Showing papers on "Large cell published in 2021"

MAP-kinase and JAK-STAT pathways dysregulation in plasmablastic lymphoma

Abstract: Plasmablastic lymphoma (PBL) is an aggressive B-cell lymphoma with an immunoblastic/large cell morphology and plasmacytic differentiation. The differential diagnosis with Burkitt lymphoma (BL), plasma cell myeloma (PCM) and some variants of diffuse large B-cell lymphoma (DLBCL) may be challenging due to the overlapping morphological, genetic and immunophenotypic features. Furthermore, the genomic landscape in PBL is not well known. To characterize the genetic and molecular heterogeneity of these tumors, we investigated thirty-four PBL using an integrated approach, including fluorescence in situ hybridization, targeted sequencing of 94 B-cell lymphoma related genes, and copy-number arrays. PBL were characterized by high genetic complexity including MYC translocations (87%), gains of 1q21.1-q44, trisomy 7, 8q23.2-q24.21, 11p13-p11.2, 11q14.2-q25, 12p and 19p13.3-p13.13, losses of 1p33, 1p31.1-p22.3, 13q and 17p13.3-p11.2, and recurrent mutations of STAT3 (37%), NRAS and TP53 (33%), MYC and EP300 (19%) and CARD11, SOCS1 and TET2 (11%). Pathway enrichment analysis suggested a cooperative action between MYC alterations and MAPK (49%) and JAK-STAT (40%) signaling pathways. Of note, EBVnegative PBL cases had higher mutational and copy-number load and more frequent TP53, CARD11 and MYC mutations, whereas EBV-positive PBL tended to have more mutations affecting the JAK-STAT pathway. In conclusion, these findings further unravel the distinctive molecular heterogeneity of PBL identifying novel molecular targets and the different genetic profile of these tumors related to EBV infection.

LncRNA CBR3-AS1 potentiates Wnt/β-catenin signaling to regulate lung adenocarcinoma cells proliferation, migration and invasion.

Abstract: Long non-coding RNAs (lncRNAs) are pervasively transcribed in genome and emerging as a new player in tumorigenesis due to their functions in transcriptional, posttranscriptional and epigenetic mechanisms of gene regulation. As the most frequent malignancy and the foremost source of cancer mortality, lung cancer is a heterogeneous disorder. The most common type of lung cancer is Non-small cell lung cancer (NSCLC), occupying 85% of the total cases, and the main subtypes of NSCLC include lung adenocarcinoma (LAD), large cell carcinoma (LCC), and lung squamous cell carcinoma (LSCC). Recently, numerous lncRNAs have been reported to be strongly linked to NSCLC. In the present study, we found that a new lncRNA CBR3-AS1 is highly expressed in lung cancer. In addition, we also examined the expression of lncRNA CBR3-AS1 in 60 of LADs, 40 of LCCs and 40 of LSCCs patient samples, finding that CBR3-AS1 was specificity highly expressed in LAD cancer tissues. Mechanically, we discovered that CBR3-AS1 could regulate the proliferation, migration and invasion of LAD cells through targeting Wnt/β-catenin signaling. Real-time PCR, RNA-pulldown, RIP, western blotting, lentivirus transfection, luciferase reporter assays, cell proliferation assays, colony formation assays, wound healing scratch assays and transwell assays were employed to examine the relationship between lncRNA CBR3-AS1 and its regulation of Wnt/β-catenin signaling in LAD cells. LncRNA CBR3-AS1 is highly-expressed in LAD and cell lines. LncRNA CBR3-AS1 shows physical association with β-catenin. CBR3-AS1 could facilitate Wnt/β-catenin signaling activation thought promoting nuclear localization of β-catenin. CBR3-AS1 promotes LAD cell proliferation, migration and invasion by targeting Wnt/β-catenin signaling. It can be found that a new functional lncRNA CBR3-AS1 could promote nuclear localization of β-catenin so as to facilitate Wnt/β-catenin signaling activation and regulate the proliferation, migration and invasion of LAD cells.

Developing a 3D B Cell Lymphoma Culture System to Model Antibody Therapy.

Abstract: Diffuse large cell B cell lymphoma (DLBCL) accounts for approximately 30%-40% of all non-Hodgkin lymphoma (NHL) cases. Current first line DLBCL treatment results in long-term remission in more than 60% of cases. However, those patients with primary refractory disease or early relapse exhibit poor prognosis, highlighting a requirement for alternative therapies. Our aim was to develop a novel model of DLBCL that facilitates in vitro testing of current and novel therapies by replicating key components of the tumor microenvironment (TME) in a three-dimensional (3D) culture system that would enable primary DLBCL cell survival and study ex vivo. The TME is a complex ecosystem, comprising malignant and non-malignant cells, including cancer-associated fibroblasts (CAF) and tumor-associated macrophages (TAM) whose reciprocal crosstalk drives tumor initiation and growth while fostering an immunosuppressive milieu enabling its persistence. The requirement to recapitulate, at least to some degree, this complex, interactive network is exemplified by the rapid cell death of primary DLBCL cells removed from their TME and cultured alone in vitro. Building on previously described methodologies to generate lymphoid-like fibroblasts from adipocyte derived stem cells (ADSC), we confirmed lymphocytes, specifically B cells, interacted with this ADSC-derived stroma, in the presence or absence of monocyte-derived macrophages (MDM), in both two-dimensional (2D) cultures and a 3D collagen-based spheroid system. Furthermore, we demonstrated that DLBCL cells cultured in this system interact with its constituent components, resulting in their improved viability as compared to ex-vivo 2D monocultures. We then assessed the utility of this system as a platform to study therapeutics in the context of antibody-directed phagocytosis, using rituximab as a model immunotherapeutic antibody. Overall, we describe a novel 3D spheroid co-culture system comprising key components of the DLBCL TME with the potential to serve as a testbed for novel therapeutics, targeting key cellular constituents of the TME, such as CAF and/or TAM.

High-grade Neuroendocrine Carcinomas of the Vulva: A Clinicopathologic Study of 16 Cases

Abstract: Vulvar high-grade neuroendocrine carcinomas (HGNECs) are rare and primarily thought to represent Merkel cell carcinoma (MCC). We present the clinicopathologic features of 16 such cases, the largest series to date. Patients were most often White, postmenopausal, and symptomatic from a palpable vulvar mass/nodule. Tumors ranged from 0.7 to 6 cm and most commonly involved the labium majus. Majority of the cases were pure HGNECs (15/16) with small cell (SC) morphology (14/16); 2 were large cell neuroendocrine carcinomas, of which 1 was combined with moderately differentiated adenocarcinoma. All tumors expressed synaptophysin. Of the 14 HGNECs with SC morphology, 6 were CK20-positive MCCs with characteristic CAM5.2 and neurofilament (NF) expression. Five of these MCCs were positive for Merkel cell polyoma virus large T-antigen (MCPyVLTAg). In contrast, 6 HGNECs with SC morphology were negative for CK20, NF, and MCPyVLTAg and classified as SCNECs. High-risk human papilloma virus was positive in all SCNECs and negative in all MCCs. One case of HGNEC with SC morphology could not be entirely characterized due to lack of tissue for ancillary testing. Five of 12 (42%) cases had a discrepant diagnosis initially rendered. Most patients (10/15) presented with International Federation of Gynecology and Obstetrics stage III or IV disease. Usual sites of metastasis included inguinal lymph node, liver, bone, and lung. Twelve patients underwent surgery with adjuvant chemotherapy and/or radiation therapy, 1 received adjuvant immunotherapy, and 1 patient received neoadjuvant chemotherapy followed by surgery and adjuvant radiation therapy. Median overall survival was 24 months (range: 7 to 103 mo), and overall 5-year survival was 12% (95% confidence interval: 1% to 39%). In summary, vulvar HGNECs are rare, aggressive neoplasms that can be further subclassified into MCC, SCNEC, and large cell neuroendocrine carcinoma. CK20, CAM5.2, NF, TTF-1, MCPyVLTAg, and high-risk human papilloma virus facilitate the distinction of MCC from SCNEC. Proper identification of vulvar HGNECs is critical for patient management.

Undifferentiated large cell/rhabdoid carcinoma presenting in the intestines of patients with concurrent or recent non-small cell lung cancer (NSCLC): clinicopathologic and molecular analysis of 14 cases indicates an unusual pattern of dedifferentiated metastases.

Abstract: Undifferentiated carcinoma metastatic to the bowel is uncommon in surgical pathology practice and might be confused with primary gastrointestinal carcinoma, melanoma, lymphoma, and others. We present 14 cases of uni- (n = 9) or multifocal (n = 5) undifferentiated large cell/rhabdoid carcinoma presenting in the bowel of patients with concurrent (n = 9) or recent (diagnosed 1 to 25 months earlier; median, 4) non-small cell lung cancer (NSCLC). Patients were 6 females and 8 males, aged 52 to 85 years. Primary NSCLC was verified histologically in 10 cases and by imaging in 4. The undifferentiated histology was present in the lung biopsy in 4/10 patients (as sole pattern in 3 and combined with adenocarcinoma in 1) and was limited to the intestinal metastases in the remainder. PDL1 was strongly expressed in 7/9 cases (CPS: 41 to 100). Loss of at least one SWI/SNF subunit was detected in 7/13 cases (54%). SMARCA2 loss (n = 6) was most frequent and was combined with SMARCA4 loss in one case. PBRM1 loss was observed in one tumor. Successful molecular testing of 11 cases revealed BRAF mutations in 4 (3 were non-V600E variants), KRAS mutations in 3, and wildtype in 4. None had EGFR mutations. Analysis of 4 paired samples revealed concordant KRAS (2) and BRAF (1) mutations or wildtype (1). Our study indicates that undifferentiated carcinoma within the intestines of patients with concurrent/recent NSCLC represents dedifferentiated metastasis from the NSCLC. Recognition of this unusual presentation is cardinal to avoid misdiagnosis with inappropriate therapeutic and prognostic implications.

Small cell transformation of non-small cell lung cancer under immunotherapy: Case series and literature review

Abstract: In advanced lung cancer treatment, immunotherapy provides durable responses in some patients. However, other patients experience progressive disease and the resistance mechanisms to immunotherapy have yet been fully elucidated. Small cell transformation of non-small cell lung cancer (NSCLC) is commonly recognized as one of the resistance mechanisms to epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors in EGFR-mutant NSCLC treatment. As a resistant mechanism for immunotherapy, we report the first case of small cell transformation in 2017. Since then, eight similar cases have been reported and the concept of small cell transformation is now becoming more prevalent as a mechanism of immunotherapy resistance. In our facility, we have experienced four cases of small cell transformation after immunotherapy (including the reported case in 2017). The histology of each primary tumor was squamous cell carcinoma, large cell type neuroendocrine carcinoma, or poorly differentiated NSCLC. None had driver gene mutations. Nivolumab was administered in all four cases and atezolizumab was administered as a next line to nivolumab treatment in one case. The best response to immunotherapy was partial response or stable disease. There was a wide range of periods from the start of immunotherapy to confirmation of small cell transformation (from 2 weeks to almost 3 years). In conclusion, small cell transformation is an important resistance mechanism in cancer immunotherapy. When NSCLC progresses after immunotherapy, the possibility of small cell transformation and rebiopsy should always be encouraged, as it leads to clarification of the resistance mechanisms and frequency.

CD20-Negative Nodular Lymphocyte-Predominant Hodgkin Lymphoma: A 20-Year Consecutive Case Series From a Tertiary Cancer Center.

Abstract: Context.— Nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) is a rare, indolent Hodgkin lymphoma subtype with distinct clinicopathologic features and treatment paradigms. The neoplastic lymphocyte-predominant cells typically express bright CD20 and other B-cell antigens, which distinguishes them from Hodgkin/Reed-Sternberg cells of lymphocyte-rich classic Hodgkin lymphoma. Objective.— To characterize the clinicopathologic features of CD20-negative NLPHL at a single institution. Design.— A retrospective search for CD20-negative NLPHL in our pathology archives and medical records was conducted. Results.— Of 486 NLPHL patients identified with CD20 available for review, 14 (2.8%) had LP cells with absent CD20 expression. Patients with prior rituximab administration (n = 7) and insufficient clinical history (n = 1) were excluded, leaving 6 patients with rituximab-naive, CD20-negative NLPHL. A broad immunohistochemical panel showed the LP cells in all cases expressed B-cell antigens, particularly Oct-2, although PAX5 and CD79a were frequently also dim. CD30, CD15, and Epstein-Barr virus-encoded small RNAs were negative in all evaluated cases. Two patients had high-risk variant immunoarchitectural pattern D. One patient had extranodal disease, involving the spleen and bone, and was suspected to have large cell transformation. Standard NLPHL therapy was given, including local radiation and/or chemotherapy. Of 5 patients with available follow-up, 4 are alive in complete remission after therapy, and 1 is alive with relapsed disease. Conclusions.— NLPHL can lack CD20 de novo without prior rituximab therapy. In such cases, extensive immunophenotyping helps distinguish NLPHL from lymphocyte-rich classic Hodgkin lymphoma, which differ in clinical behavior and therapy. In our series, CD20-negative NLPHL showed both classic and variant histologic patterns and the expected range of clinical behavior seen in NLPHL, including 1 case with suspected large cell transformation.

Large cell neuroendocrine lung carcinoma: consensus statement from The British Thoracic Oncology Group and the Association of Pulmonary Pathologists.

Abstract: Over the past 10 years, lung cancer clinical and translational research has been characterised by exponential progress, exemplified by the introduction of molecularly targeted therapies, immunotherapy and chemo-immunotherapy combinations to stage III and IV non-small cell lung cancer. Along with squamous and small cell lung cancers, large cell neuroendocrine carcinoma (LCNEC) now represents an area of unmet need, particularly hampered by the lack of an encompassing pathological definition that can facilitate real-world and clinical trial progress. The steps we have proposed in this article represent an iterative and rational path forward towards clinical breakthroughs that can be modelled on success in other lung cancer pathologies.

Absence of CD74 Isoform at 41kDa Prevents the Heterotypic Associations between CD74 and CD44 in Human Lung Adenocarcinoma-derived Cells.

Abstract: Lung cancer is a leading cause of cancer-associated death in all over the globe. This study was undertaken to determine the expression and interaction of membrane-bound receptors CD74 and CD44 in human lung adenocarcinoma cells and their associated signaling was also attempted. Levels of CD74 and CD44 were studied in human lung adenocarcinoma-evolved cells A549 and H460. CD74-mediated downstream signaling was studied by the nuclear-transcription-factor NF-κB and prostaglandin E (PGE) production. Flow-cytometric analysis showed that both CD74 and CD44 were perfectly expressed in A549 cells. Importantly, Western immunoblotting showed that A549 cells expressed only two isoforms of CD74 at 33 and 35 kDa but isoform at 41 kDa was absent. These results were verified in H460 cells. Confocal microscopy showed CD74 and CD44 was colocalized but heterotypic interaction between them was missing in both A549 and H460 cells. Activation of NF-κB and production of PGE in human lung cancer cells were comparable with other cancer cells. In conclusion, this is the first study that shows A549 and H460 cells expressed two distinctive isoforms of CD74 but isoform at 41 kDa was absent. Due to the absence of this isoform, the direct physical interaction between them CD74 and CD44 was lacking. Furthermore, the data also demonstrated that lacking of direct physical interaction between CD74 and CD44 had no effect on NF-κB activation and PGE production indicating that CD74-mediated downstream signaling occurs either through coreceptors or indirect interaction with CD44 in human lung cancer cells. Abbreviation: CD: cluster of differentiation; SCLC: small cell lung cancer; NSCLC: nonsmall cell lung cancer; SCC: squamous cell carcinoma; ADC: adenocarcinoma; LCC: large cell carcinoma.

Prominent Blasts in Primary Cutaneous CD4+ Small/Medium T-Cell Lymphoproliferative Disorder. A Reconsideration of Diagnostic Criteria.

Abstract: Primary cutaneous CD4+ small/medium T-cell lymphoproliferative disorder (PCSM-LPD), recently downgraded from a T-cell lymphoma, is a poorly characterized histopathological entity. Presenting as a solitary lesion that often grows rapidly, it may raise suspicion for a cutaneous B-cell lymphoma. However, classically, the dermal lymphoid proliferation is predominantly CD4+ with a follicular T-helper profile and a smaller B-cell fraction. Diagnostic uncertainty may arise when B cells are present in large numbers, a B-cell clone is present, or large cell populations are seen. To meet the diagnostic criterion of PCSM-LPD, large cells should not constitute more than 30% of the infiltrate. The 2 cases presented in this article caused diagnostic uncertainty owing to the observation of high numbers of large cells and in one case the presence of a B-cell clone, on the background of otherwise typical clinicopathological features of PCSM-LPD. We review the literature specifically regarding the prevalence of large cell populations and their immunophenotypic characteristics and in light of this discuss whether a current diagnostic criterion should be reconsidered.

Large-cell neuroendocrine tumor of the prostate: a case report and review of the literature.

Abstract: Primitive neuroendocrine prostate neoplasms are rarely reported. This entity comprises carcinoid tumors and poorly differentiated neuroendocrine tumors, mainly those of the small-cell type. Large-cell-type primitive tumors are exceptional, and only nine cases are reported in the literature. Similar to neuroendocrine tumors of the prostate, large-cell-type primitive tumors may be observed in the context of conventional adenocarcinoma during androgen deprivation therapy or as prostatic metastasis of a distant neuroendocrine tumor, mainly pulmonary neoplasms. We report a Caucasian case of a mixed prostatic carcinoma, with the largest component being the large-cell neuroendocine carcinoma, in a patient who underwent a total prostatectomy for a localized cancer. Diagnostic, histological, therapeutic and evolutive aspects are reported and discussed. Large-cell primitive prostate neuroendocrine carcinoma is a rare but aggressive histological entity, which can be associated or not with an adenocarcinomatous component. Mixed forms have a better outcome, mainly when diagnosed at an early stage.

Diagnosis-to-surgery interval and survival for different histologies of stage I–IIA lung cancer

Abstract: Background Guidelines on timeliness of lung cancer surgery are inconsistent. Lung cancer histologic subtypes have different prognosis and treatment. It is important to understand the consequences of delayed surgery for each lung cancer histologic subtype. This study aimed to examine the association between diagnosis-to-surgery time interval and survival for early stage lung cancer and selected histologic subtypes. Methods Patients diagnosed with stage I-IIA lung cancer between 2004 and 2015 receiving definitive surgery and being followed up until Dec. 31, 2018, were identified from Surveillance, Epidemiology, and End Results database. Histologic subtypes included adenocarcinoma, squamous or epidermoid carcinoma, bronchioloalveolar carcinoma, large cell carcinoma, adenosquamous carcinoma, carcinoid carcinoma, and small cell carcinoma. Diagnosis-to-surgery interval was treated as multi-categorical variables ( Results With a median follow-up time of 51 months, a total of 40,612 patients were analyzed, including 40.1% adenocarcinoma and 24.5% squamous or epidermoid carcinoma. The proportion of patients receiving surgery Conclusions Our findings support the guidelines of undertaking surgery within 1 month from diagnosis in patients with stage I-IIA lung cancer. The observed dose-dependent effects emphasize the clinical importance of early surgery. Future studies with larger sample size of less frequent histologic subtypes are warranted to provide more evidence for histology-specific lung cancer treatment guidelines.

Small Cell Size Circulating Aneuploid Cells as a Biomarker of Prognosis in Resectable Non-Small Cell Lung Cancer.

Abstract: Objective: To study the distribution of circulating aneuploid cells (CACs) and its clinical significance in resectable non-small cell lung cancer (NSCLC). Patients and Methods: A total of 50 patients with resectable NSCLC were enrolled in this study. Blood samples (50 pre-surgery and 35 post-surgery) were collected, and these were used for the detection of CAC chromosome 8 heteroploidy through the subtraction enrichment and immunostaining fluorescence in situ hybridization (SE-iFISH) method. Results: Less than 20% of small cell size and more than 80% of large cell size CACs were detected among the patients. Karyotypes including triploid, tetraploid, and multiploid have variable distribution among the CACs. The triploid subtype accounted for the majority of small cell size CAC, whereas the multiploid subtype accounted for the majority of large cell size CAC. We found that patients with triploid total small cell size, and triploid small cell size CACs but not large cell size CACs derived from pre-surgery samples had shorter disease-free survival. Moreover, triploid total small cell size and triploid small cell size CACs were associated with TNM stage and/or recurrence. Nevertheless, the variation between pre- and post-surgery CAC was not related to survival among patients with resectable NSCLC. Conclusions: Pre-surgery small cell size CAC, especially the triploid subtype, could be regarded as a potential prognostic biomarker for patients with resectable NSCL

Utility of SOX6 and DAB2 for the Diagnosis of Malignant Mesothelioma.

Abstract: The separation of malignant mesothelioma from non-small cell lung carcinomas can be a difficult problem Sex-determining region Y box 6 (SOX6) and disabled homolog 2 (DAB2) have recently been proposed as sensitive/specific markers of mesothelial lineage, but have not yet been independently tested for utility in mesothelioma diagnosis Using tissue microarrays containing mesotheliomas (epithelioid: n=40, sarcomatoid: n=23) and non-small cell lung carcinomas (adenocarcinoma: n=52, squamous cell carcinoma: n=57, large cell carcinoma: n=12) we evaluated the performance of SOX6 and DAB2 by themselves, in conjunction with other established mesothelioma markers (calretinin, WT1, D2-40, CK5/6, HEG1) and combined with 3 broad-spectrum established carcinoma markers: claudin-4, MOC31, and BerEP4 For epithelioid mesothelioma, SOX6 and DAB2 had sensitivities of 85% and 98%, respectively For sarcomatoid mesothelioma, SOX6 had a sensitivity of 13% and DAB2 could not be assessed due to background stromal staining For SOX6 alone, specificity for mesothelioma versus adenocarcinoma, squamous cell carcinoma, and large cell carcinoma was 94%, 79%, and 92%, respectively, while for DAB2 specificity was 77%, 86%, and 67% Combinations of SOX6 and established mesothelioma markers produced sensitivities of 95% or greater A combination of SOX6 positive/claudin-4 negative staining was 95% to 100% specific for mesothelioma versus carcinoma with a sensitivity of 85% SOX6 is a promising marker for the diagnosis of mesothelioma and potentially could be combined with other mesothelial markers or a broad-spectrum carcinoma marker to reach an accurate diagnosis with relatively few immunostains, The relatively low specificity and difficulty of interpreting DAB2 staining limits its utility for mesothelioma diagnosis

A Novel Strategy for the Diagnosis of Pulmonary High-Grade Neuroendocrine Tumor

Abstract: Correctly diagnosing a histologic type of lung cancer is important for selecting the appropriate treatment because the aggressiveness, chemotherapy regimen, surgical approach, and prognosis vary significantly among histologic types. Pulmonary NETs, which are characterized by neuroendocrine morphologies, represent approximately 20% of all lung cancers. In particular, high-grade neuroendocrine tumors (small cell lung cancer and large cell neuroendocrine tumor) are highly proliferative cancers that have a poorer prognosis than other non-small cell lung cancers. The combination of hematoxylin and eosin staining, Ki-67, and immunostaining of classic neuroendocrine markers, such as chromogranin A, CD56, and synaptophysin, are normally used to diagnose high-grade neuroendocrine tumors; however, they are frequently heterogeneous. This article reviews the diagnostic methods of lung cancer diagnosis focused on immunostaining. In particular, we describe the usefulness of immunostaining by Stathmin-1, which is a cytosolic phosphoprotein and a key regulator of cell division due to its microtubule depolymerization in a phosphorylation-dependent manner, for the diagnosis of high-grade neuroendocrine tumors.

Pure large cell neuroendocrine carcinoma of the gallbladder, is surgical relentlessness beneficial? A case report and literature review

Abstract: Pure large cell neuroendocrine carcinoma of the gallbladder is a rare disease. However, the prognosis of this aggressive tumor is poor with short survival after diagnosis. We are describing in this manuscript a case of pure large cell neuroendocrine carcinoma in which survival exceeded 26 months, after performing two curative surgeries. We are reporting the case of a 68-year-old woman with a history of recovered right breast carcinoma and operated 6 years later for a completely asymptomatic gallbladder tumor of 31 mm. In this case, curative surgery was performed allowing monobloc resection of the gallbladder and the hepatic segments IVb and V, a lymph node dissection was performed to. The histological examination of the specimen and immunohistochemistry confirms that the tumor was a grade 3 pure large cell neuroendocrine carcinoma of gallbladder with lymph node invasion, the hepatic and biliary surgical margins were free. Postoperative adjuvant chemotherapy was administered and the evolution was eventless until the discovery at 20 months of a lymph node considered being metastatic recurrence. A second surgery was performed allowing removal of three lymph nodes. This time, a different protocol of chemotherapy was administered to our patient who remains alive and without recurrence at 26 months from her first surgery. Surgical relentlessness with free margins resections associated with appropriate chemotherapy probably improves the survival of patients suffering from this rare and aggressive tumor.

The association between thrombocytosis and subtype of lung cancer: a systematic review and meta-analysis

Abstract: Background Thrombocytosis is associated with poor lung cancer prognosis and has recently been identified as having a high predictive value in lung cancer detection Lung cancer has multiple histological and genetic subtypes and it is not known whether platelet levels differ across subtypes Methods PubMed and Embase were systematically searched for studies that reported pre-treatment platelet count, as either averages or proportion of patients with thrombocytosis, by histological subtype of lung cancer Suitable studies were synthesised in meta-analyses; subgroup analyses examined for differences across subtypes Results The prevalence of pre-treatment thrombocytosis across all lung cancer patients was 27% (95% CI: 17 to 37%) By subtype, this was 22% (95% CI: 7 to 41%) for adenocarcinoma (ADC), 28% (95% CI: 15 to 43%) for squamous cell carcinoma (SCC), 36% (95% CI: 13 to 62%) for large cell carcinoma, and 30% (95% CI: 8 to 58%) for small cell lung cancer (SCLC) The pooled mean platelet count for lung cancer patients was 289×109 /L (95% CI: 268 to 311) By subtype, this was 282×109 /L (95% CI: 259 to 306) for ADC, 297×109 /L (95% CI: 238 to 356) for SCC, 290×109 /L (95% CI: 176 to 404) for LCC, and 293×109 /L (95% CI: 244 to 342) for SCLC There was no difference in thrombocytosis prevalence (p=076) or mean platelet count (p=096) across the subtypes Conclusion We report no evidence of differences in platelet levels across the major subtypes of lung cancer A high platelet level is likely to be generic across all lung cancer subtypes KEY MESSAGES What is the key question? Which (if any) subtype(s) of lung cancer are more associated with thrombocytosis? What is the bottom line? This can facilitate lung cancer diagnostics and provide insights into the biological mechanism between lung cancer and thrombocytosis Why read on? This is the first systematic review to compare platelet count across different subtypes of lung cancer, combining data from 9,891 patients across 38 studies

Overexpression of Human Aspartyl (Asparaginyl) β-hydroxylase in NSCLC: Its Diagnostic Value by Means of Exosomes of Bronchoalveolar Lavage.

Abstract: The human aspartyl β-hydroxylase (ASPH) is overexpressed in tumor tissues. Bronchoalveolar lavage (BAL) is a diagnostic procedure for infections and malignancies. The aim of this study was to investigate whether tumor exosomes carrying ASPH gene marker were present in bronchoalveolar fluid of patients with non-small cell lung cancer (NSCLC). A tissue microarray analysis was applied to explore the expression of ASPH in different histologic NSCLC. The human NSCLC cell lines and normal bronchial cell lines were used to study exosomal ASPH exprerssion. A total of 27 NSCLC, 21 benign tumor, and 15 healthy controls underwent BAL. Immunohistochemistry was performed to study the ASPH expression in malignant and normal lung tissues. The expression characteristics of ASPH in different NSCLC and normal bronchial cells and pneumocytes were confirmed by cell blocks. A reverse transcription-quantitative polymerase chain reaction was carried out to study the levels of exosomal ASPH expression. Immunohistochemical staining of tissue microarray demonstrated that overexpression of ASPH was found in NSCLC tissues including adenocarcinoma, large cell carcinoma, and squamous cell carcinoma, but absent in adjacent normal tissues. All NSCLC specimens exhibited high levels of ASPH immunoreactivity, while nonmalignant and normal lung tissues exhibited a very low level of expression. Overexpression of ASPH was found in exosomes from NSCLC cell lines but absent from the normal bronchial cell line NL-20. ASPH level from BAL exosomes was significantly increased in NSCLC patients compared with that from nonmalignant or health group. Our method of isolation of BAL exosomes was easily performed in the clinical laboratory. BAL exosomal ASPH can be a potential biomarker for NSCLC diagnosis.

Primary large cell neuroendocrine carcinoma of the ovary: A rare entity.

Abstract: Background Large-cell neuroendocrine carcinoma (LCNEC) of the ovary is rare, highly aggressive tumor and diagnosed at advanced stages. Immunohistochemistry is required for the diagnosis. The optimal treatment management is not codified because of its rarity. Case presentation We report the case of a 36-year-old woman with a locally advanced stage LCNEC of the ovary managed by surgery and adjuvant chemotherapy with etoposide and cisplatin. She remained disease free until now four years after the end of chemotherapy. Conclusion This report suggests the necessity of immunohistochemical analysis in the diagnosis of LCNEC of the ovary. Due to the rarity of LCNC, the general consensus on treatment is not standardized. We used adjuvant chemotherapy regimen similar to large cell carcinoma of the lung.

Mixed large cell neuroendocrine carcinoma and squamous cell carcinoma of the colon: detailed molecular characterisation of two cases indicates a distinct colorectal cancer entity.

Abstract: We present two rare cases of mixed large cell neuroendocrine carcinoma and squamous cell carcinoma of the colon. A literature search revealed only three published cases with similar histology but none of these reports provided profound molecular and mutational analyses. Our two cases exhibited a distinct, colon-like immunophenotype with strong nuclear CDX2 and β-catenin expression in more than 90% of the tumour cells of both components. We analysed the two carcinomas regarding microsatellite stability, RAS, BRAF and PD-L1 status. In addition, next-generation panel sequencing with Ion AmpliSeq™ Cancer Hotspot Panel v2 was performed. This approach revealed mutations in FBXW7, CTNNB1 and PIK3CA in the first case and FBXW7 and RB1 mutations in the second case. We looked for similar mutational patterns in three publicly available colorectal adenocarcinoma data sets, as well as in collections of colorectal mixed neuroendocrine-non-neuroendocrine neoplasms (MiNENs) and colorectal neuroendocrine carcinomas. This approach indicated that the FBXW7 point mutation, without being accompanied by classical adenoma-carcinoma sequence mutations, such as APC, KRAS and TP53, likely occurs at a relatively high frequency in mixed neuroendocrine and squamous cell carcinoma and therefore may be characteristic for this rare tumour type. FBXW7 codifies the substrate recognition element of an ubiquitin ligase, and inactivating FBXW7 mutations lead to an exceptional accumulation of its target β-catenin which results in overactivation of the Wnt-signalling pathway. In line with previously described hypotheses of de-differentiation of colon cells by enhanced Wnt-signalling, our data indicate a crucial role for mutant FBXW7 in the unusual morphological switch that determines these rare neoplasms. Therefore, mixed large cell neuroendocrine and a squamous cell carcinoma can be considered as a distinct carcinoma entity in the colon, defined by morphology, immunophenotype and distinct molecular genetic alteration(s).

In-depth molecular analysis of combined and co-primary pulmonary large cell neuroendocrine carcinoma and adenocarcinoma.

Abstract: Up to 14% of large cell neuroendocrine carcinomas (LCNEC) are diagnosed in continuity with non-small cell lung carcinoma. In addition to these combined lesions, 1-7% of lung tumors present as co-primary tumors with multiple synchronous lesions. We evaluated molecular and clinicopathological characteristics of combined and co-primary LCNEC-adenocarcinoma (ADC) tumors. Ten patients with LCNEC-ADC (combined) and 5 patients with multiple synchronous ipsilateral LCNEC and ADC tumors (co-primary) were included. DNA was isolated from distinct tumor parts and 65 cancer genes were analyzed by next generation sequencing. Immunohistochemistry was performed including neuroendocrine markers, pRb, Ascl1 and Rest. Pure ADC (N=37) and LCNEC (N=17) cases were used for reference. At least 1 shared mutation, indicating tumor clonality, was found in LCNEC- and ADC-parts of 10/10 combined tumors but only in 1/5 co-primary tumors. A range of identical mutations was observed in both parts of combined tumors: 8/10 contained ADC-related (EGFR/KRAS/STK11 and/or KEAP1), 4/10 RB1 and 9/10 TP53 mutations. Loss of pRb IHC was observed in 6/10 LCNEC- and 4/10 ADC-parts. The number and intensity of expression of Ascl1 and neuroendocrine markers increased from pure ADC (low) to combined ADC (intermediate) and combined and pure LCNEC (high). The opposite was true for Rest expression. In conclusion, all combined LCNEC-ADC tumors were clonally related indicating a common origin. A relatively high frequency of pRb inactivation was observed in both LCNEC- and ADC-parts, suggesting an underlying role in LCNEC-ADC development. Furthermore, neuroendocrine differentiation might be modulated by Ascl1(+) and Rest(-) expression. This article is protected by copyright. All rights reserved.

MRI features of breast implant-associated anaplastic large cell lymphoma

Abstract: Breast implant-associated anaplastic large cell lymphoma (BIA-ALCL) is a rare and newly recognized subtype of T cell Non-Hodgkin Lymphoma (NHLs) associated with breast implants.The mechanism involved in the development of this kind of lymphoma is still uncertain.BIA-ALCL is generally an indolent disease localized to the breast implant and its capsule and effectively treated with capsulectomy alone without chemotherapy.Clinically, BIA-ALCL may typically present a sudden-onset breast-swelling secondary to periimplant effusion. The minority of BIA-ALCL patients present a more aggressive mass-forming subtype, for which systemic therapy is mandatory.Despite the number of cases has recently increased, BIA-ALCL remains a rare disease described mainly in several case reports and small case series.Breast imaging, including mammography, ultrasound and breast MRI are routinely used in the screening of breast cancer; however, guidelines for the imaging and pathological diagnosis of this disease have only recently been proposed and included in the 2019 National Comprehensive Cancer Network (NCCN) consensus guidelines for BIA-ALCL.The main purpose of this pictorial is to illustrate the MRI signs of BIA-ALCL and correlate them with the corresponding pathology features in order to improve the knowledge of the principals MRI features of this type of lymphoma.

Is immunohistochemical expression of GATA3 helpful in the differential diagnosis of transformed mycosis fungoides and primary cutaneous CD30-positive T cell lymphoproliferative disorders?

Abstract: Mycosis fungoides with large cell transformation (MFLCT) can be difficult to distinguish from primary cutaneous CD30+ T cell lymphoproliferative disorders (PC CD30+ LPD), especially primary cutaneous anaplastic large cell lymphoma (PC-ALCL). This diagnostic distinction is critical for appropriate patient management. GATA3 has been proposed to be useful in the discrimination between these two entities. We identified 25 cases of MFLCT and 24 cases of PC CD30+ LPDs (including lymphomatoid papulosis (n=14), PC-ALCL (n=6), and CD30+ LPD, not otherwise specified (n=4)) diagnosed at our institution from 2002 to 2019. Sections from archived specimens were stained to evaluate for GATA3 expression by immunohistochemistry and compared among cutaneous CD30+ T cell LPDs. The majority of the MFLCT cohort had strong, diffuse expression of GATA3 ranging from 0 to 100% of dermal T cells (mean 53.20%) with 15/25 cases (60%) showing GATA3 expression greater than 50%, while the PC CD30+ LPD group showed variable, moderate GATA3 labeling ranging from 0 to 60% of dermal T cells (mean 23.26%), with 5/6 cases (83%) showing GATA3 expression less than 40% (p =0.003). The calculated sensitivity and specificity were 56% and 74%, while positive and negative predictive values were 70% and 61%, respectively. Based on the percent staining of positive cells, using 50% as a cutoff value for expression, GATA3 might be a useful immunohistochemical marker to discriminate MFLCT from PC CD30+ LPDs, including PC-ALCL.