Inhibition of orthotopic castration-resistant prostate cancer growth and metastasis in mice by JC VLPs carrying a suicide gene driven by the PSA promoter.

Metastatic castration-resistant prostate cancer (mCRPC) is challenging to treat. Virus-like particles (VLPs), originating from JC polyomavirus (JCPyV) and carrying a suicide gene driven by the PSA promoter (PSAtk-VLPs), can inhibit tumor growth in animal models of human prostate cancer. However, the efficacy of suppression of orthotopic PCa growth and metastasis by PSAtk-VLPs remains undetermined. Here, we established an iRFP stable expression CRPC cell line suitable for deep-tissue observation using fluorescence molecular tomography (FMT). These cells were implanted into murine prostate tissue, and PSAtk-VLPs were systemically administered via the tail vein along with the prodrug ganciclovir (GCV), allowing for the real-time observation of orthotopic prostate tumor growth and CRPC tumor metastasis. Our findings demonstrated that systemic PSAtk-VLPs administration with GCV and subsequent FMT scanning facilitated real-time observation of the suppressed growth in mouse iRFP CRPC orthotopic tumors, which further revealed a notable metastasis rate reduction. Systemic PSAtk-VLPs and GCV administration effectively inhibited orthotopic prostate cancer growth and metastasis. These findings suggest the potential of JCPyV VLPs as a promising vector for mCRPC gene therapy. Conclusively, systemically administered JCPyV VLPs carrying a tissue-specific promoter, JCPyV VLPs can protect genes within the bloodstream to be specifically expressed in specific organs.

Peptidylarginine Deiminase Type 2 Predicts Tumor Progression and Poor Prognosis in Patients with Curatively Resected Biliary Tract Cancer.

(1) Background: PADI2 is a post-translational modification (PTM) enzyme that catalyzes citrullination, which then triggers autoimmune disease and cancer. This study aimed to evaluate the prognostic value of peptidylarginine deiminase 2 (PADI2) protein expression in biliary tract cancer (BTC) patients. (2) Methods: Using immunohistochemistry, the PADI2 protein expression in BTC tissues was analyzed. The correlations between PADI2 protein expression and clinicopathologic characteristics were analyzed using Chi-square tests. The Kaplan-Meier procedure was used for comparing survival distributions. We used Cox proportional hazards regression for univariate and multivariate analyses. From 2014 to 2020, 30 resected BTC patients were enrolled in this study. (3) Results: Patients with high PADI2 protein expression were associated with shorter progress-free survival (PFS; p = 0.041), disease-specific survival (DSS; p = 0.025), and overall survival (OS; p = 0.017) than patients with low PADI2 protein expression. (4) Conclusions: The results indicated that PADI2 protein expression was an independent poor prognostic factor for BTC patients regarding PFS, DSS, and OS.

Targeted Next-generation Sequencing Reveals a Wide Morphologic and Immunophenotypic Spectrum of Monomorphic Epitheliotropic Intestinal T-Cell Lymphoma.

Primary intestinal T-cell lymphoma (PITL) is highly aggressive and includes celiac disease-related enteropathy-associated T-cell lymphoma (EATL), monomorphic epitheliotropic intestinal T-cell lymphoma (MEITL), and primary intestinal peripheral T-cell lymphoma, not otherwise specified (ITCL-NOS). MEITL is the most common PITL in Asia, comprising of monomorphic medium-sized cells typically expressing CD8, CD56, and cytotoxic granules. Occasional cases with intermediate features between MEITL and ITCL-NOS are difficult to be classified and warrant further investigation. We collected 54 surgically resected PITLs from Taiwan, with 80% presenting with bowel perforation. The overall outcome was poor with a median survival of 7 months. Based on histopathology (monomorphic vs. pleomorphic) and immunophenotype, we classified these cases into 4 groups: MEITL with typical immunophenotype (n=34), MEITL with atypical immunophenotype (n=5), pleomorphic PITL with MEITL-like immunophenotype (n=6), and ITCL-NOS (n=9). There was no EATL in our cohort. Targeted next-generation sequencing of the first 3 groups showed highly prevalent loss-of-function mutations for SETD2 (85%, 80%, and 83%, respectively) and frequent activating mutations for STAT5B (64%, 60%, and 50%, respectively) and JAK3 (38%, 20%, and 50%, respectively). In contrast, ITCL-NOS cases had less frequent mutations of SETD2 (56%) and STAT5B (11%) and rare JAK3 mutations (11%). Our results suggest that there is a wider morphologic and immunophenotypic spectrum of MEITL as currently defined in the 2017 WHO classification. MEITL with atypical immunophenotype and PITL with MEITL-like immunophenotype shared clinicopathologic and molecular features similar to MEITL but distinct from ITCL-NOS, indicating that such cases may be considered as immunophenotypic or histopathologic variants of MEITL.

Molecular Characterization of Metanephric Adenoma, Epithelial Wilms Tumor, and Overlap Lesions: An Integrated Whole-exome and Transcriptome Sequencing Analysis.

Metanephric adenoma (MA) and Wilms tumor (WT) represent 2 prototypes of primary renal neoplasms closely resembling embryonal renal tubules. Tumors with overlapping features may occur, requiring differential diagnoses between the 2. Evidence of divergent oncogenic pathways has been reported, suggesting that MA is driven by BRAF mutation while most WT is of the BRAF wild-type. We collected 4 MA cases, 3 cases of monophasic epithelial WT, and 1 overlap metanephric tumor that contains both conventional MA and high-grade components similar to epithelial WT. Whole-exome sequencing and whole transcriptome sequencing were performed to discover mutations, somatic copy number variation, and differential expression. The findings were compared with those of WT of the TARGET database (WT-TARGET). BRAF V600E mutation was detected in all MAs as well as the overlap tumor but was undetectable in all epithelial WTs and WT-TARGET. The overlap tumor showed an additional pathogenic mutation of SETD2. Three frequent gene mutations observed in WT-TARGET were not common in epithelial WT, in which the mutations appeared sporadic. The profiles of recurrent copy number variations were all different among MA, epithelial WT, and WT-TARGET. Differential expression and unsupervised hierarchical cluster analyses revealed distinct clusters of the 3 categories. Remarkably, the overlap tumor coclustered with MA, separated from epithelial WT and WT-TARGET. The distinctiveness of MA and WT were demonstrated corresponding to BRAF-mutated and non-BRAF-mutated pathways from the molecular perspective. BRAF assay has diagnostic implication for overlap tumors.

Synchronous pulmonary adenocarcinoma and primary leptomeningeal large B-cell lymphoma-Diagnostic challenge in cerebrospinal fluid: A brief report.

Lung cancer is one of the most common causes of cancer-related deaths worldwide. During or after the treatment of lung cancer, patients might develop another malignant neoplasm. To our knowledge, synchronous pulmonary adenocarcinoma and leptomeningeal large B-cell lymphoma have not been reported in the literature. Herein, we report the first case of synchronous pulmonary adenocarcinoma and primary leptomeningeal lymphoma, which is challenging in cytological diagnosis using cerebrospinal fluid (CSF). Knowledge of this rare situation by cytopathologists might avoid misdiagnosis or erroneous tumor classification during the cytological diagnosis of CSF in the future.

Primary cutaneous gamma/delta T-cell lymphoma in Taiwan: A series of six cases with frequent solitary presentation and relatively indolent behavior.

BACKGROUND: Primary cutaneous gamma/delta T-cell lymphoma (PCDG-TCL) is aggressive, frequently presenting as multiple plaques, tumors, and/or subcutaneous nodules. METHODS: In this study, we conducted a retrospective study in a tertiary center in Taiwan to characterize this rare tumor. RESULTS: We identified six patients. Five presented with a solitary lesion, including two with clinical impression of epidermal inclusion cyst or lipoma. Two of four evaluable cases exhibited epidermotropism, with one mimicking Pautrier microabscess. The neoplastic cells were pleomorphic and mostly medium- to large-sized. In all cases, the neoplastic cells expressed T-cell receptor (TCR)-γ and/or TCR-δ, with four co-expressing ßF1. Two of these ßF1+ cases co-expressed TCR-γ but not TCR-δ (two different clones). All were negative for Epstein-Barr virus (EBV), low stage, and treated with radiotherapy alone or combined chemotherapy and radiotherapy. In two patients, lymphoma relapsed in 3 and 7 months, respectively, and one patient died of the disease in 7 months. Four other patients were free of disease for 6 to 126 months. CONCLUSION: PCGD-TCL cases in Taiwan are more commonly solitary, frequently with indolent courses. The two currently available TCR-δ clones alone might be insufficient to detect all tumors.

Scrotal Fibroepithelial Polyp With Acute and Chronic Inflammation Mimics Malignancy on 18F-FDG PET/CT Imaging.

Computed tomography (CT) of a 68-year-old man showed multiple small nodules in the bilateral lungs (maximum 14 mm in the left upper lobe). CT-guided biopsy of left upper lobe lesion showed no tumor or granuloma. Fluorodeoxyglucose (FDG) PET/CT showed multiple nodules with background-to-mild FDG-avid activity, and an incidental left scrotal skin lesion with intensely increased accumulation of F-FDG (SUVmax, 11.7), suspected malignant. After urologist consultation, local dermatological findings suggested a huge wart. Excision was done, and pathology concluded nodular papillary fibroepithelial polyp with acute and chronic inflammation.

Using Percutaneous Endoscopic Outside-In Technique to Treat Selected Patients with Refractory Discogenic Low Back Pain.

BACKGROUND: Controversy is not uncommon in the diagnosis of discogenic low back pain (DLBP) and in the identification of the location of the pain source for the symptomatic disc in patients with DLBP. Various techniques, from minimally invasive procedures to fusion surgery, are used to treat chronic DLBP, but the clinical outcomes are variable. Percutaneous endoscopic discectomy by transforaminal or interlaminar approach is considered to be an effective method to treat DLBP, but the evidence is limited; the lack of clear evidence may be associated with patient selection and surgical technique. OBJECTIVES: The purpose of this study is to evaluate the clinical results of percutaneous endoscopic treatment for annular tear in selected patients with DLBP by using the outside-in technique. STUDY DESIGN: A prospective study and retrospective observations were performed on 24 consecutive patients with a minimum 2 years of follow-up. This study was approved by the Institutional Review Board (IRB) of Buddhist Dalin Tzu-Chi General Hospital Foundation (IRB number: 10504004) and written informed consent was obtained from all patients. SETTING: This research took place within an interventional pain management and spine practice. METHODS: Twenty-four consecutive patients with single-level DLBP diagnosed by positive high-intensity zone on magnetic resonance imaging, positive provocative discography, and block test underwent a percutaneous endoscopic procedure from January 2014 to December 2015. The transforaminal approach or interlaminar approach was selected according to the location of the annular tear. The torn lesions were visualized directly and treated by puncture and debridement of the inflammatory tissues from the outer annulus fibrosus to the inner nucleus using the outside-in technique. The Visual Analog Scale (VAS) score and Oswestry Disability Index (ODI) score were evaluated before and after surgery. The clinical global outcomes were assessed on the basis of modified MacNab criteria. RESULTS: These patients included 13 men and 11 women with a mean age of 43.8 years (range, 32-55 yrs). There were 15 lesion levels at L4/L5 and 9 lesion levels at L5/S1. Among them, 15 levels were accessed by transforaminal approach and 9 levels by interlaminar approach. No serious complications were observed during the follow-up periods. All except 2 patients experienced significant symptomatic and functional improvements at the 2-year follow-up with a success rate of 91.7%. LIMITATIONS: Significant limitations include nonrandom format and small sample size. Future research may focus on controlled prospective studies with larger sample sizes and long-term follow-up to examine the validity of this protocol. CONCLUSIONS: The percutaneous endoscopic procedure provides a safe and effective treatment for selected patients with DLBP. The outside-in technique allows the surgeons to visualize and treat the torn or inflammatory lesions directly, and the success rate is high at 2 years follow-up. KEY WORDS: Transforaminal, interlaminar, outside-in technique, endoscopic discectomy, discogenic low back pain.

Spontaneous colonic rupture related to the segmental absence of muscularis propria in an adult.

Colonic perforation is a medical emergency that may be fatal if surgery cannot be performed in a timely manner. Colonic rupture in adults is caused by primary (idiopathic) and secondary factors. Although the segmental absence of muscularis propria (SAMP) is a recognized cause of secondary colonic rupture in neonates and infants, few cases have been reported in adults. Here, we present the case of a large colonic rupture caused by SAMP in a 60-year-old woman and a review of the literature. We suggest that SAMP should be included in the differential diagnosis of large perforation and/or periperforation membranous thinning of the colonic wall in adults.

Mutated genes and driver pathways involved in myelodysplastic syndromes­a transcriptome sequencing based approach.

Myelodysplastic syndromes are a heterogeneous group of clonal disorders of hematopoietic progenitors and have potentiality to progress into acute myelogenous leukemia. Development of effective treatments has been impeded by limited insight into pathogenic pathways. In this study, we applied RNA-seq technology to study the transcriptome on 20 MDS patients and 5 age-matched controls, and developed a pipeline for analyzing this data. After analysis, we identified 38 mutated genes contributing to MDS pathogenesis. 37 out of 38 genes have not been reported previously, suggesting our pipeline is critical for identifying novel mutated genes in MDS. The most recurrent mutation happened in gene IFRD1, which involved 30% of patient samples. Biological relationships among these mutated genes were mined using Ingenuity Pathway Analysis, and the results demonstrated that top two networks with highest scores were highly associated with cancer and hematological diseases, indicating that the mutated genes identified by our method were highly relevant to MDS. We then integrated the pathways in KEGG database and the identified mutated genes using our novel rule-based mutated driver pathway scoring approach for detecting mutated driver pathways. The results indicated two mutated driver pathways are important for the pathogenesis of MDS: pathway in cancer and in regulation of actin cytoskeleton. The latter, which likely contributes to the hallmark morphologic dysplasia observed in MDS, has not been reported, to the best of our knowledge. These results provide us new insights into the pathogenesis of MDS, which, in turn, may lead to novel therapeutics for this disease.

Myoepithelial carcinoma of the stomach: a diagnostic pitfall.

Myoepithelioma/myoepithelial carcinomas are not commonly found in soft tissues and are especially rare at visceral sites. This report describes a case of a rare low-grade myoepithelial carcinoma of the stomach. A 61-year-old female patient presented with postprandial abdominal discomfort. Endoscopy revealed a 1.1 cm submucosal lesion. Local excision was performed after malignancy was confirmed by biopsy. The resection margin is free of tumor and she received no adjuvant therapy. The tumor was characterized by multinodular growth with biphasic epithelioid and spindle components. Infiltrative margin and nuclear pleomorphism are seen. Tumor cells were positive for both epithelial and myoepithelial markers. Evidence of epithelial differentiation was confirmed by electron microscopy. No EWSR1 rearrangement was detected. The final diagnosis was low-grade myoepithelial gastric carcinoma. The patient is currently well, and no evidence of recurrence or metastasis was found after ten-month of follow-up. Myoepithelial carcinoma should be considered in the differential diagnosis of a biphasic gastric tumor.

Inhibition of human diffuse large B-cell lymphoma growth by JC polyomavirus-like particles delivering a suicide gene.

BACKGROUND: Diffuse large B-cell lymphoma (DLBCL) is one of the most common types of aggressive B-cell non-Hodgkin lymphoma. About one-third of patients are either refractory to the treatment or experience relapse afterwards, pointing to the necessity of developing other effective therapies for DLBCL. Human B-lymphocytes are susceptible to JC polyomavirus (JCPyV) infection, and JCPyV virus-like particles (VLPs) can effectively deliver exogenous genes to susceptible cells for expression, suggesting the feasibility of using JCPyV VLPs as gene therapy vectors for DLBCL. METHODS: The JCPyV VLPs packaged with a GFP reporter gene were used to infect human DLBCL cells for gene delivery assay. Furthermore, we packaged JCPyV VLPs with a suicide gene encoding thymidine kinase (TK) to inhibit the growth of DLBCL in vitro and in vivo. RESULTS: Here, we show that JCPyV VLPs effectively entered human germinal center B-cell-like (GCB-like) DLBCL and activated B-cell-like (ABC-like) DLBCL and expressed the packaged reporter gene in vitro. As measured by the MTT assay, treatment with tk-VLPs in combination with gancyclovir (GCV) reduced the viability of DLBCL cells by 60%. In the xenograft mouse model, injection of tk-VLPs through the tail vein in combination with GCV administration resulted in a potent 80% inhibition of DLBCL tumor nodule growth. CONCLUSIONS: Our results demonstrate the effectiveness of JCPyV VLPs as gene therapy vectors for human DLBCL and provide a potential new strategy for the treatment of DLBCL.

DNA methylome analysis identifies epigenetic silencing of FHIT as a determining factor for radiosensitivity in oral cancer: an outcome-predicting and treatment-implicating study.

Radioresistance is still an emerging problem for radiotherapy of oral cancer. Aberrant epigenetic alterations play an important role in cancer development, yet the role of such alterations in radioresistance of oral cancer is not fully explored. Using a methylation microarray, we identified promoter hypermethylation of FHIT (fragile histidine triad) in radioresistant OML1-R cells, established from hypo-fractionated irradiation of parental OML1 radiosensitive oral cancer cells. Further analysis confirmed that transcriptional repression of FHIT was due to promoter hypermethylation, H3K27me3 and overexpression of methyltransferase EZH2 in OML1-R cells. Epigenetic interventions or depletion of EZH2 restored FHIT expression. Ectopic expression of FHIT inhibited tumor growth in both in vitro and in vivo models, while also resensitizing radioresistant cancer cells to irradiation, by restoring Chk2 phosphorylation and G2/M arrest. Clinically, promoter hypermethylation of FHIT inversely correlated with its expression and independently predicted both locoregional control and overall survival in 40 match-paired oral cancer patient samples. Further in vivo therapeutic experiments confirmed that inhibition of DNA methylation significantly resensitized radioresistant oral cancer cell xenograft tumors. These results show that epigenetic silencing of FHIT contributes partially to radioresistance and predicts clinical outcomes in irradiated oral cancer. The radiosensitizing effect of epigenetic interventions warrants further clinical investigation.

Spectrum of Epstein-Barr virus-associated T-cell lymphoproliferative disorder in adolescents and young adults in Taiwan.

Epstein-Barr Virus (EBV) is a herpesvirus usually infecting B-cells but may occasionally infect T- or natural killer (NK)-cells. EBV-associated T- or NK-cell lymphoproliferations represent a continuous spectrum of diseases ranging from asymptomatic infection, infectious mononucleosis (IM), to clonal and malignant lymphoproliferations including systemic EBV-positive T/NK-cell lymphoproliferative disease (EBV-T/NK-LPD) of childhood and hydroa-vacciniforme-like lymphoma of the skin. The clonal diseases are more prevalent in East Asia and exhibit overlapping clinical and pathological features with chronic active EBV infection. Here we report our experience on 10 cases of EBV-associated T-cell lymphoproliferation from Taiwan including five males and five females with a median age of 18 years old (range, 15-28). The most common clinical symptoms were fever, neck mass and hepatosplenomegaly. Eight of these patients showed elevated lactate dehydrogenase level and half of the patients had cytopenia. All patients had either elevated EBV antibody titers or increased serum EBV DNA levels. Five cases were clinically IM-like with polyclonal (3 cases) or clonal (2 cases) T-cell lymphoproliferation. Two patients each had chronic active EBV infection (CAEBV) and hemophagocytic lymphohistiocytosis (HLH). One patient had both CAEBV and HLH. One of the HLH patients with marrow infiltration by intra-sinusoidal large atypical lymphocytes experienced a fulminant course. In a median follow-up time of 21.5 months, seven patients were free of disease, one was alive with disease, and two died of disease in 31 and 3 months, respectively, despite chemotherapy. We confirmed a wide clinicopathological range of EVB-associated T-cell lymphoproliferation in Taiwan. Furthermore, monomorphic LPD and the single case with fulminant course as defined by Ohshima et al (Pathol Int 2018) as categories A3 and B, respectively, died of disease despite chemotherapy. Our report, the largest series in the recent decade from Taiwan, adds to the understanding of these rare diseases with variable clinical and histopathological presentations.

Tumor rupture as an initial manifestation of malignant mesonephric mixed tumor: a case report and review of the literature.

Malignant mesonephric mixed tumor (MMMT), or mesonephric carcinosarcoma, is a rare tumor with malignant epithelial and mesenchymal components, and is found mostly in the uterine cervix. While diagnosed at the early stage in most cases, MMMT can have an aggressive course. The clinical significance of the presence of sarcomatous components remains unsettled. We report a case of MMMT of the uterine cervix in a patient who presented with tumor rupture, instead of the common presentation, vaginal bleeding. This unusual presentation has not been reported in the literature. It implies that MMMT may progress rapidly without any prodrome and pose a surgical emergency. Unlike most cervical adenocarcinomas, both mesonephric adenocarcinoma and MMMT are not related to human papilloma virus (HPV) infection. Because mesonephric neoplasms have a different etiology, their prevention, screening, and treatment should be further investigated. Thirteen cases of MMMT reported in the literature are also reviewed.

Donor-derived Cryptococcus infection in liver transplant: case report and literature review.

Cryptococcosis occurring within 30 days after transplant is unusual. We present a case of cryptococcosis diagnosed within 2 weeks of liver transplant and cryptococcal infection transmitted by liver transplant is considered as the cause. A 63-year-old woman with hepatitis C virus-related cirrhosis and hepatocellular carcinoma had an orthotopic liver transplant from a 45-year-old donor. The immediate postoperative course was smooth, although she was confused with a fever, tachycardia, respiratory failure of 1 week's duration after the orthotopic liver transplant. A liver biopsy was performed for hyperbilirubinemia 2 weeks after the orthotopic liver transplant that showed a Cryptococcus-like yeast. Her blood culture was reexamined, and it was confirmed as Cryptococcus neoformans that had been misinterpreted as candida initially. At the time of the re-examination, her sputum was clear. We checked her preoperative blood sample, retrospectively, for serum cryptococcal antigen with negative result. She was on liposomal amphotericin treatment for 1 month when her blood culture became negative. She was discharged home, with good liver function and a low antigen titer for cryptococcal infection. Cryptococcal disease usually develops at a mean of 5.6 months after transplant. However an early occurrence is rare. Apart from that, its variable clinical presentations make early detection difficult. It might be an early reactivation or a donor-derived infection. The latter usually occurs in unusual sites (eg, the transplanted organ as the sole site of involvement). Our case presented as cryptococcoma and liver involvement was diagnosed by an unintentional liver biopsy.

Synchronous adenocarcinoma and extranodal natural killer/T-cell lymphoma of the colon: a case report and literature review.

Extranodal natural killer/T-cell lymphoma (ENKTL) is a distinct subtype of non-Hodgkin's lymphoma and is rare in the colon. Synchronous adenocarcinoma and ENKTL of the colon has not been reported in the literature. In the present study, we report a 63-year-old male who suffered from intermittent bloody stools for 2 mo. He did not have fever, body weight loss or night sweat. Endoscopic and imaging studies revealed a 4.5-cm ulcerative mass in the ascending colon and a 3.0-cm polypoid, easy bleeding mass in the sigmoid colon, respectively. Thought to have double carcinoma of the colon, he received simultaneous right hemicolectomy and sigmoidectomy. The pathological diagnosis was a synchronous ENKTL (ascending colon) and adenocarcinoma (sigmoid colon). The literature on synchronous adenocarcinoma and malignant lymphoma of the colon was also reviewed.

Epigenetic deregulation of the anaplastic lymphoma kinase gene modulates mesenchymal characteristics of oral squamous cell carcinomas.

DNA hypermethylation of promoter CpG islands is associated with epigenetic silencing of tumor suppressor genes in oral squamous cell carcinomas (OSCCs). We used a methyl-CpG-binding domain protein capture method coupled with next-generation sequencing (MBDCap-seq) to survey global DNA methylation patterns in OSCCs with and without nodal metastasis and normal mucosa (total n = 58). Of 1462 differentially methylated CpG islands identified in OSCCs relative to normal controls, MBDCap-seq profiling uncovered 359 loci linked to lymph node metastasis. Interactive network analysis revealed a subset of these loci (n = 23), including the anaplastic lymphoma kinase (ALK) gene, are potential regulators and effectors of invasiveness and metastatic progression. Promoter methylation of ALK was preferentially observed in OSCCs without node metastasis, whereas relatively lower methylation levels were present in metastatic tumors, implicating an active state of ALK transcription in the latter group. The OSCC cell line, SCC4, displayed reduced ALK expression that corresponded to extensive promoter CpG island methylation. SCC4 treatment with demethylating agents induced ALK expression and increased invasion and migration characteristics. Inhibition of ALK activity in OSCC cells with high ALK expression (CAL27, HSC3 and SCC25), decreased cell growth and resulted in changes in invasive potential and mesenchymal marker expression that were cell-line dependent. Although ALK is susceptible to epigenetic silencing during oral tumorigenesis, overwriting this default state may be necessary for modulating invasive processes involved in nodal metastases. Given the complex response of OSCC cells to ALK inhibition, future studies are required to assess the feasibility of targeting ALK to treat invasive OSCCs.

CD4 and CD8 double-negative adult T-cell leukemia/lymphoma with monomorphic cells expressing CD99: a diagnostic challenge in a country non-endemic for human T-cell leukemia virus.

Adult T-cell leukemia/lymphoma (ATLL) is a peripheral T-cell neoplasm caused by human T-cell lymphotropic virus type I (HTLV-I). The neoplastic cells are highly pleomorphic and are usually CD4+ and CD8- phenotypically. We reported the case of a 46-year-old woman presenting with fever, abdominal distention, lymphadenopathy, leukocytosis and hypercalcemia. Nodal biopsy showed diffuse infiltration by monomorphic small to medium-sized atypical lymphocytes expressing CD3, CD25, CD30 and CD99, but not CD1a, CD4, CD8, CD34, terminal deoxynucleotidyl transferase or ALK. An initial diagnosis of T-lymphoblastic leukemia/lymphoma was made based on cytomorphology, CD4 and CD8 double negativity, and the expression of CD99. The diagnosis was later revised to ATLL based on the positive serology study for anti-HTLV I/II antibody and confirmation by the clonal integration of HTLV-I proviral DNA into the tumor tissues by Southern blotting analysis. The patient had a stage IVB disease and died of septic shock after 2 courses of chemotherapy 3 months after diagnosis. Immunohistochemical staining for CD99 in archival ATLL tissues showed a positive rate of 67% (4 of 6 tumors). Our case showed that ATLL with atypical morphology and immunophenotype in HTLV non-endemic areas might pose a diagnostic challenge and CD99 expression is frequent in ATLL.