PseudoCell: Hard Negative Mining as Pseudo Labeling for Deep Learning-Based Centroblast Cell Detection.

Background: Deep learning models for patch classification in whole-slide images (WSIs) have shown promise in assisting follicular lymphoma grading. However, these models often require pathologists to identify centroblasts and manually provide refined labels for model optimization. Objective: To address this limitation, we propose PseudoCell, an object detection framework for automated centroblast detection in WSI, eliminating the need for extensive pathologist's refined labels. Methods: PseudoCell leverages a combination of pathologist-provided centroblast labels and pseudo-negative labels generated from undersampled false-positive predictions based on cell morphology features. This approach reduces the reliance on time-consuming manual annotations. Results: Our framework significantly reduces the workload for pathologists by accurately identifying and narrowing down areas of interest containing centroblasts. Depending on the confidence threshold, PseudoCell can eliminate 58.18-99.35% of irrelevant tissue areas on WSI, streamlining the diagnostic process. Conclusion: This study presents PseudoCell as a practical and efficient prescreening method for centroblast detection, eliminating the need for refined labels from pathologists. The discussion section provides detailed guidance for implementing PseudoCell in clinical practice.

Adding MYC/BCL2 double expression to NCCN-IPI may not improve prognostic value to an acceptable level.

BACKGROUND: MYC/BCL2 double expression (DE) is associated with poor prognosis in patients with diffuse large B-cell lymphoma (DLBCL) receiving rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone (R-CHOP). This study aimed to determine whether the addition of DE to the National Comprehensive Cancer Network Internal Prognostic Index (NCCN-IPI) could improve the prediction of disease progression in patients with DLBCL treated with R-CHOP. METHODS: This confirmatory prognostic factor study retrospectively recruited patients with newly diagnosed DLBCL between January 1, 2014, and January 31, 2018, at Ramathibodi Hospital (RA) and Thammasat University Hospital (TU). The follow-up period ended on July 1, 2022. Tumors expressing MYC ≥ 40% and BCL2 ≥ 50% were classified as DE. We calculated the hazard ratios (HR) for progression-free survival (PFS) from the date of diagnosis to refractory disease, relapse, or death. Discrimination of the 5-year prediction was based on Cox models using Harrell's concordance index (c-index). RESULTS: A total of 111 patients had DE (39%), NCCN-IPI (8%), and disease progression (46%). The NCCN-IPI adjusted HR of DE was 1.6 (95% confidence interval [CI]: 0.9-2.8; P = 0.117). The baseline NCCN-IPI c-index was 0.63. Adding DE to the NCCN-IPI slightly increased Harrell's concordance index (c-index) to 0.66 (P = 0.119). CONCLUSIONS: Adding DE to the NCCN-IPI may not improve the prognostic value to an acceptable level in resource-limited settings. Multiple independent confirmatory studies from a large cohort of lymphoma registries have provided additional evidence for the clinical utility of DE.

Detection of centroblast cells in H&E stained whole slide image based on object detection.

Introduction: Detection and counting of Centroblast cells (CB) in hematoxylin & eosin (H&E) stained whole slide image (WSI) is an important workflow in grading Lymphoma. Each high power field (HPF) patch of a WSI is inspected for the number of CB cells and compared with the World Health Organization (WHO) guideline that organizes lymphoma into 3 grades. Spotting and counting CBs is time-consuming and labor intensive. Moreover, there is often disagreement between different readers, and even a single reader may not be able to perform consistently due to many factors. Method: We propose an artificial intelligence system that can scan patches from a WSI and detect CBs automatically. The AI system works on the principle of object detection, where the CB is the single class of object of interest. We trained the AI model on 1,669 example instances of CBs that originate from WSI of 5 different patients. The data was split 80%/20% for training and validation respectively. Result: The best performance was from YOLOv5x6 model that used the preprocessed CB dataset achieved precision of 0.808, recall of 0.776, mAP at 0.5 IoU of 0.800 and overall mAP of 0.647. Discussion: The results show that centroblast cells can be detected in WSI with relatively high precision and recall.

Unusual manifestation of gastric adenocarcinoma presenting with lymphedema, chylothorax, and chylous ascites.

A 62-year-old Thai man with a 2-year history of bilateral lymphedema and an unprovoked left axillary vein thrombosis presented with progressive leg, scrotal, and abdominal swelling, and shortness of breath. He denied any gastrointestinal symptoms. His lymphedema had initially been diagnosed as chronic filariasis due to positive blood tests for anti-filarial antibodies; however, treatment with anti-filarial drugs failed to improve his symptoms. Subsequently, he underwent surgical lymphaticovenular anastomosis with scrotal reduction, which proved to be of limited symptomatic relief. Later investigations revealed bilateral chylothorax and chylous ascites, with the presence of metastatic adenocarcinoma. Histopathological examination of the patient's skin and scrotum biopsy from his previous surgery revealed invasion of the lymphatics by neoplastic cells with signet ring cell formation. Gastroscopy uncovered a gastric mass, and biopsy confirmed the diagnosis of stage IV gastric adenocarcinoma with signet ring cell. He later received palliative chemotherapy. For the management of chyle leakage, he was prescribed a very low-fat diet and supplemented with parenteral nutrition. Despite treatment, he developed cutaneous metastasis and was transitioned to best supportive care. The patient passed away 14 months after diagnosis.

Cutaneous Methotrexate-Related Epstein-Barr Virus-Positive Diffuse Large B-Cell Lymphoma in a Patient with Granulomatous Cutaneous T-Cell Lymphoma: A Case Report and Literature Review.

Methotrexate-related lymphoproliferative disorders (MTX-LPDs) are immunodeficiency diseases following methotrexate (MTX) administration, mainly occurring in rheumatoid arthritis patients. Although uncommon, MTX-LPDs have been reported in some patients with psoriasis, dermatomyositis, and cutaneous T-cell lymphoma (CTCL) who received MTX. Granulomatous mycosis fungoides (GMF) is a rare subtype of cutaneous T-cell lymphoma, where MTX is one of the treatment options in recalcitrant cases. Herein, we report a case of a 72-year-old female patient with GMF who additionally developed cutaneous Epstein-Barr virus (EBV)-positive diffuse large B-cell lymphoma (DLBCL) during MTX treatment. According to the 5th edition of the WHO classification of Haematolymphoid Tumors (WHO-HAEM), this condition is currently categorized as "lymphoma arising in immunodeficiency/dysregulation". In this article, we also reviewed published literature on cutaneous MTX-LPDs in the setting of CTCL. This entity should be considered in cases of new, atypical skin nodules and/or plaques in CTCL patients receiving long-term MTX treatment.

External validation and comparison of IPI, R-IPI, and NCCN-IPI in diffuse large B-cell lymphoma patients treated with R-CHOP to predict 2-year progression-free survival.

BACKGROUND: Diffuse large B-cell lymphoma (DLBCL) is the most common aggressive lymphoma. The standard first-line therapy for DLBCL consists of rituximab cyclophosphamide doxorubicin vincristine and prednisone (R-CHOP). About 50-70% of patients may be cured by R-CHOP. There was no data on external validation and comparison of the international prognostic index, revised-IPI (R-IPI), and enhanced-IPI (NCCN-IPI) to predict treatment outcomes in the middle-income country with a resourced-limited setting. OBJECTIVES: We aimed to externally validate and compare IPI, R-IPI, and NCCN-IPI in predicting 2-year progression-free survival (2-y PFS) of newly diagnosed DLBCL patients treated with R-CHOP. METHODS: This ambispective observational study recruited consecutive patients diagnosed between 1 January 2014 and 30 June 2020, with the last follow-up on 1 July 2022 from Thammasat University Hospital and Ramathibodi Hospital. We assessed discrimination by Harrell's concordance index (c-index), calibration by calibration plot, and absolute difference in survival (ADS) between the lowest-and the highest-risk groups. RESULTS: The cohort of 292 patients (median age 63 years and median follow-up 3.6 years) had 131 progressions and 96 deaths. The 2-y PFS was 63%. The c-indices were NCCN-IPI 0.6216, R-IPI 0.6004 (P = 0.215), and IPI 0.6104 (P = 0.463). The calibration plots of NCCN-IPI and R-IPI showed nearly perfect agreement (moderate strength), while IPI had miscalibrations. The ADSs were NCCN-IPI 52%, R-IPI 42%, and IPI 25%. CONCLUSION: NCCN-IPI is the best prognostic index compared to IPI and R-IPI in prior studies. However, the prognostic model for DLBCL patients treated with R-CHOP requires updating or integrating biomarkers to improve discrimination to the acceptable level (c-index 0.7).

Treatment Outcomes and Clinical Relevance in Patients with Double Expressor DLBCL.

BACKGROUND: Double-expressor lymphoma (DEL) was found to account for 20-30% of DLBCL. We conducted this study to analyze the survival, the clinical presentation, and the factors associated with treatment outcomes in DEL-DLBCL. METHODS: A retrospective study of 291 patients diagnosed with DLBCL during January 2015 - December 2018 was conducted. RESULTS: Of the 291 patients, the median age was 63 years, germinal center B cell-like DLBCL (GCB) and non-GCB subtypes were found in 32% and 68%, respectively. DEL was found in 46% of 264 patients with available immunohistochemistry staining for MYC protein. Patients with DEL was significantly more common in elderly patients (p= 0.017) and non-GCB subtype (p= 0.006). High serum lactate dehydrogenase (LDH) levels and high Ki-67 index were significantly found in DEL patients than non-DEL patients (p= 0.024 and p= 0.04, respectively). The 3y-OS rate was shorter in the DEL group than in the non-DEL group, 58.7% versus 78.9% (p=0.026), whereas no significant difference in 3y-DFS was identified between these groups (58.4% versus 67.7%, p= 0.343). Independent factors affecting OS and DFS in DEL patients were ECOG 3-4, high LDH levels, extranodal involvement> 1 site, high IPI, and stage III-IV in univariate analysis. CONCLUSIONS: High incidence of DEL was observed in this study, especially in patients aged 60 years or older and non-GCB subtype. Patients with DEL showed dismal DFS and OS.

Prognostic Value of Concurrent Expression of C-MYC and BCL2 in Intravascular Large B-Cell Lymphoma: A 10-Year Retrospective Study.

BACKGROUND: Intravascular large B-cell lymphoma (IVLBCL) is a variant of extranodal diffuse large B-cell lymphoma (DLBCL), characterized by the presence of a B-lymphoma cell in the lumina of small blood vessels or capillaries. Due to its extremely variable clinical manifestations, IVLBCL typically results in a delayed diagnosis and poor disease prognosis. Skin biopsy, particularly random skin biopsy, has shown a potential role in the diagnosis of IVLBCL. However, information of clinicopathological features in patients with IVLBCL diagnosed by skin biopsy is limited. OBJECTIVES: To study the clinicopathological features in relation to immunohistochemical features and to identify prognostic factors in IVLBCL patients diagnosed by skin biopsy. MATERIALS AND METHODS: Clinical characteristics; laboratory, histological, and immunohistochemical findings; and therapeutic response of all biopsy-confirmed IVLBCL patients during the years 2008-2017 were retrospectively reviewed. RESULTS: The mean age was 67.4 (±9.8) years. Fever was the most common presenting symptom, accounting for 64.7%. Cutaneous and bone marrow involvement was found in 23.5% and 35.3% of patients, respectively. Patients receiving R-CHOP showed more favorable therapeutic outcome. C-MYC/BCL2 double expressors showed significantly higher incidence rate to mortality compared with nondouble expressors (p = 0.042). One-year and two-year overall survival rates were 67.2% and 53.8%, respectively. CONCLUSIONS: Skin biopsy is an effective diagnostic method for IVLBCL. Concurrent expression of C-MYC and BCL2 may be a useful prognostic indicator and should be performed in order to predict the prognosis in IVLBCL patients.

Treatment outcome and prognostic factors in PCNSL.

OBJECTIVES: Standard treatment with a thiotepa-based regimen in countries with a limited resource is less feasible. Aims of the study were to evaluate the treatment outcome, and identify the prognostic factors in patients with primary central nervous system lymphoma (PCNSL). METHODS: We conducted a retrospective study of 43 patients diagnosed with PCNSL, DLBCL subtype, who were treated with either HDMTX-based regimen, whole brain radiotherapy (WBRT), or both between 2010 and 2017. RESULTS: There were 43 patients with a median age of 65 years (range 34-89 years). Protein expression of CD10, Bcl6, MUM1, Bcl2 and MYC were found in 19, 86, 91, 91 and 23%, respectively. Both germinal center B cell (GCB) and double-expressor (MYC+/Bcl2+) lymphomas were found in 21%. Multiple brain lesions and maximum tumor diameter (MTD) ≥5 cm were seen in 27 and 10 patients, respectively. Chemotherapy combined with WBRT, chemotherapy and WBRT were given to 20, 14 and 9 patients, respectively. Overall complete remission (CR) rate was 55.8%. Those receiving a combined-modality therapy had a higher CR rate than those treated with either chemotherapy (75% versus 36%, p = 0.036) or WBRT (75% versus 44%, p = 0.109). Median follow-up time was 17 months, and a 7-year overall survival (OS) was 40%. Features associated with a prolonged OS were an ECOG score ≤ 2 (p = 0.001), multiple brain lesions (p = 0.010), multiple area of brain involvement (p = 0.023), MTD < 5 cm (p = 0.004), GCB subtype (p = 0.003) and positive CD10 staining (p = 0.007). Expression of Bcl2 protein was associated with a significantly worse OS in the non-GCB DLBCL patients. DISCUSSION: The factors affecting treatment outcomes in PCNSL were cell of origin of DLBCL, lesion characteristics, patients' status and treatment regimen.

Clinicopathologic, immunophenotypic, and molecular analysis of subcutaneous panniculitis-like T-cell lymphoma: A retrospective study in a tertiary care center.

BACKGROUND: Subcutaneous panniculitis-like T-cell lymphoma (SPTL) as strictly defined by World Health Organization-European Organization for Research and Treatment of Cancer classification is a rare cytotoxic α/ß T-cell lymphoma, characterized by primary involvement of subcutaneous tissue mimicking panniculitis. OBJECTIVES: To describe the clinicopathologic, immunophenotypic, and molecular features of SPTL. METHODS: A 10-year retrospective study of 18 patients diagnosed with SPTL was thoroughly reviewed according to clinicopathology, immunophenotype, and T-cell receptor (TCR) gene rearrangement. RESULTS: Of the 18 patients, 16 patients were definitely diagnosed with SPTL. The median age was 26 years (ranged 14-53 years) with female predominance. Most patients presented with prolonged fever and subcutaneous nodules and/or plaques, usually located on lower extremities. 37.5% of patients had hemophagocytic syndrome. The main histopathology was lobular panniculitis with rimming of atypical lymphocytes highlighted by CD3+, CD8+, Beta-F1+, granzyme B+, and Ki-67 (50%-90%). Monoclonal TCR gene rearrangement was found in 50% of patients and upper extremities involvement indicated a poor prognosis. CONCLUSION: The correlation between clinicopathologic and immunophenotypic study is the most helpful method to give a precise diagnosis of SPTL. Rimming of CD8+ atypical lymphocytes highlighted by high Ki-67 index is highly specific for the diagnosis of SPTL.

The Frequency of SF3B1 Mutations in Thai Patients with Myelodysplastic Syndrome

Genetic mutations in genes encoding critical component of RNA splicing machinery including SF3B1 are frequently identified and recognized as the pathogenesis in the development of myelodysplatic syndrome (MDS). In this study, PCR sequencings specific for SF3B1 exon 13, 14, 15, and 16 were performed to analyse genomic DNA isolated from bone marrow samples of 72 newly diagnosed MDS patients. We found that 10 of 72 (14%) patients harbor SF3B1 missense mutations including E622D (1/72), R625C/G (2/72), H662Q (1/72), K666T (1/72), K700E (4/72) and G740E (1/72), respectively. Mutations were predominantly located on exon 14 and 15 of SF3B1 coding sequence. Interestingly, patients with SF3B1 mutations exhibited higher platelet counts (195×109/L VS. 140×109/L, p-value = 0.025) as well as lower hemoglobin levels (81 g/L VS. 92 g/L, p-value = 0.009) and associated with ring sideroblast phenotype (p-value < 0.001) when compared with patients without the SF3B1 mutation. In summary, we reported the frequency of SF3B1 mutations in Thai patients with different subtypes of MDS. SF3B1 mutations were predominantly occurred in MDS-RS and considered as favourable prognosis value. This study further highlighted the clinical important of SF3B1 mutations analysis for the classification of MDS.

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.

Synchronous gallbladder and pancreatic cancer associated with pancreaticobiliary maljunction.

We report the case of a 46-year-old woman who presented with chronic intermittent abdominal pain without jaundice; abdominal ultrasonography showed thickening of the gallbladder wall and dilatation of the bile duct. Endoscopic retrograde cholangiopancreaticography showed pancreatobiliary maljunction with proximal common bile duct dilatation. Pancreatobiliary maljunction was diagnosed. A computed tomography scan of the abdomen showed suspected gallbladder cancer and distal common bile duct obstruction. A pancreatic head mass was incidentally found intraoperative. Radical cholecystectomy with pancreatoduodenectomy was performed. The pathological report showed gallbladder cancer that was synchronous with pancreatic head cancer. In the pancreatobiliary maljunction with pancreatobiliary reflux condition, double primary cancer of the pancreatobiliary system should be awared.

Fungal appendicitis: a case series and review of the literature.

Appendicitis is a condition characterized by inflammation of the vermiform appendix, which is commonly caused by bacterial infections and rarely caused by fungal organisms. In the present study, we reviewed the prevalence, clinicopathological features, and therapeutic management of fungal appendicitis. During July 2010 to June 2011, the pathology of 262 resected vermiform appendices was reviewed. Fungal appendicitis occurred in 1.15%, including two cases of Candida spp and one case of Aspergillus spp infection. All patients were immunocompromised and presented with the classical signs and symptoms of appendicitis with the onset of illness less than two days. They were considered for acute appendicitis and underwent appendectomy. The histopathology of the resected vermiform appendix showed fungal organisms with suppurative inflammation and secondary periappendiceal peritonitis. The curative treatment was presented in 1-out-of-3 cases. One patient was alive during a follow-up of eight months. Two patients died, and an autopsy was performed in one case. Although fungal appendicitis was uncommon, the disease might occur among immunosuppressed patients who have developed classical signs and symptoms of appendicitis. Early diagnosis and prompt surgery with medical treatment are associated with a survival advantage.

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.

Adrenal histoplasmosis: a case series and review of the literature.

Adrenal histoplasmosis is an uncommon mycotic disease typically caused by Histoplasma capsulatum. The objective was to determine the clinicopathological findings in adrenal histoplasmosis. Pathological records were searched from the database at the Department of Pathology, Faculty of Medicine Ramathibodi Hospital, Mahidol University from 1993 to 2008 for cases of adrenal histoplasmosis. The keywords were "histoplasmosis" and "adrenal gland". Adrenal histoplasmosis was diagnosed by histopathology and Gomori-Grocott methenamine silver staining. Histoplasma capsulatum was confirmed by tissue culture and/or serology. The authors report seven cases of adrenal histoplasmosis in immunocompetent patients. The mean age at diagnosis was 67 years. All patients presented as chronic fatigue syndrome. The onset of symptoms ranged from one to three months. Addison's disease was found in adrenal histoplasmosis in one case (14.3%). The computed tomography revealed adrenal nodules measuring 1.2 to 7.8 cm in diameter. The histopathology showed granulomatous inflammation with caseous necrosis. Culture of adrenal tissue from two patients revealed Histoplasma capsulatum. Serum Histoplasma antibodies were positive in four cases. A cure was accomplished in 6 out of 7 cases (85.7%). The patients were followed up for 2.5 to 16.5 years.

Case report combined hepatocellular and cholangiocarcinoma with sarcomatous transformation.

Combined hepatocellular and cholangiocarcinoma with sarcomatous transformation was first recognized in Ramathibodi Hospital in 2005. This variant of carcinoma has been increasingly reported particularly from Asian countries. Dedifferentiation of the epithelial component to various sarcomatous components is likely the underlying mechanism. The causative factors of hepatocarcinogenesis in Thailand include chronic viral hepatitis B or C, exposures to aflatoxin B1 and nitrosamine(s) and occasionally some certain nodular hepatocellular lesions due to arterial hyperperfusion. It is suggested that the recent change of the Thai peoples' life style to an increased consumption of fast foods containing food preservatives especially nitrate or nitrite, the nitrosamine precursor may allow heavy exposure(s) to the chemical carcinogen(s) i.e. nitrosamine(s) leading to sarcomatous transformation of the carcinoma.