Diffuse-type tenosynovial giant cell tumors\' (D-TGCTs) intra- and extra-articular expansion about the knee often necessitates an anterior and posterior surgical approach to facilitate an extensive synovectomy. There is no consensus on whether two-sided synovectomies should be performed in one or two stages. This retrospective study included 191 D-TGCT patients from nine sarcoma centers worldwide to compare the postoperative short-term outcomes between both treatments. Secondary outcomes were rates of radiological progression and subsequent treatments. Between 2000 and 2020, 117 patients underwent one-stage and 74 patients underwent two-stage synovectomies. The maximum range of motion achieved within one year postoperatively was similar (flexion 123-120°, p = 0.109; extension 0°, p = 0.093). Patients undergoing two-stage synovectomies stayed longer in the hospital (6 vs. 4 days, p < 0.0001). Complications occurred more often after two-stage synovectomies, although this was not statistically different (36% vs. 24%, p = 0.095). Patients treated with two-stage synovectomies exhibited more radiological progression and required subsequent treatments more often than patients treated with one-stage synovectomies (52% vs. 37%, p = 0.036) (54% vs. 34%, p = 0.007). In conclusion, D-TGCT of the knee requiring two-side synovectomies should be treated by one-stage synovectomies if feasible, since patients achieve a similar range of motion, do not have more complications, but stay for a shorter time in the hospital.

OBJECTIVE: To propose a magnetic resonance imaging (MRI) prediction model for diffuse-type tenosynovial giant cell tumors (D-TSGCTs).
METHODS: Anatomic locations were classified and then nodularity, margin, peripheral and internal hypointensity, and bone and cartilage involvement were evaluated on MRI. Student\'s t-test, chi-square test, diagnostic performance, logistic regression analysis, and decision tree were performed.
RESULTS: Nineteen intra-articular (11 localized; eight diffuse) and 55 extra-articular (44 localized; 11 diffuse) TSGCTs were included. Extra-articular D-TSGCTs showed significantly more frequent multinodular (72.7% vs. 25.0%, p = 0.009), and infiltrative lesions (90.9% vs. 34.1%, p = 0.002), without peripheral hypointensity (90.9% vs. 18.2%, p < 0.001), and contained granular internal hypointensity (72.7% vs. 31.8%; p = 0.003) with more frequent bone (81.8% vs. 27.3%; p = 0.003) and cartilage (50.0% vs. 0.0%; p = 0.038) involvement than localized-type. Intra-articular D-TSGCT also showed significance in all MRI features (100.0% vs. 9.1%, p = 0.001; 100.0% vs. 27.3%, p = 0.007; 100.0% vs. 36.4%, p = 0.018; 100.0% vs. 27.3%, p = 0.007; 50.0% vs. 0.0%, p = 0.038), except bone involvement (37.5% vs. 9.1%, p = 0.352) than localized-type. Cartilage involvement revealed the highest specificity (88.6-100.0%), regardless of location. Nodularity (100.0%; odds-ratio [OR]: 70.000) and peripheral hypointensity (90.9%; OR: 62.250) demonstrated the highest sensitivities ORs for D-TSGCT in intra-articular and extra-articular cases, respectively. MRI models for D-TSGCG beginning with the cartilage involvement in both anatomic locations and next on nodularity and peripheral hypointensity in intra-articular and extra-articular locations, respectively, exhibited sensitivity and specificity of 100% and 90.9% for intra-articular and 100% and 77.2% for extra-articular TSGCTs, respectively.
CONCLUSIONS: MRI can suggest the risk of D-TSGCT by combining imaging features with anatomic locations.

Gastric cancer (GC) is one of the most common malignancies worldwide. The histology- and morphology-based Lauren classification of GC has been widely used for over 50 years in clinical practice. The Lauren classification divides GC into intestinal and diffuse types, which have distinct etiology, molecular profiles, and clinicopathological features. Diffuse-type GC (DGC) accounts for approximately 30% of GCs. Tumor cells lack adhesion and infiltrate the stroma as single cells or small subgroups, leading to easy dissemination in the abdominal cavity. Clinically, DGC has aggressive traits with a high risk of recurrence and metastasis, which results in unfavorable prognosis. Although systemic chemotherapy is the main therapeutic approach for recurrent or metastatic GC patients, clinical benefits are limited for patients with DGC. Therefore, it is urgent to develop effective therapeutic strategies for DGC patients. Considerable research studies have characterized the molecular and genomic landscape of DGC, of which tight junction protein claudin-18 isoform 2 (CLDN18.2) and fibroblast growing factors receptor-2 isoform IIIb (FGFR2-IIIb) are the most attractive targets because of their close association with DGC. Recently, the impressive results of two phase II FAST and FIGHT trials demonstrate proof-of-concept, suggesting that anti-CLDN18.2 antibody (zolbetuximab) and FGFR2-IIIb antibody (bemarituzumab) are promising approaches for patients with CLDN18.2-positive and FGFR2-IIIb-positive GC, respectively. In this review, we summarize the clinicopathological features and molecular profiles of DGC and highlight a potential therapeutic target based on the findings of pivotal clinical trials.

OBJECTIVE: Multiplex gene panel tests using next-generation sequencing (NGS) are clinically available for gastric cancer (GC). The NGS tests can reveal unexpected pathogenic variants to be associated with hereditary diseases, i.e., secondary genetic findings. We investigated whether GC patients at high risk of having hereditary gastric cancer (HGC) can be identified by their clinicopathological variables before they undergo NGS cancer gene panel tests.
METHODS: The cases of 2,286 patients with GC treated at our hospital during the years 1999-2017 were retrospectively analyzed; of them, 143 patients were identified as being at high risk of having HGC (HR-HGC), and the remaining 2,143 patients were classified as having sporadic gastric cancer (SGC).
RESULTS: Compared to the SGC group, the HR-HGC status was significantly associated with younger age, female gender, macroscopic type IV and a histologically diffuse type. In a multivariate analysis, being young (i.e., ≤50 years old) was an independent risk factor for HR-HGC.
CONCLUSIONS: Female and young patients with diffuse-type GC are closely associated with a high risk of having HGC, and these factors might predict the detection of secondary genetic findings by NGS testing.

RhoA is a member of Rho family small GTPases that regulates diverse cellular functions. Recent large-scale sequencing studies have identified recurrent somatic mutations of RHOA in diffuse-type gastric carcinoma (DGC), indicating that RHOA is a driver of DGC. In this study, we investigated the possible abnormalities of RHOA in a panel of gastric carcinoma (GC) cell lines. Pulldown assay and immunoblot analysis showed that the activity and expression of RhoA were detectable in all GC cell lines tested, except for two DGC cell lines, HSC-59 and GSU. RHOA coding region sequencing revealed that aberrant alternative splicing of RHOA occurred in these cell lines. Quantitative real-time PCR analysis showed that the expression of wild-type RHOA was nearly undetectable, whereas splicing variants were almost exclusively expressed in HSC-59 and GSU cell lines. However, the expression levels of RHOA splicing variants were very low and the corresponding proteins were not detected by immunoblotting. Moreover, the splicing isoforms of RhoA protein were neither efficiently expressed nor activated even if ectopically expressed in cells. These results indicate that aberrant alternative splicing of RHOA results in the loss of its activity and expression in DGC cells.

OBJECTIVE: Because of the poor prognosis of diffuse-type gastric cancer, early detection is important. We investigated the clinical characteristics and prognosis of diffuse-type early gastric cancer (EGC) diagnosed in subjects during health check-ups.
METHODS: Among 121,111 subjects who underwent gastroscopy during a routine health check-up, we identified 282 patients with 286 EGC lesions and reviewed their clinical and tumor-specific parameters.
RESULTS: Patients with diffuse-type EGC were younger, and 48.1% of them were female. Serum anti-Helicobacter pylori IgG (Hp-IgG) was positive in 90.7% of diffuse-type EGC patients (vs 75.9% of intestinal-type EGC, p=0.002), and the proportion of diffuse-type EGC cases increased significantly with increasing Hp-IgG serum titers (p<0.001). Diffuse-type EGC had pale discolorations on the tumor surface (26.4% vs 4.0% in intestinal-type EGC, p<0.001) and were often located in the middle third of the stomach. Submucosal invasion or regional nodal metastasis was observed more commonly in patients with diffuse-type EGC. However, during the median follow-up period of 50 months, 5-year disease-free survival rates did not differ between the groups.
CONCLUSIONS: Diffuse-type EGC shows different clinical and endoscopic characteristics. Diffuse-type EGC is more closely associated with Hp-IgG seropositivity and a higher serum titer. Early detection results in excellent prognosis.

BACKGROUND: While gastric cancer is a common cancer in the world and Iran, its molecular mechanisms are not fully understood as yet. Epigenetic modifications can lead to alteration of gene expression and development of tumorigenesis mechanisms.
METHODS: To clarify the difference in DNA methylation pattern of histological types in gastric carcinoma, CpG islands in the promoters of retinoic acid receptor β gene (RAR-β) was studied using methylation-specific PCR.
RESULTS: In gastric cancer tissues, hypermethylation frequency of RAR-β gene was respectively 61 and 33% for diffuse and intestinal type. In diffuse type, hypermethylation of RAR-β has been significantly associated with invasion (P= 0.007), differentiation (P= 0.033) and location (P= 0.012) of the tumor. However, hypermethylation of RAR-β correlated only with tumor size (P= 0.029) in intestinal type. For adjacent non-tumor samples, hypermethylation of RAR-β was not detected and there was no significant association between age of diagnosis and hypermethylation of RAR-β in both types of gastric cancer.
CONCLUSIONS: These results support previous findings denoting a distinct profile of promoter hypermethylation status in the development of the intestinal and diffuse type of gastric carcinoma and the process of the tumorigenesis in these subtypes of gastric cancer is different from each other.

BACKGROUND: It has been reported that multifocal and diffuse hepatic hemangiomas are true infantile hemangiomas for which a continuum probably exists. We determined the similarities and fine differences between the two types of hemangioma and identified the multifocal subgroup of type, which needs timely treatment.
METHODS: Twenty-four patients (4 males and 20 females; age 114±142days) with multifocal or diffuse hepatic hemangiomas who were treated between January 2000 and June 2015 were studied. For the multifocal type, patients were divided into countable (MC) and uncountable (MU) subgroups. The medical data were analyzed retrospectively.
RESULTS: The clinical presentations included hepatomegaly (n=11), dyspnea (n=7), heart failure (n=9), hypothyroidism (n=6), and anemia (n=1). There were 19 and 5 patients with multifocal and diffuse types, and 6 and 13 patients in the MC and MU groups, respectively. There were significant differences between the multifocal and diffuse types with respect to hepatomegaly, heart failure, dyspnea, and hypothyroidism. However, there was no difference between the MU group and the diffuse type except for hypothyroidism. Observation was commonly recommended for patients with the multifocal type, and their survival rate was clearly higher than for patients with the diffuse type. Both the MU and diffuse-type groups needed treatment, unlike MC patients. The complete remission rate was higher in the MC group than in the MU and diffuse-type groups. Patients with the diffuse type were more likely to die.
CONCLUSIONS: Patients with diffuse-type hepatic hemangioma are at high risk and need active treatment. The MU group for the multifocal type is unique and has high similarities to the diffuse type with respect to clinical presentation and treatment, which suggests that a continuum of the disease phenotypes exists.
METHODS: Case-control study, level III.

Mutations in genes involved in the PI3K/AKT pathway and amplifications of the PIK3CA gene in gastric cancer and their associations with clinicopathological characteristics and EBV infection were analyzed in this study. A total of 431 patients with gastric adenocarcinomas were enrolled, and 39 mutation hotspots were evaluated in these patients using MALDI-TOF mass spectrometry were analyzed. PIK3CA amplifications were analyzed using real-time quantitative PCR. Regarding patients with intestinal-type gastric cancer, those with mutations in PI3K/AKT pathway genes were also more likely to have tumors located in the lower-third of the stomach than were those without mutations. Regarding patients with diffuse-type gastric cancer, those with PI3K/AKT pathway mutations were more likely to have tumors located in the upper-third of the stomach and to have more hematogenous metastases, particularly in the liver and lungs, than were patients without such mutations (22.2% vs. 4.5%). No significant survival difference was observed between patients with vs. without PI3K/AKT pathway mutations. Mutations in PI3K/AKT pathway genes were associated with hematogenous metastasis in patients with diffuse-type gastric cancer. Only when the tumors were located in the middle-third of stomach, tumor with mutations of the PIK3CA gene or mutations of the PI3K/AKT pathway genes were associated with more EBV infection than those without mutations. Patients with PIK3CA amplifications were more likely to have diffuse-type and poorly differentiated gastric cancers and were more likely to experience peritoneal recurrence compared with those without PIK3CA amplifications. Even upon subgroup analysis, PI3KCA amplifications were found to not affect the patients\' outcomes.

Histologic mimics of poorly cohesive gastric carcinoma are uncommon but are important for pathologists to recognize. Here we report 2 cases of a novel histologic pattern mimicking poorly cohesive gastric carcinoma. In both cases, light microscopy revealed sheets of discohesive epithelial cells with prominent mitoses that have high proliferative activity, with a Ki67 proliferation index greater than 70%. One case was diagnosed as poorly cohesive carcinoma at an outside hospital and the other was referred in consultation as atypia of undetermined significance. Reexamination of the hematoxylin-eosin slides revealed morphologic clues that these sheets of discohesive cells represent artifactual extrusion of the highly proliferative neck zone from the surrounding benign mucosa. In contrast to poorly cohesive cancer, this artifact lacks all of the following diagnostic features: nuclear atypia, signet ring cell morphology, and intercellular stroma with infiltrating single cells between glands. Eight and 14 months later, both patients remain cancer free.