Unusual case of intraosseous primary intracranial malignant melanoma.

Primary intracranial malignant melanoma (PIMM) represents 0.07% of central nervous system tumours; clinical behaviour and prognosis are not well documented. Preoperative diagnosis of PIMM is complex and it could be easily misdiagnosed, especially with malignant meningioma.We are reporting a case of a man with a history of rapidly arising motor slowing associated with urinary incontinence, presenting with mild convergent strabismus caused by paralysis in abduction in the right eye. A brain CT showed a lesion compatible with malignant spheno-orbital meningioma, and the patient underwent gross total resection. Intraoperatively, the blackish lesion infiltrated and eroded the bone; it was placed externally on the dura mater with a mild reaction and without attachment. Histological examination confirmed PIMM.Intraosseous localisation of PIMM has been observed in the basic bone structure of the oral cavity. We report the first intraosseous spheno-orbital PIMM case and present an embryological theory about how this unusual tumour can develop.

Claudin-18 expression in oesophagogastric adenocarcinomas: a tissue microarray study of 523 molecularly profiled cases.

BACKGROUND: Claudin-18 (CLDN18) is a highly specific tight junction protein of the gastric mucosa. An isoform of CLDN18, the Claudin 18.2, has recently emerged as an innovative drug target for metastatic gastric cancer. METHODS: We investigated the immunohistochemical profile of CLDN18, p53, p16, E-cadherin, MSH2, MSH6, MLH1, PSM2, HER2, and PDL-1 in a large series of 523 primary gastric carcinomas (GCs; n = 408) and gastro-oesophageal carcinomas (GECs; n = 115) and 135 matched and synchronous nodal metastases. The status of HER2 and EBER by means of chromogenic in situ hybridisation (CISH) was also evaluated. RESULTS: High membranous CLDN18 expression was present in 150/510 (29.4%) primary cases and in 45/132 (34.1%) metastases. An abnormal expression (i.e. nuclear and/or cytoplasmic) was observed in 115 (22.5%) primary cases and in 33 (25.0%) metastases. A 38.8% of the cases showed significant CLDN18 intratumoural variability among the different tissue microarray cores obtained from the same tumour. Positive membrane CLDN18 expression was statistically associated with non-antral GCs (p = 0.016), Lauren diffuse type (p = 0.009), and with EBV-associated cancers (p < 0.001). CONCLUSIONS: CLDN18 is frequently expressed in gastric and gastro-oesophageal cancers; further studies should investigate the prognostic significance of CLDN18 heterogeneity in order to implement its test into clinical practice.

Human papillomavirus infection is not involved in esophageal verrucous carcinoma.

Verrucous carcinoma of the esophagus (VCE) is a rare variant of squamous cell cancer, with a puzzling clinical, etiological, and molecular profile. The etiological involvement of human papillomavirus (HPV) in the cancer's natural history is controversial. This study considers 9 cases of VCE, focusing on patients' clinical history before surgery, histologic phenotype, immunophenotype (epidermal growth factor receptor [EGFR], E-cadherin, cyclin D1, p16, and p53 expression), HPV infection, and TP53 gene mutational status (exons 5-8). Using 3 different molecular test methods, not one of these cases of VCE featured HPV infection. The only case with synchronous nodal metastasis was characterized by a TP53 missense point mutation in association with high EGFR and low E-cadherin expression levels. In conclusion, HPV infection is probably not involved with VCE, while TP53 gene mutation, EGFR overexpression, and E-cadherin loss might fuel the tumor's proliferation and lend it a metastatic potential.

LONG-NONCODING RNAs in gastroesophageal cancers.

Despite continuing improvements in multimodal therapies, gastro-esophageal malignances remain widely prevalent in the population and is characterized by poor overall and disease-free survival rates. Due to the lack of understanding about the pathogenesis and absence of reliable markers, gastro-esophageal cancers are associated with delayed diagnosis. The increasing understanding about cancer's molecular landscape in the recent years, offers the possibility of identifying 'targetable' molecular events and in particular facilitates novel treatment strategies and development of biomarkers for early stage diagnosis. At least 98% of our genome is actively transcribed into non-coding RNAs encompassing long non-coding RNAs (lncRNAs) constituted of transcripts longer than 200 nucleotides with no protein-coding capacity. Many studies have demonstrated that lncRNAs are functional genomic elements playing pivotal roles in main oncogenic processes. LncRNA can act at multiple levels developing a complex molecular network that can modulate directly or indirectly the expression of genes involved in tumorigenesis. In this review, we focus on lncRNAs as emerging players in gastro-esophageal carcinogenesis and critically assess their potential as reliable noninvasive biomarkers and in next generation targeted therapies.

OLGA Gastritis Staging for the Prediction of Gastric Cancer Risk: A Long-term Follow-up Study of 7436 Patients.

OBJECTIVES: Gastritis OLGA-staging ranks the risk for gastric cancer (GC) in progressive stages (0-IV). This long-term follow-up study quantifies the GC risk associated with each OLGA stage. METHODS: Consecutive patients (7436) underwent esophagogastroscopy (T-0), with mapped gastric biopsies, OLGA staging, and H. pylori status assessment. Patients with neoplastic lesion (invasive or non-invasive) at the index endoscopy (and/or within 12 months) were excluded. All patients were followed-up (T-1) by combining different sources of clinical/pathological information (Regional Registries of: (i) esophagogastroduodenoscopies; (ii) pathology reports; (iii) cancer, (iv) mortality). The endpoint was histologically documented development of gastric epithelial neoplasia. RESULTS: At T-0, the patients' distribution by OLGA stage was: Stage 0 = 80.8%; Stage I = 12.6%; Stage II = 4.3%; Stage III = 2.0%; Stage IV = 0.3%; H. pylori infection was detected in 25.9% of patients. At the end of the follow-up (mean/median = 6.3/6.6 years), 28 incident neoplasia were documented (overall prevalence = 0.60 per 103/person-years; low-grade intraepithelial neoplasia = 17/28; high-grade intraepithelial neoplasia = 4/28; GC = 7/28). By OLGA stage at the enrollment, the rate of incident neoplasia was: Stage 0 = 1 case; rate/103 person-years = 0.03; 95%CI: 0.004-0.19; Stage I = 2 cases; rate/103 person-years = 0.34; 95%CI: 0.09-1.36; Stage II = 3 cases; rate/103 person-years = 1.48; 95%CI: 0.48-4.58; Stage III = 17 cases; rate/103 person-years = 19.1; 95%CI: 11.9-30.7; Stage IV = 5 cases; rate/103 person-years = 41.2; 95%CI: 17.2-99.3. Multivariate analysis including gender, age, H. pylori status, and OLGA stage at enrollment only disclosed OLGA stage as predictor of neoplastic progression (OLGA stage III: HR = 712.4, 95%CI = 92.543-5484.5; OLGA stage IV: HR = 1450.7, 95%CI = 166.7-12626.0). CONCLUSIONS: Among 7436 patients, OLGA stages at the enrollment correlated significantly with different risk for gastric neoplasia. Based on the obtained results, gastritis staging is a critical adjunct in endoscopy follow-up protocols aimed at GC secondary prevention.

Presentation of a meningioma in a transwoman after nine years of cyproterone acetate and estradiol intake: case report and literature review.

The administration of cyproterone acetate (CPA) and estradiol is a common regimen used by male-to-female transsexuals (transwoman) to adjust their body to their gender identity. Major adverse events are uncommon in these subjects in spite of long-term, high dose cross-sex steroid treatments. We describe the occurrence of a meningioma in a transwoman treated with estrogens and CPA over a period of nine years. The meningioma was revealed during a magnetic resonance imaging (MRI) scan performed as follow-up of a previous surgery for ganglioglioma. CPA intake was discontinued and tumor resection was performed. Histological diagnosis confirmed a strong progesterone receptor-positive and slight estrogen positive meningioma. After surgery, the patient continued her treatment with leuprorelina acetate and estradiol. At one-year follow-up, the MRI scan reveals no recurrence of the tumor. This is the ninth case in literature of a meningioma in a transwoman treated with estrogens and CPA, confirming a possible association between female sex steroids and meningioma. Although there is no still strong evidence of an association between meningioma and CPA, this report may suggest use of alternative treatment for transwomen. This report highlights the importance to record all the cases of meningiomas in high dose CPA-users, in order to improve data.

Early miR-223 Upregulation in Gastroesophageal Carcinogenesis.

OBJECTIVES: To test miR-223 upregulation during gastric (intestinal-type) and Barrett esophageal carcinogenesis. METHODS: miR-223 expression was assessed by quantitative reverse transcription polymerase chain reaction in a series of 280 gastroesophageal biopsy samples representative of the whole spectrum of phenotypic changes involved in both carcinogenetic cascades. The results were further validated by in situ hybridization on multiple tissue specimens obtained from six surgically treated gastroesophageal adenocarcinomas. miR-223 expression was also assessed in plasma samples from 30 patients with early stage (ie, stages I and II) gastroesophageal adenocarcinoma and relative controls. RESULTS: In both gastric and esophageal models, miR-223 expression significantly increased along with the severity of the considered lesions (analysis of variance, P < .001). Among atrophic gastritis and long-segment Barrett esophagus samples, miR-223 overexpression was significantly associated with the score of intestinal metaplasia. miR-223 plasma levels were significantly upregulated in patients with cancer compared with controls ( t test, both P < .001). CONCLUSIONS: miR-223 early upregulation observed in tissue samples and its diagnostic value in discriminating patients with early adenocarcinoma by plasma testing provide a solid rationale for further exploring the diagnostic reliability of this microRNA as a novel biomarker in gastroesophageal adenocarcinoma secondary prevention strategies.

Let-7c down-regulation in Helicobacter pylori-related gastric carcinogenesis.

Aberrant let-7c microRNA (miRNA) expression has been observed in Helicobacter pylori-related gastric cancer (GC) but fragmentary information is available on the let-7c dysregulation occurring with each phenotypic change involved in gastric carcinogenesis. Let-7c expression was assessed (qRT-PCR) in a series of 175 gastric biopsy samples representative of the whole spectrum of phenotypic changes involved in H. pylori-related gastric oncogenesis including: i) normal gastric mucosa, as obtained from dyspeptic controls (40 biopsy samples); ii) non-atrophic gastritis (40 samples); iii) atrophic-metaplastic gastritis (35 samples); iv) intra-epithelial neoplasia (30 samples); v) GC (30 samples). Let-7c expression was also tested in 20 biopsy samples obtained from 10 patients before and after H. pylori eradication therapy (median follow-up: 10 weeks; range: 7-14). The results obtained were further validated by in situ hybridization on multiple tissue specimens obtained from 5 surgically treated H. pylori-related GCs. The study also included 40 oxyntic biopsy samples obtained from serologically/histologically confirmed autoimmune gastritis (AIG: 20 corpus-restricted, non-atrophic; 20 corpus-restricted, atrophic-metaplastic). Let-7c expression dropped from non-atrophic gastritis to atrophic-metaplastic gastritis, intra-epithelial neoplasia, and invasive GC (p<0.001). It rose again significantly following H. pylori eradication (p=0.009). As in the H. pylori model, AIG also featured a significant let-7c down-regulation (p<0.001). The earliest phases of the two pathways to gastric oncogenesis (H. pylori-environmental and autoimmune host-related) are characterized by similar let-7c dysregulations. In H. pylori infection, let-7c down-regulation regresses after the bacterium's eradication, while it progresses significantly with the increasing severity of the histological lesions.

Autoimmune gastritis: Pathologist's viewpoint.

Western countries are seeing a constant decline in the incidence of Helicobacter pylori-associated gastritis, coupled with a rising epidemiological and clinical impact of autoimmune gastritis. This latter gastropathy is due to autoimmune aggression targeting parietal cells through a complex interaction of auto-antibodies against the parietal cell proton pump and intrinsic factor, and sensitized T cells. Given the specific target of this aggression, autoimmune gastritis is typically restricted to the gastric corpus-fundus mucosa. In advanced cases, the oxyntic epithelia are replaced by atrophic (and metaplastic) mucosa, creating the phenotypic background in which both gastric neuroendocrine tumors and (intestinal-type) adenocarcinomas may develop. Despite improvements in our understanding of the phenotypic changes or cascades occurring in this autoimmune setting, no reliable biomarkers are available for identifying patients at higher risk of developing a gastric neoplasm. The standardization of autoimmune gastritis histology reports and classifications in diagnostic practice is a prerequisite for implementing definitive secondary prevention strategies based on multidisciplinary diagnostic approaches integrating endoscopy, serology, histology and molecular profiling.