Tubular Tumors Research Articles

Intra-ampullary Papillary Tubular Neoplasm (IAPN): Clinicopathologic Analysis of 72 Cases Highlights the Distinctive Characteristics of a Poorly Recognized Entity.

The guidelines recently recognized the intra-ampullary papillary tubular neoplasm (IAPN) as a distinct tumor entity. However, the data on IAPN and its distinction from other ampullary tumors remain limited. A detailed clinicopathologic analysis of 72 previously unpublished IAPNs was performed. The patients were: male/female=1.8; mean age=67 years (range: 42 to 86 y); mean size=2.3cm. Gross-microscopic correlation was crucial. From the duodenal perspective, the ampulla was typically raised symmetrically, with a patulous orifice, and was otherwise covered by stretched normal duodenal mucosa. However, in 6 cases, the protrusion of the intra-ampullary tumor to the duodenal surface gave the impression of an "ampullary-duodenal tumor," with the accurate diagnosis of IAPN established only by microscopic correlation illustrating the abrupt ending of the lesion at the edge of the ampulla. Microscopically, the preinvasive component often revealed mixed phenotypes (44.4% predominantly nonintestinal). The invasion was common (94%), typically small (mean=1.2cm), primarily pancreatobiliary-type (75%), and showed aggressive features (lymphovascular invasion in 66%, perineural invasion in 41%, high budding in 30%). In 6 cases, the preinvasive component was pure intestinal, but the invasive component was pancreatobiliary. LN metastasis was identified in 42% (32% in those with ≤1cm invasion). The prognosis was significantly better than ampullary-ductal carcinomas (median: 69 vs. 41months; 3-year: 68% vs. 55%; and 5-year: 51% vs. 35%, P =0.047). In conclusion, unlike ampullary-duodenal carcinomas, IAPNs are often (44.4%) predominantly nonintestinal and commonly (94%) invasive, displaying aggressive features and LN metastasis even when minimally invasive, all of which render them less amenable to ampullectomy. However, their prognosis is still better than that of the "ampullary-ductal" carcinomas, with which IAPNs are currently grouped in CAP protocols (while IAPNs are kindreds of intraductal tumors of the pancreatobiliary tract, the latter represents the ampullary counterpart of pancreatic adenocarcinoma/cholangiocarcinoma).

A rare case of intraductal tumor of the pancreas in which an intraductal tubulopapillary neoplasm was mixed with a widely spreading gastric-type intraductal papillary-mucinous neoplasm

A 70-year-old man receiving treatment for diabetes mellitus presented with a cystic mass in the border area of the pancreatic body and tail on plain computed tomography (CT) due to impaired glucose intolerance. Contrast-enhanced CT showed a faint hyperattenuated nodular mass extending from the dilated main pancreatic duct (MPD) to the branch duct. Endoscopic retrograde cholangiopancreatography revealed a mildly dilated orifice of the papilla of Vater and MPD stenosis with entire upstream and immediate downstream dilatations. The patient underwent distal pancreatectomy due to the suspicion of mixed-type intraductal papillary-mucinous carcinoma. A pathological examination showed an intraductal solid-nodular mass measuring 25mm in length, consisting of two types of neoplasms. One showed tubulopapillary growth with entirely high-grade (HG) atypical cuboidal epithelium, in which immunohistochemical examinations were positive for MUC6 but negative for human gastric mucin (HGM), MUC1, MUC2, and MUC5AC, fitting the concept of intraductal tubulopapillary neoplasm (ITPN). The other showed the same growth of low-grade (LG) atypical columnar cells positive for HGM and MUC5AC and negative for MUC1 and MUC2, which corresponded to gastric-type intraductal papillary-mucinous neoplasm (IPMN) -LG. The tumor had not invaded the duct walls, and no metastatic lymph nodes were observed. The ITPN was adjacent to the IPMN mainly composed of tubular glands mimicking pyloric glands with LG dysplasia that corresponded to the so-called IPMN-pyloric gland variant. Moreover, the proliferation of low-papillary gastric-type IPMN spread around the intraductal tumors. Consequently, the patient was diagnosed with an intraductal tubular neoplasm comprising a noninvasive ITPN and gastric-type IPMN-LG. ITPN is a recently identified intraductal neoplasm of the pancreas proposed by Yamaguchi et al. and is distinguished by intraductal tubulopapillary growth with HG cellular atypia without overt mucin production, in contrast to IPMN. To date, no cases of intraductal nodular tumors comprising ITPN and IPMN have been reported. We report this original case with imaging and pathological observations and discuss potential processes via which ITPN and IPMN may arise adjacent to each other in the same pancreatic duct.

Mucins expression in gastric cancer: connection of MUC status with clinical, morphological and prognostic characteristics of the tumor

Clarification of the prognostic value and relationship of MUC-phenotypes of gastric cancer with clinical and morphological parameters. Surgical material from 310 patients with a verified diagnosis of gastric cancer was studied. Samples were immunohistochemically stained with antibodies to MUC2, CD10, MUC5AC. The results were compared with clinical and morphological characteristics of gastric cancer and patient survival data. The MUC-null and MUC-mix groups significantly differ in the prevalence of subtotal/total tumors from the MUC-I group (p=0.022 and p=0.007, respectively), where there are significantly fewer such tumors. Tubular tumors were more common in the MUC-null group compared to the MUC-G (p=0.026) and MUC-mix (p=0.006) groups, and there were fewer cases with the presence of "signet-ring" cells in the MUC-null group (p=0.000). When studying the discohesive histological type, the literature data on smaller tumor sizes and a lower frequency of lymph node metastasis for MUC-G status were not confirmed, but a more frequent proximal localization of MUC-I tumors was found (p=0.003). No statistically significant differences in survival were found in the analysis of the total sample. Differences in survival were found only in discohesive cancers, where the best survival was recorded for the MUC-null group, and the worst for the MUC-mix group (p=0.022). MUC status is not an independent predictor of gastric cancer (HR=1.662, p=0.093). Between tumors with different MUC statuses, there were differences in localization and belonging to individual histological types. Significant differences in survival were found only for discohesive cancers with MUC-null and MUC-mix statuses. Separation of gastric cancers according to MUC status may have only limited predictive value in selected histological forms of cancer.

Medullary carcinoma of the ampulla has distinct clinicopathologic characteristics including common association with microsatellite instability and PD-L1 expression

Medullary carcinomas have not yet been fully characterized in the ampulla. Here, 359 ampullary carcinomas (ACs) were reviewed and 11 medullary-type carcinomas (3%) were found and analyzed. In addition to the diagnostic medullary pattern, 6 showed focal mucinousand 8 had focal abortive gland-like formations. They occurred in younger patients (57 versus 65y; P=.02), had larger invasion size (mean, 3.2 versus 1.9cm; P=.01), formed nodular polypoid or plaque-like tumors, and often lacked preinvasive component. In addition to the lymphoplasmacytic infiltrates, they also had prominent eosinophils in 5 of 11 cases. Eight were papilla Vateri-NOS (not otherwise specified) tumors, 2 were ampullary-duodenal origin, 1 had a minor intra-ampullary papillary tubular neoplasm component, and none were ampullary-ductal. Although they had pushing-border infiltration, perineural and vascular invasion was common. They were strongly associated with DNA mismatch repair (MMR) protein deficient (7/11, 64%). The 5-yr survival rate (53%) appeared to be comparable with, and perhaps even better than that of nonmedullary ACs (47%), although this did not reach statistical significance (P=.47). Programmed cell death ligand-1 (PD-L1) expression levels were assessed in 8, and all 4 that were MMR deficient were positive both by combined positive score (CPS) ≥1 and tumor proportion score (TPS) ≥1, and of the 4 MMR proficient cases, 3 were positive by CPS; 2 by TPS. Overall, only 1 of the 8 available for analysis failed to show PD-L1 positivity by CPS. In contrast, nonmedullary MMR-deficient carcinomas expressed PD-L1 in only 33% of tumors by CPS, and none by TPS. One medullary carcinoma was also EBV associated. Unlike 'medullary carcinomas' of the kidney, INI1 was retained in all 8 cases tested. In conclusion, medullary carcinomas are 3% of ACs, have a strong association with MMR-D, and may be less aggressive despite their larger size. PD-L1 expression appears to be closely associated with medullary ACs regardless of MMR status, and thus targeted therapies can be considered for all medullary carcinomas of this site.

Imaging Features of Premalignant Biliary Lesions and Predisposing Conditions with Pathologic Correlation.

Biliary malignancies include those arising from the intrahepatic and extrahepatic bile ducts as well as the gallbladder and hepatopancreatic ampulla of Vater. The majority of intrahepatic and extrahepatic malignancies are cholangiocarcinomas (CCAs). They arise owing to a complex interplay between the patient-specific genetic background and multiple risk factors and may occur in the liver (intrahepatic CCA), hilum (perihilar CCA), or extrahepatic bile ducts (distal CCA). Biliary-type adenocarcinoma constitutes the most common histologic type of ampullary and gallbladder malignancies. Its prognosis is poor and surgical resection is considered curative, so early detection is key, with multimodality imaging playing a central role in making the diagnosis. There are several risk factors for biliary malignancy as well as predisposing conditions that increase the risk; this review highlights the pertinent imaging features of these entities with histopathologic correlation. The predisposing factors are broken down into three major categories: (a) congenital malformations such as choledochal cyst and pancreaticobiliary maljunction; (b) infectious or inflammatory conditions such as parasitic infections, hepatolithiasis, primary sclerosing cholangitis, and porcelain gallbladder; and (c) preinvasive epithelial neoplasms such as biliary intraepithelial neoplasm, intraductal papillary neoplasm of the bile duct, intra-ampullary papillary tubular neoplasm, and intracholecystic papillary neoplasm of the gallbladder. Recognizing the baseline features of these premalignant biliary entities and changes in their appearance over time that indicate the advent of malignancy in high-risk patients can lead to early diagnosis and potentially curative management. An invited commentary by Volpacchio is available online. Online supplemental material is available for this article. ©RSNA, 2022.

Reconstruction of postoperative defects using carbon nanostructured implants with intramedullary osteosynthesis after extremity long bone resection for primary and metastatic tumors

Background. Recent studies have shown that a combination of surgery with chemotherapy and radiotherapy can signifcantly improve survival in patients with primary and metastatic bone tumors. Reconstruction of bone defects after resection of long bones is critical for successful functional limb salvage. The choice of the reconstruction technique depends on the tumor location, tumor extension, presence of pathological fracture, and somatic status of the patient. Reconstruction of bone defects in cases with diaphyseal tumor location can pose a surgical challenge. For the reconstruction of diaphyseal bone defects, endoprostheses, alloimplants, and autologous bone grafts are used. To achieve stability of the affected segment of the limb, various options for osteosynthesis are used. Modern technological achievements provide the emergence of materials with characteristics close to those of human bone tissue, however, without the disadvantages inherent in allo- and autologous implants. The purpose of the study was to improve surgical treatment outcomes in patients with long tubular bone tumors. Material and Methods. For the reconstruction of postoperative long bone defects, we used carbon nanostructured implants (СNI) in combination with intramedullary osteosynthesis with a blocked pin. A total of 25 patients underwent surgery (including 9 patients with a pathological fracture), 24 of them had metastases. Results. There were no intraoperative and postoperative complications. All patients had a signifcant decrease in pain 1 month after surgery. At 3 months after surgery, functional outcomes were satisfactory. None of the patients had a local recurrence, instability of the operated limb segment, or a reaction of rejection of a carbon nanostructured implant. Conclusion. Reconstruction of postoperative defects with carbon nanostructured implants after resection of long tubular bones for metastatic cancer provides good functional results and satisfactory local control.

Transduodenal surgical ampullectomy for intra-ampullary papillary tubular neoplasm (IAPN): A case report

Introduction and importanceIntra-ampullary papillary tubular neoplasms (IAPNs) are relatively rare kind of neoplasms occurring in the region of the papilla which exhibit significant malignant transformation. The patient was concerned about his pain and the possibility of malignancy.Case presentationWe report a case of a 47-year-old male who presented with persistent upper abdomen pain. Following detail investigations, he was diagnosed as IAPN and managed by transduonal ampullectomy (TDA).Clinical discussionThe insidious onset of IAPN along with its high risk of malignancy makes it mandatory for its proper treatment. Although, endoscopic approach is advantageous for initial therapy, it has some technical difficulties. Hence TDA forms the cornerstone in the management of IAPN with good prognosis.ConclusionTransduodenal ampullectomy is a safe and feasible option for IAPN. It can be the first choice of treatment in selected cases where endoscopic papillectomy is not available.

Biliary intraductal tubule-forming neoplasm: a whole exome sequencing study of MUC5AC-positive and -negative cases.

Biliary intraductal tubular neoplasms that are non-mucinous and negative for mucin 5AC (MUC5AC) are called intraductal tubulopapillary neoplasms (ITPNs). Intraductal tubular neoplasms with mucinous cytoplasm and MUC5AC positivity also occur and their nature remains unclear, although some pathologists may classify these as 'intraductal papillary neoplasms of the bile duct (IPNBs) of gastric type'. This study aimed to elucidate genetic features of biliary intraductal tubular neoplasms. Six resected cases of biliary intraductal neoplasm with>70% tubular configuration were characterised by clinicopathological examination and whole exome sequencing, and the findings obtained were compared between MUC5AC-negative (n=2) and -positive cases (n=4). The intraductal tumours consisted of the pancreatobiliary-type epithelium with high-grade dysplasia arranged in back-to-back tubules. Both of the two MUC5AC-negative cases were non-invasive neoplasms and developed in the liver, whereas all MUC5AC-positive cases had invasive carcinoma and were present in the intrahepatic (n=2), perihilar (n=1) and distal bile ducts (n=1). In an exome-sequencing study, MUC5AC-negative cases harboured mutations in CTNNB1, SF3B1, BAP1 and BRCA1 (one case each). KRAS mutations were observed in three of four MUC5AC-positive cases (75%) but none of the MUC5AC-negative neoplasms. Compared to published data, known driver genes of other intraductal neoplasms of the pancreatobiliary system (e.g. APC, CTNNB1, STK11, GNAS and PIK3CA) were wild-type in all but one MUC5AC-negative case with CTNNB1 mutation. Chromatin modifiers (ARID1A, BAP1 and KMT2C) were also altered in MUC5AC-positive cases, similar to usual cholangiocarcinomas. This exome-sequencing study suggested that MUC5AC-negative biliary ITPNs are genetically distinct from pancreatic ITPNs and IPNBs. They may also biologically differ from MUC5AC-positive tubular neoplasms despite morphological resemblance.

Intra Cholecystic Papillary Tubular Neoplasm-A Case Report Of A Rare Differential Diagnosis Of Carcinoma Gall Bladder

We present a case report of a 57 year old lady who presented with complaints of right sided upper abdominal pain. The patient was initially diagnosed with carcinoma gall bladder(CAGB) by CECT Abdomen and PET CT imaging studies. Intra cholecystic papillary tubular neoplasm of the gall bladder(ICPN) was diagnosed after histopathological examination of the radical cholecystectomy specimen. ICPN can be managed with a cholecystectomy if the diagnosis is known pre operatively as the prognosis for ICPN is much better as compared with that for gallbladder adenocarcinoma.

1275 Intestinal-Type Intracholecystic Papillary Tubular Neoplasm (ICPN) Presenting as Acute Hemorrhagic Cholecystitis

INTRODUCTION: The term Intracholecystic Papillary Tubular Neoplasm (ICPN) was coined by Adsay et al (2012). ICPN includes mass-forming (papillary or polypoid), intramucosal and preinvasive gallbladder neoplasms larger than one cm in size. CASE DESCRIPTION/METHODS: A 73-year-old man presented with acute and sharp right upper quadrant abdominal pain for one day. He denied nausea, vomiting, diarrhea, fever or chills. Past medical history included COPD, non-Hodgkin lymphoma in remission and hypertension. He was not receiving anticoagulants or antiplatelet medications. On abdominal examination, there was marked tenderness in the right upper quadrant area with a positive Murphy's sign. Laboratory testing revealed leukocytosis of 22,000/µL with neutrophilia and normal liver chemistry tests and a serum lipase level. Abdominal ultrasonography showed a markedly distended gallbladder with mural thickening of up to 1.0 cm and numerous gallstones with a positive sonographic Murphy's sign. Non-contrast CT showed mixed attenuation suggesting hemorrhage into the gallbladder lumen and suggestive of acute hemorrhagic cholecystitis. He underwent open cholecystectomy. Surgical findings were a distended gallbladder with a thickened and inflamed wall. Half of the gallbladder lumen was occupied by stones and the remainder was filled with detached, friable, tan-red hemorrhagic material. Microscopic examination of several of detached fragments and intact mucosa showed an abundant ICPN of intestinal-type origin and a tubular-papillary growth pattern. There was marked acute and chronic inflammation of the gallbladder wall without mural perforation. DISCUSSION: ICPNs are usually seen in middle-aged individuals, with a 2- fold higher prevalence in women. Macroscopically, ICPNs are exophytic tumors: tubular/lobulated types are soft, friable and can get easily detached appearing as sludge or debris, while granular or papillary types are sessile and feathery filling the gallbladder lumen. ICPN exhibits a variety of cell lineages such as biliary (50%), gastric (25%), intestinal (8%, as in our patient), oncocytic (6%) and mixtures of lineages (∼10%). In our patient, the two most plausible pathogenic processes are either diagnosis of an incidental ICPN due to the associated acute calculus hemorrhagic cholecystitis or acute “acalculous” cholecystitis from tumor shedding and bleeding into the gallbladder lumen and causing cystic duct obstruction associated with asymptomatic (incidental) cholelithiasis.

Intracholecystic papillary-tubular neoplasm of gallbladder: A 5-year retrospective pathological study.

Intracholecystic papillary-tubular neoplasm (ICPN) is a relatively new entity which includes neoplastic polyps, adenomas, and papillary neoplasms that are ≥1.0 cm. This study is done to evaluate the pathological features of ICPN and to find out the factors associated with invasion. This is a 5-year retrospective study in a referral pathology center. A total of 19 cases of ICPN are found. The cases are analyzed for age and sex distribution, clinical suspicion, stages, histological architecture, differentiation, and grade of dysplasia. Descriptive statistics and test of significance by Chi-square and t-test are used in the study. ICPN comprises 23.5% of all gallbladder neoplasms. Two-thirds of the cases were suspected radiologically. Age range is 26-65 years with mean age of 50 years. They are 2.8 times more common in female. Approximately one-third of the cases show invasion. The most common histological pattern is papillary, followed by papillary-tubular and finally by tubular pattern. Pyloric and biliary are the most common differentiation pattern followed by oncocytic and intestinal pattern. About three-fourths of the cases are associated with high-grade dysplasia mostly diffuse high-grade dysplasia. We have found the younger age of presentation, less proportion of invasive tumors, fewer tumors with biliary phenotypes, and fewer tumors with high-grade dysplasia as compared to previous studies. Factors significantly associated with invasion are grade and extent of dysplasia particularly diffuse high-grade dysplasia.

Renal tubular and adrenal medullary tumors in the 2-year rat study with canagliflozin confirmed to be secondary to carbohydrate (glucose) malabsorption in the 15-month mechanistic rat study

During preclinical development of canagliflozin, an SGLT2 inhibitor, treatment-related pheochromocytomas, renal tubular tumors (RTT), and testicular Leydig cell tumors were reported in the 2-year rat toxicology study.In a previous 6-month rat mechanistic study, feeding a glucose free diet prevented canagliflozin effects on carbohydrate malabsorption as well as the increase in cell proliferation in adrenal medulla and kidneys, implicating carbohydrate malabsorption as the mechanism for tumor formation.In this chronic study male Sprague-Dawley rats were dosed orally with canagliflozin at high dose-levels (65 or 100 mg/kg/day) for 15 months and received either a standard diet or a glucose-free diet. Canagliflozin-dosed rats on standard diet showed presence of basophilic renal tubular tumors (6/90) and an increased incidence of adrenal medullary hyperplasia (35/90), which was fully prevented by feeding a glucose-free diet (no RTT's; adrenal medullary hyperplasia in ≤5/90).These data further confirm that kidney and adrenal medullary tumors in the 2-year rat study were secondary to carbohydrate (glucose) malabsorption and were not due to a direct effect of canagliflozin on these target tissues.

Reflux-Associated Cholecystopathy: Analysis of 76 Gallbladders From Patients With Supra-Oddi Union of the Pancreatic Duct and Common Bile Duct (Pancreatobiliary Maljunction) Elucidates a Specific Diagnostic Pattern of Mucosal Hyperplasia as a Prelude to Carcinoma.

Pancreaticobiliary maljunction (PBM) is the anomalous union of the main pancreatic duct and common bile duct outside the Oddi-sphincter, allowing the reflux of pancreatic juice to the gallbladder. There is only limited awareness and understanding of the pathologic correlates of this condition, mostly from Japan; this entity is largely unrecognized in the West. In this study, 76 gallbladders from patients with PBM (64 from Japan; 12 from the United States) were analyzed and contrasted with 66 from non-PBM patients. These were predominantly females (54 vs. 22), mean age, 53 (range: 14 to 81). Cholelithiasis was uncommon (16% vs. 80% in non-PBM, P<0.01) whereas cholesterolosis was more common (49% vs. 29%, P=0.02) suggesting an altered chemical milieu. There was a distinctive diffuse mucosal hyperplasia (82% vs. 42%, P<0.01) with markedly elongated folds (mean: 1.1 vs. 0.7 mm, P<0.01) composed of compact villoglandular proliferation, often showing broad-based pushing into muscle, accompanied by prominent and more complex Rokitansky-Aschoff sinus formation (2.0 vs. 1.0/cm, P<0.01) at the base. At the tips, this villiform hyperplasia displayed frequent horizontal bridging of the folds (68% vs. 47%, P=0.01), bulbous dilatation (52% vs. 21%, P<0.01) as well as deposition of a peculiar amyloid-like hyaline material (56% vs. 15%, P<0.01). Despite paucity of inflammation and gallstones, findings attributed to mucosal injury were common including: pyloric gland metaplasia (70% vs. 48%, P=0.01) and intestinal metaplasia (24% vs. 6%, P<0.01). Invasive gallbladder carcinoma was present in 22 (29%) of the cases with 6 of these (27%) arising in association with intracholecystic papillary tubular neoplasm. Five cases had bile duct carcinoma at the time of cholecystectomy and 1 developed it 4 years after. In conclusion, gallbladders with patients with PBM display a distinctive pattern of mucosal hyperplasia with distinguishing features, which in constellation render it a microscopically diagnosable specific entity. We propose to refer to this entity as "reflux-associated cholecystopathy." Recognition of the pathologic characteristics of this entity is important so that investigation for, as well as treatment and prevention of, PBM-associated complications (biliary tract cancers and pancreatitis) can be instituted. This group also offers a distinct model of carcinogenesis (chemical rather than inflammatory) in the gallbladder for cancer researchers to scrutinize.

Pax8, Napsin A, and CD10 as Immunohistochemical Markers of Canine Renal Cell Carcinoma.

Pax8, napsin A, and CD10 are useful immunohistochemical markers of human renal cell carcinoma (RCC); however, their diagnostic utility in canine RCC is unclear. Forty formalin-fixed paraffin-embedded renal cell carcinomas from dogs (15 papillary, 12 solid, and 13 tubular) and 10 metastases were evaluated for expression of Pax8, napsin A, and CD10. Thirty-nine (98%), 24 (60%), and 19 (50%) tumors expressed Pax8 (nuclear labeling), napsin A (cytoplasmic labeling), and CD10 (cytoplasmic and membranous labeling), respectively. Pax8 was expressed in 92% of solid, 100% of papillary, and 100% of tubular tumors. Napsin A was expressed in 58% of solid, 60% of papillary, and 62% of tubular RCC. CD10 was expressed in 33% of solid, 47% of papillary, and 62% of tubular RCC. Pax8 was expressed in 80% of the metastatic tumors, napsin A in 60%, and CD10 in 50%. Additionally, Pax8 immunoreactivity was stronger overall than that of napsin A or CD10. In summary, Pax8 is a more sensitive marker than napsin A or CD10 for primary and metastatic canine RCC; its nuclear and more intense reactivity also makes it easier to interpret. Tubular and papillary RCCs were more likely than solid RCC to express all 3 markers. These findings highlight the utility of Pax8 as an immunohistochemical marker in diagnosing all major subtypes of canine primary and metastatic renal cell carcinoma.

Comprehensive genomic profiling (CGP) of esophageal and tubular GI tumors to identify frequencies of ErbB family member amplification with therapeutic implications.

8 Background: As described in the MyPathway study, amplification and other mutations in ErbB-family proteins are actionable events across solid tumors. Targeting ERBB2 amplifications (amp) in tubular GI cancers (TGC) improves patient outcomes. ErbB family comparisons across anatomic sites is lacking and here we describe the largest known series in TGC. Methods: DNA was extracted from 12,685 FFPE clinical TGC specimens, including 1,720 esophageal CA*. CGP was performed on hybrid-capture, adaptor ligation based libraries to a mean coverage depth of 720X for up to 315 genes plus 47 introns from 19 genes frequently rearranged in cancer. Results: Across all TGC cases, amp was the most frequent genomic alteration among ErbB members at 8.7%. ERBB2 amp was 2.3x as common as EGFR amp across TGC. Across TGC sites, EGFR amp was most frequent in esophageal SCC (13.7%) and ERBB2 amp was most common in gastroesophageal junction adenoCA (21%) compared with overall frequencies of 2.7% and 5.5% respectively. ERBB3 and ERBB4 amp were rare, and most common in gastroesophageal adenoCA relative to other TGC. Clinical support with outcomes for patients treated with anti-ErbB targeted therapy across TGC will be presented, including profiling from cases of acquired resistance to anti-ErbB targeted therapy. Conclusions: Among TGC, esophageal CA harbored the most ErbB family member amp with variation by histology. Profiling across ErbB proteins in TGC suggests biologic differences and may affect response to treatment. CGP can expand the population who may benefit from anti-ErbB directed therapies and refine treatment choices. Further research is warranted. [Table: see text]

Cholangiocarcinoma with intraductal tubular growth pattern versus intraductal papillary growth pattern

Intraductal neoplasms of the bile duct are macroscopically characterized by exophytic or polypoid growth patterns and have a favorable prognosis. Although some tumors with a predominantly tubular microscopic pattern have been reported, they have not been well characterized clinicopathologically. The purpose of the present study was to compare the newly recognized cholangiocarcinoma with an intraductal tubular growth pattern and cholangiocarcinoma with an intraductal papillary growth pattern and to investigate the pathological and prognostic significance of the former. This study analyzed 161 patients with tumors with exophytic or polypoid growth patterns from a large series of 733 cholangiocarcinoma cases surgically resected from January 1998 to May 2013. The study patients were divided into two groups: those whose tumors showed a predominantly tubular growth pattern (n=52) and those whose tumors exhibited a predominantly papillary growth pattern (n=109). Tubular growth pattern was associated with combined vascular resection and the absence of macroscopic mucin. Several histological indexes were significantly higher for the tubular growth pattern than the papillary one, including tubular adenocarcinoma, depth of invasion, microscopic lymphatic invasion, venous invasion, perineural invasion, and necrosis. Although the survival curves overlapped (P=0.693), the rate of liver metastasis was significantly higher for the tubular growth pattern than for the papillary one (P=0.012). Genomic DNA analysis focusing on somatic mutations in codons 12 and 13 of KRAS and codon 600 of BRAF revealed only one (4%) KRAS and no BRAF mutation among the 25 tubular cases examined. In conclusion, the tubular growth pattern exhibited differences in some histologic indexes, in addition to a higher hepatic metastasis rate and a lower KRAS mutation frequency, compared with the papillary growth pattern, but no difference in prognosis was observed. The distinctiveness of this tubular neoplasm should be further examined in the future.

Characteristics and diagnostic value of multi-slice spiral computed tomography examination of gastrointestinal lipoma

Objective To investigate the characteristics and diagnostic value of multi-slice spiral computed tomography (MSCT) examination of gastrointestinal lipoma. Methods The cross-sectional study was adopted.The clinicopathological data of 96 patients with gastrointestinal lipoma including 32 from the Second Hospital Affiliated to Wenzhou Medical University, 30 from the First Hospital Affiliated to Wenzhou Medical University, 17 from the Ruian People's Hospital of Zhejiang, 11 from the Yueqing People's Hospital, 3 from the Wenzhou Central Hospital and 3 from the Wenzhou People's Hospital from December 2006 to September 2015 were collected. All patients were fasted for 8 hours prior to the examination, and partial patients underwent enhanced scan after the conventional CT scanning with breathless scanning and no abdominal pressure. Coronal and sagittal images of gastrointestinal tract including the tumor were administrated with planar reconstruction (MPR) techniques of Reformat software. Based on MPR images, the curves along the gastrointestinal tract were drawn, voxel distributed along the curve track were reconstructed, and curved planar reconstruction (CPR) images were obtained. The patients received operation or follow-up according to individual characteristics after examinations. The patients undergoing operation were followed up for detecting tumor recurrence and metastasis by CT examination and patients receiving follow-up were observed by endoscopy for detecting changes of tumor size and morphology up to June 2015. The analysis indexes included tumor location and size, performance of MSCT examination (tumor shape, density, margin, intussusceptions, enhanced MSCT examination), intraoperative findings, results of pathological examination and results of follow-up. Measurement data with normal distribution were presented as ±s. Results All the 96 patients received MSCT plain scan and the 42 received enhanced MSCT scan. The CPR images in 30 patients were collected. (1) Tumor location and size: 3 tumors were located in the stomach, 16 in the duodenal, 27 in the jejunum, 23 in the ileal, 2 in the ileocecus, 9 in the sigmoid colon, 9 in the ascending colon, 3 in the descending colon, 3 in the transverse colon and 1 in the appendix. The diameter of tumor was (3.8±2.3)cm. (2) Performance of MSCT examination: of the 96 patients, round or oval tumors were detected in 68 patients, tubular tumors in 15 patients and lobulated tumors in 13 patients. Tumors showed homogeneous density in 67 patients and inhomogeneous density in 29 patients. The CT value of tumors was -110--53 HU with a median value of -80 HU. Tumors of the 96 patients had clear boundaries and smooth margins. Twenty-four patients were complicated with intussusceptions with nested length of (28±4)cm, including 10 cases of multiple concentric rings , 7 cases of double-target sign and 7 cases of banana sign . Enhanced MSCT scan showed that capsule around tumors in the 96 patients demonstrated slightly intensified, tumor body demonstrated no enhancement and that angiolipoma in 10 patients had cable strip like enhancement in the tumors. (3) Intraoperative findings: of the 96 patients, 59 patients underwent surgical resection with single tumor, 24 patients were concomitant with intussusceptions, 9 patients showed aphtha in the center of tumors and 1 patient had partial lipoma in the prepyloric region dropped into the duodenal. Thirty-seven patients received endoscopic examination, showing submucous nodular protrusive lesions of 1.7-3.5 cm. (4) Results of pathological examination: of 59 patients undergoing surgical resection, submucosal, subserous and intramural tumors were detected in 45, 9 and 5 patients, respectively, with complete capsule and pedunculated or non-pedunculated. Of the 59 patients, tumors showed round or oval shape in 41 patients, tubular shape in 10 patients and lobulated shape in 8 patients. The section of tumors showed yellowish-white. Specimens from endoscopic and surgical resections were observed under microscopy, the tumors were composed of mature-differentiated adipocytes, different quantities of fibrous connective tissues, blood vessels and mucus ingredients. Tumor cells were round shape with hypochromatic cytoplast and became polygeal and vacuolated after squeezing, nucleus was compressed to peripheral area and cytoplasm was full of lipid droplets. The results of immunohistochemistry stain showed Vimentin, CD34, D2-40, CD68 were positive and AE1/3 and Calretinin were negative. All tumors were diagnosed as benign lipomas. Fifty-nine patients who underwent surgical resection were followed up for 0.5-5.0 years and 37 patients of which specimens were obstained by endoscopic resection were followed up for 1.0-2.0 years after the pathological diagnosis with no significant change. Conclusion The MSCT finding of the gastrointestinal lipoma has characteristic appearance, and MSCT examination can clearly show lipoma location, size, shape and properties, with a widespread application value. Key words: Lipoma, gastrointestinal tract; Tomography, X-ray computed

Renal Tumors in 26-Week Tg.Rash2 Mice Carcinogenicity Studies.

We report renal tubular adenomas and a carcinoma in 26-week Tg.rasH2 mouse carcinogenicity studies, which have not been reported to date either at our facility or in other published data. However, during the year 2014, renal tubular tumors were present in 4 studies conducted at our facility. Because of their morphological similarity to the amphophilic-vacuolar (AV) phenotypic variant of renal tubule tumors noted in Sprague-Dawley and Fischer 344 rats, which are thought to be familial, as well as the genetic homogeneity of Tg.rasH2 mice, we tracked the parents of these mice with tumors in each study. The origin of these tumors could not be traced back to any of the parents or even an animal barrier, and these tumors were not attributed to the vehicle or test article. Although the exact mechanism of tumorigenesis was not known, based on the available information, the development of renal tumors in these mice was considered random and spontaneous.

Successful integration of nonclinical and clinical findings in interpreting the clinical relevance of rodent neoplasia with a new chemical entity.

Canagliflozin, a sodium glucose co-transporter 2 (SGLT2) inhibitor, has been developed for the treatment of adults with type 2 diabetes mellitus (T2DM). During the phase 3 program, treatment-related pheochromocytomas, renal tubular tumors, and testicular Leydig cell tumors were reported in the 2-year rat toxicology study. Treatment-related tumors were not seen in the 2-year mouse study. A cross-functional, mechanism-based approach was undertaken to determine whether the mechanisms responsible for tumorigenesis in the rat were of relevance to humans. Based on findings from nonclinical and clinical studies, the treatment-related tumors observed in rats were not deemed to be of clinical relevance. Here, we describe the scientific and regulatory journey from learning of the 2-year rat study findings to the approval of canagliflozin for the treatment of T2DM.

Gastric high-grade dysplasia can be associated with submucosal invasion: evaluation of its prevalence in a series of 121 endoscopically resected specimens.

Gastric neoplasms classified as high-grade dysplasia (HGD) by Western pathologists are frequently diagnosed as tubular adenocarcinoma in Japan. Here, we evaluated the prevalence of submucosal and lymphovascular invasion in a series of 125 endoscopically resected gastric neoplasms. On the basis of Western criteria, the lesions were classified as poorly cohesive carcinomas (n=4) (excluded from further analysis), low-grade dysplasia (n=4), pure HGD (n=78), HGD with tubular adenocarcinoma (n=4), and pure tubular adenocarcinoma (n=35). Submucosal invasion was found in 3.8% of the 78 HGDs, 75.0% of the 4 HGDs combined with adenocarcinoma, and 11.4% of the 35 adenocarcinomas. Venous invasion was detected in 1.3% of the 78 HGDs, 75% of the 4 HGDs combined with adenocarcinoma, and none of the 35 tubular adenocarcinomas. Lymphatic invasion was absent in HGD but noted in 25% of the HGDs combined with adenocarcinoma, and 2.9% of the tubular adenocarcinomas. Thus, we demonstrated that lesions characterized as HGD on the basis of Western criteria can be associated with submucosal and lymphovascular invasion. Endoscopic therapy has made it less crucial to differentiate between HGD and intramucosal adenocarcinoma in biopsy samples of small tubular neoplasms. However, it is important to recognize that the criteria for dysplasia currently used in the West may understate the degree of malignant potential. To limit any diagnostic discrepancy between biopsy, endoscopic resection, and surgical specimens, it is suggested that the features of HGD and adenocarcinoma be reevaluated, which may result in some lesions being classified as mucosal adenocarcinoma.