Poorly-differentiated Adenocarcinoma Research Articles

Coexisting tubular adenoma with a neuroendocrine carcinoma of colon allowing early surgical intervention and implicating a shared stem cell origin

High-grade colonic neuroendocrine carcinomas (NECs) are uncommon but extremely aggressive. Their co-existence with tubular adenoma (TA) has rarely been reported. We present a 68-year-old man who was found on routine colonoscopy to have multiple colorectal TAs and an ulcerated lesion in the ascending colon. Microscopically, a poorly-differentiated invasive carcinoma juxtaposed with a TA was identified. Differential diagnosis included a poorly-differentiated adenocarcinoma, medullary carcinoma, high-grade NEC and lymphoma. The immunohistochemical profile showed positive staining for keratins, synaptophysin and chromogranin but negative for LCA, CDX2, CK7, CK20, TTF-1 and PSA, supporting the NEC diagnosis. Upon subsequent laparoscopic right hemicolectomy, the tumor was identified as a 3.0 cm umbilicated and ulcerated mass with an adjacent TA. Both TA and NEC showed positive staining for β-catenin indicating a shared colonic origin. The mitotic counts (77/10 high power fields) and a high proliferation rate (75% by Ki-67) corroborated a high-grade stratification. Mutational analysis indicated a wild-type BRAF and KRAS with mismatch repair proficiency. The AJCC (7th edition) pathologic stage is pT3, pN0, pMx. The patient received adjuvant chemotherapy with cisplatin/etoposides for three cycles and will be followed up for a year to detect recurrence. In conclusion, the co-existence of TA with high grade-NEC in our case allowed early identification and intervention of the otherwise asymptomatic but aggressive tumor. In addition, the finding of a high-grade NEC within a large TA in this case suggests a link between the two lesions and could represent a shared stem cell origin.

P2.03b-025 Mutation Profile and Histology Subtype According to IASLC/ERS/ATC as Risk Factors for Brain Metastases in Lung Adenocarcinoma: Topic: Biomarkers

Brain metastases (BM) are common among patients with adenocarcinoma, affecting treatment response, quality of life and overall survival (OS). We examine the impact of the main histological pattern and the genetic alterations in EGFR and ALK on the incidence of BM in patients with advanced non-small cell lung cancer (NSCLC). From January 2004 through December 2014 the medical records of 991 patients with NSCLC were reviewed for eligibility, among them 711 had adenocarcinoma histology. We describe the factors associated with the overall incidence of BM as well as the incidence of BM stratified on the histological grade pattern according to the ERS/ATC/IASLC classification (lepidic vs acinar+papilar vs micropapilar+solid). Among 711 patients, 53.6% were female, 47.1% were less than 60 years-old at the time of diagnosis, exposure to tobacco, wood-smoke and asbestos were found in 52.0%, 40.5% and 13.8%, respectively. Seventy-six percent had a good performance status, and nearly sixty percent (59.8%) had oligometastatic disease. Most of the patients had a stage IV disease at the time of diagnosis (79.3%). Regarding histological grade classification, male patients were more likely to have a poorly differentiated adenocarcinoma in comparison with women (61.2% vs. 51.2%, p=0.027), as well as ever-smokers compared with non-smokers (61.4% vs. 49.9%). Likewise, patients harboring an ALK rearrangement were more likely to have a highly- or moderate differentiated adenocarcinoma (100% vs. 43.6%, p=0.008). A total of 122 patients (17.1 %) had a brain metastasis at diagnosis and 37.4% had baseline carcinoembryonic levels above 20 pg/ml. By Kaplan-Meier method 6.45% and 12.10% of patients developed BM at 12 and 24 months. The factors associated with a high incidence of BM were: female gender (40.9% vs. 34.4%; p=0.036), age < 60 years (44.4% vs. 32.1%, p≤0.001), EGFR activating mutation (53.9% vs. 39.3%; p=0.001), advanced metastatic disease (IIIB vs IV 42.8% vs. 20.3%; p≤0.0001), serological carcinoembryonic level >20pg/ml (47.2% vs. 32.8%; p≤0.0001) Finally, brain metastases were more likely to be found among patients with moderate and poorly-differentiated adenocarcinomas in comparison with highly differentiated adenocarcinomas (54.2, and 48.1% vs. 7.7%; p=0.050). In the multivariate analysis EGFR (HR:0.63; 95% CI 0.44-0.92, p=0.017) and highly differentiated adenocarcinomas EGFR (HR:1.59; 95% CI 1.03-2.44, p=0.034) were found to be independent factors for the development of BM. Adenocarcinoma histological-architectural-grade differentiation according to ERS/ATC/IASCL classification was found to be a predictive factor for development of BM like other previously described clinically characteristics (e.g. gender, age, EGFR activating mutations and carcinoembryonic-antigen).

Medullary colonic carcinoma with microsatellite instability has lower survival compared with conventional colonic adenocarcinoma with microsatellite instability.

IntroductionColorectal medullary carcinoma (MC) is a rare subtype of poorly differentiated adenocarcinoma (PDA) with unclear prognostic significance. Microsatellite instable (MSI) colorectal carcinomas have demonstrated better prognosis in clinical stage II.AimTo analyze the survival and clinicopathological characteristics of MCs versus PDAs with MSI in clinical stage III.Material and methodsWe studied 22 cases of PDAs with MSI versus 10 MCs.ResultsOf the 10 MCs, 7 patients were men; the mean age was 57.8 ±5.6 years. The mean tumor size was 9.6 ±4.1 cm, and the primary site was the right colon in 9; 7 patients showed lymph node metastases (LNM) and lymphovascular invasion (LVI). Of the 22 PDA cases, 12 (54.5%) were women with a mean age of 75 ±16.1 years. The mean tumor size was 6.4 ±3.2 cm. Twelve (54.5%) presented in the right colon, 21 (95.5%) showed LNM and 7 (31.8%) LVI. Follow-up was 32 ±8 months, with a 5-year overall survival of 42.9% for MCs and 76.6% for PDAs (p = 0.048). Univariate analysis found local recurrence (p = 0.001) and medullary subtype (p = 0.043) associated with lower survival.ConclusionsMedullary carcinomas were of greater tumor size and associated with more LVI and worse survival versus PDAs with MSI in stage III.

A Case Report of Carbohydrate Antigen 19-9 Producing Advanced Gastric Cancer

&lt;p class="cco-body"&gt;&lt;span lang="EN-GB"&gt;The gastric cancer producing carbohydrate antigen 19-9 (CA 19-9) is a rare and unknown that characterize informations.&lt;/span&gt;&lt;/p&gt;&lt;p class="cco-body"&gt;&lt;span lang="EN-GB"&gt;74-year-old woman who was admitted with complaints of epigastric discomfort. An advanced cancer was found in her lower gastric region; biopsy of the tumor revealed poorly-differentiated adenocarcinoma. Her serum CA 19-9 was extremely elevated at 2322 U/ml and computed tomography demonstrated enlargement of the para-aortic lymph node; thus the tumor was considered unresectable. The patient received 8 cycles of chemotherapy with S-1/cisplatin, which shrank the para-aortic lymph node dramatically, hence she underwent D2 gastrectomy. Immunohistochemical staining of the resected cancer revealed that a third of the cancer cells were positive for CA 19-9. In addition, her serum CA 19-9 decreased rapidly after surgery and she remains alive without recurrence three years after surgery.&lt;/span&gt;&lt;/p&gt;&lt;p class="cco-body"&gt;&lt;span lang="EN-GB"&gt;We report one high level of CA 19-9 gastric cancer case with dramatically chemosensitive.&lt;/span&gt;&lt;/p&gt;

Effect of World Health Organization (WHO) Histological Classification on Predicting Lymph Node Metastasis and Recurrence in Early Gastric Cancer.

BackgroundThe World Health Organization (WHO) histological classification for gastric cancer is widely accepted and used. However, its impact on predicting lymph node metastasis and recurrence in early gastric cancer (EGC) is not well studied.Material/MethodsFrom 1987 to 2005, 2873 EGC patients with known WHO histological type who had undergone curative resection were enrolled in this study. In all, 637 well-differentiated adenocarcinomas (WD), 802 moderately-differentiated adenocarcinomas (MD), 689 poorly-differentiated adenocarcinomas (PD), and 745 signet-ring cell adenocarcinomas (SRC) were identified.ResultsThe distribution of demographic and clinical features in early gastric cancer among WD, MD, PD, and SRC were significantly different. Lymph node metastasis was observed in 317 patients (11.0%), with the lymph node metastasis rate being 5.3%, 14.8%, 17.0%, and 6.3% in WD, MD, PD, and SRC, respectively. Univariate and multivariate analyses indicated that gender, tumor size, gross appearance, depth of invasion, and WHO classification were significantly associated with lymph node metastasis. Recurrence was observed in 83 patients (2.9%), with the recurrence rate being 2.2%, 4.5%, 3.0%, and 1.6% in WD, MD, PD, and SRC, respectively. Multivariate analysis confirmed that MD, elevated gross type, and lymph node metastasis were independent risk factors for recurrence in EGC. MD patients showed worse disease-free survival than non-MD patients (P=0.001).ConclusionsWHO classification is useful and necessary to evaluate during the perioperative management of EGC. Treatment strategies for EGC should be made prudently according to WHO classification, especially for MD patients.

Abstract 2750: Mutations on the homologous recombination pathway in 13 cancer types

Abstract Homologous recombination (HR) is important in DNA double-strand break repair. HR defects promote carcinogenesis and are associated with selective sensitivity to PARP-inhibitors and DNA-damaging agents. We collected 1029 tumor samples in 13 cancer types and used next-generation sequencing (NGS) to survey genes in the HR pathway. NGS on 591 genes was performed using formalin-fixed paraffin-embedded samples on the Illumina NextSeq platform (Caris Life Sciences, AZ). Mutations in as low as 5% of cells can be detected with &amp;gt; 99% confidence. Deletions larger than 27bp may not be detected by this method. Pathogenic or presumed pathogenic variants are counted as mutations. The table summarizes mutation rates of 7 key genes—ATM, BRCA1, BRCA2, CHEK1, CHEK2, PALB2 and PTEN—included in this pilot study. Another 17 HR genes—ATR, ATRX, BARD1, BLM, BRIP1, FANCA, FANCC, FANCD2, FANCE, FANCF, FANCG, FANCL, MRE11A, NBN, RAD50, RAD51, and RAD51B—were also analyzed. PTEN mutations were seen in 6.3% of tumors, ATM in 5%, BRCA1 in 2%, BRCA2 in 2%, PALB2 in 1%, and CHEK2 in 1%. No CHEK1 mutations were observed. Overall, 15% of tumors carry at least one mutation in any of the 7 key genes. The highest mutation rates were seen in endometrial (43%), glioblastoma (34%), and gastric cancers (23%). The highest rates of ATM (9.7%), BRCA2 (6.5%), and PALB2 (6.5%) were seen in gastric cancer, while the highest CHEK2 (5.6%), BRCA1 (7.3%) and PTEN (44%) mutations were seen in cholangiocarcinoma, ovarian and endometrial tumors, respectively. One 53-year old pt with metastatic poorly-differentiated gastric adenocarcinoma experienced ongoing radiographic partial response and dramatic symptom relief following 4 cycles of FOLFOX without surgery; tumor analysis revealed a nonsense PALB2 (S326*) gene mutation, while the other 23 HR genes were wild type. ERCC1 showed intact expression by IHC. Mutation rates of 7 genes on the HR pathway in 13 cancer typesEndometrialATMBRCA1BRCA2CHEK1CHEK2PALB2PTENAny of the 7 genesEndometrial (N = 35)00002.9%3.0%44.1%42.9%GBM (N = 47)2.1%2.1%000030.4%34.0%Gastric (N = 31)9.7%06.5%006.5%022.6%Bladder (N = 38)2.6%05.4%00010.8%18.4%Kidney (N = 41)2.5%0005.0%010.0%17.1%Ovarian (N = 82)3.7%7.3%1.2%01.2%01.3%14.6%Breast (N = 108)4.6%2.8%1.9%00.9%1.0%3.8%13.9%Cholangiocarcinoma (N = 36)2.8%02.8%05.6%02.9%13.9%CRC(N = 254)6.3%2.0%1.6%00.4%04.0%13.0%Pancreatic (N = 62)4.8%1.6%3.2%001.7%3.3%12.9%NSCLC(N = 234)6.5%00.9%001.4%2.6%11.1%Neuroendocrine(N = 35)2.9%000005.7%8.6%Esophageal (N = 26)3.8%000004.0%7.7%Overall(N = 1029)5.0%1.6%1.6%00.8%0.8%6.3%15.2% Thus, mutation rates of at least 8 to 43% in the HR pathway are reported from 13 cancer types. This method can potentially identify responders to DNA-damaging agents including platinum. Citation Format: Joanne Xiu, Ryan Bender, Brian Abbott, Zoran Gatalica, Sandeep Reddy, Mohamed Salem, Shelly Seward. Mutations on the homologous recombination pathway in 13 cancer types. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2750.

Concomitant multifocal gastrinomas and adenocarcinoma in the stomach: A case report and literature review

The stomach is an uncommon location for gastrinomas. Here we report a rare case of multifocal gastrinomas in the antrum with concomitant gastric adenocarcinoma and neuroendocrine cell hyperplasia. The patient was a 35-year-old man who presented with mild upper abdominal discomfort for 3months. Serum gastrin level was elevated to 542pg/mL (normal: <100pg/mL). Endoscopic examination revealed multiple polyps in the antrum, which proved to be carcinoid tumors on biopsy. Partial gastrectomy was performed. The surgical specimen contained multiple pedunculated polyps measuring up to 2cm in greatest dimension. Additionally, many small, sessile polyps with central umbilication were identified in the antrum and the pylorus. Histological and immunohistochemical studies of the polyps showed nests of low-grade tumor cells that were positive for gastrin, confirming a diagnosis of multifocal gastrinoma. Incidentally, one large polyp was found to harbor a focus of poorly-differentiated adenocarcinoma with signet ring cell features. Diffuse enterochromaffin-like cell hyperplasia and small carcinoid tumors were identified in the body of the stomach. Regional lymph nodes were positive for both adenocarcinoma and gastrinoma. In addition, Helicobacter pylori-like organisms were detected in the antral mucosa. The post-operative course was uneventful, and the patient's serum gastrin level dropped to 30pg/mL. He is currently receiving chemotherapy for the adenocarcinoma. This is a rare case of multifocal gastrinoma in an unusual location. It has already been established that hypergastrinemia plays a role in the pathogenesis of gastric adenocarcinoma and neuroendocrine neoplasms. Therefore, it is important to rule out these concomitant lesions, both clinically and pathologically, when dealing with a proven gastrinoma.

A Risk Prediction Model Based on Lymph-Node Metastasis in Poorly Differentiated-Type Intramucosal Gastric Cancer.

Background and AimEndoscopic submucosal dissection (ESD) for undifferentiated type early gastric cancer is regarded as an investigational treatment. Few studies have tried to identify the risk factors that predict lymph-node metastasis (LNM) in intramucosal poorly differentiated adenocarcinomas (PDC). This study was designed to develop a risk scoring system (RSS) for predicting LNM in intramucosal PDC.MethodsFrom January 2002 to July 2015, patients diagnosed with mucosa-confined PDC, among those who underwent curative gastrectomy with lymph node dissection were reviewed. A risk model based on independent predicting factors of LNM was developed, and its performance was internally validated using a split sample approach.ResultsOverall, LNM was observed in 5.2% (61) of 1169 patients. Four risk factors [Female sex, tumor size ≥ 3.2 cm, muscularis mucosa (M3) invasion, and lymphatic-vascular involvement] were significantly associated with LNM, which were incorporated into the RSS. The area under the receiver operating characteristic curve for predicting LNM after internal validation was 0.69 [95% confidence interval (CI), 0.59–0.79]. A total score of 2 points corresponded to the optimal RSS threshold with a discrimination of 0.75 (95% CI 0.69–0.81). The LNM rates were 1.6% for low risk (<2 points) and 8.9% for high-risk (≥2 points) patients, with a negative predictive value of 98.6% (95% CI 0.98–1.00).ConclusionsA RSS could be useful in clinical practice to determine which patients with intramucosal PDC have low risk of LNM.

Outcome and CT differentiation of gallbladder neuroendocrine tumours from adenocarcinomas.

To retrospectively investigate clinical outcome and differential CT features of gallbladder (GB) neuroendocrine tumours (NETs) from adenocarcinomas (ADCs). Nineteen patients with poorly-differentiated (PD) NETs and 19 patients with PD ADCs were enrolled. Clinical outcome was compared by the Kaplan-Meier method. We assessed qualitative and quantitative CT features to identify significant differential CT features of PD NETs from ADCs using univariate and multivariate analyses. Receiver operating characteristic (ROC) analysis was used for quantitative CT features. PD NETs showed poorer prognosis with significantly shorter median survival days than ADCs (363 vs. 590days, P = 0.03). On univariate analysis, NETs more frequently manifested as GB-replacing type and showed well-defined margins accompanied with intact overlying mucosa. On multivariate analysis, well-defined margin was the sole significant CT differentiator (odds ratio = 27.817, P = 0.045). Maximum size of hepatic and lymph node (LN) metastases was significantly larger in NETs (11.0cm and 4.62cm) than ADCs (2.40cm and 2.41cm). Areas under ROC curves for tumour-to-mucosa ratio, maximum size of hepatic and LN metastasis were 0.772, 0.932 and 0.919, respectively (P < 0.05). GB PD NETs show poorer prognosis than ADCs. Well-defined margin, larger hepatic and LN metastases are useful CT differentiators of GB NETs from ADCs. • A well-defined margin is a useful CT differentiator of GB NETs from ADCs. • Hepatic and LN metastases are significantly larger in NETs than in ADCs. • Primary tumour and hepatic metastasis of NETs are more hyperattenuated than ADCs.

Interlaboratory Variability in the Histologic Grading of Colorectal Adenocarcinomas in a Nationwide Cohort.

Differentiation grade of colorectal adenocarcinoma (CRC) is a prognostic factor and important for therapy selection. In patients with stage II colon cancer, poor differentiation is an indication for adjuvant chemotherapy. The variability in daily practice in the grading of CRC was assessed in a nationwide cohort. Using the Dutch Pathology Registry (PALGA), all synoptically reported CRC resections from 2010 to 2013 were identified. Proportions of poorly differentiated (PD) adenocarcinomas were determined and compared between 35 laboratories by univariable and multivariable logistic regression analyses. In total, 11,719 resections of 11,681 patients were included, of which 1427 (12.2%) were PD (range between 35 laboratories: 5.0% to 33.2%). After adjustment for case mix, 4 (11%) laboratories still reported a significantly lower (n=2) or higher (n=2) proportion of PD adenocarcinoma compared with the reference laboratory. Seven of 8 investigated laboratories showed considerable intralaboratory variation between pathologists as well. In a subgroup of 2812 patients (2813 tumors) who could have been eligible for adjuvant chemotherapy solely on the basis of the differentiation grade (stage II colon cancer patients without other high-risk factors [ie, T4, <10 lymph nodes evaluated, perforation, ileus, or angioinvasion]), 258 (9.2%) were PD (range between laboratories: 0% to 22.7%). In this subgroup, 4 laboratories still diagnosed significantly more PD adenocarcinomas after multivariable logistic regression analysis, increasing the number of colon cancer patients eligible for adjuvant therapy. In conclusion, this large nationwide cohort demonstrates considerable interlaboratory and intralaboratory variation in differentiation grading of CRC. Better standardization of grading criteria is needed for optimal determination of prognosis and treatment selection.

The efficacy of diffusion weighted imaging and apparent diffusion coefficients mapping for liver metastasis of colonic adenocarcinomas.

Objectives:To establish retrospectively the relation between the histopathologic grade of colorectal liver metastasis and apparent diffusion coefficient (ADC) values of hepatic metastases of colorectal adenocarcinomas.Methods:The diagnoses of liver metastases were confirmed with biopsy, surgery, and follow-up imaging findings. Twenty-six patients with 94 liver metastasis were included in the study. Of 94 masses, 59 were poorly-differentiated adenocarcinoma, 18 were moderately-differentiated adenocarcinoma, and 17 were well-differentiated regarding the diameters, ADC values, and ratio index (RI) values. Kolmogorov-smirnov normality test, Kruskal-wallis analysis of variance, Mann-Whitney U test with Bonferroni correction, Spearman correlation analysis, and receiver operating characteristics curve methods were applied to evaluate the statistical relations.Results:There was a statistically significant difference in terms of ADC values and RI between poorly-differentiated adenocarcinoma and moderately-differentiated adenocarcinoma plus well-differentiated adenocarcinomas. Poorly-differentiated adenocarcinomas have the lowest ADC values and highest RI values among other groups.Conclusion:Use of ADC values alone can be executed for the diagnosis of focal hepatic masses and also can aid in the differentiation of benign and malignant hepatic lesions.

Surgical treatment of scirrhous gastric carcinoma

Scirrhous gastric carcinoma is a special type of gastric carcinomas and accompanied with highly interstitial fibrosis and diffuse cellular infiltration. Scirrhous gastric carcinoma is mainly composed of poor-differentiated adenocarcinoma and signet-ring cell carcinoma, with the clinical features of Borramann 4, thickening and stenosis of stomach wall, high peritoneal and lymph node metastases rates and poor prognosis. R0 resection and postoperative chemotherapy with S-1 as a main way are necessary for the patients who are able to undergo curable resection. The palliative operation should be applied to patients with ileus and urinary obstructions caused by peritoneal metastasis because of limited effect of surgical treatment. Chemo-therapy is the best choice for patients who are not able to undergo curable resection, conversional therapy can improve the prognosis of patients, and preoperative S-1/CDDP combination chemotherapy is an expectable therapy. Moreover, controlling peritoneal metastasis and effect of intraperitoneal chemotherapy are much anticipated. The efficiency of molecular targeted therapy by bevacizumab and gene therapy by adenovirus remain further study. Key words: Gastric neoplasms, scirrhous; Surgical procedures, operative; Chemotherapy

Targeted Pten deletion plus p53-R270H mutation in mouse mammary epithelium induces aggressive claudin-low and basal-like breast cancer.

BackgroundTriple-negative breast cancer (TNBC), an aggressive disease comprising several subtypes including basal-like and claudin-low, involves frequent deletions or point mutations in TP53, as well as loss of PTEN. We previously showed that combined deletion of both tumor suppressors in the mouse mammary epithelium invariably induced claudin-low-like TNBC. The effect of p53 mutation plus Pten deletion on mammary tumorigenesis and whether this combination can induce basal-like TNBC in the mouse are unknown.MethodsWAP-Cre:Ptenf/f:p53lox.stop.lox_R270H composite mice were generated in which Pten is deleted and a p53-R270H mutation in the DNA-binding domain is induced upon expression of Cre-recombinase in pregnancy-identified alveolar progenitors. Tumors were characterized by histology, marker analysis, transcriptional profiling [GEO-GSE75989], bioinformatics, high-throughput (HTP) FDA drug screen as well as orthotopic injection to quantify tumor-initiating cells (TICs) and tail vein injection to identify lung metastasis.ResultsCombined Pten deletion plus induction of p53-R270H mutation accelerated formation of four distinct mammary tumors including poorly differentiated adenocarcinoma (PDA) and spindle/mesenchymal-like lesions. Transplantation assays revealed highest frequency of TICs in PDA and spindle tumors compared with other subtypes. Hierarchical clustering demonstrated that the PDA and spindle tumors grouped closely with human as well as mouse models of basal and claudin-low subtypes, respectively. HTP screens of primary Pten∆:p53∆ vs. Pten∆:p53R270H spindle tumor cells with 1120 FDA-approved drugs identified 8-azaguanine as most potent for both tumor types, but found no allele-specific inhibitor. A gene set enrichment analysis revealed increased expression of a metastasis pathway in Pten∆:p53R270H vs. Pten∆:p53∆ spindle tumors. Accordingly, following tail vein injection, both Pten∆:p53R270H spindle and PDA tumor cells induced lung metastases and morbidity significantly faster than Pten∆:p53∆ double-deletion cells, and this was associated with the ability of Pten∆:p53R270H tumor cells to upregulate E-cadherin expression in lung metastases.ConclusionsOur results demonstrate that WAP-Cre:Ptenf/f:p53lox.stop.lox_R270H mice represent a tractable model to study basal-like breast cancer because unlike p53 deletion, p53R270H mutation in the mouse does not skew tumors toward the claudin-low subtype. The WAP-Cre:Ptenf/f:p53lox.stop.lox_R270H mice develop basal-like breast cancer that is enriched in TICs, can readily form lung metastasis, and provides a preclinical model to study both basal-like and claudin-low TNBC in immune-competent mice.Electronic supplementary materialThe online version of this article (doi:10.1186/s13058-015-0668-y) contains supplementary material, which is available to authorized users.

Sm胃癌術後，急速に成長するリンパ節再発に対し腹腔鏡補助下膵体尾部切除術を施行した1例

A 73-year-old man diagnosed with gastric cancer underwent laparoscopic total gastrectomy at our hospital 12 months ago. The histopathological diagnosis was a poorly-differentiated adenocarcinoma limited to the gastric submucosa, pT1b (SM2) , pN0, stage IA. Computed tomography (CT) performed at the outpatient follow-up 6 months after surgery revealed a pancreatic body. No other definite mass shadow was detected. Positron emission tomography (PET) -CT revealed high accumulation (SUVmax) near the site of the pancreatic body. We performed laparoscope-assisted distal pancreatectomy to remove the tumor which had gradually increased over the intervening 6 months. The histopathlogical diagnosis was a poorly-differntiated adenocarcinoma resulting from lymph node metastasis of the gastric cancer. In general, skip metastasis is due to the presence of a metastatic lymph node in an extraperigastric area without perigastric involvement. The mechanism and prognosis are still unknown. The frequency of skip metastasis along the proximal splenic artery is rare. Since adhesions after previous laparoscopic surgery were mild, it was possible to perform laparoscopic surgery once again, taking advantage of its benefits, both during surgery and in the post-operative healing period.

Is the recent WHO histological classification for gastric cancer helpful for application to endoscopic resection?

Endoscopic resection is performed in undifferentiated-type early gastric cancer (UD-EGC), including poorly differentiated (PD) adenocarcinoma and signet ring cell (SRC) carcinoma. We previously found that different approaches are needed for PD adenocarcinoma and SRC carcinoma for curative resection. However, according to the 2010 WHO classification, diffuse-type PD adenocarcinoma and SRC carcinoma are categorized in the "poorly cohesive carcinomas." Thus, we assessed whether the WHO classification is helpful when endoscopic resection is performed for treatment of UD-EGC. We analyzed clinicopathological features of 1295 lesions with SRC carcinoma and PD adenocarcinoma treated by open surgery. We recategorized them into intestinal-type PD adenocarcinomas and poorly cohesive carcinomas (SRC carcinoma, diffuse-type PD adenocarcinoma). We also recategorized 176 lesions treated by endoscopic resection into intestinal-type PD adenocarcinomas and poorly cohesive carcinomas. According to the open surgery data, the rates of lymph node metastasis (LNM) and lymphovascular invasion were significantly lower in SRC carcinoma than in diffuse-type and intestinal-type PD adenocarcinomas. The rates of LNM and lymphovascular invasion were significantly higher in diffuse-type PD adenocarcinoma than in SRC carcinoma. Endoscopic resection data showed no recurrence if the carcinoma was curatively resected. However, the commonest cause of noncurative resection was different in SRC carcinoma and PD adenocarcinoma. A positive lateral margin was the commonest cause in SRC carcinoma versus a positive vertical margin in both intestinal-type and diffuse-type PD adenocarcinoma. The clinical behavior differs in diffuse-type PD adenocarcinoma and SRC carcinoma. On the basis of LNM and outcomes of endoscopic resection, the recent WHO classification may not be helpful when endoscopic resection is performed for treatment of UD-EGC.

Molecular characteristics of colorectal neuroendocrine carcinoma; similarities with adenocarcinoma rather than neuroendocrine tumor

To further clarify the molecular features of colorectal neuroendocrine carcinomas (NECs), we immunohistochemically examined tumor samples from 25 NECs, including 9 small cell NECs (SCNECs) and 16 large cell NECs (LCNECs), 20 neuroendocrine tumors (NETs), and 21 poorly differentiated adenocarcinomas (PDCs) for the expression of several biomarkers (p53, β-catenin, Bcl-2, Rb, p16, p21, cyclin D1, and cyclin E) and used sequencing analysis to identify gene alterations of TP53, APC, CTNNB1, KRAS, and BRAF. The frequencies of aberrant p53 expression (88%), β-catenin nuclear expression (48%), and high expression of cyclin E (84%) were significantly higher in NECs than in NETs (0%, 5%, and 5%, P < .01, respectively). The immunohistochemical results of NECs and PDCs were similar. TP53, APC, KRAS, and BRAF gene mutations were variously detected in NECs and PDCs but not in any NETs. The frequencies of decreased expression of Rb (56%) and high expression of p16 (56%) and Bcl-2 (64%) were significantly higher in NECs than in PDCs (5%, 19%, and 5%, P < .05, respectively) or NETs (10%, 5%, and 5%, P < .01, respectively). Such immunohistochemical characteristics of NECs were more evident in SCNECs than in large cell NECs (P < .01). In conclusion, the molecular features of colorectal NECs are similar to those of adenocarcinomas and not to those of NETs. Decreased expression of Rb and high expression of p16 and Bcl-2 are characteristics of NECs, suggesting that Rb-p16 pathway disruption may contribute to the promotion of proliferative activity in colorectal NECs. SCNECs may be a prototype of NECs.

A Retrospective Analysis for Patients with HER2-Positive Gastric Cancer Who Were Treated with Trastuzumab-Based Chemotherapy: In the Perspectives of Ethnicity and Histology.

PurposeWhile the Trastuzumab for Gastric Cancer (ToGA) trial demonstrated the efficacy and safety of trastuzumab-based chemotherapy in HER2-positive metastatic gastric cancer, the overall survival (OS) benefit was not found in Asian and diffuse-type cancer patients. The aim of the study is to investigate predictive markers for trastuzumab-based chemotherapy.Materials and MethodsData of patients with HER2-positive gastric cancer treated with trastuzumab-based chemotherapy were analyzed retrospectively.ResultsA total of 168 Asian patients were included. The median age was 60 years (range, 27 to 85 years) and the male:female ratio was 118 (70.2%):50 (29.8%). Fourteen (8.3%), 63 (37.5%), 75 (44.6%), and 11 (6.5%) patients had well, moderately, poorly-differentiated tubular adenocarcinoma and signet ring cell carcinoma, respectively. With 14 complete responses and 73 partial responses, the response rate was 50.6%. The median progression-free survival (PFS) was 10.2 months (95% confidence interval [CI], 8.7 to 11.7), and the median OS was 18.5 months (95% CI, 16.4 to 50.6). Next, we investigated the effect of poorly-differentiated histology (PDH, poorly-differentiated tubular adenocarcinoma+signet ring cell carcinoma) on clinical outcomes. The median PFS (8.9 months vs. 11.5 months, p=0.16) was slightly inferior in PDH patients, and the median OS was significantly shorter in PDH patients (14.6 months vs. 19.0 months, p=0.025).ConclusionWhile subset analysis of the ToGA trial demonstrated that trastuzumab-based chemotherapy may not be beneficial for Asians and patients with PDH, our data may suggest that even in Asian patients and patients with PDH, trastuzumab-based chemotherapy could be associated with improved clinical outcomes in patients with HER2-positive gastric cancer.

Expression of adhesion molecules and epithelial-mesenchymal transition factors in medullary carcinoma of the colorectum.

Medullary carcinoma (MC) of the colorectum is known as a rare variant with favorable prognosis despite its poorly differentiated morphology. The mechanism of its favorable behavior has been unclear. Here, we compared the expressions of adhesion molecules and epithelial-mesenchymal transition (EMT)-related proteins in the central portion and invasive front between 43 MCs and 30 poorly differentiated adenocarcinomas (PDAs). The expressions of membranous E-cadherin (P < .0001), β-catenin (P < .0001) and claudin 1 (P = .0036) were significantly preserved in the invasive front of the MCs compared to those in the invasive front of the PDAs. E-cadherin membranous expression was also significantly preserved in the central portion of the MCs (P = .0178). Nuclear β-catenin expression in both the central portion (P = .0463) and invasive front (P = .0346) of the MCs was significantly less frequent compared to that in the PDAs. Snail (P = .0035) and Twist1 (P = .0463) expressions in the invasive front of the MCs were significantly less frequent compared to the PDAs, suggesting that the EMT phenomenon may occur rarely in colorectal MC. Reduced membranous E-cadherin expression in the MC central portion was significantly correlated with poor clinical outcome (P = .0086). Our immunohistochemical results indicate that preserved adhesion molecule protein and less frequent expression of EMT-related transcription factors in the invasive front contribute to the favorable prognosis of colorectal MCs. We suggest that a reduced expression of E-cadherin in the central portion might be a good biomarker for an unfavorable prognosis in cases of MC.

Claudin-1, but not claudin-4, exhibits differential expression patterns between well- to moderately-differentiated and poorly-differentiated gastric adenocarcinoma.

Claudins are members of a large family of transmembrane proteins, which are essential in the formation of tight junctions and have previously been associated with the process of tumor progression. Studies have reported the aberrant expression of claudin-1 and claudin-4 in numerous types of cancer. The present study aimed to investigate the expression of claudin-1 and claudin-4 in gastric adenocarcinoma tissue. Surgically resected gastric adenocarcinoma tissue specimens were obtained from 94 patients. Protein expression levels of claudin-1 and claudin-4 were determined using immunohistochemical staining; the association between claudin-1 or claudin-4 expression and various clinicopathological parameters were then analyzed. In gastric adenocarcinoma specimens, the expression rates of claudin-1 and claudin-4 were 43.6 and 87.2%, respectively. Claudin-1 expression demonstrated a significant correlation with histological type (P<0.01) and was significantly higher in well- to moderately-differentiated gastric adenocarcinomas compared with poorly-differentiated tumors. However, no correlation was observed between claudin-4 expression in adenocarcinoma and clinicopathological parameters. In conclusion, downregulation of claudin-1 expression in poorly-differentiated gastric adenocarcinoma may be involved in the biological transformation of tumors. The present findings suggested that claudin-1 may be an important protein associated with histological type and therefore may have potential for use as a prognostic marker for gastric adenocarcinoma. Further studies are required to elucidate the precise mechanism of claudin expression and its involvement in tumor progression.

Modified simultaneous integrated boost radiotherapy for large retroperitoneal malignant tumor: A case report.

The current study reports the case of a large retroperitoneal tumor treated with modified simultaneous integrated boost (SIB) radiotherapy. A 45-year-old female presented to the emergency department complaining of left abdominal pain and fever. A computed tomography scan detected a retroperitoneal tumor of 12×16×16 cm, and a biopsy revealed a poorly-differentiated adenocarcinoma. The patient was diagnosed with a large adenocarcinoma originating from the left ureter, with no distant metastasis. Due to the patient's poor physical condition, surgery was not recommended, and the patient was referred to the Department of Radiation Oncology (Yamagata University Hospital, Yamagata, Japan). Modified SIB radiotherapy was administered following the acquisition of written consent from the patient. The total irradiation dose to the center of the tumor and to the surrounding healthy tissue was ∼96 Gy/33 fractions and <60 Gy/33 fractions, respectively. At the end of the radiotherapeutic course, the tumor volume was reduced by ≥80%, and the residual tumor was surgically resected. As a result of the resection, a complete pathological response was confirmed; the patient has been recurrence-free for >3 years with no complications. Modified SIB radiotherapy may be safely administered, with favorable outcomes. Complete recovery can be achieved with this technique, even in a patient with a large radioresistant tumor.