International consensus on the management of metastatic gastric cancer: step by step in the foggy landscape : Bertinoro Workshop, November 2022.

BACKGROUND: Many gastric cancer patients in Western countries are diagnosed as metastatic with a median overall survival of less than twelve months using standard chemotherapy. Innovative treatments, like targeted therapy or immunotherapy, have recently proved to ameliorate prognosis, but a general agreement on managing oligometastatic disease has yet to be achieved. An international multi-disciplinary workshop was held in Bertinoro, Italy, in November 2022 to verify whether achieving a consensus on at least some topics was possible. METHODS: A two-round Delphi process was carried out, where participants were asked to answer 32 multiple-choice questions about CT, laparoscopic staging and biomarkers, systemic treatment for different localization, role and indication of palliative care. Consensus was established with at least a 67% agreement. RESULTS: The assembly agreed to define oligometastases as a "dynamic" disease which either regresses or remains stable in response to systemic treatment. In addition, the definition of oligometastases was restricted to the following sites: para-aortic nodal stations, liver, lung, and peritoneum, excluding bones. In detail, the following conditions should be considered as oligometastases: involvement of para-aortic stations, in particular 16a2 or 16b1; up to three technically resectable liver metastases; three unilateral or two bilateral lung metastases; peritoneal carcinomatosis with PCI ≤ 6. No consensus was achieved on how to classify positive cytology, which was considered as oligometastatic by 55% of participants only if converted to negative after chemotherapy. CONCLUSION: As assessed at the time of diagnosis, surgical treatment of oligometastases should aim at R0 curativity on the entire disease volume, including both the primary tumor and its metastases. Conversion surgery was defined as surgery on the residual volume of disease, which was initially not resectable for technical and/or oncological reasons but nevertheless responded to first-line treatment.

Clinical and Genomic Characterization of Pancreatic Ductal Adenocarcinoma with Signet-Ring/Poorly Cohesive Cells.

Signet-ring cell (SRC)/poorly cohesive cell carcinoma is an aggressive variant of pancreatic ductal adenocarcinoma (PDAC). This study aimed to clarify its clinicopathologic and molecular profiles based on a multi-institutional cohort of 20 cases. The molecular profiles were investigated using DNA and RNA sequencing. The clinicopathologic parameters and molecular alterations were analyzed based on survival indices and using a validation/comparative cohort of 480 conventional PDAC patients. The primary findings were as follows: (1) clinicopathologic features: SRC carcinomas are highly aggressive neoplasms with poor prognosis, and the lungs are elective metastatic sites; (2) survival analysis: a higher SRC component was indicative of poorer prognosis. In particular, the most clinically significant threshold of SRC was 80%, showing statistically significant differences in both disease-specific and disease-free survival; (3) genomic profiles: SRC carcinomas are similar to conventional PDAC with the most common alterations affecting the classic PDAC drivers KRAS (70% of cases), TP53 (55%), SMAD4 (25%), and CDKN2A (20%). EGFR alterations, RET::CCDC6 fusion gene, and microsatellite instability (3 different cases, 1 alteration per case) represent novel targets for precision oncology. The occurrence of SMAD4 mutations was associated with poorer prognosis; (4) pancreatic SRC carcinomas are genetically different from gastric SRC carcinomas: CDH1, the classic driver gene of gastric SRC carcinoma, is not altered in pancreatic SRC carcinoma; (5) transcriptome analysis: the cases clustered into 2 groups, one classical/exocrine-like, and the other squamous-like; and (6) SRC carcinoma-derived organoids can be successfully generated, and their cultures preserve the histologic and molecular features of parental SRC carcinoma. Although pancreatic SRC carcinoma shares similarities with conventional PDAC regarding the most important genetic drivers, it also exhibits important differences. A personalized approach for patients with this tumor type should consider the clinical relevance of histologic determination of the SRC component and the presence of potentially actionable molecular targets.

hERG1 Potassium Channel Expression in Colorectal Adenomas: Comparison with Other Preneoplastic Lesions of the Gastrointestinal Tract.

Preneoplastic lesions represent a useful target for early diagnosis and follow-up of gastrointestinal malignancies. hERG1 channel expression was tested by immunohistochemistry (IHC) in a cohort of colorectal adenoma samples belonging to Italian subjects. Overall, hERG1 was expressed in 56.5% of cases with both high staining intensity and a high percentage of positive cells. Moreover, hERG1 was expressed in a higher percentage of dysplastic adenomas with respect to hyperplastic lesions, and the proportion of positive samples further increased in patients with high-grade dysplasia. Comparing hERG1 expression in other preneoplastic lesions of the GI tract (gastric dysplasia and Barrett's esophagus), it emerged that in all the conditions, hERG1 was expressed with a diffused pattern, throughout the cell, with variable staining intensity within the samples. The highest expression was detected in gastric dysplasia samples and the lowest in Barrett's esophagus at similar levels observed in colorectal adenomas. Our results show that hERG1 is aberrantly expressed in human preneoplastic lesions of the gastrointestinal tract and has a different pattern of expression and role in the different sites. Overall, the detection of hERG1 expression in preneoplastic lesions could represent a novel diagnostic or prognostic marker of progression in the gastrointestinal tract.

Early Gastric Cancer: identification of molecular markers able to distinguish submucosa-penetrating lesions with different prognosis.

BACKGROUND: Early Gastric Cancer (EGC) reaches 25% of the gastric cancers surgically treated in some areas of Northeastern Italy and is usually characterized by a good prognosis. However, among EGCs classified according to Kodama's criteria, Pen A subgroup is characterized by extensive submucosal invasion, lymph node metastases and worse prognosis, whereas Pen B subgroup by better prognosis. The aim of the study was to characterize the differences between Pen A, Pen B and locally advanced gastric cancer (T3N0) in order to identify biomarkers involved in aggressiveness and clinical outcome. METHODS: We selected 33 Pen A, 34 Pen B and 20 T3N0 tumors and performed immunohistochemistry of mucins, copy number variation analysis of a gene panel, microsatellite instability (MSI), TP53 mutation and loss of heterozygosity (LOH) analyses. RESULTS: Pen A subgroup was characterized by MUC6 overexpression (p = 0.021). Otherwise, the Pen B subgroup was significantly associated with the amplification of GATA6 gene (p = 0.002). The higher percentage of MSI tumors was observed in T3N0 group (p = 0.002), but no significant differences between EGC types were found. Finally, TP53 gene analysis showed that 32.8% of Pen tumors have a mutation in exons 5-8 and 50.0% presented LOH. Co-occurrence of TP53 mutation and LOH mainly characterized Pen A tumors (p = 0.022). CONCLUSIONS: Our analyses revealed that clinico-pathological parameters, microsatellite status and frequency of TP53 mutations do not seem to distinguish Pen subgroups. Conversely, the amplification of GATA6 was associated with Pen B, as well as the overexpression of MUC6 and the TP53mut/LOH significantly characterized Pen A.

Molecular Alterations in Gastric Preneoplastic Lesions and Early Gastric Cancer.

Prognosis of gastric cancer is dramatically improved by early diagnosis. Correa's cascade correlates the expression of some molecular markers with the progression of preneoplastic lesions toward carcinoma. This article reviews the diagnostic and prognostic values of molecular markers in complete (MUC2) and incomplete (MUC2, MUC5AC, and MUC6) intestinal metaplasia, gastric dysplasia/intra-epithelial neoplasia, and early gastric cancer. In particular, considering preinvasive neoplasia and early gastric cancer, some studies have demonstrated a correlation between molecular alterations and prognosis, for example, mucins phenotype in gastric dysplasia, and GATA6, TP53 mutation/LOH and MUC6 in early gastric cancer. Moreover, this review considers novelties from the literature regarding the (immuno)histochemical characterization of diffuse-type/signet ring cell gastric cancer, with particular attention to clinical outcomes of patients. The aim of this review is the evaluation of the state of the art regarding suitable biomarkers used in the pre-surgical phase, which can distinguish patients with different prognoses and help decide the best therapeutic strategy.

Molecular Landscapes of Gastric Pre-Neoplastic and Pre-Invasive Lesions.

Gastric carcinoma (GC) represents one of the most common and most lethal malignancies worldwide. The histopathological characterization of GC precursor lesions has provided great knowledge about gastric carcinogenesis, with the consequent introduction of effective strategies of primary and secondary prevention. In recent years, a large amount of data about the molecular events in GC development is emerging, flanking the histomorphological descriptions. In this review, we describe the landscape of molecular alterations in gastric pre-invasive lesions with a glance at their potential use in the diagnostic and therapeutic decision-making process.

Atypical polypoid adenomyoma of the endometrium: diagnosis and treatment. A case report.

Atypical polypoid adenomyoma (APA) is a rare uterine lesion that commonly recurs after local excision and is occasionally associated with or anticipates the development of atypical hyperplasia or endometrioid adenocarcinoma. We report a case of a 45-year-old woman affected by APA treated with local resection.

Liver metastasis from a non-recurrent atypical cranial meningioma: a case report.

Extracranial metastases from atypical meningioma are rare, and even more so in the liver. We report a case of a 68-years-old patient with atypical meningioma, treated with partial surgical resection in 2012, and gamma knife radiotherapy in 2014 in another hospital, exhibiting a liver metastasis 6 years after the initial surgical resection.

Neoplastic and pre-neoplastic lesions of the oesophagus and gastro-oesophageal junction.

Oesophageal and gastro-oesophageal junction (GOJ) neoplasms, and their predisposing conditions, may be encountered by the practicing pathologist both as biopsy samples and as surgical specimens in daily practice. Changes in incidence of oesophageal squamous cell carcinomas (such as a decrease in western countries) and in oesophageal and GOJ adenocarcinomas (such as a sharp increase in western countries) are being reported globally. New modes of treatment have changed our histologic reports as specific aspects must be detailed such as in post endoscopic resections or with regards to post neo-adjuvant therapy tumour regression grades. The main aim of this overview is therefore to provide an up-to-date, easily available and clear diagnostic approach to neoplastic and pre-neoplastic conditions of the oesophagus and GOJ, based on the most recent available guidelines and literature.

Precancerous lesions of the stomach, gastric cancer and hereditary gastric cancer syndromes.

Gastric cancer accounts for about 6% of cancers worldwide, being the fifth most frequently diagnosed malignancy and the third leading cause of cancer related death. Gastric carcinogenesis is a multistep and multifactorial process and is the result of the complex interplay between genetic susceptibility and environmental factors. The identification of predisposing conditions and of precancerous lesions is the basis for screening programs and early stage treatment. Furthermore, although most gastric cancers are sporadic, familial clustering is observed in up to 10% of patients. Among them, hereditary cases, related to known cancer susceptibility syndromes and/or genetic causes are thought to account for 1-3% of all gastric cancers. The pathology report of gastric resections specimens therefore requires a standardized approach as well as in depth knowledge of prognostic and treatment associated factors.

Celiac disease: histology-differential diagnosis-complications. A practical approach.

Celiac disease is a multi-factorial chronic inflammatory intestinal disease, characterized by malabsorption resulting from mucosal injury after ingestion of wheat gluten or related rye and barley proteins. Inappropriate T-cell-mediated immune response against ingested gluten in genetically predisposed people, leads to characteristic histological lesions, as villous atrophy and intraepithelial lymphocytosis. Nevertheless, celiac disease is a comprehensive diagnosis with clinical, serological and genetic characteristics integrated with histological features. Biopsy of duodenal mucosa remains the gold standard in the diagnosis of celiac disease with the recognition of the spectrum of histological changes and classification of mucosa damage based on updated Corazza-Villanacci system. Appropriate differential diagnosis evaluation and clinical context also for the diagnosis of complications is, moreover, needed for correct histological features interpretation and clinical management.

E-cadherin Downregulation and microRNAs in Sporadic Intestinal-Type Gastric Cancer.

CDH1 gene, encoding E-cadherin, is a tumor suppressor gene frequently altered in gastric cancers (GCs) of both diffuse (DGC) and intestinal (IGC) histotypes, albeit through different mechanisms. The study aimed to characterize CDH1 expression in sporadic IGC and to investigate whether microRNAs (miRs) are involved in its transcriptional control. We evaluated CDH1 expression by quantitative real-time PCR (RT-qPCR) in 33 IGC patients and found a significant downregulation in tumor tissues compared to normal counterparts (p-value = 0.025). Moreover, 14 miRs, predicted to be involved in CDH1 regulation in both a direct and indirect manner, were selected and analyzed by RT-qPCR in an independent case series of 17 IGCs and matched normal tissues. miR-101, miR-26b, and miR-200c emerged as significantly downregulated and were confirmed in the case series of 33 patients (p-value < 0.001). Finally, we evaluated EZH2 expression, a target of both miR-101 and miR-26b, which showed significant upregulation in IGCs (p-value = 0.005). A significant inverse correlation was observed between EZH2 overexpression and CDH1, miR-101, and miR-26b levels (p-value < 0.001). Our results reinforce the link between CDH1 and IGC, highlighting the role of miRs in its transcriptional control and improving our understanding of GC subtypes and biomarkers.

Early Gastric Cancer: Clinical Behavior and Treatment Options. Results of an Italian Multicenter Study on Behalf of the Italian Gastric Cancer Research Group (GIRCG).

BACKGROUND: Early gastric cancer (EGC) generally has a good prognosis. However, the current definition of EGC includes various subgroups of patients with different pathological characteristics and different prognoses, some of whom have aggressive disease with a biological behavior similar to that of advanced carcinoma. MATERIALS AND METHODS: We retrospectively evaluated 1,074 patients with EGC who had undergone surgery between 1982 and 2009. The cumulative incidence function of cancer-specific mortality and competing mortality were estimated using the Fine and Gray method. RESULTS: The median follow-up period was 193 months (range 1-324). Five hundred and sixty-two (52.3%) patients died, 96 (8.9%) from EGC. The 5-, 10-, and 15-year cumulative incidence rates for mortality of all causes were 20.5% (95% confidence interval [CI] 18.0-22.9), 37.1% (95% CI 34.7-40.7), and 52.6% (95% CI 49.1-56.0), respectively; for cancer-specific mortality, 6.0% (95% CI 4.5-7.6), 9.9% (95% CI 7.9-11.9), and 11.1% (95% CI 8.8-13.3), respectively; and for mortality of other causes, 14.4% (95% CI 12.1-16.6), 27.2% (95% CI 24.2-30.2), and 41.5% (95% CI 38.1-43.3), respectively. A significant increase in the risk of cancer-specific mortality was observed for lesions >2 cm (adjusted hazard ratio [HR] = 1.44, 95% CI 1.07-1.94), Pen A-type disease (adjusted HR = 1.73, 95% CI 1.15-2.61), and node-positive cancers (adjusted HR = 2.28, 95% CI 1.61-3.21). CONCLUSION: Patients with EGC with tumors >2 cm, Pen A-type disease according to Kodama, or lymph node metastases show a poorer prognosis and an increased risk of cancer-specific mortality. IMPLICATIONS FOR PRACTICE: Early gastric cancer generally has a good prognosis, and some patients can be treated radically by endoscopic resection. However, the current definition of early gastric cancer includes subgroups of patients with an aggressive disease. In particular, patients with lymph node metastases and Pen A-type tumors according to Kodama's classification need a more invasive treatment, such as subtotal or total gastrectomy with an extended D2 lymphadenectomy, plus eventual adjuvant chemotherapy.

Incidence and Prognostic Value of Metastases to "Posterior" and Para-aortic Lymph Nodes in Resectable Gastric Cancer.

BACKGROUND: The purpose of this retrospective study was to evaluate the incidence and prognostic value of metastases to "posterior" (8p, 12b/p, 13) and para-aortic lymph nodes in a large cohort of Western patients submitted to D2 plus lymphadenectomy. METHODS: Removal of "posterior" nodes was performed in 743 patients, and para-aortic lymphadenectomy in a subgroup of 390 patients. After lymph node mapping and retrieval on the fresh specimen, a median number of 41 total lymph nodes were analyzed. The median follow-up period was 37 months for the entire series and 68 months for survivors. RESULTS: Of 743 included patients, 23 (3.1%) had metastases in station 8p, 12 (1.6%) in station 12b/p, and 19 (2.6%) in station 13. On the whole, 47 of 743 patients (6.3%) had positive "posterior" nodes. Para-aortic metastases were present in 42 of 390 patients (10.8%). Metastases to "posterior" stations were significantly related to depth of invasion, number of positive nodes, and surgical radicality. Distal tumors showed higher trend to metastasize to "posterior" nodes than upper third, whereas for para-aortic metastases it was the reverse. 5-year survival in patients with positivity to "posterior" nodes was 17%, with no significant difference according to 8p, 12b/p, and 13 stations; long-term outcome was overlapping to pN3b stage. 5-year survival in para-aortic positive cases was 11%, and a trend to better outcome was observed in proximal tumors. CONCLUSIONS: Although metastases to "posterior" and para-aortic nodes are expression of an advanced nodal stage, not negligible survival rates are observed in subgroups of patients.

The Italian Research Group for Gastric Cancer (GIRCG) guidelines for gastric cancer staging and treatment: 2015.

This article reports the guidelines for gastric cancer staging and treatment developed by the GIRCG, and contains comprehensive indications for clinical management, including radiological, endoscopic, surgical, pathological, and oncological paths.

pRb2/p130 localizes to the cytoplasm in diffuse gastric cancer.

pRb2/p130 is a key tumor suppressor, whose oncosuppressive activity has mainly been attributed to its ability to negatively regulate cell cycle by interacting with the E2F4 and E2F5 transcription factors. Indeed, pRb2/p130 has been found altered in various cancer types in which it functions as a valuable prognostic marker. Here, we analyzed pRb2/p130 expression in gastric cancer tissue samples of diffuse histotype, in comparison with their normal counterparts. We found a cytoplasmic localization of pRb2/p130 in cancer tissue samples, whereas, in normal counterparts, we observed the expected nuclear localization. pRb2/p130 cytoplasmic delocalization can lead to cell cycle deregulation, but considering the emerging involvement of pRb2/p130 in other key cellular processes, it could contribute to gastric tumorigenesis also through other mechanisms. Our data support the necessity of further investigations to verify the possibility of using pRb2/p130 as a biomarker or potential therapeutic target for diffuse gastric cancer.

Follow-up after gastrectomy for cancer: an appraisal of the Italian research group for gastric cancer.

BACKGROUND: The Italian Research Group for Gastric Cancer supports the practice of follow-up after radical surgery for gastric cancer. METHODS: This multicenter, retrospective study (1998-2009) included patients with T1-4N0-3M0 gastric cancer who had undergone D2 gastrectomy and lymphadenectomy, with at least 15 lymph nodes examined, and who had developed recurrent disease. Timing and site of recurrence were correlated to the actual scheduled follow-up timing and modalities. RESULTS: From eight centers, 814 patients with recurrent cancer and over 1,754 (46.4 %) patients undergoing gastrectomy were investigated (median follow-up 31 months). The most frequent sites of recurrence were local/regional lymph nodes (35.4 %), liver (24.3 %), peritoneum (30.3 %), lung (10.4 %) and intraluminal (7.5 %). Ninety-four percent of the recurrences were diagnosed within 2 years and 98 % within 3 years. Thoracoabdominal computed tomography (CT) scan and (18)F-fluoro-2-deoxy-D-glucose positron emission tomography (18-FDG-PET) detected more than 90 % of recurrences, abdominal ultrasound detected 70 % and tumor markers detected 40 %, while <10 % were identified by physical examination, chest X-ray, and upper gastrointestinal endoscopy. Twenty-six percent of patients with recurrence were treated, but only 3.2 % were treated with potentially radical intent. CONCLUSION: Oncological follow-up after radical surgery for gastric cancer should be focused in the first 3 years, and based mainly on thoracoabdominal CT scan and 18-FDG-PET.

Gene methylation in rectal cancer: predictive marker of response to chemoradiotherapy?

Although numerous studies have focused on the link between CpG island methylator phenotypes and the development of colorectal cancer, few studies have dealt specifically with methylation profiling in rectal cancer and its role in predicting response to neoadjuvant chemoradiotherapy (NCRT). We characterized methylation profiles in normal and neoplastic tissue samples from patients with rectal cancer and assessed the role of this molecular profile in predicting chemoradioactivity. We evaluated 74 pretreatment tumor samples and 16 apparently normal tissue biopsies from rectal cancer patients submitted to NCRT. The methylation profile of 24 different tumor suppressor genes was analyzed from FFPE samples by methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA). Methylation status was studied in relation to tissue type and clinical pathological parameters, in particular, pathological response evaluated by tumor regression grade (TRG). ESR1, CDH13, RARB, IGSF4, and APC genes showed high methylation levels in tumor samples (range 18.92-49.77) with respect to normal tissue. Methylation levels of the remaining genes were low and similar in both normal (range 1.91-14.56) and tumor tissue (range 1.84-11). Analysis of the association between methylation and response to therapy in tumor samples showed that only TIMP3 methylation status differed significantly within the four TRG classes (ANOVA, P < 0.05). Results from the present explorative study suggest that quantitative epigenetic classification of rectal cancer by MS-MLPA clearly distinguishes tumor tissue from apparently normal mucosa. Conversely, with the exception of TIMP3 gene, the methylation of selected genes does not seem to correlate with response to NCRT.