Showing papers on "Large cell published in 2020"
TL;DR: The molecular characteristics of the main lung cancer subtypes are discussed and the current guidelines and novel targeted therapies, including checkpoint immunotherapy are discussed.
195 citations
TL;DR: This series characterizes SMARCA4-deficient sinonasal carcinoma as a genetically distinct aggressive entity in the spectrum of undifferentiated sinonal carcinomas, at the same time expanding the topographic distribution of SMAR CA4-related malignancies.
Abstract: The molecular pathogenesis of poorly differentiated sinonasal carcinoma received significant attention in recent years. As a consequence, several unclassified carcinomas in the morphologic spectrum of sinonasal undifferentiated carcinoma have been reclassified as distinctive genetically defined variants or entities. Among the latter are NUT-rearranged carcinoma and SMARCB1-deficient carcinomas. In this study, we further characterize a rare variant of sinonasal undifferentiated carcinoma-like tumors characterized by inactivation of the SWItch/Sucrose Nonfermentable chromatin remodeler SMARCA4 (BRG1) detectable by immunohistochemistry. Patients were 7 males and 3 females aged 20 to 67 years (median, 44). Tumors originated in the nasal cavity (6), nose and sinuses (2), or at unspecified site (2). Six tumors were initially misdiagnosed as small cell neuroendocrine carcinoma (SCNEC) or large cell neuroendocrine carcinoma (LCNEC). Histologically, the tumors were composed of small basaloid (3 cases) or large epithelioid (7) cells disposed into nests and solid sheets with extensive areas of necrosis. No glands or other differentiating features were noted. Abortive rosettes were seen in 1 case. Immunohistochemistry showed consistent expression of pankeratin and absence of CK5, p63, p16, and NUT in all tumors tested. Other tested markers were variably positive: CK7 (2/6), synaptophysin (9/10; mostly focal and weak), chromogranin-A (4/10; focal), and CD56 (3/5; focal). All tumors showed total loss of SMARCA4 and retained expression of SMARCB1/INI1. Co-loss of SMARCA2 was seen in 1 of 8 cases. Limited data were available on treatment and follow-up. Two patients received surgery (1 also radiotherapy) and 3 received chemotherapy. Metastases (cervical nodes, liver, bone, and lung/mediastinal) were detected in 3 patients; 2 were alive under palliative chemotherapy at 8 and 9 months while 1 died of progressive lung disease at 7 months. Three patients (1 with brain invasion) died soon after diagnosis (1 to 3 mo). In total, 4 of 6 patients (66%) with follow-up died of disease (median, 3 mo). This series characterizes SMARCA4-deficient sinonasal carcinoma as a genetically distinct aggressive entity in the spectrum of undifferentiated sinonasal carcinomas. These variants add to the spectrum of SWItch/Sucrose Nonfermentable-deficient sinonasal carcinomas, at the same time expanding the topographic distribution of SMARCA4-related malignancies.
77 citations
TL;DR: Diagnostic procedures used in the evaluation of patients with suspected BIA-ALCL focused on the processing of the seroma fluid/effusion surrounding the implant, the handling of capsulectomy specimens following removal of implant(s), and the preoperative evaluation of the patient with suspected biliary large cell lymphoma.
Abstract: PURPOSETo provide guidelines for the accurate pathologic diagnosis of breast implant–associated anaplastic large cell lymphoma (BIA-ALCL), the preoperative evaluation of the patient with suspected ...
47 citations
TL;DR: Understanding the immune biology of lymphoid neoplasms has helped to identify the specific lymphoma types that are vulnerable to PD-1 inhibitors, such as CHL, and specific subtypes of DLBCL.
Abstract: Programmed cell death protein-1 (PD-1) is currently the most extensively studied inhibitory checkpoint molecule. Many malignant neoplasms express the PD-1 ligands, PD-L1, and/or PD-L2, which bind to PD-1 on T cells and induce T cell “exhaustion.” By doing so, the malignant cells escape from an antitumor immune response (immune evasion). Blockade of the PD-1/PD-L1 pathway releases T cells from the inhibitory effects exerted by tumor cells and restores a T cell-mediated antitumor immune response. Here, we focus on understanding the immune biology of the PD-1/PD-L1 pathway in large-cell lymphomas, including classic Hodgkin lymphoma (CHL), diffuse large B cell lymphoma (DLBCL), and anaplastic large-cell lymphoma (ALCL), and the current status of PD-1 blockade immunotherapy in treating patients with these lymphomas. PD-1/PD-L1 pathway and PD-1 inhibitors have been widely tested in patients with a variety of lymphomas. Nivolumab and pembrolizumab have been approved by the U.S. Food and Drug Administration for treating patients with some types of relapsed or refractory (R/R) lymphomas. The highest response rate has been achieved in patients with CHL, due to a high frequency of genetic alterations of 9p24.1 and high expression of PD-1 ligands. The frequency of alterations of chromosome 9p24.1 and expression of PD-L1/PD-L1 in DLBCL (except some specific subtypes) is low; therefore, it is not recommended to treat unselected DLBCL patients with PD-1 inhibitors. Studies have shown a high frequency of PD-L1 expression in ALCL, especially in anaplastic lymphoma kinase (ALK)+ type. Several cases reports have described a dramatic and durable response to PD-1 blockade in patients with R/R ALCL, suggesting that patients with R/R ALCL may be potential candidates for PD-1 blockade immunotherapy. Understanding the immune biology of lymphoid neoplasms has helped us identify the specific lymphoma types that are vulnerable to PD-1 inhibitors, such as CHL, and specific subtypes of DLBCL. However, our knowledge of many other lymphomas, including ALCL, in this area is still very limited and the future of PD-1 inhibitors in treating those lymphomas remains unclear.
44 citations
TL;DR: It is revealed that INSM1 is highly sensitive and specific to detect SCLC and can estimate prognosis and will be a promising marker for SclC.
Abstract: To diagnose small cell lung carcinoma (SCLC), neuroendocrine (NE) phenotype markers such as chromogranin A, synaptophysin, and CD56 are helpful. However, because they are dispensable, SCLCs occur without apparent NE phenotypes. Insulinoma-associated protein 1 (INSM1) is a transcription factor for NE differentiation and has emerged as a single practical marker for SCLC. Using the surgical samples of 141 pulmonary NE tumors (78 SCLCs, 44 large cell NE carcinomas, and 19 carcinoids), and 246 non-NE carcinomas, we examined the immunohistochemical expression and prognostic relevance of INSM1 in association with NE phenotype markers. We evaluated its sensitivity and specificity for SCLC diagnosis, as well as its usefulness to diagnose SCLC without NE marker expression and to estimate the prognosis. INSM1 was expressed in SCLCs (92%, 72/78), large cell NE carcinomas (68%, 30/44), and carcinoids (95%, 18/19). In addition, among SCLCs with no expression of NE phenotype markers (n=12), 9 (75%) were positive for INSM1. These data suggest the superiority of INSM1 to the phenotype markers. Only 7% of adenocarcinomas (9/134) and 4% of squamous cell carcinomas (4/112) were positive for INSM1. SCLC with low-INSM1 expression (n=28) had a significantly better prognosis (P=0.040) than the high-INSM1 group (n=50). Our study revealed that INSM1 is highly sensitive and specific to detect SCLC and can estimate prognosis. INSM1 will be a promising marker for SCLC.
41 citations
TL;DR: The authors detail key indications, strengths, and limitations of the panoply of radiologic techniques for BIA-ALCL and propose multiparametric imaging paradigms for management of the peri-implant effusion and mass-forming or advanced disease subtypes, with the goal of accurate optimal patient care.
Abstract: Breast implant-associated anaplastic large cell lymphoma (BIA-ALCL) is a new provisional category in the 2016 World Health Organization (WHO) classification of lymphoid neoplasms, and its incidence is rising owing to increasing recognition of this complication of breast implant insertion. At a median of 10 years after implant insertion, the typical presenting features are sudden-onset breast swelling secondary to peri-implant effusion and less frequently mass-forming disease. Histologic features comprise pleomorphic cells expressing CD30 and negative anaplastic lymphoma kinase (ALK) receptor, similar to systemic and cutaneous ALK-negative anaplastic large cell lymphoma (ALCL). The effusion-only subtype is generally indolent and curable with surgery, unlike the more aggressive mass-forming disease, for which systemic therapy is advocated. High clinical suspicion and pertinent use of radiologic and pathology modalities are essential for timely and accurate diagnosis of BIA-ALCL. Contemporary imaging techniques including US, mammography, breast MRI, CT, and PET/CT are routinely used in breast disease and lymphomas; however, the unique behavior of BIA-ALCL presents significant diagnostic and radiologic interpretative challenges, with numerous nuanced imaging features being pertinent, and current lymphoma staging and response guidelines are not easily applicable to BIA-ALCL. The authors evaluate available evidence in this evolving field; detail key indications, strengths, and limitations of the panoply of radiologic techniques for BIA-ALCL; and propose multiparametric imaging paradigms for management of the peri-implant effusion and mass-forming or advanced disease subtypes, with the goal of accurate optimal patient care. The authors also predict a future model of multimodal assessment using novel imaging and molecular techniques and define key research directions. ©RSNA, 2020.
39 citations
TL;DR: Although Insulinoma-associated protein 1 might be a meaningful adjunct in the differential diagnosis of neuroendocrine neoplasias, a general uncritical vote for replacing the traditional markers by INSM1 may not be justified.
Abstract: Objective Recognition of neuroendocrine differentiation is important for tumor classification and treatment stratification. To detect and confirm neuroendocrine differentiation, a combination of morphology and immunohistochemistry is often required. In this regard, synaptophysin, chromogranin A, and CD56 are established immunohistochemical markers. Insulinoma-associated protein 1 (INSM1) has been suggested as a novel stand-alone marker with the potential to replace the current standard panel. In this study, we compared the sensitivity and specificity of INSM1 and established markers. Materials and methods A cohort of 493 lung tumors including 112 typical, 39 atypical carcinoids, 77 large cell neuroendocrine carcinomas, 144 small cell lung cancers, 30 thoracic paragangliomas, 47 adenocarcinomas, and 44 squamous cell carcinomas were selected and tissue microarrays were constructed. Synaptophysin, chromogranin A, CD56, and INSM1 were stained on all cases and evaluated manually as well as with an analysis software. Positivity was defined as ≥1% stained tumor cells in at least 1 of 2 cores per patient. Results INSM1 was positive in 305 of 402 tumors with expected neuroendocrine differentiation (typical and atypical carcinoids, large cell neuroendocrine carcinomas, small cell lung cancers, and paraganglioma; sensitivity: 76%). INSM1 was negative in all but 1 of 91 analyzed non-neuroendocrine tumors (adenocarcinomas, squamous cell carcinomas; specificity: 99%). All conventional markers, as well as their combination, had a higher sensitivity (97%) and a lower specificity (78%) for neuroendocrine differentiation compared with INSM1. Conclusions Although INSM1 might be a meaningful adjunct in the differential diagnosis of neuroendocrine neoplasias, a general uncritical vote for replacing the traditional markers by INSM1 may not be justified.
33 citations
TL;DR: Current research suggests that therapies targeting JAK proteins warrant investigation in BIA-ALCL, a CD30-positive, anaplastic lymphoma kinase–negative T-cell lymphoma, with an excellent prognosis after implant and capsule removal.
Abstract: Breast implant–associated anaplastic large-cell lymphoma (BIA-ALCL) is a CD30-positive, anaplastic lymphoma kinase–negative T-cell lymphoma. Nearly all cases have been associated with textured implants. Most cases are of effusion-limited, indolent disease, with an excellent prognosis after implant and capsule removal. However, capsular invasion and tumor mass have a more aggressive course and a fatal outcome risk. This review summarizes the current knowledge on BIA-ALCL cell of origin and immunologic factors underlying its pathogenesis. Cytokine expression profiling of BIA-ALCL cell lines and clinical specimens reveals a predominantly type 17 helper T-cell (Th17)/Th1 signature, implicating this as its cell of origin. However, a Th2 allergic inflammatory response is suggested by the presence of IL-13, with infiltration of eosinophils and IgE-coated mast cells in clinical specimens of BIA-ALCL. The microenvironment-induced T-cell plasticity, a factor increasingly appreciated, may partially explain these divergent results. Mutations resulting in constitutive Janus kinase (JAK)–STAT activation have been detected and associated with BIA-ALCL pathogenesis in a small number of cases. One possible scenario is that an inflammatory microenvironment stimulates an immune response, followed by polyclonal expansion of Th17/Th1 cell subsets with release of inflammatory cytokines and chemokines and accumulation of seroma. JAK-STAT3 gain-of-function mutations within this pathway and others may subsequently lead to monoclonal T-cell proliferation and clinical BIA-ALCL. Current research suggests that therapies targeting JAK proteins warrant investigation in BIA-ALCL.
29 citations
29 citations
TL;DR: P16 expression may suggest a cervical origin of NEC; however, it must be always integrated by clinical and instrumental data, and the expression of SST2 and SST5 could support a role for SSAs in the diagnosis and therapy of patients with cervical NECs.
Abstract: Background. Gynecological neuroendocrine neoplasms (NENs) are extremely rare, accounting for 1.2–2.4% of the NENs. The aim of this study was to test cervical NENs for novel markers of potential utility for differential diagnosis and target therapy. Methods. All cases of our center (n = 16) were retrieved and tested by immunohistochemistry (IHC) for 12 markers including markers of neuroendocrine differentiation (chromogranin A, synaptophysin, CD56), transcription factors (CDX2 and TTF1), proteins p40, p63, p16INK4a, and p53, somatostatin receptors subtypes (SST2-SST5) and the proliferation marker Ki67 (MIB1). Results. All cases were poorly differentiated neuroendocrine carcinomas (NECs), 10 small cell types (small cell–neuroendocrine carcinomas, SCNECs) and 6 large cell types (large cell–neuroendocrine carcinomas, LCNECs); in 3 cases a predominant associated adenocarcinoma component was observed. Neuroendocrine cancer cells expressed at least 2 of the 3 tested neuroendocrine markers; p16 was intensely expressed in 14 (87.5%) cases; SST5 in 11 (56.25%, score 2–3, in 9 cases); SST2 in 8 (50%, score 2–3 in 8), CDX2 in 8 (50%), TTF1 in 5 (31.25%), and p53 in 1 case (0.06%). P63 and p40 expressions were negative, with the exception of one case that showed moderate expression for p63. Conclusions. P40 is a more useful marker for the differential diagnosis compared to squamous cell carcinoma. Neither CDX2 nor TTF1 expression may help the differential diagnosis versus potential cervical metastasis. P16 expression may suggest a cervical origin of NEC; however, it must be always integrated by clinical and instrumental data. The expression of SST2 and SST5 could support a role for SSAs (Somatostatin Analogues) in the diagnosis and therapy of patients with cervical NECs.
28 citations
TL;DR: Shorter time to relapse was the strongest predictor of subsequent relapse, and allogeneic SCT offers a chance for cure in patients with high-risk ALCL relapse; however, it was not effective for early relapses.
Abstract: PURPOSETo analyze the efficacy of a risk-stratified treatment of children with relapsed anaplastic large cell lymphoma (ALCL). The ALCL-Relapse trial (ClinicalTrials.gov identifier: NCT00317408) st...
TL;DR: Weak, focal INSM1 expression alone is insufficient as a diagnostic marker for small cell carcinoma, but is sensitive and specific, easy to interpret in small biopsies, and makes a valuable addition to a diagnostic panel.
TL;DR: The term aggressive variant prostate cancer (AVPCa) refers to androgen receptor (AR)-independent anaplastic forms of prostate cancer, clinically characterized by a rapidly progressive disease course as mentioned in this paper.
Abstract: The term aggressive variant prostate cancer (AVPCa) refers to androgen receptor (AR)-independent anaplastic forms of prostate cancer (PCa), clinically characterized by a rapidly progressive disease course. This involves hormone refractoriness and metastasis in visceral sites. Morphologically, AVPCa is made up of solid sheets of cells devoid of pleomorphism, with round and enlarged nuclei with prominent nucleoli and slightly basophilic cytoplasm. The cells do not show the typical architectural features of prostatic adenocarcinoma and mimic the undifferentiated carcinoma of other organs and locations. The final diagnosis is based on the immunohistochemical expression of markers usually seen in the prostate, such as prostate-specific membrane antigen (PSMA). A subset of AVPCa can also express neuroendocrine (NE) markers such as chromogranin A, synaptophysin and CD56. This letter subset represents an intermediate part of the spectrum of NE tumors which ranges from small cell to large cell carcinoma. All such tumors can develop following potent androgen receptor pathway inhibition. This means that castration-resistant prostate cancer (CRPCa) transdifferentiates and becomes a treatment-related NE PCa in a clonally divergent manner. The tumors that do not show NE differentiation might harbor somatic and/or germline alterations in the DNA repair pathway. The identification of these subtypes has direct clinical relevance with regard to the potential benefit of platinum-based chemotherapy, poly (ADP-ribose) polymerase inhibitors and likely further therapies.
TL;DR: RNA sequencing and gene set enrichment analysis support classification of BIA-ALCL as a distinct entity and uncover opportunities for investigating hypoxia-related proteins such as CA9 as novel biomarkers and therapeutic targets in this disease.
Abstract: Breast implant-associated anaplastic large cell lymphoma (BIA-ALCL) is a recently characterized T-cell malignancy that has raised significant patient safety concerns and led to worldwide impact on the implants used and clinical management of patients undergoing reconstructive or cosmetic breast surgery. Molecular signatures distinguishing BIA-ALCL from other ALCLs have not been fully elucidated and classification of BIA-ALCL as a WHO entity remains provisional. We performed RNA sequencing and gene set enrichment analysis comparing BIA-ALCLs to non-BIA-ALCLs and identified dramatic upregulation of hypoxia signaling genes including the hypoxia-associated biomarker CA9 (carbonic anyhydrase-9). Immunohistochemistry validated CA9 expression in all BIA-ALCLs, with only minimal expression in non-BIA-ALCLs. Growth induction in BIA-ALCL-derived cell lines cultured under hypoxic conditions was proportional to up-regulation of CA9 expression, and RNA sequencing demonstrated induction of the same gene signature observed in BIA-ALCL tissue samples compared to non-BIA-ALCLs. CA9 silencing blocked hypoxia-induced BIA-ALCL cell growth and cell cycle-associated gene expression, whereas CA9 overexpression in BIA-ALCL cells promoted growth in a xenograft mouse model. Furthermore, CA9 was secreted into BIA-ALCL cell line supernatants and was markedly elevated in human BIA-ALCL seroma samples. Finally, serum CA9 concentrations in mice bearing BIA-ALCL xenografts were significantly elevated compared to control serum. Together, these findings characterize BIA-ALCL as a hypoxia-associated neoplasm, likely attributable to the unique microenvironment in which it arises. These data support classification of BIA-ALCL as a distinct entity and uncover opportunities for investigating hypoxia-related proteins such as CA9 as novel biomarkers and therapeutic targets in this disease.
TL;DR: Pure high-grade neuroendocrine cervical carcinomas were microsatellite stable and overwhelmingly negative for PD-L1 expression, and inclusion of PARP inhibitors in future clinical trials may be considered.
Abstract: Objectives Women with recurrent high-grade neuroendocrine cervical cancer have few effective treatment options. The aim of this study was to identify potential therapeutic targets for women with this disease. Methods Specimens from patients with high-grade neuroendocrine carcinomas of the cervix were identified from pathology files at MD Anderson Cancer Center. Immunohistochemical stains for PD-L1 (DAKO, clone 22-C3), mismatch repair proteins (MLH1, MSH2, MSH6, PMS2), somatostatin, and Poly (ADP-ribose) polymerase (PARP) were performed on sections from formalin-fixed paraffin-embedded tissue blocks. Nuclear PARP-1 staining was quantified using the H-score with a score of Results Forty pathologic specimens from patients with high-grade neuroendocrine carcinomas of the cervix were examined (23 small cell, 5 large cell, 3 high-grade neuroendocrine, not otherwise specified, and 9 mixed). The mean age of the cohort was 43 years and the majority of patients (70%) were identified as white non-Hispanic. All 28 (100%) samples tested stained for mismatch repair proteins demonstrated intact expression, suggesting they were microsatellite stable tumors. Of the 31 samples tested for PD-L1 expression, only two (8%) of the 25 pure high-grade neuroendocrine carcinomas were positive whereas three (50%) of the six mixed carcinoma tumors tested positive. Of the 11 small cell specimens tested for PARP-1, 10 (91%) showed PARP expression with six (55%) demonstrating high expression and four (36%) showing moderate expression. Somatostatin staining was negative in 18 of 19 small cell cases (95%). Conclusions Pure high-grade neuroendocrine cervical carcinomas were microsatellite stable and overwhelmingly negative for PD-L1 expression. As the majority of tumors tested expressed PARP-1, inclusion of PARP inhibitors in future clinical trials may be considered.
TL;DR: High proportion of CD8+ Tc cells correlated with improved prognostic outcome in stage I-III NSCLC, and this analysis indicated that Th cells and Treg cells have implications on outcome with respect to tumor histology and biology.
Abstract: Background T cell infiltration in non-small cell lung cancer (NSCLC) is essential for the immunological response to malignant tissue, especially in the era of immune-checkpoint inhibition. To investigate the prognostic impact of CD4+ T helper cells (Th), CD8+ cytotoxic (Tc) and FOXP3+ regulatory T (Treg) cells in NSCLC, we performed this analysis. Methods By counterstaining of CD4, CD8 and FOXP3 we used immunohistochemistry on tissue microarrays (TMA) to evaluate peritumoral Th cells, Treg cells and Tc cells in n=294 NSCLC patients with pTNM stage I-III disease. Results Strong CD4+ infiltration was associated with higher tumor stages and lymphonodal spread. However, strong CD4+ infiltration yielded improved overall survival (OS) (P=0.014) in adenocarcinoma (ADC) and large cell carcinoma (LCC) but not in squamous cell carcinoma (SCC). A CD4/CD8 ratio 0.05). Here, prognostic effects were prominent in PD-L1 positive SCC (P=0.023) but not in PD-L1 negative SCC (P=0.236). Conclusions High proportion of CD8+ Tc cells correlated with improved prognostic outcome in stage I-III NSCLC. Th cells and Treg cells have implications on outcome with respect to tumor histology and biology.
TL;DR: This study conducted targeted metabolomic and global metabolomic analyses of non–small‐cell lung cancer (NSCLC) cell lines in combination with exome and transcriptome analyses to clarify the metabolic features of NRF2‐activated lung cancers and provides useful information for the exploration of new metabolic nodes for selective toxicity towards NRF 2‐activated NSCLC.
Abstract: Aberrant activation of NRF2 is as a critical prognostic factor that drives the malignant progression of various cancers. Cancer cells with persistent NRF2 activation heavily rely on NRF2 activity for therapeutic resistance and aggressive tumorigenic capacity. To clarify the metabolic features of NRF2-activated lung cancers, we conducted targeted metabolomic (T-Met) and global metabolomic (G-Met) analyses of non-small-cell lung cancer (NSCLC) cell lines in combination with exome and transcriptome analyses. Exome analysis of 88 cell lines (49 adenocarcinoma, 14 large cell carcinoma, 15 squamous cell carcinoma and 10 others) identified non-synonymous mutations in the KEAP1, NRF2 and CUL3 genes. Judging from the elevated expression of NRF2 target genes, these mutations are expected to result in the constitutive stabilization of NRF2. Out of the 88 cell lines, 52 NSCLC cell lines (29 adenocarcinoma, 10 large cell carcinoma, 9 squamous cell carcinoma and 4 others) were subjected to T-Met analysis. Classification of the 52 cell lines into three groups according to the NRF2 target gene expression enabled us to draw typical metabolomic signatures induced by NRF2 activation. From the 52 cell lines, 18 NSCLC cell lines (14 adenocarcinoma, 2 large cell carcinoma, 1 squamous cell carcinoma and 1 others) were further chosen for G-Met and detailed transcriptome analyses. G-Met analysis of their culture supernatants revealed novel metabolites associated with NRF2 activity, which may be potential diagnostic biomarkers of NRF2 activation. This study also provides useful information for the exploration of new metabolic nodes for selective toxicity towards NRF2-activated NSCLC.
TL;DR: A single-center, single-arm, phase two study with crizotinib administered as monotherapy to 12 ALK+ ALCL patients R/R to at least one line of previous cytotoxic therapy found that three patients who obtained CR were resistant to previous BV administration.
Abstract: To the Editor: Crizotinib, an inhibitor of anaplastic lymphoma kinase (ALK) and c-ros oncogene 1 (ROS1), is approved for the treatment of patients with ALK-positive (ALK+) or ROS1-positive (ROS1+) advanced non-smallcell lung cancer (NSCLC). The ALK rearrangements are also implicated in anaplastic large-cell lymphoma (ALCL), which is characterized by the presence of the fusion-protein NPM-ALK. Note, ALK+ ALCL responds to chemotherapy, but relapses are frequent and progression-free survival (PFS) at 4 years is <50%. Brentuximabvedotin (BV) is considered a standard treatment for patients with relapsed/refractory ALCL and is currently used in many countries even as first line treatment. Due to the need for intravenous infusion and the cumulative peripheral neuropathy, prolonged treatment with BV may be difficult to manage in the setting of refractory/relapsed (R/R) patients. Crizotinib has previously been shown to have therapeutic activity in R/R refractory ALK+ lymphomas with a favorable tolerability profile and could therefore represent a potential treatment option in this setting. However, no formal phase two study has been performed in adult patients. We herein present the results of a single-center, single-arm, phase two study (CRU1; ClinicalTrials.gov Identifier: NCT02419287) with crizotinib administered as monotherapy (dosage 250 mg BID) to 12 ALK+ ALCL patients R/R to at least one line of previous cytotoxic therapy. Median age at the enrollment was 31 years (range 18-83); six patients were male and median number of previous lines of chemotherapy was two (range 1-6) (Table S1 in Appendix S1). The primary endpoint was the overall response rate (ORR), according to Response Evaluation Criteria in Lymphoma (RECIL) 2017. In the analysis set, the proportion of patients with CR or partial response (PR) as the best response is regarded as the ORR. Tumor assessments were performed with CT or CT/PET at baseline, after 4 weeks, 12 weeks and then every 12 weeks (Table S2 in Appendix S1). Since the NPM-ALK fusion protein detected by immunohistochemistry exhibited a nuclear and cytoplasmatic staining pattern in all ALCL patients, qualitative real time polymerase chain reaction (RT-PCR) was used to measure NPM-ALK fusion transcript in peripheral blood samples at the same time points, and then every 12 weeks throughout the study (supplementary information methods in Appendix S1). The Overall Response Rate (ORR) was 10/12, or 83.3% (95% CI, 55.2%-95.3%). Seven patients (58.3%; 95% CI, 32.0%-80.7%) achieved complete remission (CR) and three patients (25%; 95% CI, 8.9%-53.2%) achieved partial remission (PR) (Table S1 and S3 in Appendix S1). Interestingly, three patients who obtained CR were resistant to previous BV administration. One patient in CR stopped crizotinib after only 1 month of treatment, then underwent an allogenic-HSCT and was therefore censored. Only one of three patients in PR is still alive and in response at the latest follow up under continuous crizotinib administration. The other two patients in PR had PD in the CNS after 2 and 3 months of therapy, respectively. Two patients (16.7%; 95% CI, 4.7%-44.8%) did not respond to crizotinib. One patient obtained a stable disease (SD) after the first month of treatment, then had a rapid systemic disease progression and died. The second patient progressed early after the start of treatment and died quickly. Real-time polymerase chain Reaction (RT-PCR) for NPM-ALK became negative within 1 month in 6/8 evaluable patients (75%; 95% CI 40.9%-92.8%) (Table S1 and S3 in Appendix S1). Early negativity by RT-PCR for NPM-ALK in previously positive NPM-ALK patients seemed to correlate with the depth and durability of response; RT-PCR could indeed represent an effective method to monitor minimal residual disease in adult ALK+ lymphoma, similar to what has previously been observed in pediatric patients.. Crizotinib may therefore offer a potential long-term treatment option in patients with relapsed/refractory ALCL, with a 2-year PFS and OS of 65% and 66%, respectively (Figure 1). All responding patients obtained their best response after only 1 month of treatment and almost all patients with only one previous line of cytotoxic therapy (4/5, 80%; 95% CI 37.6%-96.4%) showed durable responses; this fact could indicate that an early treatment with crizotinib after the failure of first-line treatment may produce better results than when administered later on. Moreover, all patients who progressed/relapsed did it within the initial 90 days of treatment and no further progressions/ relapses were noted thereafter. Median duration of treatment (DOT) is 16.5 months (range 0.5-66 months), but for patients with durable response median DOT exceeds 40 months (range 12-66 months) (Table S3 in Appendix S1). To our knowledge, the treatment duration (up to 66 months) in this study is currently the longest reported in literature in adult patients and therefore provides new information about the long-term safety of crizotinib. Treatment was generally welltolerated and no patient dropped out in association with any adverse event. The safety profile observed was similar to that reported previously; the most common treatment related adverse events were transient gastrointestinal and visual disorders graded 1/2 (Table S4). The needed duration of treatment is presently unknown; however, abrupt Received: 6 August 2020 Revised: 15 August 2020 Accepted: 15 August 2020
01 Mar 2020
TL;DR: Five-year survival in patients managed in French non-academic hospitals for primary NSCLC in 2010 remained poor (<15%), whatever the histologic type, and independent positive prognostic factors were young age and female gender for ADC.
Abstract: Objective To estimate five-year survival in non-small-cell lung cancer (NSCLC) patients according to histology and to identify independent prognostic factors by histology. Methods Data were obtained during the KBP-2010-CPHG study, which included all new cases of primary lung cancer diagnosed in 2010 in 104 non-academic hospitals. Results In all, 3199 patients had adenocarcinoma (ADC), 1852 squamous cell carcinoma (SCC), 754 large cell carcinoma (LCC). Five-year survival was 13.3% [12.1%–14.5%] for ADC, 14.3% [12.7%–16.0%] for SCC, 9.6% [7.6%–11.9%] for LCC (P 70 years; P = 0.004), male gender (P Conclusions Five-year survival in patients managed in French non-academic hospitals for primary NSCLC in 2010 remained poor (
TL;DR: A review of the current knowledge of Hurthle cell carcinoma, including clinical, pathological, and molecular features, with the aim of improving clinical management, is presented in this article.
Abstract: Hurthle cell carcinoma (HCC) represents 3-4% of thyroid carcinoma cases. It is considered to be more aggressive than non-oncocytic thyroid carcinomas. However, due to its rarity, the pathological characteristics and biological behavior of HCC remain to be elucidated. The Hurthle cell is characterized cytologically as a large cell with abundant eosinophilic, granular cytoplasm, and a large hyperchromatic nucleus with a prominent nucleolus. Cytoplasmic granularity is due to the presence of numerous mitochondria. These mitochondria display packed stacking cristae and are arranged in the center. HCC is more often observed in females in their 50-60s. Preoperative diagnosis is challenging, but indicators of malignancy are male, older age, tumor size > 4 cm, a solid nodule with an irregular border, or the presence of psammoma calcifications according to ultrasound. Thyroid lobectomy alone is sufficient treatment for small, unifocal, intrathyroidal carcinomas, or clinically detectable cervical nodal metastases, but total thyroidectomy is recommended for tumors larger than 4 cm. The effectiveness of radioactive iodine is still debated. Molecular changes involve cellular signaling pathways and mitochondria-related DNA. Current knowledge of Hurthle cell carcinoma, including clinical, pathological, and molecular features, with the aim of improving clinical management, is reviewed.
TL;DR: In general, PD-L1 positivity is highly variable and seen in lower percentage of these tumors, and biomarkers other than PD- L1 should also be investigated in these tumors.
Abstract: High-grade neuroendocrine tumors (HGNET) have distinctive tumor biology/behaviour. Newer modalities of treatment (immunotherapy) for them have been included in recent NCCN guidelines. Detection of programmed death receptor-ligand 1 (PD-L1) expression by immunohistochemistry have made easy identification of patients eligible for immunotherapy. We aimed to ascertain expression of PD-L1 on small cell and large cell neuroendocrine carcinomas of lung and review existing literature. Eighty-five cases of HGNET lung (primary/metastatic), were retrieved and reviewed. Immunostaining for PD-L1 using clone SP263 was done. Any amount/intensity of membranous staining of > = 1% tumor cells was cut-off for positivity. Previously published studies using Google and/Pubmed search engines were reviewed. Of 85 cases, 70 were small-cell lung cancer (SCLC), 11 large-cell neuroendocrine carcinoma (LCNEC) and 4 combined SCLC. Median age was 46.5 years with male preponderance. No PD-L1 expression was seen in 91.6% cases. The 7 positive cases were 4 LCNEC, 2 SCLC and 1 combined SCLC. The percentage positivity varied from 1–100%; lower percentage positivity was seen in SCLC. PD-L1 expression on immune cells was seen in 31.3% cases. Sixteen studies evaluating 1992 NET were found; E1L3N PD-L1 clone was commonly used clone. PD-L1 positivity was associated with better prognosis in most studies. There are only a few studies available in literature related to PDL1 expression in high grade neuroendocrine carcinomas of lung. In general, PD-L1 positivity is highly variable and seen in lower percentage of these tumors. With the recent approval of immunotherapy, biomarkers other than PD-L1 should also be investigated in these tumors.
TL;DR: A review of the current literature and report on three cases of BIA-ALCL at an institution, which serve to illustrate the approach to diagnosis and management of this disease.
TL;DR: SCLC/LCNEC was the most common type of SCLC and patients' DFS and OS were also longer than other combined types and groups of whether tumor invaded the pleura, lymph node stage and the courses of adjuvant chemotherapy.
TL;DR: This retrospective study describes and correlates the presenting clinical signs, flow cytometry, and outcomes of 119 dogs diagnosed with nodal, non-TZL, CD8+ or CD4- CD8- TCL by flow cytometers to identify the less common TCL phenotypes.
Abstract: Canine T-cell lymphoma (TCL) encompasses a heterogeneous group of diseases with variable clinical presentation, cytomorphology, immunophenotype, and biologic behaviour. The most common types of TCL in dogs involving peripheral lymph nodes include indolent T-zone lymphoma (TZL) and biologically aggressive peripheral T-cell lymphoma (PTCL). TCL phenotypes can be categorized by expression of the surface antigen molecules CD4 and CD8. The majority of TCL cases are CD4+ , with far fewer cases being CD8+ or CD4- CD8- . The clinical features of CD4+ TCLs have been previously described. The less common TCL phenotypes, however, are poorly characterized with little to no information about prognosis. In this retrospective study, we describe and correlate the presenting clinical signs, flow cytometry, and outcomes of 119 dogs diagnosed with nodal, non-TZL, CD8+ or CD4- CD8- TCL by flow cytometry. Skin lesions present at the time of diagnosis were more commonly observed in the CD8+ TCL group. Mediastinal enlargement and/or hypercalcemia were more commonly seen in the CD4- CD8- TCL group. Dogs with either CD8+ or CD4- CD8- TCLs had aggressive clinical disease with median overall survival (OS) times of 198 days and 145 days, respectively. In both groups, neoplastic cell size determined by flow cytometry ranged from small to large, and large cell size was associated with shorter OS times (median OS = 61 days). Cases classified as small cell had a median OS of 257 days. Expression levels of major histocompatibility complex (MHC) class II and CD5 were highly variable among cases but were not prognostically significant in this group of patients.
TL;DR: The treatment strategy for LCNEC is not yet established because of its reclassification from a variant of “large cell carcinoma” to a new category of ”neuroendocrine tumor”.
Abstract: In 1970, neuroendocrine tumors of the lung were classified into three categories: typical carcinoid (TC), atypical carcinoid (AC), and small cell lung carcinoma (SCLC). The third edition of the World Health Organization (WHO) classification in 1999 defined large cell neuroendocrine carcinoma (LCNEC) as a variant of large cell carcinomas, whereas the fourth edition of the WHO classification redefined LCNEC as a neuroendocrine tumor. Currently, neuroendocrine tumors of the lung are classified into four main categories: TC, AC, LCNEC, and SCLC. Although the treatments for TC, AC, and SCLC have not changed remarkably, the treatment strategy for LCNEC is not yet established because of its reclassification from a variant of "large cell carcinoma" to a new category of "neuroendocrine tumor". In this review article, we discuss the pathological findings, biological behavior, and treatment of neuroendocrine tumors of the lung.
TL;DR: Efforts are required to better understand the genomic and molecular characterizations of gynecological LCNEC to elucidate the underlying oncogenic pathways and driver mutations as potential targets.
Abstract: Large cell neuroendocrine carcinomas (LCNEC) are rare, aggressive high-grade neuroendocrine neoplasms within the neuroendocrine cell lineage spectrum. This manuscript provides a detailed review of ...
TL;DR: A process following a brief checklist that focuses on diffuse large B-cell lymphoma, the most common entity, and rules out other similar lymphomas in a stepwise fashion is proposed.
Abstract: Context.— Large B-cell lymphomas represent the most common non-Hodgkin lymphomas and often present as extranodal masses with advanced stage similar to metastatic tumors. Without proper intraoperati...
TL;DR: The results revealed that the different lung cancer cell lines had different expression levels of SCGN, and the SCGN protein was localized in the nucleus and cytoplasm of A549 cells detected using immunofluorescence, and SCGN displayed more sensitivity and specificity in lung cancer cells with NE differentiation.
Abstract: A common method to distinguish large cell neuroendocrine carcinoma (LCNEC) from non-neuroendocrine large cell carcinoma (non-NE LCC) is from using specific immunohistochemistry markers, such as CgA, Syn, CD56 and Napsin A, however, the results remain controversial using these markers. Secretagogin (SCGN) is a newly discovered biomarker of neuroendocrine cells. In the present study, the expression of SCGN in 33 cases of human lung large cell carcinoma (LCC), including 17 cases of LCNEC and 16 cases of non-neuroendocrine (NE) LCC and lung cancer cell lines (A549, H1650, H358, H292 and H661). The association between SCGN expression and the clinicopathological characteristics of patients, including sex, age, clinical stage and metastasis, was analyzed. The results revealed that the different lung cancer cell lines had different expression levels of SCGN, and the SCGN protein was localized in the nucleus and cytoplasm of A549 cells detected using immunofluorescence. A total of 54.5% (18/33) of specimens positively expressed the SCGN protein. Of the 17 patients with LCNEC, only 23.5% (4/17) of cases were CgA positive, 35.29% (6/17) were Syn positive, 41.2% (7/17) were CD56 positive, and 41.2% (7/17) were Napsin A positive. However, SCGN was positively detected in 94.1% (16/17) of patients with LCNEC, which was more frequent compared with that in CgA, Syn, CD56 and Napsin A. Analysis of the clinical characteristics indicated that SCGN expression was only significantly associated with pathological type in patients with lung cancer (P<0.001). Furthermore, a positive correlation was observed between SCGN expression and CgA, Syn, and CD56 expression in patients with LCNEC. SCGN was co-localized with the NE markers (CgA, Syn, and CD56) in A549 lung cancer cells and in LCNEC tissues. Thus, SCGN displayed more sensitivity and specificity in lung cancer cells with NE differentiation. A combined analysis of SCGN and other common NE markers may be a potential tool for diagnosing these tumors.