Binary semantic segmentation for detection of prostate adenocarcinoma using an ensemble with attention and residual U-Net architectures.

An accurate determination of the Gleason Score (GS) or Gleason Pattern (GP) is crucial in the diagnosis of prostate cancer (PCa) because it is one of the criterion used to guide treatment decisions for prognostic-risk groups. However, the manually designation of GP by a pathologist using a microscope is prone to error and subject to significant inter-observer variability. Deep learning has been used to automatically differentiate GP on digitized slides, aiding pathologists and reducing inter-observer variability, especially in the early GP of cancer. This article presents a binary semantic segmentation for the GP of prostate adenocarcinoma. The segmentation separates benign and malignant tissues, with the malignant class consisting of adenocarcinoma GP3 and GP4 tissues annotated from 50 unique digitized whole slide images (WSIs) of prostate needle core biopsy specimens stained with hematoxylin and eosin. The pyramidal digitized WSIs were extracted into image patches with a size of 256 × 256 pixels at a magnification of 20×. An ensemble approach is proposed combining U-Net-based architectures, including traditional U-Net, attention-based U-Net, and residual attention-based U-Net. This work initially considers a PCa tissue analysis using a combination of attention gate units with residual convolution units. The performance evaluation revealed a mean Intersection-over-Union of 0.79 for the two classes, 0.88 for the benign class, and 0.70 for the malignant class. The proposed method was then used to produce pixel-level segmentation maps of PCa adenocarcinoma tissue slides in the testing set. We developed a screening tool to discriminate between benign and malignant prostate tissue in digitized images of needle biopsy samples using an AI approach. We aimed to identify malignant adenocarcinoma tissues from our own collected, annotated, and organized dataset. Our approach returned the performance which was accepted by the pathologists.

Impact of EFEMP1 on the survival outcome of biliary atresia in Thai infants.

Genome-wide association studies (GWASs) have identified a genetic associated between EFEMP1 and biliary atresia (BA). To examine the susceptibility of single nucleotide polymorphisms (SNPs) in EFEMP1 in Thai BA patients, we performed an analysis of the genetic associations and biological interactions with previously reported key SNPs in ADD3, a key gene associated with BA. The study also used high-throughput sequencing to detect novel variants in both genes. In addition, the clinical impact of EFEMP1 SNPs in terms of survival association was also evaluated. The genotypes of 60 BA patients and 179 controls were evaluated using a TaqMan genotyping assay for rs2501577 and rs17095355 in ADD3 and rs6761893 and rs727878 in EFEMP1. The genotype frequencies were analyzed together with the SNP-SNP interactions. Fine mapping by whole-exome sequencing was performed to identify deleterious variants within both genes, and the survival analysis results were analyzed with the EFEMP1 SNPs. The recessive genotypes of rs2501577, rs17095355 and rs6761893 showed significantly higher frequencies in the BA patients than the controls, and a logistic regression showed that minor alleles of those SNPs increased the BA risk by ORs of 1.86, 1.67, and 1.84, respectively. Moreover, the SNP-SNP interference suggested that a combination of recessive alleles from the 2 genes resulted in an additive risk to BA. In addition, rare missense variants in the gene coding sequences were identified in 7 cases. Immunohistochemical studies revealed a pattern of ADD3 downregulation and EFEMP1 overexpression in the bile ducts of BA patients. Patients with the AA genotype of rs6761893 had significantly lower 5-year native liver survival (34.0%) than those with AT/TT (75.0%), with a log-rank p value of 0.041. Variants in EFEMP1 are associated with the occurrence of BA in Thai patients. In addition, these variants have an additive influence on BA risk when combined with ADD3 variants. Moreover, rs6761893 in EFEMP1 was indicative of survival in Thai BA patients.

Appendiceal tumors in patients undergoing primary surgery for mucinous ovarian tumors in a tertiary hospital, in Southern Thailand.

OBJECTIVE: To evaluate the prevalence of appendiceal tumors in patients diagnosed with mucinous ovarian tumors and to determine factors associated with coexisting appendiceal tumors. MATERIALS AND METHODS: Retrospective review of all patients who were diagnosed with mucinous ovarian tumors and underwent an appendectomy during surgery between January 2002 and June 2017 was performed. Univariate and multivariate logistic regression analyses were used to identify risk factors for coexisting appendiceal tumors. RESULTS: A total of 303 patients with mucinous ovarian tumors who underwent appendectomy were identified, including 77 (25.4%) mucinous cystadenoma and 226 (74.6%) mucinous borderline tumor or carcinoma. Twenty-one (6.9%) had coexisting appendiceal tumors including 8 that were primary appendiceal mucinous adenocarcinomas, 6 low-grade appendiceal mucinous neoplasms, 6 secondary appendiceal metastasis from the ovary, and one hyperplastic polyp. None of mucinous cystadenoma had coexisting appendiceal tumors. Multivariate analysis revealed advanced age ≥50 years, previous rupture of ovarian tumors, abdominal extension of tumors, and grossly abnormal appendix were independent factors for coexisting appendiceal tumors. CONCLUSION: Prevalence of coexisting appendiceal tumors in mucinous ovarian tumors was not uncommon. The risk factors were grossly abnormal appendix, abdominal extension of tumor, previous rupture of ovarian tumors, and advanced age.

IgG4-related disease in patients with idiopathic orbital inflammation.

BACKGROUND: To identify the prevalence of positive IgG4 immunostaining in orbital tissue among patients previously diagnosed with nongranulomatous idiopathic orbital inflammation (IOI) and to compare the clinical characteristics of patients with and without IgG4-positive cells. METHODS: A retrospective review of all patients with a histopathologic diagnosis of IOI was performed. Immunohistochemical staining was performed to identify IgG-positive cells and IgG4-positive cells. Multivariate analysis was performed using likelihood ratio-test logistic regression on the differences between IgG4-related disease (IgG4-RD) and non-IgG4-RD. RESULTS: Of the 45 patients included, 21 patients (46.7%) had IgG4-positive cells, with 52.4% being male and a mean age of 55.9 ± 13.4 years. Bilateral ocular adnexal involvement (adjusted odds ratio [aOR] = 9.45; P = 0.016) and infraorbital nerve enlargement (aOR = 12.11; P = 0.008) were frequently found in IgG4-RD patients. Complete remission occurred in 23.8% of IgG4-RD patients and 41.7% of non-IgG4-RD patients. IgG4-RD patients had more frequent recurrent disease than non-IgG4-RD patients. CONCLUSIONS: Nearly 50% of IgG4-RD patients were previously diagnosed with biopsy-proven IOI. IgG4-RD was more frequent in patients with bilateral disease and infraorbital nerve enlargement, showing the importance of tissue biopsy in these patients. Immunohistochemistry studies of all histopathology slides showing nongranulomatous IOI are highly recommended to evaluate for IgG4-RD.

Anti-cancer effect of engineered recombinant interleukin 18.

BACKGROUND: Interleukin 18 (IL-18) is an inflammatory cytokine belonging to the interleukin 1 (IL-1) superfamily, and is known for its role in anti-cancer activity by promoting type 1 immune response, and thus may be applied to cancer immunotherapy. Our previous report has showed 16 times higher activity of engineered E6K+T63A IL-18 than of native IL-18 in vitro. However, no data has been acquired for its anti-cancer effect in animal model. OBJECTIVES: To investigate the anti-cancer effect of engineered E6K+T63A IL-18 as an immune stimulant in vivo. MATERIAL AND METHODS: Tumor-bearing mice were treated with native IL-18 or E6K or E6K+T63A IL-18 once a day for 10 days after the tumor reached the volume of 100 mm3. Tumor volume and the number of certain immune cell type in the tumor microenvironment were investigated in this study. RESULTS: The results showed that tumor progression in mice treated with E6K+T63A was slower than in mice treated with E6K and native IL-18. The volume of the tumor was also smaller and the lifespan longer in the E6K+T63A IL-18-treated mice. The proportions of type 1 helper T cell (Th1) and cytotoxic T lymphocyte (CTL) were significantly higher in mice treated with E6K+T63A IL-18. CONCLUSIONS: These results suggest that our engineered IL-18 conferred strong anti-tumor immunity in the animal model.

Variants Associated with Infantile Cholestatic Syndromes Detected in Extrahepatic Biliary Atresia by Whole Exome Studies: A 20-Case Series from Thailand.

Biliary atresia (BA) is the most severe form of obstructive cholangiopathy occurring in infants. Definitive diagnosis of BA usually relies on operative findings together with supporting pathological patterns found in the extrahepatic bile duct. In infancy, overlapping clinical patterns of cholestasis can be found in other diseases including biliary hypoplasia and progressive familial intrahepatic cholestasis. In addition, BA has been reported as a phenotype in some rare genetic syndromes. Unlike BA, other cholangiopathic phenotypes have their own established genetic markers. In this study, we used these markers to look for other cholestasis entities in cases diagnosed with BA. DNA from 20 cases of BA, diagnosed by operative findings and histopathology, were subjected to a study of 19 genes associated with infantile cholestasis syndromes, using whole exome sequencing. Variant selection focused on those with allele frequencies in dbSNP150 of less than 0.01. All selected variants were verified by polymerase chain reaction-direct sequencing. Of the 20 cases studied, 13 rare variants were detected in 9 genes: 4 in JAG1 (Alagille syndrome), 2 in MYO5B (progressive familial intrahepatic cholestasis [PFIC] type 6), and one each in ABCC2 (Dubin-Johnson syndrome), ABCB11 (PFIC type 2), UG1A1 (Crigler-Najjar syndrome), MLL2 (Kabuki syndrome), RFX6 (Mitchell-Riley syndrome), ERCC4 (Fanconi anemia), and KCNH1 (Zimmermann-Laband syndrome). Genetic lesions associated with various cholestatic syndromes detected in cases diagnosed with BA raised the hypothesis that severe inflammatory cholangiopathy in BA may not be a distinct disease entity, but a shared pathology among several infantile cholestatic syndromes.

Non-Hodgkin lymphoma in South East Asia: An analysis of the histopathology, clinical features, and survival from Thailand.

Systemic reports on the descriptive epidemiology of non-Hodgkin lymphoma (NHL) from Southeast Asia are scarce. A nationwide multi-institutional registry was conducted to compare the histopathology, clinical features, and survival of Thai adult patients with NHL using large registries, especially those from Far East Asia (FEA). Using a web-based registry system, 13 major medical centers from the 4 geographic regions of Thailand prospectively collected, from 2007 to 2014, the diagnostic pathology, according to the World Health Organization classification, 2008, clinical features and survival of 4056 patients who were newly diagnosed with NHL. The median age of the patients was 56 years (range, 16-99 years). The male-to-female ratio was 1.3:1. From the total of 4056 patients, T/NK-cell lymphoma (TNKCL) accounted for 12.6% of cases, and 5.1% had human immunodeficiency virus-associated lymphoma. The four leading histological subtypes were diffuse large B-cell lymphoma, not otherwise specified (58.1%); follicular lymphoma (5.6%); extranodal mucosa-associated lymphoid tissue lymphoma (5.2%); and peripheral T-cell lymphoma, not otherwise specified (4.0%). With a median follow-up duration of 46.1 months, the median overall survival of B-cell NHL was significantly longer than that of patients with TNKCL (76.5 vs 28.8 months, P = .0001). Compared to FEA, the Thai registry had an approximately one-half lower relative frequency of TNKCL; the prevalence of extranodal mucosa-associated lymphoid tissue lymphoma was much lower than in Korea, and the frequency of extranodal TNKCL, nasal type, was strikingly low compared to China. It is concluded that while the median age of Thai patients with NHL was approximately a decade younger than for Caucasians, the long-term survival rates for most histological subtypes were comparable. While the histological distribution generally complied with the characteristic Asian features, some differences from FEA were observed.

An Uncommon Cause of Small Bowel Bleeding from Appendiceal Carcinoma.

Massive hematochezia caused by a small bowel lesion is a rare entity. Currently, video capsule endoscopy and balloon-assisted enteroscopy are effective in identifying the source of small intestine bleeding. Herein, we report a case of small bowel bleeding caused by a nonmucinous appendiceal adenocarcinoma with ileal invasion which was detected by video capsule endoscopy and single-balloon endoscopy. Despite the advanced disease stage with hepatic and peritoneal metastases, as of September 2016 the patient has had 8 years' disease-free survival after surgical resection and chemotherapy.

Erythema multiforme-like cutaneous lesions in monomorphic epitheliotropic intestinal T-cell lymphoma: a rare case report.

Monomorphic epitheliotropic intestinal T-cell lymphoma (MEITL), also known as Type II enteropathy-associated T-cell lymphoma (EATL), is an aggressive peripheral T-cell lymphoma. EATL generally presents in adults with gastrointestinal symptoms. Skin involvement is very rare, found only in approximately five percent of patients. The authors report a 67-year-old Asian male who presented with chronic diarrhea and developed erythema multiforme-like cutaneous lesions. A skin biopsy revealed extensive pagetoid spread of atypical lymphocytes in the epidermis. The results of an immunohistochemistry test led to a diagnosis of MEITL. This report points to the need for dermatologists and dermatopathologists to consider a possible diagnosis of MEITL when encountering similar cases.

Senescence Process in Primary Wilms' Tumor Cell Culture Induced by p53 Independent p21 Expression.

Wilms tumor (WT) is an embryonal tumor occurring in developing kidney tissue. WT cells showing invasive cancer characteristics, also retain renal stem cell behaviours. In-vitro culture of WT is hampered by limited replicative potential. This study aimed to establish a longterm culture of WT cells to enable the study of molecular events to attempt to explain its cellular senescence. METHODS: Primary cell cultures from fresh WT tumor specimen were established. Of 5 cultures tried, only 1 could be propagated for more than 7 passages. One culture, identified as PSU-SK-1, could be maintained > 35 passages and was then subjected to molecular characterization and evaluation for cancer characteristics. The cells consistently harbored concomitant mutations of CTNNB1 (Ser45Pro) and WT1 (Arg413Stop) thorough the cultivation. On Transwell invasion assays, the cells exhibited migration and invasion at 55% and 27% capability of the lung cancer cells, A549. On gelatin zymography, PSU-SK-1 showed high expression of the matrix metaloproteinase. The cells exhibited continuous proliferation with 24-hour doubling time until passages 28-30 when the growth slowed, showing increased cell size, retention of cells in G1/S proportion and positive ß-galactosidase staining. As with those evidence of senescence in advanced cell passages, expression of p21 and cyclin D1 increased when the expression of ß-catenin and its downstream protein, TCF, declined. There was also loss-of-expression of p53 in this cell line. In conclusion, cellular senescence was responsible for limited proliferation in the primary culture of WT, which was also associated with increased expression of p21 and was independent of p53 expression. Decreased activation of the Wnt signalling might explain the induction of p21 expression.

The Expressions of P53, Bcl-2, and P-Glycoprotein and Prognostic Impact in Patients with Peripheral T-Cell Lymphoma (PTCL).

OBJECTIVE: To define the expressions of p53, Bcl-2, and p-glycoprotein and prognostic impact in patients with peripheral T-cell lymphoma (PTCL). MATERIAL AND METHOD: Adult patients with newly diagnosed as PTCL were reviewedfrom 2001 to 2012. Clinical parameters and outcome data were extracted The specimens were stained for p53, Bcl-2, and p-glycoprotein. The results were analyzed for association with disease stage, International Prognostic Index (IPI), Prognostic Index for T-cell lymphoma (PIT), overall response rate (ORR), and overall survival (OS). RESULTS: Of eligible 159 patients (113 males, 46 females), median age was 53 years old The histological subtypes included peripheral T-cell lymphoma, not otherwise specified (PTCL, NOS) 35.8%, angioimmunoblastic T-cell lymphoma (AITL) 18.2%, extranodal NK/T-cell lymphoma (ENKL) 17.0%, subcutaneous panniculitis-like T-cell lymphoma (SPTCL) 12.6%, cutaneous T-cell lymphoma (CTCL) 11.3%, anaplastic large cell lymphoma (ALCL) 4.4%, and enteropathy-associated T-cell lymphoma (EATL) 0.6%. Tissue samples were obtainedfor analysis in 135 patients. P53, Bcl-2, and p-glycoprotein were positive in 87%, 49%, and 28%, respectively. Median OS was 25 months. The expressions of p53, Bcl-2, and p-glycoprotein were not significantly correlated with advanced stage, high prognostic scores, ORR, and OS. However Bcl-2 expression was statistically associated with histological subtypes. From Cox regression analyses, advanced stage, high prognostic scores, and histological subtypes were independent prognostic factors for OS. CONCLUSION: The biomarker expressions varied in different types of PTCL and did not show any correlation with prognostic factors, ORR, or OS.

Interobserver variation in classifying lymphomas among hematopathologists.

BACKGROUND: Lymphomas are common malignancies that have various subtypes with many overlapping histologic, immunophenotypic and genetic features. Therefore, discordance in classifying lymphoma among pathologists may be encountered. But this issue is not well characterized. We conducted the present study to demonstrate discordances among Thai hematopathologists as well as to highlight common arguing points for classifying lymphomas. METHODS: The 117 lymphoma cases were randomly retrieved and individually reviewed by 7 hematopathologists, members of the "Thai Hematopathologist Group," without knowing the original diagnoses. The consensus diagnoses were given from a discussion by all members. In each case, the diagnosis from each participant was compared with the consensus diagnosis and classified into 4 categories as follow: 1) concordance, 2) minor discordance, 3) major discordance and 4) serious discordance. RESULTS: There were approximately 11% discordances between original and consensus diagnoses. The average discordances among all pathologists according to minor, major and serious discordances were 10%, 3.5% and 0.3%, respectively. Diffuse large B-cell lymphoma had the least discordance (7%). Small biopsies had been found to increase discordances in some lymphoma subtypes. CONCLUSIONS: The present study reveals some degrees of interobserver variation in classifying of lymphoma by using the 2008 WHO classification among hematopathologists. Some types of lymphomas on small biopsies were found to have a significant higher discordance rate. This study also described some common diagnostic discordances regarded as potential pitfalls in classifying lymphomas. VIRTUAL SLIDES: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/13000_2014_162.

A rare case of primary muscular non-Hodgkin's lymphoma and a review of how imaging can assist in its diagnosis.

Primary malignant non-Hodgkin's lymphoma of the muscle is rare. Currently, imaging tools are necessary to enable its diagnosis. Herein, we report the case of a patient who presented with swelling and pain in the right thigh and pelvis. Computed tomography findings revealed isodense masses in the patient's right thigh and left iliacus muscle, leading to the initial diagnosis of either primary muscular lymphoma or soft tissue sarcoma. Further investigation with magnetic resonance imaging was done, and a biopsy was performed. The ensuing histological diagnosis was that of diffuse large B-cell lymphoma.

Clinical presentation, treatment, and prognosis of periocular and orbital amyloidosis in a university-based referral center.

OBJECTIVE: The purpose was to present the demographic data, clinical presentation, and treatment options, and to evaluate prognosis, for periocular and orbital amyloidosis in patients at the Songklanagarind Hospital, Thailand. METHOD: This was a retrospective study that reviewed the clinical records of six patients who were diagnosed with periocular and orbital amyloidosis between January 1, 2002 and December 31, 2011. RESULTS: The series included six patients (five female and one male). The mean age was 39.7 years (range 15-79 years). There were five cases of unilateral lesion and one case of bilateral lesion. The most common symptom was a mass lesion (83.3%), followed by irritation (66.7%), bloody tears (16.7%), epiphora (16.7%), eye pain (16.7%), and ptosis (16.7%). Five cases had periocular involvement and one case had orbital involvement. Five cases were investigated to rule out systemic amyloidosis, and no systemic involvement was found in these cases. The median duration of symptoms was 6 months, but the mean was 31 months. The main treatment option was surgical excision. The mean follow-up time was 41 months. There was disease progression in 20% of cases after definitive treatment. CONCLUSION: Periocular and orbital amyloidosis presented with a variety of symptoms, depending on the location of the disease. A mass lesion was the most common symptom. The intent of the treatment modalities was to spare function.

Extranodal NK/T-cell lymphoma, nasal type, includes cases of natural killer cell and αß, γδ, and αß/γδ T-cell origin: a comprehensive clinicopathologic and phenotypic study.

Extranodal NK/T-cell lymphoma (ENKTL), nasal type, may be of NK or T-cell origin; however, the proportion of T-ENKTLs and whether they are of αß or γδ type remains uncertain. To elucidate the cell of origin and detailed phenotype of ENKTL and assess any clinicopathologic associations, 67 cases of ENKTL from Thailand were investigated, together with 5 γδ enteropathy-associated T-cell lymphomas (EATLs) for comparison. In all, 70% of the ENKTL were T-cell receptor (TCR) ß,γ and, in cases tested, δ negative (presumptive NK origin); 5% were TCR γδ, 3% were TCR αß, 1% were TCR αß/γδ, and 21% were indeterminate. Out of 17 presumptive NK-ENKTLs tested, 3 had clonal TCR rearrangements. All cases were EBV and TIA-1; >85% were positive for CD3, CD2, granzyme B, pSTAT3, and Lsk/MATK; and all were CD16. Presumptive NK-ENKTLs had significantly more frequent CD56 (83% vs. 33%) and CXCL13 (59% vs. 0%) but less frequent PD-1 (0% vs. 40%) compared with T-ENKTLs. Of the NK-ENKTLs, 38% were Oct-2 compared with 0% of T-ENKTLs, and 54% were IRF4/MUM1 compared with 20% of T-ENKTLs. Only αß T-ENKTLs were CD5. Intestinal ENKTLs were EBV and had significantly more frequent CD30, pSTAT3, and IRF4/MUM1 expression but less frequent CD16 compared with γδ EATL. Significant adverse prognostic indicators included a primary non-upper aerodigestive tract site, high stage, bone marrow involvement, International Prognostic Index ≥2, lack of radiotherapy, Ki67 >40%, and CD25 expression. The upper aerodigestive tract ENKTLs of T-cell origin compared with those of presumptive NK origin showed a trend for better survival. Thus, at least 11% of evaluable ENKTLs are of T-cell origin. Although T-ENKTLs have phenotypic and some possible clinical differences, they share many similarities with ENKTLs that lack TCR expression and are distinct from intestinal γδ EATL.

Isolated orbital neurofibroma in NF-1 negative patients.

Isolated orbital neurofibroma unassociated with systemic neurofibromatosis is relatively rare and may be difficult to clinically differentiate from other orbital tumors. The authors report a case of isolated orbital neurofibroma without neurofibromatosis type 1.

No Prognostic Impact of p53 and P-Glycoprotein Expression in Patients with Diffuse Large B-Cell Lymphoma.

The aim of this study was to determine the clinical significances of p53 and p-glycoprotein (P-gp) expression on outcome predictors for patients with DLBC. We assessed the immunohistochemical expression of p53 and P-gp using formalin-fixed, paraffin-embedded specimens in 108 patients diagnosed with de novo DLBC. A high expression of p53 was found in 53.7% of the patients. No expression of P-gp was demonstrated in any of the specimens. There were no significant differences in the complete remission (CR) rate (P = 0.79), overall survival (OS) (P = 0.73), or disease-free survival (DFS) (P = 31) between the p53-positive and p53-negative groups. The final model from multivariate analysis that revealed poor performance status was significantly associated with CR (P < 0.001) and OS (P < 0.001). Moreover, the advanced stage was a significant predictor of DFS (P = 0.03). This study demonstrated no impact of the expression of p53 on either response or survival rates.

Cushing's syndrome in an infant secondary to malignant adrenocortical tumors with somatic mutation of beta-catenin.

A role of beta-catenin (CTNNB1) in the molecular pathogenesis of adrenocortical carcinoma (ACC) has been suspected in adult ACC and pediatric pigmented nodular adrenocortical disease, but it has never been reported in pediatric ACC. We present the case of a 4-month-old Thai infant who had Cushing's syndrome secondary to bilateral adrenal tumors with hepatic metastasis. The child was successfully treated with a bilateral adrenalectomy and wedge resection of the liver nodule. Histopathology revealed bilateral adrenocortical tumors with different histologic grades; the right tumor had a higher score, according to modified Weiss criteria. On molecular study, a deletion mutation of beta-catenin involving codons 44 to 45 was detected in the right adrenal tumor. The same mutation was found in peripheral blood before treatment; this mutation disappeared after tumor removal. The left tumor harbored wild-type beta-catenin. Immunohistochemistry showed nuclear accumulation of beta-catenin on the right adrenal tumor and the metastatic nodule. In summary, we present evidence that supports the role of the Wnt-signaling pathway in the carcinogenesis of pediatric adrenocortical carcinoma.