The updated WHO classification of digestive system tumours-gastric adenocarcinoma and dysplasia.

The fifth edition of the World Health Organization (WHO) classification of digestive system tumours was published in 2019. The classification of invasive carcinoma is basically the same as in the fourth edition, but the description of each histological type has been updated, and some rare subtypes such as micropapillary carcinoma, gastric adenocarcinoma of the fundic gland type and undifferentiated carcinoma have been added and explained. Although this classification did not provide specific numerical criteria for the diagnosis of signet-ring cell carcinoma in poorly cohesive carcinoma, an additional study defined signet-ring cell carcinoma as having more than 90% signet-ring cells. The molecular classification of gastric cancer (Epstein-Barr virus-positive type, microsatellite instability type, genomically stable type, chromosomally unstable type) was additionally introduced. Many pages in the present classification have been devoted to precancerous lesions, and this article focuses on foveolar-type adenoma/dysplasia.

Mucin expression in gastric- and gastro-oesophageal signet-ring cell cancer: results from a comprehensive literature review and a large cohort study of Caucasian and Asian gastric cancer.

BACKGROUND: The literature on the prognostic relevance of signet-ring cell (SRC) histology in gastric cancer (GC) is controversial which is most likely related to inconsistent SRC classification based on haematoxylin-eosin staining. We hypothesised that mucin stains can consistently identify SRC-GC and predict GC patient outcome. METHODS: We performed a comprehensive literature review on mucin stains in SRC-GC and characterised the mucin expression in 851 Caucasian GC and 410 Asian GC using Alcian Blue (AB)-Periodic Acid-Schiff (PAS), MUC2 (intestinal-type mucin), and MUC5AC (gastric-type mucin). The relationship between mucin expression and histological phenotype [poorly cohesive (PC) including proportion of SRCs, non-poorly cohesive (non-PC), or mucinous (MC)], clinicopathological variables, and patient outcome was analysed. RESULTS: Depending on mucin expression and cut-offs, the positivity rates of SRC-GC reported in the literature varied from 6 to 100%. Patients with MUC2 positive SRC-GC or SRC-GC with (gastro)intestinal phenotype had poorest outcome. In our cohort study, PC with ≥ 10% SRCs expressed more frequently MUC2, MUC5AC, and ABPAS (p < 0.001, p = 0.004 and p < 0.001, respectively). Caucasians with AB positive GC or combined ABPAS-MUC2 positive and MUC5AC negative had poorest outcome (all p = 0.002). This association was not seen in Asian patients. CONCLUSIONS: This is the first study to suggest that mucin stains do not help to differentiate between SRC-GC and non-SRC-GC. However, mucin stains appear to be able to identify GC patients with different outcome. To our surprise, the relationship between outcome and mucin expression seems to differ between Caucasian and Asian GC patients which warrants further investigations.

Effect of L-thyroxine supplementation on very low birth weight infants with transient hypothyroxinemia of prematurity at 3 years of age.

OBJECTIVE: To evaluate the effects of levothyroxine (L-T4) supplementation on growth and neurodevelopmental outcomes at 3 years of age in very low birth weight (VLBW) infants with transient hypothyroxinemia of prematurity (THOP). STUDY DESIGN: VLBW infants with plasma thyroid-stimulating hormone concentrations <10 mIU l-1 and free thyroxine concentrations <0.8 ng dl-1 were defined as having THOP and randomly assigned to the Treated (20 infants) or Untreated (31 infants) group. The Treated group received L-T4 at a dose of 5 µg kg-1 day-1. Growth and neurodevelopmental outcomes at 3 years of age were compared between the two groups. RESULTS: There were no significant differences in body length, body weight or head circumference mean s.d. scores or in neurodevelopmental outcomes between the two groups. CONCLUSION: L-T4 supplementation in VLBW infants with THOP demonstrated no beneficial effect at 3 years of age.

Brain metastases in gastro-oesophageal adenocarcinoma: insights into the role of the human epidermal growth factor receptor 2 (HER2).

BACKGROUND: Gastro-oesophageal adenocarcinomas rarely metastasize to the central nervous system (CNS). The role of the human epidermal growth factor receptor 2 (HER2) in patients with these cancers and CNS involvement is presently unknown. PATIENTS AND METHODS: A multicentre registry was established to collect data from patients with gastro-oesophageal adenocarcinomas and CNS involvement both retrospectively and prospectively. Inclusion in the study required a predefined clinical data set, a central neuro-radiological or histopathological confirmation of metastatic CNS involvement and central assessment of HER2 by immunohistochemistry (IHC) and in situ hybridisation (ISH). In addition, expression of E-cadherin and DNA mismatch repair (MMR) proteins were assessed by IHC. RESULTS: One hundred patients fulfilled the inclusion criteria. The population's median age was 59 years (interquartile range: 54-68), of which 85 (85%) were male. Twenty-five patients were of Asian and 75 of Caucasian origin. HER2 status was positive in 36% (95% CI: 26.6-46.2) of cases. Median time from initial diagnosis to the development of brain metastases (BMets) or leptomeningeal carcinomatosis (LC) was 9.9 months (95% CI: 8.5-15.0). Median overall survival from diagnosis was 16.9 months (95% CI: 14.0-20.7) and was not related to the HER2 status. E-cadherin loss was observed in 9% of cases and loss of expression in at least one DNA MMR proteins in 6%. CONCLUSIONS: The proportion of a positive HER2 status in patients with gastro-oesophageal adenocarcinoma and CNS involvement was higher than expected. The impact of anti-HER2 therapies should be studied prospectively.

Activating GNAS and KRAS mutations in gastric foveolar metaplasia, gastric heterotopia, and adenocarcinoma of the duodenum.

BACKGROUND: Heterotopic gastric-type epithelium, including gastric foveolar metaplasia (GFM) and gastric heterotopia (GH), is a common finding in duodenal biopsy specimens; however, there is still controversy regarding their histogenetic backgrounds. METHODS: We analysed a total of 177 duodenal lesions, including 66 GFM lesions, 81 GH lesions, and 30 adenocarcinomas, for the presence of GNAS, KRAS, and BRAF mutations. RESULTS: Activating GNAS mutations were identified in 27 GFM lesions (41%) and 23 GH lesions (28%). The KRAS mutations were found in 17 GFM lesions (26%) and 2 GH lesions (2%). A BRAF mutation was found in only one GFM lesion (2%). These mutations were absent in all 32 normal duodenal mucosa specimens that were examined, suggesting a somatic nature. Among the GFM lesions, GNAS mutations were more common in lesions without active inflammation. Analyses of adenocarcinomas identified GNAS and KRAS mutations in 5 (17%) and 11 lesions (37%), respectively. Immunohistochemically, all the GNAS-mutated adenocarcinomas diffusely expressed MUC5AC, indicating gastric epithelial differentiation. CONCLUSIONS: A significant proportion of GFM and GH harbours GNAS and/or KRAS mutations. The common presence of these mutations in duodenal adenoma and adenocarcinoma with a gastric epithelial phenotype implies that GFM and GH might be precursors of these tumours.

RET-rearranged non-small-cell lung carcinoma: a clinicopathological and molecular analysis.

BACKGROUND: To elucidate clinicopathological characteristics of non-small-cell lung carcinoma (NSCLC) cases carrying RET rearrangements causing oncogenic fusions to identify responders to therapy with RET tyrosine kinase inhibitors. METHODS: We investigated 1874 patients with carcinomas, including 1620 adenocarcinomas (ADCs), 203 squamous cell carcinomas (SCCs), 8 large cell carcinomas, and 43 sarcomatoid carcinomas (SACs). Fluorescence in situ hybridisation (FISH) and/or reverse transcription-PCR (RT-PCR) were performed to detect RET gene rearrangement. RESULTS: In all, 22 cases (1.2%) showed RET rearrangements; all cases were of ADC histology. Of the 22 patients, 19 possessed KIF5B-RET fusion genes, whereas 3 possessed CCDC6-RET fusion genes. The RET-rearranged tumours were significantly more common in younger patients (P=0.038) and tended to occur in patients with no history of smoking (P=0.051). In addition, RET rearrangements were not associated with gender, occupational history (particularly radioactive exposure), tumour size, lymph node status, tumour stage, or patient survival. The predominant growth pattern in RET-rearranged ADCs was lepidic in 6 cases, papillary in 9 cases, acinar in 2 cases, micropapillary in 1 case, and solid in 4 cases. Cells with cytoplasmic mucin production were at least focally present in 12 of the 22 (54.5%) RET-rearranged ADC cases. Among the 21 analysed RET-rearranged tumours, RET immunopositivity was observed in 15 cases (71.4%), and was significantly associated with RET rearrangement (P<0.001). CONCLUSIONS: The RET rearrangements were observed in 1.2% of NSCLCs. All cases of RET rearrangement were ADCs. The RET rearrangements were more likely to be observed in younger patients. Although cytoplasmic mucin production was at least focally present in 54.5% of RET-rearranged ADCs, specific histological features were not detected.

Clinicopathological features of nonsmall cell lung carcinomas with BRAF mutations.

BACKGROUND: Recently, driver tyrosine kinase gene mutations have been detected in malignant tumors, including lung tumors. Notwithstanding their attractiveness as targets for molecular therapy, limited information is available regarding BRAF-mutated lung carcinomas. MATERIALS AND METHODS: BRAF mutation status was determined in 2001 surgically resected nonsmall-cell lung cancer (NSCLC) cases using high-resolution melting analysis (HRMA) followed by Sanger sequencing and/or deep sequencing using next generation sequencer. RESULTS: BRAF mutations were detected in 26 (1.3%) of 2001 NSCLC cases (25 adenocarcinomas and 1 squamous cell carcinoma). In the 26 cases, 13 mutation genotypes were identified, including V600E (8 of 26; 30.8%), G469A (6 of 26; 23.1%), K601E (4 of 26; 15.4%), and other residual mutations (1 of 26; 0.04%). Of the 13 genotypes, 4 genotypes (G464E, G596R, A598T, and G606R) had not been previously reported in lung cancer. The overall survival rate was not significantly different between patients with wild-type BRAF and those with V600E or non-V600E BRAF mutations (P = 0.49 and P = 0.15, respectively). Histomorphological analysis revealed that focal clear cell changes were present in 75% of V600E-mutated tumors. All V600E BRAF-mutated tumors were negative for other driver gene alterations including epidermal growth factor receptor (EGFR) and KRAS mutations and the anaplastic lymphoma kinase gene translocation, whereas five tumors with non-V600E BRAF mutations (four G469A and one G464E/G466R) showed concomitant EGFR mutations. CONCLUSION: The frequency of BRAF mutations in lung cancer was low in an Asian cohort. Furthermore, BRAF mutation status lacked prognostic significance in this patient population.

Frequent GNAS mutations in low-grade appendiceal mucinous neoplasms.

BACKGROUND: The molecular basis for the development of appendiceal mucinous tumours, which can be a cause of pseudomyxoma peritonei, remains largely unknown. METHODS: Thirty-five appendiceal mucinous neoplasms were analysed for GNAS and KRAS mutations. A functional analysis of mutant GNAS was performed using a colorectal cancer cell line. RESULTS: A mutational analysis identified activating GNAS mutations in 16 of 32 low-grade appendiceal mucinous neoplasms (LAMNs) but in none of three mucinous adenocarcinomas (MACs). KRAS mutations were found in 30 LAMNs and in all MACs. We additionally analysed a total of 186 extra-appendiceal mucinous tumours and found that GNAS mutations were highly prevalent in intraductal papillary mucinous tumours of the pancreas (88%) but were rare or absent in mucinous tumours of the colorectum, ovary, lung and breast (0-9%). The prevalence of KRAS mutations was quite variable among the tumours. The introduction of the mutant GNAS into a colorectal cancer cell line markedly induced MUC2 and MUC5AC expression, but did not promote cell growth either in vitro or in vivo. CONCLUSION: Activating GNAS mutations are a frequent and characteristic genetic abnormality of LAMN. Mutant GNAS might play a direct role in the prominent mucin production that is a hallmark of LAMN.

[Barrett's esophagus: analyses from human and experimental animal studies]. / Barrett-Ösophagus: Erkenntnisse beim Menschen und aus experimentellen Tierstudien.

Whereas attention in the past has been focused on goblet cells as the primary marker for Barrett's esophagus (BE), the recent change in the definition now includes the non-goblet cell columnar cell-lined esophagus. In the present study the histological features of neoplasia of the lower esophagus and esophago-gastric junction in a German cohort were examined using immunohistochemical staining for MUC, CD10, intestinal and gastric type major tight junction proteins (claudins). Experimental studies using rat duodenogastric content reflux models have also been performed and data show that most neoplastic lesions of the esophageal glands in humans express gastric mucin phenotypes. Cardiac type mucosa was the main histological type in the surrounding mucosa of neoplastic lesions; however, most cardiac type mucosa has intestinal type tight junction proteins. BE with goblet cells has been reported to originate from stem cells located in the basal layer of esophageal squamous cell epithelium in previous models. However, the cardiac type mucosa seems to develop from the site of the stomach and not from the basal layer of esophageal squamous cell epithelium according to our model.

Gastric extremely well-differentiated intestinal-type adenocarcinoma: a challenging lesion to achieve complete endoscopic resection.

Extremely well-differentiated tubular adenocarcinomas (EWDAs) of the stomach are characterized by surface maturation and their mimicking of intestinal metaplasia. Endoscopically, intramucosal EWDAs are frequently ill defined with indistinct borders due to the pallor of the neoplastic mucosa and the lack of contrast against the background atrophic and metaplastic mucosa. We evaluated the effectiveness of endoscopic resection for EWDAs after endoscopic submucosal dissection (ESD). Among 872 patients with early gastric cancer, 17 EWDAs were identified (1.9 %). Endoscopically, the flat or depressed type was significantly more common among EWDAs (88.2 %) than among early gastric cancers of other histologies (37.8 %; P < 0.01). The discrepancy between endoscopically estimated tumor size and tumor size as confirmed in pathology reports was significantly greater among EWDAs (18.4 ±â€Š22.0  mm) than among others (5.8 ±â€Š7.5  mm). Involvement of the lateral resection margin was more common (29.4 % vs. 2.5 %; P < 0.05), and complete resection was achieved less often in EWDAs (47.1 % vs. 80.4 %; P = 0.01) compared to the others. EWDAs are associated with higher rates of incomplete resection after ESD, especially along the lateral margins. Pathologists should alert endoscopists when this diagnosis is made, with its associated risks; and endoscopists should pay particular attention to the extent of these tumors during resection.

Comparison of chemotherapeutic treatment outcomes of advanced extrapulmonary neuroendocrine carcinomas and advanced small-cell lung carcinoma.

BACKGROUND: The chemotherapy for small-cell lung carcinoma (SCLC) has been adopted for advanced extrapulmonary neuroendocrine carcinomas (EP-NECs). The aim of this study was to clarify the efficacy of standard SCLC regimens when used to treat EP-NECs and to compare the outcome with that for SCLC. METHODS: We reviewed the medical records of 136 patients (41 with EP-NEC and 95 with SCLC) who were treated using a platinum-containing regimen for advanced disease between January 2000 and October 2008 at our hospital. RESULTS: The primary site of the EP-NEC was the gastrointestinal tract in 18 patients (GI tract group); the liver, biliary tract or pancreas in 16 patients (HBP group), and other sites in 7 patients ('others' group). The response rate in the SCLC patients was 77.8%, and the response rate in the EP-NEC patients was 30.8% (37.5% in the GI tract group, 12.5% in the HBP group, and 57.1% in the 'others' group). The median survival time for the SCLC patients was 13.6 months, while that for the EP-NEC patients was 9.2 months (14.9 months in the GI tract group, 7.8 months in the HBP group, and 8.9 months in the 'others' group). A multivariate analysis demonstrated that a poor performance status, liver involvement, and the treatment regimen were independent unfavorable prognostic factors. CONCLUSION: The response rate and prognosis of the patients with advanced EP-NECs were worse than those of the patients with SCLC in this study. The Eastern Cooperative Oncology Group performance status, liver involvement, and treatment regimen had a larger impact on the prognosis than the primary tumor site, as demonstrated by multivariate analysis.

Body cavity fluid can induce epithelial and mesothelial differentiation from CD34 positive peripheral blood stem cells in vitro.

OBJECTIVE: Primary culture of CD34 positive stem cells collected from human peripheral blood was performed with and without supplementation with concentrated ascitic fluid; morphological and immunocytochemical pictures of cultured cells were taken chronologically and compared. METHODS: CD34-positive stem cells collected from peripheral blood were cultured for 1, 24 and 48 hours. Concentrated ascitic fluid was added to the plates for the 24-and 48-hour cultures. For immunocytochemical studies, CD34, AE1/AE3, Ber-Ep4 (EA), EMA, EGFR, CD31, CA125 and D2-40 monoclonal antibodies were used. RESULTS: After culture, small round cells with naked nuclei began to enlarge and to exhibit various changes in the cytoplasm and nucleus. Supplementation with concentrated body cavity fluid enhanced these changes. CD34-positive cells with small round cell features were detected 1 hour after culture and these had no epithelial or mesothelial markers. After 24 hours, CD34-positive cells had disappeared and cells weakly positive for EGFR, EMA, CA125 and D2-40 were detected. Cells with strong and moderate positive reactions for EGFR, AE1/AE3, EA, EMA, D2-40 and CA125 were detected after 48 hours. Supplementation with concentrated body cavity fluid increased the intensity and number of positive cells for these markers compared with the control group. The positive reaction, not only for the epithelial markers such as EGFR and AE1/AE3, but also for mesothelial markers such as CA125 and D2-40, was found to be increased in small numbers of cells in direct proportion to the duration of the primary culture of the peripheral blood cells. CD31, characteristically expressed in endothelial cells, was negative in the cultured cells. CONCLUSION: Supplementation of peripheral blood CD34-positive stem cells with body cavity fluid in vitro enhanced their differentiation toward cells of an epithelial or mesothelial phenotype, concomitant with loss of immunoreactivity for CD34. It is assumed that the routine cytological observation of cells obtained from body cavity fluid might cause possible cytomorphological and immunophenotypical changes due to the action of the growth factors contained in the body cavity fluid.

[Tubular adenoma of the stomach with special reference to the Japanese criteria and pyloric gland adenoma]. / Das tubuläre Magenadenom. Mit Darstellung der Japanischen Kriterien unter Berücksichtigung des "pyloric gland adenoma"

The term gastric adenoma usually refers to a flat adenoma of the intestinal type. Adenomas of the gastric type, so-called pyloric gland adenomas (PGA), which was first characterized by German and Japanese pathologists in 1990, have been regarded as exceptional until recently. In 2003, we first reported systematic clinical pathological analyses of PGA, demonstrating its unstable and precancerous nature. American gastrointestinal pathologists have finally recognized this disease entity in 2009. In this article we introduce the Japanese criteria of the gastric adenoma and review and discuss the clinical pathological and molecular aspects of PGAs.

Pyloric gland adenoma-- how to diagnose?

The term "pyloric gland adenoma" reflects its etiogenesis from deep mucoid glands in the stomach. The diagnosis can be confirmed by immunohistochemistry. Typically, pyloric gland adenomas are strongly positive for Mucin 6 (deep mucoid gastric glands). These lesions express Mucin 6 over the whole lesion up to the surface often only with a small layer of columnar epithelium expressing Apomucin 5AC. The amount of mucin 5AC which is expressed on normal within the apical foveolar epithelium might vary from case to case. Combination or transdifferentiation with ordinary tubular (intestinal differentiation) adenoma can be observed. The gastric corpus mucosa of elderly female patients with autoimmune gastritis is highly affected. The frequency of pyloric gland adenoma is given in the literature being 2.7% of all gastric polyps. Therefore pyloric gland adenomas are not that rare that one might assume. Only a few publications are available which makes one think that these lesions are frequently misinterpreted. Pyloric gland adenomas can arise in gastric heterotopia and gastric metaplasia in the whole gastrointestinal tract. The clinical significance is given by a 30% rate of malignant transformation. These cases represent for the most well differentiated early adenocarcinomas which are known to have an excellent prognosis after complete polypectomy and limitation to the mucosal layer.

Adenoma with gastric differentiation (so-called pyloric gland adenoma) in a heterotopic gastric corpus mucosa in the rectum.

In a 46-year-old man, a pedunculated rectal polyp measuring 3.0x3.0x2.0 cm was diagnosed histologically as a pyloric gland-type adenoma arising in heterotopic gastric corpus mucosa. The luminal site was covered by glands of the gastric foveolar type, displaying focal marked proliferation interpreted as low-grade intraepithelial neoplasia. A bidirectional gastric differentiation was found: most lower glandular structures showed positivity for the deep gastric mucin core protein Muc 6 and superficial positivity for gastric foveolar epithelium mucin core protein Muc 5AC. Pyloric gland adenoma has so far been described in one larger series only and a few case reports of the stomach, gallbladder, pancreatic duct and within heterotopic gastric corpus mucosa of the duodenal bulb. The present case report is the first case of a pyloric gland-type adenoma within a gastric corpus heterotopia of the rectal mucosa.