tumorectomy (P = .004). Of 198 patients in the US-guided group, 23 (11.6%) underwent a second operation, as did 33 of 137 patients in the palpation group (24.1%). The sensitivity and specificity of US-guided excisions were 52.7% and 97.5%, respectively, whereas the sensitivity and the specificity of palpation-guided tumor excisions were 15.5% and 65.9%, respectively. ConclusionUS-guided BCS is superior to palpation-guided excision in predicting the closest margins, obtaining clear surgical margins, and reducing re-operations.

Proposal of a new disease concept "biliary diseases with pancreatic counterparts". Anatomical and pathological bases.

The biliary tract and pancreas are located closely anatomically, and both develop from the endoderm foregut almost at the same time. Interestingly, the lining epithelia of the bile duct and main pancreatic duct show similar morphologies and phenotypes, and both are accompanied by periductal glands. Furthermore, the exocrine pancreatic acini are remnantly found in the peribiliary glands. Based on these findings, it seems plausible that the biliary tract has features of pancreatic elements in addition to the duct system, which is specialized for the drainage of bile secreted by hepatic parenchyma, particularly, hepatocytes. Interestingly, some pancreatic and biliary diseases show similar pathological features and even biological behaviors. For example, extrahepatic cholangiocarcinoma and ductal adenocarcinoma of the pancreas share many clinicopathological features. Both of them are hypothesized to arise from similar preneoplastic and early neoplastic intraepithelial lesions. Intraductal papillary tumors, with frequent mucin hyperproduction, develop in the pancreas (intraductal papillary mucinous neoplasm) and also in the biliary tract (intraductal papillary neoplasm of the bile duct). IgG4-related disease affects the biliary tract (IgG4-related sclerosing cholangitis) and the pancreas (autoimmune pancreatitis) in the same patients, with both showing similar morphologies. Herein, we propose that these non-neoplastic and neoplastic biliary diseases showing similarities to corresponding pancreatic diseases could be included in a new disease concept "biliary diseases with pancreatic counterparts". Based on this new concept, information obtained in biliary tract diseases could be applied to the analysis of pancreatic disease and vice versa, and also novel therapeutical strategies and molecular and genetic studies on pancreatic and biliary diseases may be developed with a unified approach.

The discrete nature and distinguishing molecular features of pancreatic intraductal tubulopapillary neoplasms and intraductal papillary mucinous neoplasms of the gastric type, pyloric gland variant

Intraductal tubulopapillary neoplasms (ITPNs) are composed of tubulopapillary glands with high-grade dysplasia in the pancreatic duct. Intraductal papillary mucinous neoplasms of the gastric type, pyloric gland variant (IPMN-PGs) are composed of tubular glands mimicking pyloric glands with low-grade dysplasia and were formerly called intraductal tubular adenomas. Because of their apparent common tubular morphology, IPMN-PGs and ITPNs could be associated. While the former might progress to the latter, this has not been fully assessed. In this study, we compared the molecular features of ITPNs and IPMN-PGs to determine their association using formalin-fixed, paraffin-embedded tissues of 14 ITPNs and 15 IPMN-PGs. Somatic mutations in PIK3CA, GNAS, KRAS, and BRAF were determined by Sanger sequencing. Expression of phosphorylated AKT was examined by immunohistochemistry. Somatic PIK3CA mutations were found in 3 of 14 ITPNs (21.4%) but in none of the IPMN-PGs (p = 0.0996). In contrast, GNAS mutations were found in none of the ITPNs but in 9 of 15 IPMN-PGs (60.0%; p < 0.001). KRAS mutations were detected in 1 of 14 ITPNs (7.1%) and 12 of 15 IPMN-PGs (80.0%; p < 0.001). BRAF mutation was found in one ITPN but in none of the IPMN-PGs. Phosphorylated AKT expression in ITPNs was significantly more evident than that in IPMN-PGs (p = 0.0401). These results indicate that ITPNs and IPMN-PGs are molecularly distinct, suggesting that IPMN-PG does not progress to ITPN. Furthermore, the molecular features of IPMN-PGs are confirmed to be identical to those of IPMNs reported elsewhere. These results validate the current World Health Organization system that classifies pancreatic intraductal neoplasms into IPMN and ITPN and confirm that IPMN-PG is not a benign counterpart of ITPN. The term 'intraductal tubular adenoma' should be eliminated and replaced with IPMN-PG.

Removal of a Partially Prolapsing Intraductal Ampullar Adenoma

Figure: No Caption available.Purpose: We report a successful ampullectomy of a partially prolapsing intraductal ampullary adenoma using an improvised endoscopic technique of attaching an adjunctive tube to allow simultaneous passage of a balloon catheter and snare. Methods: A 78-year-old woman with a history of hypothyroidism was involved in a motor vehicle collision and underwent a CT scan that, incidentally, revealed a 17 x 20-mm ampullary mass. On ERCP, the ampulla bulged with a soft polypoid tissue mass. FNA showed benign glandular cells. Respecting the patient's wish to avoid Whipple procedure, we offered an endoscopic approach. The ERCP was performed in the operating room with the patient supine and surgeons on standby for a Whipple surgery. Intraductal tumor extension in the periampullary area was endoscopically seen. The ampulla was cannulated and sphincterotomy was performed, taking the cut as high as possible. Segmental resection around the ampulla edges using the hot snare removed the intraduodenal part of the mass. A sterile hollow accessory tube was then attached to the endoscope. A snare was passed through the endoscope and a balloon catheter through the accessory tube. The snare was looped around the balloon. The balloon catheter tip was manipulated with the snare to cannulate the bile duct, passed over a wire to above the lesion, and then retracted, completely prolapsing the tumor. The looped snare was advanced over the balloon catheter and the entire prolapsed ampullary adenoma, completely resecting it. The resection site was impressive for deep tissue exposure to the level of the muscle fibers with ductal mucosa widely separated from the duodenal mucosa. Pancreatic and bile duct stents were placed. Duodenocholedochal clipping was done around the stents, mimicking anastomosis. With no post-procedural complications, she was discharged home after a 24-hour observation period. A threemonth follow-up ERCP showed patent ducts and resolution of the previously-observed filling defect from the adenoma intraductal extension. EGD at six months revealed no residual adenomatous growth. Conclusion: The only definitive therapy for intraductal ampullary adenoma is complete excision, but they are suboptimal candidates for standard ampullectomy. A custom-added accessory channel allowed successful utilization of two devices to completely excise an intraductal ampullar adenoma without surgical intervention.

Malignant Intraductal Papillary Mucinous Neoplasms of the Pancreas in Two Identical Twins

Context Intraductal papillary mucinous neoplasm (IPMN) is a rare pancreatic tumor defined as intraductal mucin-producing neoplasm with tall, columnar, mucin-producing epithelium. IPMNs have already been described in association with inherited genetic disorder including familial adenomatous polyposis and Peutz-Jeghers syndrome. However, description of familial history of IPMN is very rarely reported. We present two cases of malignant IPMN in identical twins. Case report A 54-year-old woman was admitted in August 2010 with epigastric pain and high serum levels of amylase and lipase. Abdominal CT revealed dilation of main pancreatic duct (5 mm) with multiple cysts in the head of the pancreas. Serum CA 19-9 was in the normal range, and positron emission tomography with CT acquisition (PET/CT) was negative. A diagnosis of mixed type IPMN was made, and the patient underwent pancreatico­duodenectomy. Pathologic examination showed a tubular, poorly differentiated adenocarcinoma, tubular type, in combined type IPMN (pancreatico-biliary type) of the head of the pancreas with high grade dysplasia (pT3N0M0 G3). Postoperative course was uneventful, and the patient underwent adjuvant chemo-radiotherapy. Three years after surgery, there was no evidence of tumor relapse. Her sister, a 57-year-old woman, was admitted in February 2013 for obstructive jaundice and weight loss. Serum CA 19-9 was 86.2 U/mL. Magnetic resonance of the abdomen showed a 4.8 cm, pluricystic mass of the head of the pancreas, with marked dilation (10 mm) of the main pancreatic duct. FNAC under EUS examination showed mucinous epithelial cells with low-moderate dysplasia. PET/CT revealed a pathologic uptake of the radiotracer in the pancreatic head and in the right colon. Colonoscopy did not show colonic lesions. In March 2013 the patient underwent pylorus-preserving pancreaticoduodenectomy. Pathologic examination showed a colloid, poorly differentiated adenocarcinoma in main duct IPMN (intestinal type) of the head of the pancreas (pT3N0M0G3). Adjuvant therapy with gemcitabine was started, and the patient is alive 3 months after operation, without tumor relapse. Conclusion Although rare, the coexistence of IPMN reported here in two identical twins, suggests that it is due to a genetic inherited factor that remains to be elucidated. Physicians should carefully study the familial history of patients with IPMN.

Cystic lesion of pancreas - Intraductal papillary mucinous neoplasm

AbstractIntraductal papillary mucinous neoplasm (IPMN) of the pancreas is an intraductal mucin-producing epithelial neoplasm that arises from the main and/or branched pancreatic duct. It usually presents as cystic lesion of pancreas. There are well known differential diagnosis of cystic pancreatic lesion. Pancreatic cystic neoplasms are detected at an increasing frequency due to an increased use of abdominal imaging. The diagnosis and treatment of intraductal papillary mucinous tumors (IPMN) of the pancreas has evolved over the past decade. IPMN represents a spectrum of disease, ranging from benign to malignant lesions, making the early detection and characterization of these lesions important. Definitive management is surgical resection for appropriate candidates, as benign lesions harbor malignant potential. IPMN has a prognosis, which is different from adenocarcinoma of the pancreas. We report a case of a 58-year-old male with intraductal papillary neoplasm involving main duct and side branches presenting to us with clinical symptoms of chronic pancreatitis with obstructive jaundice and cholangitis treated surgically.

Proposed Classification of the Feline “Complex” Mammary Tumors as Ductal and Intraductal Papillary Mammary Tumors

When compared with the canine species, feline mammary tumors (FMTs) are much less heterogeneous, with a predominance of simple malignant neoplasm. Benign FMTs are rare, and it is unclear if complex and mixed tumors exist in the feline. In this study, we selected for immunohistochemical analyses 12 FMTs that had unusual histologic features. A group of 8 (2 benign and 6 malignant) FMTs showed a biphasic epithelial/myoepithelial population and a very regular cord-like distribution in a "Chinese lettering" pattern, within ectatic ducts. A second group (2 benign and 2 malignant) had an intraductal epithelial papillary growth pattern with a basally located monolayer of myoepithelial cells and a supporting fibrovascular stroma. The myoepithelial component always produced a standard immunohistochemical signature. All malignancies were grade I, and the subjects were all alive at 1 year postdiagnosis. On the basis of their morphology, we propose that they be classified as feline ductal adenoma/carcinoma and feline intraductal papillary adenoma/carcinoma, respectively. They overlap with their canine counterparts and lack the typical myoepithelial differentiation patterns seen in canine complex neoplasms, and therefore, the term complex should be avoided in felines. This study will add new information on FMT classification and be useful for prognostic studies.

CAM 5.2 shows specific reactivity for cytokeratin 8, but less strict reactivity for cytokeratin 7 and no reactivity for cytokeratin 18: in response to “Fujikawa T, Tanaka A, Abe T et al. ‘Undifferentiated carcinoma of the common bile duct with intraductal tumor thrombi: report of a case’. Surg Today 2011;41(4):579–84.”

CAM 5.2 shows specific reactivity for cytokeratin 8, but less strict reactivity for cytokeratin 7 and no reactivity for cytokeratin 18: in response to “Fujikawa T, Tanaka A, Abe T et al. ‘Undifferentiated carcinoma of the common bile duct with intraductal tumor thrombi: report of a case’. Surg Today 2011;41(4):579–84.”

Abstract 2735: Inactivation of activin signaling pathway accelerates the development of pancreatic intraductal papillary mucinous neoplasms in vivo.

Abstract The association of TGF-β pathway with human tumorigenesis has been rigorously demonstrated. However, little is known about activin signaling, part of the TGF-β family, in pancreatic tumorigenesis. We have previously reported sporadic mutations of the Activin receptor type 1B (ACVR1B) in human pancreatic ductal adenocarcinoma (PDAC). To investigate the significance of ACVR1B in pancreatic tumorigenesis, Acvr1bflox/flox; Pdx1-Cre mice were generated and examined. Chronic pancreatitis-like histological changes such as inflammatory cell infiltration, acinar to ductal metaplasia, and fibrosis were observed in Acvr1b mutant alone mice older than 8 months of age. In combination with mutant KrasG12D in the pancreas, Acvr1b deletion accelerated the development of pancreatic intraductal papillary mucious neoplasms (IPMN), but not the pancreatic intraepithelial neoplasias (PanINs). The IPMN progressed to invasive and metastatic cancer was observed in this model. The expressions of Cox-2 and phospho-PDK1 are dramatically increased in preneoplastic and neoplastic lesions, but activated Notch4 expression is exclusively observed in the IPMN lesions by immunohistochemistry, suggesting that Notch4 signaling may play a role in the formation or maintenance of the mucin-rich ductal phenotype in this model. Interestingly, the progression of IPMN to invasive cancer appears to require additional p16 loss in this double mutant mouse model. In human IPMN, loss of p16 expression is associated with increasing grade. Our data provide the first evidence that Acvr1b acts as a tumor-suppressor in vivo and that activin signaling plays a predominant role in the development of pancreatic IPMNs. Significance: PDAC can arise from PanINs or IPMN. It has been reported previously that disruption of TGF-β signaling promotes the progression of PanIN to PDAC in the TGFβRII knockout background. In contrast, here we present that activin signaling deficiency favors the development of IPMNs and enhances their progression to PDAC. This phenotype overlaps with those observed in the Smad4 knockout background, suggesting that the involvement of activin signaling in the IPMN to PDAC sequence is Smad4-dependent. Together these data demonstrate that TGF-β superfamily ligands play critical roles in regulating the IPMN-derived versus PanIN-derived carcinogenesis. Citation Format: Wanglong Qiu, Sophia Tang, Sohyae Lee, Andrew T. Turk, Anthony Sireci, Anne Qiu, Ralph H. Hruban, Helen E. Remotti, Gloria H. Su. Inactivation of activin signaling pathway accelerates the development of pancreatic intraductal papillary mucinous neoplasms in vivo. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2735. doi:10.1158/1538-7445.AM2013-2735