Intestinal-type Adenocarcinoma Research Articles

Distribution of gastric carcinoma in an area with a high prevalence of Helicobacter pylori.

South Asia is an enigma for gastric cancer (GC) because it is a low risk region with a high prevalence of Helicobacter pylori (H. pylori) infections. We evaluated the trend of GC clinical presentation and risk factors in patients with dyspeptic symptoms. The medical records of patients, coded by the international classification of diseases (ICD-10-CM, 2015, Diagnosis Code C16.9) for malignancies of stomach diagnosed by esophagogastroduodenoscopy (EGD) and histopathology, were studied. 394 GC cases with a mean age of 54±15 years, range of 18 to 88, were analyzed. 256 (65%) were male. Distal non-cardiac and cardiac tumors were 302 (77%) and 92 (23%) cases, respectively. The WHO classification of GC defined 222 (56%) cases as intestinal type adenocarcinoma, 68 (17%) cases as signet ring cell carcinoma (SRC), 62 (16%) cases as diffuse type and 42 (11%) cases as B cell non-Hodgkin lymphoma. The co-morbid conditions associated with GC were H. pylori infection (positive in 246 (62%) cases), diabetes mellitus type 2 (in 90 (23%) cases), and cigarette smoking (in 94 (24%) cases). Of the male patients, 88 (34%) (p<0.001) were smokers. Body mass index was abnormal in all age groups and in both sexes. Cardiac regions for GC were more common in the 46- to 60-year old age range and in males. Diffuse GC was seen in all age groups but there were significantly more common in the 18- to 45-year old age range. Gastric non-Hodgkin's lymphoma was seen at an early age of 18-45 years in 14(12%) and a later of 61-88 years in 20 (15%). Intestinal type GC is common at all ages but SRC and diffuse GC are more common in patients less than 50 years old. SRC and diffuse GC were not specific to the elderly in our study population.

OTX1 and OTX2 as possible molecular markers of sinonasal carcinomas and olfactory neuroblastomas.

OTX Homeobox genes are involved in embryonic morphogenesis and in the development of olfactory epithelium in adult. Mutations occurring in the OTX genes are reported to be associated to tumorigenisis in human. No reports correlate the expression of OTX genes and neoplasms of the nasal cavity. Thus, through immunohistochemical and Real-time PCR analysis we investigated OTX1 and OTX2 expression in the more frequent types of nasal and sinonasal tumours. Variable expression of both genes were found in normal sinonasal mucosa and in tumours. Interestingly, no expression of both OTX genes were detected in sinonasal intestinal-type adenocarcinomas; only OTX1 was found in non-intestinal-type adenocarcinomas and OTX2 was selectively expressed in olfactory neuroblastomas. In conclusion, OTX1 and OTX2 genes might have a role in the pathogenesis of different types of sinonasal neoplasms.

Prognostic significance of tumor budding and single cell invasion in gastric adenocarcinoma.

PurposeGastric carcinoma (GC) is a highly aggressive cancer and one of the leading causes of cancer-related deaths worldwide. Histopathological evaluation pertaining to invasiveness is likely to provide additional information in relation to patient outcome. In this study, we aimed to evaluate the prognostic significance of tumor budding and single cell invasion in gastric adenocarcinoma.Materials and methodsHematoxylin and eosin-stained slides generated from 296 gastric adenocarcinoma patients with full clinical and pathological and follow-up information were systematically reviewed. The patients were grouped on the basis of tumor budding, single cell invasion, large cell invasion, mitotic count, and fibrosis. The association between histopathological parameters, different classification systems, and overall survival (OS) was statistically analyzed.ResultsAmong the 296 cases that were analyzed, high-grade tumor budding was observed in 49.0% (145) of them. Single cell invasion and large cell invasion were observed in 62.8% (186) and 16.9% (50) of the cases, respectively. Following univariate analysis, patients with high-grade tumor budding had shorter OS than those with low-grade tumor budding (hazard ratio [HR]: 2.260, P<0.001). Similarly, the OS of patients with single cell invasion and large cell invasion was reduced (single cell invasion, HR: 3.553, P<0.001; large cell invasion, HR: 2.466, P<0.001). Following multivariate analysis, tumor budding and single cell invasion were observed to be independent risk factors for gastric adenocarcinoma (P<0.05). According to the Lauren classification, patients with intestinal-type adenocarcinoma had better outcomes than those with diffuse-type adenocarcinoma (HR: 2.563, P<0.001).ConclusionTumor budding and single cell invasion in gastric adenocarcinoma are associated with an unfavorable prognosis.

Genomic profiling of ampullary adenocarcinoma (AA): Insights from a comparative analysis of pancreatic and intestinal adenocarcinoma and opportunities for targeted therapies use.

300 Background: Ampullary adenocarcinoma (AA) is a rare entity. AA can originate from either intestinal or pancreaticobiliary ductal epithelium, and patients are often managed as those with pancreaticobiliary carcinomas. The study objectives were the genetic profiling of AA and the identification of specific molecular profiles according to these 2 pathological types. Methods: AA patients included in the AGEO retrospective multicenter cohort who underwent surgical resection of their tumor between 1999 and 2010 were selected. Formalin-fixed, paraffin-embedded (FFPE) archival tissue blocks were collected. Next generation sequencing (NGS) using a 50 gene panel (Ion AmpliSeq Cancer panel) on tumor DNA, and immunohistochemistry (IHC) panel including CK7, CK20, MUC1, MUC2 and CDX2, on tumor sections, were performed. Results: NGS was performed on 101 tumors from 6 hospitals, with 1 technical failure. In total, the most frequent gene mutations were: KRAS (45%), TP53 (40%), APC (15%), PIK3CA (12%), SMAD4 (9%), BRAF (8%), CDKN2A (6%). No mutation was found in 21% of tumors. According to IHC, the most common histological type was intestinal (51%), followed by pancreaticobiliary type (42%) and undetermined (7%). BRAF mutation was significantly associated with intestinal type (8 vs 0, p = 0.017). According to Cosmic database, similarities of molecular profiles exist between AA with intestinal type and colorectal adenocarcinoma, and between AA with pancreaticobiliary type and pancreas adenocarcinoma, respectively. Conclusions: This study shows that AA is a heterogeneous entity and that a large proportion of AA presents a molecular profile that is more similar to that of colorectal adenocarcinoma, compared to pancreatic adenocarcinoma. This important information could be interesting to guide treatment decision in patients with this rare disease.

Nasopharyngeal Non-Intestinal-Type Adenocarcinoma: A Case Report and Updated Review of the Literature

Non-intestinal-type adenocarcinoma is a malignancy traditionally found in the sinonasal cavity. To our knowledge, this case is the first reported of this rare condition originating in the nasopharynx. A 67-year-old woman with nasopharyngeal non-intestinal-type adenocarcinoma, with an accompanying parapharyngeal mass received primary radiation treatment for both lesions. Her tumour subsequently persisted, with a concomitant conversion in pathology from a low- to a high-grade malignancy. Non-intestinal-type and intestinal-type adenocarcinomas of the nasopharynx are extremely rare tumours and do not appear in the World Health Organization classification system. We review the pathophysiologic features of these malignancies and propose modifications to the current classification system. Non-intestinal-type adenocarcinoma should be included in the differential diagnosis of nasopharyngeal masses. In our experience, this tumour in this location showed a partial response to primary radiation but later converted from a low- to a high-grade adenocarcinoma.

Recurrent DNA copy number alterations in intestinal-type sinonasal adenocarcinoma

Intestinal-type sinonasal adenocarcinoma (ITAC) is a rare tumour related to occupational wood dust exposure. Few studies have described recurrent genetic changes on a genome-wide scale. The aim of this study was to obtain a high resolution map of recurrent genetic alterations in ITAC. Copy number alterations were evaluated by microarray CGH and MLPA in 37 primary tumours. The results were correlated with pathological characteristics and clinical outcome. Microarray CGH identified the following recurrent aberrations, in descending order: gains at 5p15 (22 cases, 60%), 8q24 (21 cases, 57%), 20q13 (20 cases, 54%), 20q11, and 8q21 (19 cases, 51%), 20p13, and 7p11 (16 cases, 43%), and losses at 5q11-qter, 8p12-pter, and 18q12-23 (15 cases, 40%), and 17p13, and 19p13 (13 cases, 35%). MLPA analysis confirmed this global pattern of gains and losses. Chromosomal loss at 4q32-ter and gains at 1q22, 6p22 and 3q29, as well as deletion of TIMP2 and CRK correlated with unfavourable clinical outcome. ITACs have a unique pattern of chromosomal abnormalities. The four different histological subtypes of ITAC appeared genetically similar. Four chromosomal gains and losses and two specific genes showed prognostic value and may be involved in tumour progression.

Prognostic value of the seventh AJCC/UICC TNM classification of intestinal-type ethmoid adenocarcinoma: Systematic review and risk prediction model.

The purpose of this study was to propose a prognostic classification of intestinal-type adenocarcinoma (ITAC) based on literature search and prognostic modeling of cohort data. We first conducted a literature search to assess the homogeneity of the reported estimates of 5-year survival and to identify the influence of T classification. We then pooled prospective data from 3 large French and Italian series to predict time to all-cause mortality. The sample was randomly split to derive and then to validate the proposed prognostic model. Literature analysis confirmed the heterogeneity in 5-year survival rates, partly explained in subsets of homogeneous T-values. The sample included 223 patients, randomly separated into a derivation (n = 141) and a validation set (n = 82). Invasion of the sphenoid lateral and/or posterior walls and dura/cerebral invasion were systematically associated with a poor survival. The incorporation of the invasion of the sphenoid lateral or posterior walls should be considered for ITAC management and prognostication. © 2017 Wiley Periodicals, Inc. Head Neck 39: 668-678, 2017.

Intensity-modulated radiation therapy for a sinonasal intestinal-type adenocarcinoma patient: a rare case report

Intestinal-type adenocarcinoma (ITAC) is a rare tumor, representing possibly 1.4% of all the sinonasal and skull base malignancies. We present a 62-year-old male with cT4bN0M0, stage IVB intestinaltype sinonasal adenocarcinoma who developed right eye blindness due to tumor-compression of the optic nerve. He received surgery and adjuvant radiotherapy at 70 Gy in 35 fractions, which improved his blindness. After 37 months of follow-up, no progression disease or distant metastasis was found. This case is a reminder of the important role radiotherapy plays in the post-operative treatment of sinonasal ITAC patients.

Identification of the intestinal type gastric adenocarcinoma transcriptomic markers using bioinformatic and gene expression analysis

Introduction . Searching for specific and sensitive molecular tumor markers is one of the important tasks of modern oncology. These markers can be used for early tumor diagnosis and prognosis as well as for prediction of therapeutic response, estimation of tumor volume or to assess disease recurrence through monitoring. Gene expression data base mining followed by experimental validation of results obtained is one of the promising approaches for searching of that kind. Objective: to identify several membrane proteins which can be used for serum diagnosis of intestinal type of gastric adenocarcinoma. Materials and methods. We used bioinformatic-driven search using Gene Ontology and The Cancer Genome Atlas (TCGA) data to identify mRNA up-regulated in gastric cancer (GC). Then, the expression levels of the mRNAs in 55 pare clinical specimens were investigated using reverse transcription polymerase chain reaction. Results. Comparative analysis of the mRNA levels in normal and tumor tissues using a new bioinformatics algorithm allowed to identify 3 high-copy transcripts (SULF1, PMEPA1 and SPARC), intracellular content of which markedly increased in GC. Expression analysis of these genes in clinical specimens showed significantly higher mRNA levels of PMEPA1 and SPARC in tumor as compared to normal gastric tissue. Interestingly more than twofold increase in expression level of these genes was observed in 75 % of intestinal-type GC. The same results were found only in 25 and 38 % of diffuse-type GC respectively. Conclusions. As a result of original bioinforamtic analysis using TCGA data base two genes (PMEPA1 and SPARC) were shown to be significantly upregulated in intestinal-type gastric adenocarcinoma. The findings show the importance of further investigation to clarify the clinical value of their expression level in stomach tumors as well as their role in carcinogenesis.

Clear Cell Adenocarcinoma of the Colon in the Setting of Attenuated Familial Polyposis: A Rare Variant of Primary Colonic Adenocarcinoma

Clear cell adenocarcinoma of the colon has been described rarely in the literature. It affects more commonly elderly men and usually appears in the left side of the colon. A 52-year-old male with a past medical history of attenuated FAP, who was diagnosed during a routine colonoscopy with bifocal tumor associated to 2 polyps of the transverse colon. Physical exam was normal. Laboratory data was unremarkable. A total colectomy with ileo-rectal anastomosis was performed. Gross examination of surgical specimen revealed 3 tumors and 6 pedicaulated polyps. Histopathology analysis of both coecal tumors conclude to an intestinal type adenocarcinoma. However, for the third one located in the left colon was histologically different displaying clear cell features. The later showed at immunohistochemistry study a positive staining for CK20, CDX2, while it was negative for CK 7 and CD 10. These results confirmed the clear cell variant of the adenocarcinoma. Clear cell adenocarcinomas usually arises from kidneys and Mullerian organs. Colorectal occurrence is rare especially in the setting of attenuated adenomatous polyposis. More research and information about this malignancy is needed, especially in regard to prognosis and in order to provide the best treatment option.

導入化学療法後に頭蓋底手術を行った篩骨洞原発腸管型腺癌の1例

導入化学療法後に頭蓋底手術を行った篩骨洞原発腸管型腺癌の1例

PUB058 Pulmonary Intestinal-Type Adenocarcinoma

Intestinal-type adenocarcinoma is a rare pulmonary cancer. Cystic change as image feature in lung cancer patients is also quite uncommon. Here we report a rare case of pulmonary intestinal-type adenocarcinoma with multiple cystic changes in CT image. Fig 2Immunohistochemical staining for cytokeratin 7(CK7) and CK20 were positive.View Large Image Figure ViewerDownload Hi-res image Download (PPT) The patient was a 67-year-old woman. A computed tomographic scan of the chest revealed multiple cystic changes in the both sides of her lung (Fig 1). Tumor markers such as CEA, cyfra211 and SCC were mild elevated. Sputum cytology and transbronchial examination didn’t find cancer. PET-CT revealed high FDG accumulation at the lesion in the lung. She did the CT guided lung biopsy . Histopathologically, the tomor consisted predominantly of colorectal carcinoma-like components, composed mainly of tall columnar cells with a brush-border and eosinophilic cytoplasm. Immunohistochemical staining for CK7 and CK20 were positive (Fig 2), whereas TTF-1 and napsin-A were negative. The final diagnosis was primary pulmonary intestinal-type adenocarcinoma. There are few reported cases of pulmonary intestinal-type adenocarcinoma. More experience of such cases is needed to further understand this rare variant of adenocarcinoma.

Murine Models of Gastric Corpus Preneoplasia.

Intestinal-type gastric adenocarcinoma evolves in a field of pre-existing metaplasia. Over the past 20 years, a number of murine models have been developed to address aspects of the physiology and pathophysiology of metaplasia induction. Although none of these models has achieved true recapitulation of the induction of adenocarcinoma, they have led to important insights into the factors that influence the induction and progression of metaplasia. Here, we review the pathologic definitions relevant to alterations in gastric corpus lineages and classification of metaplasia by specific lineage markers. In addition, we review present murine models of the induction and progression of spasmolytic polypeptide (TFF2)–expressing metaplasia, the predominant metaplastic lineage observed in murine models. These models provide a basis for the development of a broader understanding of the physiological and pathophysiological roles of metaplasia in the stomach.

Immunohistochemical Typing of Adenocarcinomas of the Pancreatobiliary System Improves Diagnosis and Prognostic Stratification.

Background & AimsAdenocarcinomas of the pancreatobiliary system are currently classified by their primary anatomical location. In particular, the pathological diagnosis of intrahepatic cholangiocarcinoma is still considered as a diagnosis of exclusion of metastatic adenocarcinoma. Periampullary cancers have been previously classified according to the histological type of differentiation (pancreatobiliary, intestinal), but overlapping morphological features hinder their differential diagnosis. We performed an integrative immunohistochemical analysis of pancreato-biliary tumors to improve their diagnosis and prediction of outcome.MethodsThis was a retrospective observational cohort study on patients with adenocarcinoma of the pancreatobiliary system who underwent diagnostic core needle biopsy or surgical resection at a tertiary referral center. 409 tumor samples were analyzed with up to 27 conventional antibodies used in diagnostic pathology. Immunohistochemical scoring system was the percentage of stained tumor cells. Bioinformatic analysis, internal validation, and survival analysis were performed.ResultsHierarchical clustering and differential expression analysis identified three immunohistochemical tumor types (extrahepatic pancreatobiliary, intestinal, and intrahepatic cholangiocarcinoma) and the discriminant markers between them. Among patients who underwent surgical resection of their primary tumor with curative intent, the intestinal type showed an adjusted hazard ratio of 0.19 for overall survival (95% confidence interval 0.05–0.72; p value = 0.014) compared to the extrahepatic pancreatobiliary type.ConclusionsIntegrative immunohistochemical classification of adenocarcinomas of the pancreatobiliary system results in a characteristic immunohistochemical profile for intrahepatic cholangiocarcinoma and intestinal type adenocarcinoma, which helps in distinguishing them from metastatic and pancreatobiliary type adenocarcinoma, respectively. A diagnostic immunohistochemical panel and additional extended panels of discriminant markers are proposed as guidance for their pathological diagnosis.

Comparative immunohistochemical characteristic of expression levels of Ki-67, p53, caspase 3 in non-invasive and invasive intestinal-type gastric adenocarcinoma

Aim. Comparison analysis of expression levels of Ki-67, p53, and caspase 3 was performed between the tumor cells and the stromal cells of non-invasive intestinal-type gastric adenocarcinoma on the one hand and the tumor cells and the stromal cells of invasive intestinal-type gastric adenocarcinoma on the other hand.Materials and methods. For this purpose, pathohistological and immunohistochemical studies were used. The surgical material of 10 patients with non-invasive (pTis, pT1) intestinal-type gastric adenocarcinoma and 10 patients with invasive (pT2, pT3, pT4) intestinal-type gastric adenocarcinoma were analyzed.Results. It was established that intestinal-type gastric adenocarcinoma is characterized by the medium Ki-67 labeling index, the low expression level of p53, the low expression level of caspase 3 in the tumor cells, and also the low Ki-67 labeling index and the extremely low expression level of caspase 3 in the stromal cells. The tumor cells of invasive intestinal-type gastric adenocarcinoma are characterized by the 2 times higher expression level of p53, than the tumor cells of non-invasive intestinal-type gastric adenocarcinoma. Moreover, direct correlation between the medium Ki-67 labeling index of the tumor cells and the low Ki-67 labeling index of the stromal cells, and also direct correlation between the medium Ki-67 labeling index in the tumor cells of intestinal-type gastric adenocarcinoma and the low expression level of p53 in these cells were identified.Conclusions. These data demonstrate a significantly more activity of proliferation and apoptosis in the tumor cells of intestinal-type gastric adenocarcinoma, in comparison with the stromal cells of this tumor. Invasive intestinal-type gastric adenocarcinoma differs by the 2 times higher expression level of p53, in comparison with the same index for non-invasive carcinoma. Furthermore, a tight association between proliferative processes in the tumor cells and in the stromal cells of intestinal-type gastric adenocarcinoma, and also an association between proliferative processes and accumulation of mutant protein p53 in the tumor cells of intestinal-type gastric adenocarcinoma were identified.

Comparative immunohistochemical characteristics of Ki-67, p53, caspase-3 expression in gastric hyperplastic polyps and non-invasive intestinal-type gastric adenocarcinoma

Aim. The problem of early diagnostic of gastric cancer has a tight connection with the issue of premalignant lesions, especially gastric polyps. The aim of this research was to compare the expression levels of Ki-67, p53 and caspase-3 in epithelial cells and stromal cells of gastric hyperplastic polyps on the one hand and tumor cells and stromal cells of non-invasive intestinal-type gastric adenocarcinoma on the other hand. Materials and methods. For this purpose, pathohistological and immunohistochemical studies were used. The biopsies of 10 patients with hyperplastic polyps (the age of the patients ranged from 52 to 73 years) and surgical material of 10 patients with non-invasive (pTis, pT1) intestinal-type gastric adenocarcinoma (the age of patients ranged from 45 to 83 years) were analyzed. Results. It was established that epithelial cells of gastric hyperplastic polyps are characterized by low expression level of Ki-67, p53 and caspase-3, just as stromal cells of hyperplastic polyps are characterized by low expression level of Ki-67 and the medium expression level of caspase-3. Moreover, it has been established that tumor cells of non-invasive intestinal-type gastric adenocarcinoma are characterized by medium expression level of Ki-67, caspase-3 and also low expression level of p53, just as stromal cells of non-invasive adenocarcinoma are characterized by low expression level of Ki-67 and low expression level of caspase-3. The differences between the expression levels of Ki-67, p53 and caspase-3, that were established for hyperplastic polyps on the one hand and non-invasive adenocarcinoma on the other hand, are statistically significant (p<0,05). Conclusion. These data demonstrate, that proliferative activity of non-invasive intestinal-type gastric adenocarcinoma tumor cells is higher than proliferative activity of gastric hyperplastic polyps epithelial cells. Moreover, non-invasive intestinal-type gastric adenocarcinoma differs by higher activity of p53 accumulation, higher level of tumor cells apoptosis and lower level of stromal cells apoptosis.

Gastric Intestinal Metaplasia and Helicobacter pylori Testing

Introduction: Gastric Intestinal metaplasia (GIM) is a frequent precancerous lesion, with 6-10 fold increase in gastric cancer risk. Helicobacter pylori (H. pylori) is believed to be the cause of majority of intestinal-type gastric adenocarcinoma by causing chronic active gastritis, which may evolve to atrophic gastritis, IM, dysplasia, and cancer. Whether H. Pylori eradication leads to reversal of IM remains controversial. Since H. pylori exhibits tissue tropism, we believe that IM drives H.pylori out of the gastric mucosa. Biopsy alone for the detection of H. pylori may be less accurate in the context of IM, especially if biopsies fail to sample non-metaplastic tissue. Hence, another method of H. Pylori testing must be performed. Methods: A retrospective chart review was conducted using Electronic Medical Records (EMR) at one hospital. After Institutional Review Board approval, a list of patients with a histological diagnosis of GIM over the past 10 years was obtained. The EMR was reviewed for patients with biopsy proven gastric intestinal metaplasia and H. Pylori testing status was documented. Results: A total of 54 patients were identified with GIM. The median age was 68 year, 94.4% were male, 83.3% were Caucasian, 79.6% were present or former smokers. Documentation of pathologic testing for H. Pylori was found for all patients with 22.2% testing positive in pathology specimen. Of the remaining 42 patients, serologic testing was done in 19 % with 50% testing positive, 25% testing negative and 25% equivocal. There were 34 patients with GIM and H pylori negative biopsies who did not have serological testing done, 2 had empiric anti-H Pylori treatment and 2 had protocol biopsies done 2 years later. Both the patientswith equivocal results on serological testing had protocol biopsies. Only 25.9%npatients were treated for H. Pylori after the diagnosis of GIM. Conclusion: Our study shows that pathologic testing for H. Pylori was completed in almost all cases of GIM and only 22.2% of patients had H. Pylori identified from their biopsy. This is in accordance with our hypothesis that gastric biopsy has lower accuracy in the presence of IM because of inability of H. Pylori to grow on metaplastic tissue. H. Pylori eradication could reduce the risk of further development of dysplasia and subsequent gastric malignancy. Therefore, we recommend that patients with intestinal metaplasia should undergo additional diagnostic tests if the initial biopsy is negative for H. Pylori.Figure 1

Adenocarcinoma ex-goblet cell carcinoid (appendiceal-type crypt cell adenocarcinoma) is a morphologically distinct entity with highly aggressive behavior and frequent association with peritoneal/intra-abdominal dissemination: an analysis of 77 cases

AbstractHigh-grade versions of appendiceal goblet cell carcinoids (‘adenocarcinoma ex-goblet cell carcinoids') are poorly characterized. We herein document 77 examples. Tumors occurred predominantly in females (74%), mean age 55 years (29–84), most with disseminated abdominal (77% peritoneal, 58% gynecologic tract involvement) and stage IV (65%) disease. Many presented to gynecologic oncologists, and nine had a working diagnosis of ovarian carcinoma. Metastases to liver (n=3) and lung (n=1) were uncommon and none arose in adenomatous lesions. Tumors had various histologic patterns, in variable combinations, most of which were fairly specific, making them recognizable as appendiceal in origin, even at metastatic sites: I: Ordinary goblet cell carcinoid/crypt pattern (rounded, non-luminal acini with well-oriented goblet cells), in variable amounts in all cases. II: Poorly cohesive goblet cell pattern (diffusely infiltrative cords/single files of signet ring-like/goblet cells). III: Poorly cohesive non-mucinous cell (diffuse-infiltrative growth of non-mucinous cells). IV: Microglandular (rosette-like glandular) pattern without goblet cells. V: Mixed ‘other' carcinoma foci (including ordinary intestinal/mucinous). VI: goblet cell carcinoid pattern with high-grade morphology (marked nuclear atypia). VII: Solid sheet-like pattern punctuated by goblet cells/microglandular units. Ordinary nested/trabecular (‘carcinoid pattern') was very uncommon. In total, 33(52%) died of disease, with median overall survival 38 months and 5-year survival 32%. On multivariate analysis perineural invasion and younger age (<55) were independently associated with worse outcome while lymph-vascular invasion, stage, and nodal status trended toward, but failed to reach, statistical significance. Worse behavior in younger patients combined with female predilection and ovarian-affinity raise the possibility of hormone-assisted tumor progression. In conclusion, ‘adenocarcinoma ex-goblet cell carcinoid' is an appendix-specific, high-grade malignant neoplasm with distinctive morphology that is recognizable at metastatic sites and recapitulates crypt cells (appendiceal crypt cell adenocarcinoma). Unlike intestinal-type adenocarcinoma, it occurs predominantly in women, is disguised as gynecologic malignancy, and spreads along peritoneal surfaces with only rare hematogenous metastasis. It appears to be significantly more aggressive than appendiceal mucinous neoplasms.

Expression of Bile Acid Receptor TGR5 in Gastric Biopsies with Intestinal Metaplasia Correlates with p53 Protein Accumulation

Introduction: Bile has been shown to be genotoxic and plays a role in gastric intestinal metaplasia and tumorigenesis. The bile acid receptor TGR5 was found to be expressed in the majority of intestinal type gastric adenocarcinoma. p53 protein accumulation as detected by immunohistochemistry (IHC) and p53 gene mutation have been detected in gastric precancerous lesions including intestinal metaplasia. The aim of this study was to determine whether TGR5 is expressed in gastric intestinal metaplasia, a precursor for intestinal-type adenocarcinoma, and to correlate this expression with clinicopathologic parameters and with p53 protein accumulation. Methods: TGR5 and p53 expression in sections of formalin fixed paraffin embedded gastric biopsies from 58 consecutive patients with gastric metaplasia were determined by IHC. TGR5 expression was correlated with p53 protein accumulation, Helicobacter pylori status, patient gender and age, history of cholecystectomy, and body mass index (BMI). Results: Thirty-four (59%) of the 58 biopsies with intestinal metaplasia showed TGR5 expression in the gastric epithelium and 24 (41%) were negative. There was no difference between patients with TGR5-positive and TGR5-negative biopsies in median age (64 years vs 61 years, p=0.658), sex (50% males vs 50% females), median BMI (28.86 vs 25.52, p=0.126), Helicobacter pylori status (positive in 32% vs 29%, p=0.796), or history of cholecystectomy (28% vs 27%, p=0.945). Eleven (42%) of the TGR5-positive biopsies were positive for p53 compared to 2 (8%) of the TGR5-negative biopsies (p=0.03). There was no significant association between Helicobacter pylori status and p53 positivity. Three (17%) of 18 biopsies with history of positive Helicobacter pylori were positive for p53 protein accumulation compared to 10 (25%) of 40 with negative Helicobacter pylori (p=0.48). Conclusion: In our patient population with intestinal metaplasia, 60% of the biopsies show TGR5 expression. Significantly more biopsies with TGR5 expression overexpress the p53 protein. Follow-up studies are needed to determine whether TGR5 expression precedes p53 overexpression in gastric biopsies with intestinal metaplasia and to explore its utility as a biomarker for selecting patients for prevention studies.

Recurrent DNA copy number alterations in intestinal-type sinonasal adenocarcinoma.

Intestinal-type sinonasal adenocarcinoma (ITAC) is a rare tumour related to occupational wood dust exposure. Few studies have described recurrent genetic changes on a genome-wide scale. The aim of this study was to obtain a high resolution map of recurrent genetic alterations in ITAC. Copy number alterations were evaluated by microarray CGH and MLPA in 37 primary tumours. The results were correlated with pathological characteristics and clinical outcome. Microarray CGH identified the following recurrent aberrations, in descending order: gains at 5p15 (22 cases, 60%), 8q24 (21 cases, 57%), 20q13 (20 cases, 54%), 20q11, and 8q21 (19 cases, 51%), 20p13, and 7p11 (16 cases, 43%), and losses at 5q11-qter, 8p12-pter, and 18q12-23 (15 cases, 40%), and 17p13, and 19p13 (13 cases, 35%). MLPA analysis confirmed this global pattern of gains and losses. Chromosomal loss at 4q32-ter and gains at 1q22, 6p22 and 3q29, as well as deletion of TIMP2 and CRK correlated with unfavourable clinical outcome. ITACs have a unique pattern of chromosomal abnormalities. The four different histological subtypes of ITAC appeared genetically similar. Four chromosomal gains and losses and two specific genes showed prognostic value and may be involved in tumour progression.