Clinicopathological findings, prognosis, and Epstein-Barr virus infection in rheumatoid arthritis patients with other iatrogenic immunodeficiency-associated T- and NK-cell lymphoproliferative disorders.

BACKGROUND: Other iatrogenic immunodeficiency-associated (OIIA) T- and natural killer (NK)-cell lymphoproliferative disorders (TNK-LPDs) are rare in patients with rheumatoid arthritis (RA). METHODS: We investigated the clinicopathological characteristics, Epstein-Barr virus (EBV) infection, genetic findings, therapeutic response, and prognostic factors in 21 RA patients with OIIA TNK-LPDs and compared these with those of 39 with OIIA B-cell LPDs (B-LPDs) and 22 with non-OIIA B-LPDs. RESULTS: Immunohistologically, 11 patients (52%) showed CD4+ T-LPDs, and 7 had a T follicular helper (TFH) phenotype. The other nine patients (43%) showed CD8+ T-LPDs, and the remaining one (5%) had features of CD3+ CD4- CD8- nasal type TNK-cell lymphoma. CD30+, p53+, and CMYC+ atypical lymphocytes were identified in seven (33%), eight (38%), and five (24%) patients, respectively. In situ hybridisation detected EBV-encoded RNA (EBER) + large atypical lymphocytes in five patients (24%). Nine of 17 patients (53%) showed clonal peaks of TCRγ by polymerase chain reaction. Withdrawal of MTX and biologic drugs was effective in 12 patients (57%), and 8 (38%) received chemotherapies. Two patients with TFH+ or EBV+ CD4+ CD30+ large cell peripheral T-cell lymphoma, one with CD8+ systemic anaplastic large cell lymphoma, and two with systemic EBV+ CD8+ T-cell lymphoma of childhood showed a lethal progressive clinical course within 13 months. Moreover, > 500 U/L LDH, large atypical lymphocytes, expression of CD30, p53, and CMYC, and EBER+ atypical lymphocytes were significantly poor prognostic factors for overall survival (p < 0.05). Median interval from RA onset to OIIA TNK-LPDs was 72 months, which was shorter than 166 months in OIIA B-LPDs (p = 0.003). EBV+ atypical and reactive lymphocytes were frequently found in 15 patients with OIIA TNK-LPDs (71%), in 27 with OIIA B-LPDs (69%), and only in 3 with non-OIIA B-LPDs (14%). CONCLUSIONS: OIIA TNK-LPDs occurred in early phase of RA, compared with OIIA B-LPDs, and occasionally showed a lethal progressive clinical course. Detection of OIIA TNK-LPD patients with poor prognostic factors is necessary. EBV infection in immunosuppressed patients due to persistent RA, MTX, and biologic drugs may play a role in forming the tumour microenvironment and lymphomagenesis of TNK-LPDs.

Outcomes of methotrexate-associated lymphoproliferative disorders in rheumatoid arthritis patients treated with disease-modifying anti-rheumatic drugs.

Recently, the use of targeted synthetic or biological disease-modifying anti-rheumatic drugs (ts/bDMARDs) in addition to conventional synthetic (cs)DMARDs including methotrexate (MTX) for rheumatoid arthritis (RA) has increased. However, whether ts/bDMARDs are associated with the development and clinicopathological features of MTX-associated lymphoproliferative disorder (MTX-LPD) in patients with RA remains unknown. Therefore, we evaluated the clinical outcomes of 121 patients with MTX-LPD. Results showed that prior use of ts/bDMARDs was not associated with the different histopathological subtypes of MTX-LPD. Patients with polymorphic-type LPD had a better event-free survival than those with diffuse large B-cell lymphoma (DLBCL), classical Hodgkin lymphoma and peripheral T-cell lymphoma. The pathological subtype of lymphoma could predict the clinical outcome of MTX-LPD. In patients with DLBCL, the use of tumour necrosis factor-alpha (TNF-α) inhibitors prior to MTX-LPD onset was associated with a higher non-relapse mortality. Further, patients with RA previously treated with Janus kinase (JAK) inhibitors more commonly required chemotherapy than those treated with csDMARDs alone, indicating disease aggressiveness. Hence, special caution should be observed when managing patients with MTX-LPD previously treated with JAK or TNF-α inhibitors for RA.

Myxoepithelioid tumour with chordoid features: a clinicopathological, immunohistochemical and genetic study of 14 cases of SMARCB1/INI1-deficient soft-tissue neoplasm.

AIMS: Complete loss of SMARCB1/INI1 in soft-tissue tumours such as malignant rhabdoid tumour, epithelioid sarcoma, myoepithelial tumour of soft tissue and extraskeletal myxoid chondrosarcoma is often associated with high-grade malignancy and poor prognosis. The diagnosis is sometimes challenging, owing to histological similarities, so careful differential diagnosis is required. Therefore, soft-tissue tumours with complete SMARCB1/INI1 loss could potentially include an unknown entity. METHODS AND RESULTS: We analysed 160 cases of SMARCB1/INI1-deficient soft-tissue tumour, and found 14 cases that were not classifiable into already existing categories and had common clinical and histological features. These involved two male and 12 female patients, ranging in age from 20 years to 61 years. The tumours were located in the the puboinguinal region (n = 13) and pelvic cavity (n = 1). Histologically, the tumours showed relatively uniform epithelioid to spindle-shaped cells with myxoid stroma. All tumours showed immunoreactivity for brachyury, epithelial membrane antigen, and progesterone receptor, and 12 of 14 cases did so for oestrogen receptor. Variable positive staining for α-smooth muscle actin, S100 and glial fibrillary acidic protein (GFAP) was seen. NR4A3 and EWSR1 gene rearrangements were not detected in 13 and 11 examined cases, respectively. Clinical follow-up data for the 14 patients showed that 13 were alive without disease and one had been lost to follow-up; four patients developed local recurrence and/or metastases. CONCLUSION: The designation 'myxoepithelioid tumour with choroid features' (METC) was proposed as a tumour with intermediate malignancy controllable with appropriate treatment, including the entity of myoepithelioma-like tumour of the vulvar region. METC represents a novel and independent subset that is histologically, biologically and clinically distinct from already existing SMARCB1/INI1-deficient soft-tissue tumours.

Automated assessment of Ki-67 in breast cancer: the utility of digital image analysis using virtual triple staining and whole slide imaging.

AIMS: Precise evaluation of proliferative activity is essential for the stratified treatment of luminal-type breast cancer (BC). Immunohistochemical staining of Ki-67 has been widely used to determine proliferative activity and is recognised to be a useful prognostic marker. However, there remains discussion concerning the methodology. We aimed to develop an automated and reliable Ki-67 assessment approach for invasive BC. MATERIALS AND RESULTS: A retrospective study was designed to include two cohorts consisting of 152 and 261 consecutive patients with luminal-type BC. Representative tissue blocks following surgery were collected, and three serial sections were stained automatically with Ki-67, pan-cytokeratin and p63. The whole slides were scanned digitally and aligned using VirtualTripleStaining - an extension to the VirtualDoubleStaining™ technique provided by Visiopharm software. The aligned files underwent automated invasive cancer detection, hot-spot identification and Ki-67 counting. The automated scores showed a significant positive correlation with the pathologists' scores (r = 0.82, P < 0.0001). Among selected patients with curative surgery and standard adjuvant therapies (n = 130), the digitally assessed low Ki-67 group (<20%) demonstrated a significantly better prognosis (breast cancer-specific survival, P = 0.030; hazard ratio = 0.038) than the high Ki-67 group. CONCLUSIONS: Digital image analysis yielded similar results to the scores determined by experienced pathologists. The prognostic utility was verified in our cohort, and an automated process is expected to have high reproducibility. Although some pitfalls were confirmed and thus need to be monitored by laboratory staff, the application could be utilised for the assessment of BC.

Prospective Cohort Study of Congenital Cytomegalovirus Infection during Pregnancy with Fetal Growth Restriction: Serologic Analysis and Placental Pathology.

OBJECTIVE: To investigate prospectively the prevalence of congenital cytomegalovirus (CMV) infection and the pathologic features of the placenta in cases of fetal growth restriction (FGR). STUDY DESIGN: Forty-eight pregnant women who were diagnosed with FGR during pregnancy were enrolled for 15 months. Maternal CMV serologic tests, pathologic examinations of the placenta, and newborn urinary CMV-DNA polymerase chain reaction tests were performed in all the cases. The clinical characteristics and laboratory findings of the pregnant women and their newborns were collected. Biomarkers for inflammation, angiogenesis, and placental hormones were measured in the maternal serum at FGR diagnosis or in the neonatal urine at birth. RESULTS: One of the 48 cases with FGR was a congenital CMV infection. CMV antigen was detected in the placenta of 7 cases with FGR. The change rate of the estimated fetal body weight was significantly lower in FGR cases with placental CMV detection. Placental villitis was observed more frequently in FGR cases with placental CMV detection. Human placental lactogen was significantly decreased in FGR cases with placental CMV detection. Increased C-reactive protein and serum amyloid A levels in the maternal serum were observed more frequently in FGR cases with placental CMV detection. Newborn urine ß-2 microglobulin levels were significantly higher in FGR cases with placental CMV detection. CONCLUSIONS: Serologic tests for maternal CMV, the change rate of the estimated fetal body weight, analysis of several biomarkers, and placental pathologic examinations might be helpful in comprehensively predicting the possibility of congenital CMV infection.

Risk factors for reflux esophagitis after eradication of Helicobacter pylori.

Objective: While there is an association between successful eradication of Helicobacter pylori (HP) and reflux esophagitis (RE), risk factors associated with RE remain obscure. The aim of this study is to determine risk factors associated with the development of RE after HP eradication.Materials and methods: Among all patients treated with successful HP eradication from 2008 to 2016, we retrospectively analyzed those who were free from RE at initial esophagogastroduodenoscopy (EGD) and who were followed up with EGD after eradication. Patients were classified according to the presence or absence of RE at the follow-up EGD. RE was defined as mucosal breaks proximal to the squamous-columnar junction. Demographic data, underlying diseases, medications and endoscopic findings at the initial EGD were compared between patients with and without RE.Results: Among 1575 patients, 142 (9.0%) had RE at the follow-up EGD. The time interval from HP eradication until EGD ranged from 4 to 24 months. The endoscopic grade of RE was higher in males than in females. Multivariate analysis revealed that male sex (odds ratio [OR], 1.51; 95% confidence interval [CI], 1.04-2.24), body mass index ≥25 kg/m2 (OR, 2.91; 95% CI, 2.00-4.22), use of calcium channel blockers (OR, 1.70; 95% CI, 1.12-2.55), and hiatal hernia (OR, 3.46; 95% CI, 2.41-5.00) were associated with the development of RE.Conclusions: Calcium channel blocker use was found to be a risk factor for the development of RE after eradication of HP.

Clinical usefulness of magnifying colonoscopy for the diagnosis of ulcerative colitis-associated neoplasia.

BACKGROUND AND AIM: The aim of this investigation was to evaluate the efficacy of Japanese magnifying colonoscopic classifications for ulcerative colitis-associated neoplasia (UCAN). METHODS: We reviewed the colonoscopy records from 2011 to 2018 at our institutions and identified cases of endoscopically or surgically resected UCAN observed by magnifying narrow-band imaging (NBI) endoscopy and magnifying chromoendoscopy. Association between magnifying endoscopic classification and histopathological findings was investigated retrospectively. Japan NBI expert team (JNET) classification and pit pattern classification were applied. RESULTS: There were 17 patients who had a diagnosis of UCAN. Tumors of types 2A, 2B and 3 by JNET classification correlated with the histopathological findings of low-grade dysplasia (LGD)/high-grade dysplasia (HGD), HGD, and massively submucosal invasive (mSM) carcinoma, respectively. Tumors of types III/IV, VI low irregularity, and VI high irregularity/VN by pit pattern classification were correlated with the histopathological findings of LGD/HGD, HGD, and mSM carcinoma, respectively. CONCLUSIONS: Japan NBI expert team classification and pit pattern classification may be predictive of the histological diagnosis and invasion depth of UCAN. This needs to be investigated prospectively in a large cohort or in a randomized clinical trial.

Insulin-like growth factor II messenger RNA-binding protein-3 is an independent prognostic factor in uterine leiomyosarcoma.

AIMS: The aim of this study was to identify the prognostic factors of uterine leiomyosarcoma (ULMS). METHODS AND RESULTS: We reviewed 60 cases of surgically resected ULMSs and investigated conventional clinicopathological factors, together with the expression of insulin-like growth factor II messenger RNA-binding protein-3 (IMP3), hormone receptors and cell cycle regulatory markers by immunohistochemistry. Mediator complex subunit 12 (MED12) mutation analysis was also performed. Univariate analyses revealed that advanced stage (P < 0.0001), older age (P = 0.0244) and IMP3 expression (P = 0.0011) were significant predictors of a poor outcome. Multivariate analysis revealed advanced stage (P < 0.0001) and IMP3 (P = 0.0373) as independent predictors of a poor prognosis. Expressions of cell cycle markers and hormone receptors, and MED12 mutations (12% in ULMSs) were not identified as prognostic markers in this study. CONCLUSIONS: IMP3 expression in ULMS could be a marker of a poor prognosis.

Prognostic and predictive impacts of tumor-infiltrating lymphocytes differ between Triple-negative and HER2-positive breast cancers treated with standard systemic therapies.

Tumor-infiltrating lymphocytes (TILs) have potential value for stratifying the treatment of breast cancer (BC), though their precise use remains unclear. We aimed to investigate the utility of TILs using an alternative approach in different settings. We reviewed patients with triple-negative (TN) or human epithelial growth factor receptor 2 (HER2)-positive invasive ductal carcinomas from a single institutional cohort and classified archived hematoxylin-eosin-stained samples in terms of TIL score as low (<10 %), intermediate, and high (>50 %). The prognostic and predictive values of TILs were analyzed retrospectively in both adjuvant and neo-adjuvant settings. In the adjuvant setting, the presence of TILs at primary surgery was a significant favorable prognostic factor among 154 TNBCs [relapse-free survival (RFS): p = 0.015], but not among 183 HER2+ BCs (RFS: p = 0.097). The TNBC low-TIL group tended to relapse earlier. In the neo-adjuvant setting, detection of TILs on biopsy before primary systemic therapy was associated with the ratio of patients achieving pathological complete response among 48 TNBCs (p = 0.024), but not among 58 HER2+ BCs (p = 0.30). The presence of TILs in surgical specimens after systemic therapy had prognostic value in HER2+ BC (RFS: p = 0.007). The impact of TILs differs between patients with TN and HER2+ BC treated with standard therapies. Our three-grade scale for TILs may contribute to our understanding of the importance of the tumor microenvironment in routine practice. TILs after primary systemic therapy may be useful for the further stratification of treatment of HER2+ BC.

Clinicopathologic Features of Inverted Serrated Lesions of the Large Bowel.

BACKGROUND/AIMS: Serrated lesions (SLs) of the large bowel occasionally manifest as inverted growths with endophytic expansion within the muscularis mucosa. The aims of this investigation were to investigate the incidence of inverted SLs (ISLs) among SLs and to describe the clinicopathologic features. METHODS: We reviewed the colonoscopy records from 2006 to 2014 at our institution and identified cases of endoscopically or surgically resected SLs, including hyperplastic polyps (HPs), sessile serrated adenomas/polyps (SSA/Ps) and traditional serrated adenomas (TSAs). The incidence of ISLs among the SLs and their colonoscopic findings were investigated retrospectively. RESULTS: There were 35 HPs in 30 patients, 80 SSA/Ps in 65 patients and 70 TSAs in 65 patients. The incidence of ISLs was significantly higher among SSA/Ps (8.8%) and HPs (5.7%) than among TSAs (0%; p = 0.04). A predominant right-sided location, a flat-elevated configuration with a central depression and round-open pit pattern or expanded crypt openings were characteristic of ISLs of the SSA/P type. CONCLUSIONS: Right-sided flat lesions with a central depression and round or expanded crypts are indicative of ISLs of the SSA/P type.

Whipple's disease diagnosed using electron microscopy and polymerase chain reaction.

A 50-year-old man presented with bloody diarrhea and 25-kg weight loss over 3 months. Upper and lower endoscopy showed diffuse shaggy white villi in the duodenum and terminal ileum. In addition, capsule endoscopy and double-balloon enteroscopy revealed shaggy white villi in the entire small intestine. Histological examination of biopsy specimens found the lamina propria of the duodenal and intestinal mucosa to be densely infiltrated by rich foamy macrophages that were periodic acid-Schiff-positive. Electron microscopy showed numerous bacilli in the lamina propria. Tropheryma whipplei DNA was detected in the specimens by polymerase chain reaction. Based on these findings, the patient was diagnosed with Whipple's disease. He was treated with a 2-week course of ceftriaxone followed by trimethoprim-sulfamethoxazole. At the 2-month follow up, diffuse white shaggy villi improved dramatically.

Clinicopathological characteristics and rituximab addition to cytotoxic therapies in patients with rheumatoid arthritis and methotrexate-associated large B lymphoproliferative disorders.

AIMS: To analyse the clinicopathological characteristics and prognosis of 40 rheumatoid arthritis (RA) patients with methotrexate (MTX)-associated large B cell lymphoproliferative disorders (MTX-BLPD). METHODS AND RESULTS: Soluble interleukin 2 receptor titres (median 1500 U/ml) in 40 patients with MTX-BLPD were lower than those of 24 RA patients with non-MTX- associated (non-MTX) BLPD (5731 U/ml) and 15 with control diffuse large B cell lymphoma (DLBCL, 5918 U/ml) (P < 0.01). Using in-situ hybridization, Epstein-Barr virus (EBV) was detected in tumour cells of 25 of 40 RA patients with MTX-BLPD (63%). Immunohistologically, BCL2 expression was detected in 35% of patients with MTX-BLPD, which was lower than 93% of control DLBCL patients (P < 0.01). Eleven patients with EBV(+) MTX-BLPD (44%) showed remission after MTX withdrawal. In RA patients with clinical stage III/IV BLPD, 15 with rituximab (R)+ cytotoxic therapies pursued better prognosis than 10 with R- cytotoxic therapies (P < 0.05). Among the 15 patients, seven with MTX-BLPD showed better overall survival than nine control DLBCL patients (P < 0.01). CONCLUSIONS: In RA patients with MTX-BLPD, immunosuppression by MTX, EBV infection and low BCL2 expression in tumour cells may play roles in tumorigenesis and tumour regression. R+ cytotoxic therapies as well as MTX withdrawal were highly effective in these patients.

Significance of a white opaque substance under magnifying narrow-band imaging colonoscopy for the diagnosis of colorectal epithelial neoplasms.

BACKGROUND AND AIMS: The aim of this study was to examine the significance of a white opaque substance (WOS) found on magnifying narrow-band imaging (M-NBI) for the diagnosis of colorectal neoplastic lesions. METHODS: We retrospectively reviewed colonoscopy records from 2006 to 2012 at our institution and identified cases of endoscopically or surgically resected colorectal epithelial neoplasms observed by M-NBI colonoscopy. The colonoscopic and histologic characteristics of the lesions were compared between WOS-positive and WOS-negative lesions. We further classified the WOS as regular or irregular and compared the histologic characteristics between the two types of lesions. RESULTS: There were 105 WOS-positive lesions and 451 WOS-negative lesions. The former were subdivided into lesions with regular and irregular WOS. The incidence of high-grade dysplasia or carcinoma was significantly higher in WOS-positive lesions (61.9%) than in WOS-negative lesions (28.6%) (P < .05). Among the WOS-positive lesions, massive submucosal invasion was more frequent in lesions with irregular WOS (82.4%) than in those with regular WOS (1.4%) (P < .05). Among cancers with massive submucosal invasion, lymph node metastasis was more frequent in cancers with irregular WOS (17.4%) than in those with regular WOS or without the WOS (0%) (P < .05). CONCLUSIONS: A WOS in colorectal neoplasms may be an optical marker for high-grade dysplasia and cancer. An irregular WOS may be indicative of massive submucosal invasion and lymph node metastasis.

DDIT3-amplified or low-polysomic pleomorphic sarcomas without MDM2 amplification: Clinicopathological review and immunohistochemical profile of nine cases.

Several high-grade pleomorphic sarcoma cases that cannot be classified into any existing established categories have been reported. These cases were provisionally classified into undifferentiated pleomorphic sarcoma (UPS). Some dedifferentiated liposarcoma (DDLS) cases may also have been classified into the UPS category due to the absence of MDM2 amplification or an atypical lipomatous tumor/well-differentiated liposarcoma component. We retrieved and reviewed 77 high-grade pleomorphic sarcoma cases, initially diagnosed as UPS in 66 cases and DDLS in 11 cases. Fluorescence in situ hybridization (FISH) analyses of DDIT3 and MDM2 were performed for available cases. Of the cases successfully subjected to DDIT3 FISH (n = 56), nine (7 UPS and 2 DDLS) showed DDIT3 amplification but no MDM2 amplification. Two UPS cases showed both telomeric (5') and centromeric (3') amplification of DDIT3 or low polysomy of chromosome 12, whereas 5 UPS and 2 DDLS cases showed 5'-predominant DDIT3 amplification. Histopathologically, all cases showed UPS-like proliferation of atypical pleomorphic tumor cells. Immunohistochemically, only one case showed focal nuclear positivity for DDIT3, supporting the previous finding that DDIT3 expression was not correlated with DDIT3 amplification. All three cases with focal MDM2 expression involved 5'-predominant amplification, two of which showed DDLS-like histological features. The majority of cases (7/9) showed decreased expression in p53 staining, suggesting that DDIT3 amplification regulates the expression of TP53 like MDM2. From a clinicopathological perspective, we hypothesize that DDIT3-amplified sarcoma, especially with 5'-predominant amplification, can be reclassified out of the UPS category.

Clinicopathological features of primary leiomyosarcoma of the gastrointestinal tract following recognition of gastrointestinal stromal tumours.

AIMS: We aimed to elucidate the clinicopathological and immunohistochemical features of leiomyosarcoma (LMS) of the gastrointestinal (GI) tract. METHODS AND RESULTS: We encountered seven cases of GI-LMS in the colon (n = 4), rectum (n = 1), jejunum (n = 1) and stomach (n = 1). They ranged from 1 to 25 cm (median, 8.5 cm) in size and had high mitotic counts (median 38 per 50 high-power fields). Morphologically, the tumours were composed mainly of spindle cells with eosinophilic cytoplasm and various degrees of nuclear atypia and pleomorphism. Immunohistochemically, the tumours were positive for α-smooth muscle actin (86%), muscle-specific actin (71%), desmin (86%), calponin (71%), h-caldesmon (57%) and smoothelin (71%). All were negative for KIT, CD34, protein kinase C theta and DOG1. Local recurrence and distant metastasis occurred in one and three patients, respectively. We then reviewed 55 cases of GI-LMS from the era following the recognition of gastrointestinal stromal tumours. Among 29 of 55 cases for whom follow-up information was available, the estimated 5-year overall survival rate was 51.6%; tumour size ≥5 cm was correlated significantly with shorter overall survival time (P = 0.0016), while mitotic count (≥50 or ≥100 per 50 high-power fields) proved to be no prognostic factor. CONCLUSIONS: GI-LMSs have distinctive clinicopathological and immunohistochemical features and exhibit aggressive biological behaviour.

[Clinicopathological features of serrated lesions of the colorectum].

We reviewed 428 subjects with colorectal serrated lesions resected endoscopically or surgically at our institution. Colorectal serrated lesions were pathologically divided into 3 groups: hyperplastic polyp (HP), sessile serrated adenoma/polyp (SSA/P), and traditional serrated adenoma (TSA). SSA/P was detected frequently in the right colon and SSA/P was mainly flat-elevated. Cancers occurring in SSA/P were found more frequently than HP or TSA. The incidence of cancer in SSA/P was equivalent to that of cancer in traditional adenoma. Further studies are warranted to clarify clinicopathological features of serrated lesions of the colorectum.

Synchronous gallbladder metastasis originating from residual gastric cancer: a case report and the review of literature.

BACKGROUND: Gastric cancer rarely metastasizes to the gallbladder. Furthermore, there has never been a case report of simultaneous gallbladder metastasis from residual gastric cancer. Here, we report a case of synchronous gallbladder metastasis originating from a residual gastric cancer. CASE PRESENTATION: A 67-year-old man underwent a follow-up upper endoscopy 18 months after a partial gastrectomy for gastric cancer; an ulcerative lesion was found in the remnant stomach at the gastrojejunal anastomosis. A biopsy revealed gastric signet-ring cell carcinoma (SRCC). A full-body examination revealed no abnormalities other than gallstones in the gallbladder. With a diagnosis of residual gastric cancer (cT2N0M0 cStage I), the patient underwent open total gastrectomy and cholecystectomy. Macroscopic findings of the resected specimen revealed thickening of the gallbladder wall; however, no obvious neoplastic lesions were found on the mucosal surface of the gallbladder. The pathological findings showed that the SRCC had invaded the submucosa of the gastrojejunostomy site with a high degree of lymphatic invasion and lymph node metastases. SRCCs were also found in the lymphatic vessels of the gallbladder wall. These findings suggested the possibility of gallbladder metastasis through lymphatic vessels. The patient and his family members refused postoperative chemotherapy. Ten months after the operation, the patient experienced respiratory failure due to lymphangitis carcinomatosa and died. CONCLUSIONS: At present, it is difficult to determine whether resection of the gallbladder contributes to an improved prognosis of gastric cancer patients. However, reports in such cases demonstrate that gallbladder metastasis could be a poor predictor of prognosis for gastric cancer.

Comparative analyses of tumour immune microenvironment between collecting duct carcinoma and fumarate hydratase-deficient renal cell carcinoma.

AIMS: Collecting duct carcinoma (CDC) and fumarate hydratase-deficient renal cell carcinoma (FH-deficient RCC) have similar histological morphologies and both show a poor prognosis. Programmed death ligand 1 (PD-L1) inhibitor has been approved for the treatment of RCC. However, tumour-infiltrating neutrophils stimulated by interleukin-8 (IL-8) interfere with PD-L1 inhibitors. Here, we retrospectively analysed PD-L1 and IL-8 expression, and examined its relationship with infiltrating immune cells. METHODS: Nine cases of CDC and seven cases of FH-deficient RCC were selected. We defined PD-L1 and IL-8 expression by the Tumour Proportion Score and Combined Positive Score (CPS). We counted the numbers of CD8+, CXCR2+, CD11b+, CD66b+ and CD33+ immune cells located in the tumour components. RESULTS: A number of CXCR2+ (p=0.0058), CD11b+ (p=0.0070) and CD66b+ (p=0.0067) immune cells infiltrating into CDC were significantly higher than those infiltrating into FH-deficient RCC. In CDC, PD-L1 expression was correlated with a high density of CD8+ lymphocytes (p=0.0389), but was not in FH-deficient RCC (p=0.6985). IL-8 CPS was significantly higher in CDC than in FH-deficient RCC (p=0.0069). In addition, among the CDC cases, IL-8 CPS showed significant positive correlations with CXCR2+, CD11b+ and CD66b+ immune cell densities (p=0.0250, p=0.0104 and p=0.0374, respectively), whereas FH-deficient RCC showed no significant correlations between IL-8 CPS and immune cell densities. CONCLUSIONS: Our results suggest the difference of each tumour microenvironment between CDC and FH-deficient RCC, and IL-8 is a potential therapeutic target for treating CDC, but not FH-deficient RCC.

Programmed cell death-ligand 1 (PD-L1)+ tumour cells and low-reacting programmed cell death 1 (PD1)+ tumour-infiltrating lymphocytes predict poor prognosis in Epstein-Barr virus+ diffuse large B-cell lymphoma.

Epstein-Barr virus (EBV)+ diffuse large B-cell lymphoma (DLBCL) has specific tumour cell characteristics, and these patients have worse outcomes than EBV-negative DLBCL patients. We compared 38 EBV+ DLBCL patients with 43 methotrexate-associated EBV+ B-cell lymphoproliferative disorders (MTX+/EBV+ BLPDs) and 30 non-germinal centre (GC) subtype DLBCL. Lymphoma cells of the EBV+ DLBCL group were positive for BCL2 in 17 patients (44.7%), CMYC in 23 patients (60.5%), and p53 in 33 patients (86.8%), which was significantly higher than in the MTX+/EBV+ BLPD group (P < 0.05), and were positive for CD30 in 29 patients (76.3%), compared with two in non-GC subtype DLBCL (6.7%) (P < 0.0001). Significantly more EBV+ DLBCL patients (n = 16, 42.1%) had programmed cell death-ligand 1 (PD-L1)+ tumour cells than patients with non-GC subtype DLBCL (n = 5, 16.7%; P = 0.024), and PD-L1+ tumour cells were more common in advanced stages than in early stages (P = 0.048). Twenty-five EBV+ DLBCL patients (69.4%) had few reactive PD1+ tumour-infiltrating lymphocytes (TILs), compared with 12 patients with MTX+/EBV+ BLPDs (37.5%) (P = 0.008). In the EBV+ DLBCL group, CD30, BCL2, CMYC, and p53 expression was not related to patient prognosis. Poor outcomes were associated with PD-L1+ tumour cells (P = 0.001) and low-reacting PD1+ TILs (P = 0.02), while their combination conferred a worse outcome (P < 0.0001). Immune evasion by PD-L1+ tumour cells and exhaustion of PD1+ TILs may occur in EBV+ DLBCL patients, and PD-L1/PD1 interactions may influence tumour progression and poor prognosis.

Novel case of laparoscopically resected gastric adenocarcinoma concurrent with lanthanum deposition.

A 73-year-old man taking lanthanum carbonate for hemodialysis showed progressing gastric mucosal changes with lanthanum deposition. Regular examination revealed concurrent gastric carcinoma. The extent and depth of its invasion were ambiguous because of the surrounding lanthanum deposition. Furthermore, there could be other potent carcinomas, and curative laparoscopic gastrectomy was performed.