First-line immunotherapy with anti-PD-1 antibody for extranodal NK/T-cell lymphoma: A retrospective study.

Anti-PD-1 antibody has shown certain effects in patients with newly diagnosed extranodal NK/T-cell lymphoma (ENKTL). Here, we evaluated the clinical efficacy and safety of first-line anti-PD-1 antibody for the treatment of patients with ENKTL and explored biomarkers for treatment response. The clinical data of 107 patients with newly diagnosed ENKTL were retrospectively analysed. Patients received either first-line anti-PD-1 antibody induction treatment or anti-PD-1 antibody combined with asparaginase-based chemotherapy (immunochemotherapy). We found that immunochemotherapy was an independent prognostic factor for longer PFS (p < 0.001). The overall response rate and complete remission rate of immunochemotherapy group was higher than immunotherapy induction group (86.11% vs. 62.86% and 72.22% vs. 52.29%, respectively, p = 0.013). We also observed pretreatment CD4/CD8 ratio >0.83 was significant associated with better response and longer PFS in ENKTL patients received first-line anti-PD1-antibody. Plasma copy number of EBV decreased more significantly in patients with CD4/CD8 ratio >0.83 after treatment. PD-L1 expression was associated with better response and PFS, while elevated plasma IL-6, IL-10 and IFN-γ were associated with poor prognosis. Anti-PD-1 antibody treatment showed promising results in newly diagnosed ENKTL patients. The assessment of pretreatment CD4/CD8 ratio in ENKTL seems feasible for identifying responders to anti-PD-1 antibody treatment.

Oxidative stress genes in patients with esophageal squamous cell carcinoma: construction of a novel prognostic signature and characterization of tumor microenvironment infiltration.

BACKGROUND: Oxidative stress plays an important role in the progression of various types of tumors. However, its role in esophageal squamous cell carcinoma (ESCC) has seldom been explored. This study aimed to discover prognostic markers associated with oxidative stress in ESCC to improve the prediction of prognosis and help in the selection of effective immunotherapy for patients. RESULTS: A consensus cluster was constructed using 14 prognostic differentially expressed oxidative stress-related genes (DEOSGs) that were remarkably related to the prognosis of patients with ESCC. The infiltration levels of neutrophils, plasma cells, and activated mast cells, along with immune score, stromal score, and estimated score, were higher in cluster 1 than in cluster 2. A prognostic signature based on 10 prognostic DEOSGs was devised that could evaluate the prognosis of patients with ESCC. Calculated risk score proved to be an independent clinical prognostic factor in the training, testing, and entire sets. P53 signaling pathway was highly enriched in the high-risk group. The calculated risk score was positively related to the infiltration levels of resting mast cells, memory B cells, and activated natural killer (NK) cells and negatively associated with the infiltration levels of M1 and M2 macrophages. The relationship between clinical characteristics and risk score has not been certified. The half-maximal inhibitory concentration (IC50) values for sorafenib and gefitinib were lower for patients in the low-risk group. CONCLUSION: Our prognostic signature based on 10 prognostic DEOSGs could predict the disease outcomes of patients with ESCC and had strong clinical value. Our study improves the understanding of oxidative stress in tumor immune microenvironment (TIME) and provides insights for developing improved and efficient immunotherapy strategies.

Thymic epithelial tumors: examining the GTF2I mutation and developing a novel prognostic signature with LncRNA pairs to predict tumor recurrence.

BACKGROUND: General transcription factor IIi (GTF2I) mutations are very common in thymic epithelial tumors (TETs) and are related to a more favorable prognosis in TET patients. However, limited research has been conducted on the role of GTF2I in the tumor immune microenvironment (TIME). Further, long non-coding RNAs (lncRNAs) have been associated with the survival of patients with TETs. Therefore, this study aimed to explore the relationship between GTF2I mutations and TIME and build a new potential signature for predicting tumor recurrence in the TETs. Research data was downloaded from The Cancer Genome Atlas database and the CIBERSORT algorithm was used to evaluate TIME differences between GTF2I mutant and wild-type TETs. Relevant differentially expressed lncRNAs based on differentially expressed immune-related genes were identified to establish lncRNA pairs. We constructed a signature using univariate and multivariate Cox regression analyses. RESULTS: GTF2I is the most commonly mutated gene in TETs, and is associated with an increased number of early-stage pathological types, as well as no history of myasthenia gravis or radiotherapy treatment. In the GTF2I wild-type group, immune score and immune cell infiltrations with M2 macrophages, activated mast cells, neutrophils, plasma, T helper follicular cells, and activated memory CD4 T cells were higher than the GTF2I mutant group. A risk model was built using five lncRNA pairs, and the 1-, 3-, and 5-year area under the curves were 0.782, 0.873, and 0.895, respectively. A higher risk score was related to more advanced histologic type. CONCLUSION: We can define the GTF2I mutant-type TET as an immune stable type and the GTF2I wild-type as an immune stressed type. A signature based on lncRNA pairs was also constructed to effectively predict tumor recurrence.

A pilot study of the use of dynamic analysis of cell-free DNA from aqueous humor and vitreous fluid for the diagnosis and treatment monitoring of vitreoretinal lymphomas.

The diagnosis of vitreoretinal lymphoma (VRL), a rare subtype of primary central nervous system lymphoma, is challenging. We aimed to investigate the mutational landscape of VRL by sequencing circulating tumor DNA (ctDNA) from aqueous humor (AH) and/or vitreous fluid (VF), as well as applying ctDNA sequencing to diagnosis and treatment monitoring. Baseline AH and/or VF specimens from 15 VRL patients underwent comprehensive genomic profiling using targeted next-generation sequencing. The molecular profiles of paired baseline AH and VF specimens were highly concordant, with comparable allele frequencies. However, the genetic alterations detected in cerebrospinal fluid ctDNA only partially overlapped with those from simultaneously collected AH/VF samples, with much lower allele frequencies. Serial post-treatment AH or VF samples were available for five patients and their changes in ctDNA allele frequency displayed a similar trend as the changes in interleukin-10 levels; an indicator of response to treatment. A cohort of 23 patients with primary central nervous system lymphoma was included as a comparison group for the genetic landscape and evaluations of the efficacy of ibrutinib. More MYD88 mutations, but fewer IRF4 mutations and CDKN2A/B copy number losses were observed in the baseline samples of primary central nervous system lymphoma than VRL patients. The objective response rate to ibrutinib treatment was much higher for patients with primary central nervous system lymphoma (64.7%, 11/17) than for those with VRL (14.3%, 1/7). In summary, we provide valuable clinical evidence that AH is a good source of tumor genomic information and can substitute VF. Moreover, molecular profiling of AH has clinical utility for the diagnosis of VRL and treatment monitoring.

A genomic-augmented multivariate prognostic model for the survival of natural-killer/T-cell lymphoma patients from an international cohort.

With lowering costs of sequencing and genetic profiling techniques, genetic drivers can now be detected readily in tumors but current prognostic models for Natural-killer/T cell lymphoma (NKTCL) have yet to fully leverage on them for prognosticating patients. Here, we used next-generation sequencing to sequence 260 NKTCL tumors, and trained a genomic prognostic model (GPM) with the genomic mutations and survival data from this retrospective cohort of patients using LASSO Cox regression. The GPM is defined by the mutational status of 13 prognostic genes and is weakly correlated with the risk-features in International Prognostic Index (IPI), Prognostic Index for Natural-Killer cell lymphoma (PINK), and PINK-Epstein-Barr virus (PINK-E). Cox-proportional hazard multivariate regression also showed that the new GPM is independent and significant for both progression-free survival (PFS, HR: 3.73, 95% CI 2.07-6.73; p < .001) and overall survival (OS, HR: 5.23, 95% CI 2.57-10.65; p = .001) with known risk-features of these indices. When we assign an additional risk-score to samples, which are mutant for the GPM, the Harrell's C-indices of GPM-augmented IPI, PINK, and PINK-E improved significantly (p < .001, χ2 test) for both PFS and OS. Thus, we report on how genomic mutational information could steer toward better prognostication of NKTCL patients.

Prevalence of NRAS Mutation, PD-L1 Expression and Amplification, and Overall Survival Analysis in 36 Primary Vaginal Melanomas.

BACKGROUND: Primary vaginal melanomas are uncommon and aggressive tumors with poor prognosis, and the development of new targeted therapies is essential. This study aimed to identify the molecular markers occurring in these patients and potentially improve treatment strategies. MATERIALS AND METHODS: The clinicopathological characteristics of 36 patients with primary vaginal melanomas were reviewed. Oncogenic mutations in BRAF, KIT, NRAS, GNAQ and GNA11 and the promoter region of telomerase reverse transcriptase (TERT) were investigated using the Sanger sequencing. The expression and copy number of programmed death-ligand 1 (PD-L1) were also assessed. RESULTS: Mutations in NRAS, KIT, and TERT promoter were identified in 13.9% (5/36), 2.9% (1/34), and 5.6% (2/36) of the primary vaginal melanomas, respectively. PD-L1 expression and amplification were observed in 27.8% (10/36) and 5.6% (2/36) of cases, respectively. PD-L1 positive expression and/or amplification was associated with older patients (p = .008). Patients who had NRAS mutations had a poorer overall survival compared with those with a wild-type NRAS (33.5 vs. 14.0 months; hazard ratio [HR], 3.09; 95% CI, 1.08-8.83). Strikingly, two patients with/without PD-L1 expression receiving immune checkpoint inhibitors had a satisfying outcome. Multivariate analysis demonstrated that >10 mitoses per mm2 (HR, 2.96; 95% CI, 1.03-8.51) was an independent prognostic factor. CONCLUSIONS: NRAS mutations and PD-L1 expression were most prevalent in our cohort of primary vaginal melanomas and can be potentially considered as therapeutic targets. IMPLICATIONS FOR PRACTICE: This study used the Sanger sequencing, immunohistochemistry, and fluorescence in situ hybridization methods to detect common genetic mutations and PD-L1 expression and copy number in 36 primary vaginal melanomas. NRAS mutations and PD-L1 expression were the most prevalent, but KIT and TERT mutations occurred at a lower occurrence in this rare malignancy. Two patients receiving immune checkpoint inhibitors had a satisfying outcome, signifying that the PD-L1 expression and amplification can be a possible predictive marker of clinical response. This study highlights the possible prospects of biomarkers that can be used for patient selection in clinical trials involving treatments with novel targeted therapies based on these molecular aberrations.

High incidence of MYC rearrangement in human immunodeficiency virus-positive plasmablastic lymphoma.

AIMS: MYC rearrangements are the main cytogenetic alterations in plasmablastic lymphoma (PBL). We aimed to investigate the relationship between MYC rearrangement and the clinicopathological features of PBL. METHODS AND RESULTS: MYC rearrangements assessed in 13 unpublished single-centre PBL cases, and an additional 85 cases from the literature, with reported MYC rearrangement information individualised by patient, were reviewed. In Asia, PBL was much less commonly diagnosed in human immunodeficiency virus (HIV)-positive patients (27% versus 84%, P = 0.000), with older age (median age at diagnosis: 52 years versus 44 years, P = 0.046) and a lower EBV infection rate (56.8% versus 81.8%, P = 0.049), than in non-Asian regions. Overall, MYC rearrangements were identified in 44 of 98 (44.9%) PBL cases, and IGH was the partner in almost all available cases (30/31, 96.8%), as confirmed with a MYC-IGH fusion probe. The MYC rearrangement rate in HIV-positive cases (33/55, 60.0%) was significantly higher than that in HIV-negative cases (11/38, 28.9%, P = 0.003). Patients with MYC rearrangement showed a trend towards an inferior median survival time (9.6 months versus 15.7 months, P = 0.122) and 2-year overall survival (17% versus 32%, P = 0.238). CONCLUSIONS: MYC rearrangement was frequently identified in PBL patients, and IGH was the partner gene in an overwhelming majority of MYC rearrangements. In addition, the MYC rearrangement rate was significantly higher in HIV-positive PBL patients than that in HIV-negative patients. MYC rearrangement may play an important role in the pathogenesis of HIV-positive PBL, but further studies are required to understand the underlying mechanisms.

High expression of RABL6 promotes cell proliferation and predicts poor prognosis in esophageal squamous cell carcinoma.

BACKGROUND: Esophageal squamous cell carcinoma (ESCC) is a common malignant carcinoma of digestive system with high mortality. RAB, member RAS oncogene family like 6 (RABL6), a member of the RAS subfamily, has been reported as an important molecule in several cancers. However, its potential role in ESCC still remains unclear. METHODS: RABL6 mRNA expression was detected in 93 frozen ESCC samples using quantitative reverse transcription-polymerase chain reaction (qRT-PCR). Immunohistochemistry was applied to evaluate the RABL6 expression in tissue microarray containing 171 pairs of ESCC tissues and paired para-cancerous tissues. We evaluated RABL6 expression and its correlation with clinicopathological characteristics and survival. Subsequently, the impact of RABL6 knockdown on the ability of cell proliferation, apoptosis, migration and epithelial-mesenchymal transition (EMT) of ESCC cells was investigated by MTS, Focus formation, flow cytometry, Transwell assays, qRT-PCR, western blot, inverted microscope observation and phalloidin staining, respectively. RESULTS: Compared to paired para-cancerous tissues, RABL6 was highly expressed in ESCC. The RABL6 high-expression was associated with worse prognosis. We also revealed silencing of RABL6 caused inhibition of cell proliferation, invasion and migration. Further experiments demonstrated that knockdown of RABL6 suppressed the aggressive biological activities of ESCC by suppressing EMT in ESCC cells. CONCLUSIONS: RABL6 functions as a tumor oncogene in ESCC. It would be a potential biomarker predicting prognosis, and a novelty target for ESCC therapy.

The role of DNMT1/hsa-miR-124-3p/BCAT1 pathway in regulating growth and invasion of esophageal squamous cell carcinoma.

BACKGROUND: Esophageal squamous cell carcinoma (ESCC) is the major subtype of esophageal cancer with high aggressiveness and poor prognosis. There is an urgent need for understanding the molecular mechanism underlying the development and progression of ESCC. METHODS: ESCC tissues and corresponding non-neoplastic tissues were collected. The expression and function of miR-124-3p and BCAT1 in two cell lines KYSE-150 and Eca109 were determined. RESULTS: We show downregulation of miR-124-3p expression in ESCC tissues, which is highly correlated with proliferation and migration of ESCC cell lines KYSE-150 and Eca109. miR-124-3p show high correlation with TNM stage and differentiation grade. Furthermore, miR-124-3p directly targets mRNA 3'UTR region of BCAT1, which results in upregulation of BCAT1 expression as observed in ESCC tissues and cell lines. Also, our data indicates that BCAT1 high expression is strongly linked to the disease-free survival, tumor size, pathologic stage, T classification and differentiation grade. On the other hand, we clarified the upstream mechanism regulating miR-124-3p expression in ESCC, which involves in the hypermethylation-silencing regulation mediated by DNA methyltransferase 1(DNMT1), which is of high expression in ESCC tissues and cell lines in the present study. In addition, DNMT1 knockdown or inhibition of DNMT1 function contributes to downregulation of miR-124-3p and BCAT1 expression. CONCLUSIONS: Our study thus clarifies a new mechanism that DNMT1/miR-124/BCAT1 axis regulates the development and progression of ESCC.

Recurrence Risk Based on Pathologic Stage After Neoadjuvant Chemoradiotherapy in Esophageal Squamous Cell Carcinoma: Implications for Risk-Based Postoperative Surveillance Strategies.

BACKGROUND: This study aimed to investigate the association between pathologic stage and recurrence risk and survival for patients with esophageal squamous cell carcinoma (SCC) after neoadjuvant chemoradiotherapy (CRT). METHODS: This retrospective analysis consisted of two patient cohorts who had esophageal SCC treated with neoadjuvant CRT and esophagectomy at two major academic institutions between 2002 and 2015. The study included 174 patients in the training cohort and 51 patients in the validation cohort. Recurrence pattern, frequency, and survival according to pathologic stage were analyzed. RESULTS: After surgery, patients in the training cohort had the following pathologic categories: stage 0 (44.8%, n = 78), stage 1 (6.9%, n = 12), stage 2 (35.6%, n = 62), and stage 3 (12.6%, n = 22). During a median follow-up period of 53.9 months, recurrences developed in 59 patients. The recurrence rates were 22.2% for stages 0 and 1, 38.7% for stage 2, and 68.2% for stage 3 (stages 0 and 1 vs. stage 2 [P = 0.028], stages 0 and 1 vs. stage 3 [P < 0.001], and stage 2 vs. stage 3 [P = 0.017]). More than 20% of patients with stages 0 and 1 or 2 disease experienced late relapses after 3 years of follow-up evaluation, whereas all the patients with pathologic stage 3 had recurrences within 2 years. The 5-year recurrence-free survival rate was 74.7% for the patients with pathologic stage 0 or 1, 61.4% for those with stage 2, and 20.9% for those with stage 3 disease (P < 0.001). These major findings were successfully reproduced in the Western validation cohort. CONCLUSIONS: Patients with a higher pathologic stage were associated with a significantly higher risk of recurrences and worse survival. Multicenter and prospective validation is warranted.

Failure pattern of elective nodal irradiation for esophageal squamous cell cancer treated with neoadjuvant chemoradiotherapy.

OBJECTIVE: To analyze the failure pattern and clinical efficacy of elective nodal irradiation in patients with esophageal squamous cell carcinoma who received neoadjuvant chemoradiotherapy. METHODS: We retrospectively analyzed 173 esophageal squamous cell carcinoma patients who received neoadjuvant chemoradiotherapy including elective nodal irradiation from 2002 to 2015. Failure pattern, survival and recurrence sites were analyzed. For patients with regional recurrences, the recurrence sites were analyzed in relation to an imaginary field of involved field irradiation. RESULTS: After a median follow-up of 55.5 months, 58 patients (33.5%) developed recurrences. Among 22 patients with regional recurrences, infield failure occurred in 19 patients (86.4%) and outfield failure occurred in 3 patients (13.6%), of whom only 1 patient had an outfield failure without synchronous distant metastasis. Compared with the involved field irradiation field, 6 patients' failure sites (27.3%) were located in the involved field irradiation field and 13 patients' failure sites (59.1%) were out of the involved field irradiation field but within the elective nodal irradiation field. CONCLUSIONS: Since only a minority of patients had outfield regional recurrences, neoadjuvant chemoradiotherapy with elective nodal irradiation yields satisfactory infield control. More than half of the regional recurrences occurred within the elective nodal irradiation field but out of the involved field irradiation field. Prospective evaluation of whether elective nodal irradiation could lead to an improved survival outcome is necessary.

Effect of Prophylactic Thoracic Duct Ligation in Reducing the Incidence of Postoperative Chylothorax during Esophagectomy: A Systematic Review and Meta-analysis.

OBJECTIVES: There is no consensus on the effectiveness of prophylactic thoracic duct ligation (PLG) in esophagectomy for reducing the incidence of postoperative chylothorax. We performed a systemic review and meta-analysis to study its efficacy. METHODS: A systemic review of the publications was performed on three databases to identify all the relevant literature on comparative outcomes of PLG and nonprophylactic thoracic duct ligation (NPLG). The primary end point was the incidence of postoperative chylothorax. RESULTS: Seven studies with comparative data on PLG (n = 2,178) versus NPLG (n = 3,048) were identify from the current publications. Comparison showed no significant difference between PLG and NPLG on the incidence of postoperative chylothorax (relative risk = 0.431; 95% confidence interval, 0.186 to 1.002; p = 0.050). CONCLUSIONS: Although some studies showed that PLG during the esophagectomy was effective to lower the incidence of postoperative chylothorax, no evidence was observed in the present meta-analysis. Further research is warranted to validate the findings.

Serum EBV EA-IgA and VCA-IgA antibodies can be used for risk group stratification and prognostic prediction in extranodal NK/T cell lymphoma: 24-year experience at a single institution.

Although extranodal NK/T cell lymphoma (ENKTCL) is consistently associated with Epstein-Barr virus (EBV) infection, the manifestation and prognostic value of serum EBV antibodies still remain unknown. One hundred and forty-one patients with ENKTCL were evaluated for serum EBV EA-IgA and VCA-IgA antibodies levels in the past 24 years in our institution. Their correlation with clinicopathological features, plasma EBV DNA load, and patients' outcomes was analyzed. EBV EA-IgA ≥1:10 and VCA-IgA ≥1:160 were found in 18.4 and 16.3% of patients, respectively. They correlated with adverse ENKTCL profile and inferior overall survival (OS) and progression-free survival (PFS). EA-IgA ≥1:10 was an independent prognostic factor on OS (RR = 2.276, p = 0.008) and associated with lower complete response (CR) rate (34.8 vs 70.6%, p = 0.001) and higher relapse rate in CR patients (62.5 vs 34.7%, p = 0.016). In subgroup analysis, both EA-IgA ≥1:10 and VCA-IgA ≥1:160 significantly correlated with inferior OS and PFS in patients with stage I/II, IPI score 0-1, plasma EBV DNA (+), and CR. Patients with plasma EBV DNA (+) and EA-IgA ≥1:10 (or VCA-IgA ≥1:160) had significantly shorter periods of OS and PFS in comparison with other corresponding groups. Elevated serum EBV EA-IgA and VCA-IgA levels were related to adverse ENKTCL profile and correlated with poor treatment response, early relapse, and poor prognosis in patients with ENKTCL. These findings provide convincing evidence for the use of serum EBV EA-IgA and VCA-IgA antibodies for risk group stratification and prognostic prediction in ENKTCL.

Osteopontin is a useful predictor of bone metastasis and survival in patients with locally advanced nasopharyngeal carcinoma.

Bone is the most common metastatic site in nasopharyngeal carcinoma (NPC). Osteopontin (OPN) and bone sialoprotein (BSP) are demonstrated to be involved in multiple steps of distant metastasis and correlate with bone metastasis (BM) in cancers. We aim to explore the impacts of OPN and BSP on the prognosis of the patients with locally advanced NPC. A tissue microarray including 162 locally advanced NPC specimens was generated for immunohistochemical evaluation. All of the patients received curative treatment. Twenty-two patients developed BM during follow-up. The OPN expression level was higher in patients with BM than in those without BM (p = 0.005), whereas no significant difference of the BSP expression level was noted (p = 0.634). Univariate analysis demonstrated that a higher level of OPN expression associated with a poorer 8-year metastasis-free survival (MFS) rate (p < 0.001), 8-year bone metastasis-free survival (BMFS) rate (93.6 vs. 87.5 vs. 64.5% for immunoreactivity score 1, 2 and 3, respectively; p = 0.001) and median overall survival (OS) time (p < 0.001). Multivariate Cox analysis confirmed that high level of OPN expression was independent factor associated with decreased BMFS (p = 0.02), MFS (p < 0.001) and OS (p < 0.001). Our findings indicate that OPN is a prognostic biomarker for BM and survival in patients with locally advanced NPC, and therefore it is useful in identifying the patients with an increased risk of cancer progression and BM to guide tailored therapy.

[Analysis of mature T-cell and NK-cell lymphoma with CD30 expression based on latest WHO classification].

OBJECTIVE: To investigate the frequency of different types of mature T- and NK-cell lymphomas diagnosed in a 4-year period at Sun Yat-sen University Cancer Center, and to study baseline CD30 for potential anti-CD30 targeted therapy in mature T- and NK-cell lymphoma. METHODS: All cases of mature T- and NK-cell lymphoma diagnosed at Sun Yat-sen University Cancer Center from September 1, 2009 to August 31, 2013, were reviewed. Paraffin-blocks of available 164 consecutive cases were stained for CD30 immunohistochemistry using EnVision protocol. RESULTS: A total of 625 cases of mature T- and NK-cell lymphomas were diagnosed and the most common type was extranodal NK/T cell lymphoma (ENKTL), nasal type 319 (51.0%) cases, followed by angioimmunoblastic T-cell lymphoma (AITL) (119 cases, 19.0%), peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS) (81 cases, 13.0%), and anaplastic large-cell lymphoma (ALCL), including 48 cases (7.7%) of systematic ALCL and 11 cases (1.8%) of primary cutaneous ALCL. Besides ALCL, ENKTL had the highest expression rate of CD30 among the 164 cases, with positivity observed in 41 cases (62.1%, 41/66). Only 1 case of PTCL-NOS was CD30 positive. CD30 was not expressed in all 28 cases of AITL and other rare types of mature T- and NK-cell lymphoma. CONCLUSIONS: The frequency of different types of mature T- and NK-cell lymphoma encountered at Sun Yat-sen University Cancer Center was similar to that seen in other areas of China and other Asia countries. CD30 expression is different among several types of mature T- and NK-cell lymphoma. In addition to ALCL, ENKTL has the highest expression rate of CD30, which may be a candidate disease for anti-CD30 targeted therapy.

Extranodal NK/T-Cell Lymphoma Predominantly Composed of Anaplastic Cells: A Frequently Misdiagnosed and Highly Aggressive Variant.

Extranodal NK/T-cell lymphoma (ENKTL) is a non-Hodgkin lymphoma associated with the Epstein-Barr virus that primarily affects individuals in East Asia and indigenous populations in Central and South America. Morphologically, ENKTL typically consists of medium-sized cells or a combination of small and large cells. This report presents 10 cases characterized by predominantly anaplastic cells with diffuse expression of CD30, resembling anaplastic lymphoma kinase-negative anaplastic large cell lymphoma (ALK-negative ALCL) and demonstrating highly aggressive behavior. The cohort included 9 males and 1 female, ranging in age from 29 to 65 years (median age: 47 y). Eight patients presented with nasal disease, while 2 had non-nasal disease. Five patients had stage I/II disease, and the remaining 5 had stage III/IV disease. Morphologically, necrosis was observed in 9 cases, angiocentric-angiodestructive growth in 3 cases, and pseudoepitheliomatous hyperplasia in 2 cases. Anaplastic cells predominated in all cases, with some displaying eccentric, horseshoe-shaped, or kidney-shaped nuclei (referred to as "Hallmark" cells). The morphology profile was monomorphic in 3 cases and polymorphic in 7 cases. Immunohistochemically, all cases tested positive for cytotoxic granule markers (TIA1 and granzymeB) and Epstein-Barr virus-encoded RNA. Cytoplasmic expression of CD3ε and CD56 was observed in 9 of 10 cases. Interestingly, most cases (7 of 8) exhibited variable expression of MuM1, ranging from 10% to 90%. All cases showed diffuse positivity for CD30 but were negative for ALK, resulting in 3 cases being initially misdiagnosed as ALK-negative ALCL. Compared with nonanaplastic cases, anaplastic cells predominant ENKTL had a significantly higher frequency of "B" symptoms, bone marrow involvement, hemophagocytic lymphohistiocytosis, and higher Ki67 proliferative index. These findings provide valuable information for pathologists, expanding their understanding of the cytologic spectrum of ENKTL. This rare variant of ENKTL, characterized by the predominance of anaplastic cells and diffuse CD30 expression, exhibits high aggressiveness and should be differentiated from ALK-negative ALCL. Awareness of this uncommon variant is crucial in preventing misdiagnosis and ensuring the timely initiation of therapy.

Signet-ring cell carcinoma of the breast: a case report.

Signet-ring cell carcinoma (SRCC) can arise from virtually all organs. However, primary SRCC of the breast is very rare. Until 2003, SRCC was placed under 'mucin-producing carcinomas' and separated from other carcinomas by the World Health Organization (WHO). To date, only a few cases have been reported. A case of a 46-year-old woman with primary SRCC of the breast is presented in this report. The patient underwent a right modified radical mastectomy with axillary lymph node dissection. Characteristic features and differential diagnosis of this tumor are discussed in the light of pertinent literature.

Clinical characteristics, prognostic factors, and treatment modalities for head and neck lymphoepithelioma-like carcinoma: A real-world study from southern China.

BACKGROUND: We aimed to elucidate the clinical characteristics, prognostic factors and optimal treatment modalities of head and neck lymphoepithelioma-like carcinoma (HNLELC). METHODS: Consecutive patients newly-diagnosed with non-metastatic HNLELC between December 2001 and March 2021 treated with curative intent were retrospectively reviewed. RESULTS: A total of 288 patients were included, of whom 87 (30.2%) underwent radical surgery alone, 43 (14.9%) underwent definitive radiotherapy with or without concurrent chemotherapy, and 158 (54.9%) underwent surgery followed by postoperative radiotherapy (SRT). Epstein-Barr virus-encoded small RNA (EBER) was positive in 94.8% (239/252) of patients. Cervical node infiltration was seen in 52.8% (152/288) of patients. No significant difference was found in nodal metastasis rate between T1-2 and T3-4 classifications (49.5% vs. 56.5%, p = 0.308). The 3-year overall survival (OS), disease-free survival, locoregional relapse-free survival, and distant metastasis-free survival rates were 89.4%, 78.7%, 89.2%, and 87.7%, respectively. Compared to SRT, surgery alone associated with significant reduced 3-year local (92.8% vs. 96.5%, p = 0.012) and regional relapse-free survival rates (89.3% vs. 96.8%, p = 0.002). Definitive radiotherapy and SRT demonstrated comparable results in all 3-year survival outcomes (all p＞0.05). Multivariate analysis found EBER status was an independent favorable prognostic factor for OS (HR = 0.356, 95% CI: 0.144-0.882, p = 0.026). CONCLUSION: HNLELC was observed to associate with EBV infection and cervical nodal infiltration. Definitive radiotherapy achieved similar survival outcomes compared to SRT, and may serve as a good substitute for patients unfit or unwilling to undergo surgery.

Macrophage migration inhibitory factor may contribute to the occurrence of multiple primary lung adenocarcinomas.

BACKGROUND: This study aimed to identify the key genes involved in the development of multiple primary lung cancers. METHODS: Differential expression analysis was performed, followed by comparing the infiltration levels of 22 immune cell types between multiple and single primary lung adenocarcinomas. Marker genes for epithelial cells with different proportions between the two types of lung adenocarcinomas were identified. The common genes between the marker genes and differentially expressed genes were identified. Finally, the effects of the key genes were tested on the in vitro proliferation, migration and morphology. RESULTS: The infiltration levels of helper follicular T cells, resting NK cells, activated NK cells, M2 macrophages and resting mast cells were higher in the patients with multiple than in those with single primary lung adenocarcinomas. A total of 1553 differentially expressed genes and 4414 marker genes of epithelial cells were identified. Logistic regression analysis was performed on the 164 resulting genes. The macrophage migration inhibitory factor expression was positively associated with the occurrence of multiple primary lung adenocarcinomas. Moreover, its signalling pathway was the key pathway among the epithelial cells and multiple and single primary lung adenocarcinoma cells, and it was upregulated in lung adenocarcinoma cells. It also increased the expression of lung cancer markers, including NES and CA125, induced morphological changes in alveolar epithelial type II cells, and promoted their proliferation, migration and invasion. CONCLUSIONS: Multiple and single primary lung adenocarcinomas have different tumour immune microenvironments, and migration inhibitory factor may be a key factor in the occurrence of multiple primary lung adenocarcinomas.

Hypothyroidism reduces the risk of lung cancer through oxidative stress response and the PI3K/Akt signaling pathway: An RNA-seq and Mendelian randomization study.

Hypothyroidism has been suggested to play a role in tumor progression. However, the causal association between hypothyroidism and lung cancer remains unknow. To elucidate the potential association between hypothyroidism and lung cancer risk, we employ a Mendelian randomization (MR) approach. MR was performed to analyze pooled data from the International Lung Cancer Consortium (11,348 cases and 15,861 controls; European ancestry) to determine the causal relationship between hypothyroidism and lung cancer. We used 36, 83, and 14 single nucleotide polymorphisms as instrumental variables for hypothyroidism/myxoedema, hypothyroidism, and exercise, respectively. We further investigated the mechanisms involved in transcriptome analysis using data from The Cancer Genome Atlas and Genotype-Tissue Expression database. We conducted an initial validation of intermediary factor using a two-step MR analysis. Genetically predicted hypothyroidism was significantly related to the risk of overall lung cancer, specifically the risk of lung squamous cell cancer (LSCC) but not with the risk of lung adenocarcinoma (LUAD) as assessed using the inverse-variance weighted (IVM) method. A similar causal association was found between hypothyroidism/myxoedema and the risk of lung cancer, LSCC, and LUAD. Transcriptome analysis showed that genes associated with hypothyroidism, lung cancer, and LSCC were enriched in the PI3K/Akt signaling pathway and oxidative stress response. However, genes related to hypothyroidism and LUAD did not exhibit enrichment in these pathways. Hypothyroidism was significantly associated with strenuous sports or other exercises. Moreover, genetically predicted exercise was significantly related to the risk of overall lung cancer, and LSCC, but not LUAD. We detected no horizontal pleiotropy using the MR-PRESSO and MR Egger regression intercept. Hypothyroidism was causally associated with a lower risk of lung cancer, and these effects might be mediated by the oxidative stress response and the PI3K/Akt signaling pathway. Therefore, our study suggests that the potential factors and viable etiologies of hypothyroidism that contributed to lung cancer risk deserve further investigation.