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AIMS: Burkitt lymphoma (BL) is an aggressive B-cell lymphoma that, in some instances, may show a granulomatous reaction associated with a favourable prognosis and occasional spontaneous regression. In the present study, we aimed to define the tumour microenvironment (TME) in four such cases, two of which regressed spontaneously. METHODS AND RESULTS: All cases showed aggregates of tumour cells with the typical morphology, molecular cytogenetics and immunophenotype of BL surrounded by a florid epithelioid granulomatous reaction. All four cases were Epstein-Barr virus (EBV)-positive with type I latency. Investigation of the TME showed similar features in all four cases. The analysis revealed a proinflammatory response triggered by Th1 lymphocytes and M1 polarised macrophages encircling the neoplastic cells with a peculiar topographic distribution. CONCLUSIONS: Our data provide an in-vivo picture of the role that specific immune cell subsets might play during the early phase of BL, which may be capable of maintaining the tumour in a self-limited state or inducing its regression. These novel results may provide insights into new potential therapeutic avenues in EBV-positive BL patients in the era of cellular immunotherapy.
Assuntos
Linfoma de Burkitt/patologia , Infecções por Vírus Epstein-Barr/patologia , Macrófagos/patologia , Células Th1/patologia , Microambiente Tumoral , Adolescente , Idoso , Feminino , Herpesvirus Humano 4 , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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The Epstein-Barr virus (EBV) is linked to various B-cell lymphomas, including Burkitt lymphoma (BL), classical Hodgkin lymphoma (cHL) and diffuse large B-cell lymphoma (DLBCL) at frequencies ranging, by routine techniques, from 5 to 10% of cases in DLBCL to >95% in endemic BL. Using higher-sensitivity methods, we recently detected EBV traces in a few EBV-negative BL cases, possibly suggesting a "hit-and-run" mechanism. Here, we used routine and higher-sensitivity methods (qPCR and ddPCR for conserved EBV genomic regions and miRNAs on microdissected tumor cells; EBNA1 mRNA In situ detection by RNAscope) to assess EBV infection in a larger lymphoma cohort [19 BL, 34 DLBCL, 44 cHL, 50 follicular lymphomas (FL), 10 T-lymphoblastic lymphomas (T-LL), 20 hairy cell leukemias (HCL), 10 mantle cell lymphomas (MCL)], as well as in several lymphoma cell lines (9 cHL and 6 BL). qPCR, ddPCR, and RNAscope consistently documented the presence of multiple EBV nucleic acids in rare tumor cells of several cases EBV-negative by conventional methods that all belonged to lymphoma entities clearly related to EBV (BL, 6/9 cases; cHL, 16/32 cases; DLBCL, 11/30 cases), in contrast to fewer cases (3/47 cases) of FL (where the role of EBV is more elusive) and no cases (0/40) of control lymphomas unrelated to EBV (HCL, T-LL, MCL). Similarly, we revealed traces of EBV infection in 4/5 BL and 6/7 HL cell lines otherwise conventionally classified as EBV negative. Interestingly, additional EBV-positive cases (1 DLBCL, 2 cHL) relapsed as EBV-negative by routine methods while showing EBNA1 expression in rare tumor cells by RNAscope. The relapse specimens were clonally identical to their onset biopsies, indicating that the lymphoma clone can largely loose the EBV genome over time but traces of EBV infection are still detectable by high-sensitivity methods. We suggest EBV may contribute to lymphoma pathogenesis more widely than currently acknowledged.
Assuntos
Infecções por Vírus Epstein-Barr/virologia , Antígenos Nucleares do Vírus Epstein-Barr/genética , Herpesvirus Humano 4/genética , Doença de Hodgkin/virologia , Linfoma não Hodgkin/virologia , RNA Mensageiro/genética , RNA Viral/genética , Infecções por Vírus Epstein-Barr/diagnóstico , Doença de Hodgkin/diagnóstico , Humanos , Itália , Linfoma não Hodgkin/diagnóstico , Técnicas de Diagnóstico Molecular , Células U937 , Carga ViralRESUMO
Uterine carcinosarcomas are biphasic neoplasms consisting of mixed epithelial and mesenchymal elements, representing less than 5% of all uterine malignancies. Carcinosarcomas are rare, although the most common cause of uterine cancer-specific death. Few information is available on the pathogenesis, and molecular characterization is poorly investigated. Consequently, the treatment has not changed over the last years and is far too being tailored, consisting of surgery and traditional chemotherapy and radiotherapy. Molecular characterization of liquid biopsy by circulating tumor DNA (ctDNA)/circulating cell-free DNA (ccfDNA) evaluation in a patient with uterine carcinosarcoma. Here, we describe a case report of an 83-year-old woman with carcinosarcomas, stage T3aN0M0. Cancer cells did not express estrogen nor progesterone receptors, while p53 and p16 were positive. Molecular characterization of ccfDNA and of ctDNA was performed by quantitative PCR, amplification-refractory mutation system technology. The presence of phosphatidylInositol-4,5-bisphosphate 3-Kinase catalytic subunit alpha p.E545A mutation was detected in plasma. This approach may suggest the use of liquid biopsy and the development of specific targeted therapy for precision personalized medicine even in rare carcinosarcomas.
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Carcinossarcoma/patologia , DNA Tumoral Circulante/genética , Classe I de Fosfatidilinositol 3-Quinases/genética , Mutação , Neoplasias Uterinas/patologia , Idoso de 80 Anos ou mais , Carcinossarcoma/sangue , Carcinossarcoma/genética , DNA Tumoral Circulante/sangue , Classe I de Fosfatidilinositol 3-Quinases/sangue , Feminino , Humanos , Terapia de Alvo Molecular , Prognóstico , Neoplasias Uterinas/sangue , Neoplasias Uterinas/genéticaRESUMO
BACKGROUND: Merkel cell carcinoma (MCC) is a rare neuroendocrine malignancy of the skin characterized by high aggressiveness. Four main factors are implicated in its development: immunosuppression, ultraviolet radiation, age and the Merkel cell polyomavirus (MCPyV). In recent years, immune checkpoint inhibitors have shown clinical activity in MCC treatment. CASE PRESENTATION: We report the case of an 82-year-old man with a lung adenocarcinoma diagnosis, who underwent immunotherapy with nivolumab as second-line treatment. Seven months after the diagnosis of lung cancer during the nivolumab treatment, the patient developed an eyelid MCC, initially misdiagnosed as a chalazion. A palliative radiotherapy was performed with clinical benefit. After a total of seven cycles of nivolumab, computed tomography showed a lung and cerebral disease progression. In addition, clinical conditions worsened leading to the patient's death 13 months after the initial lung cancer diagnosis. CONCLUSIONS: Cases of co-occurrence of MCC and non-small cell lung cancer (NSCLC) have rarely been reported. Interestingly, common risk factors may be postulated for both cancers. Considering the rarity of this adverse event, its short-term temporal relation with the administration of the drug, which makes a relation improbable, and the coexistence of other risk factors, which may provide plausible explanations, it is possible to conclude according to the WHO Adverse Reaction Terminology that a causal relation between the occurrence of this serious adverse event and the exposure to the drug is unlikely. However, the case deserves to be reported in the literature.
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Adenocarcinoma de Pulmão/diagnóstico , Carcinoma de Célula de Merkel/diagnóstico , Carcinoma de Célula de Merkel/etiologia , Neoplasias Palpebrais/diagnóstico , Neoplasias Palpebrais/etiologia , Segunda Neoplasia Primária , Idoso de 80 Anos ou mais , Antineoplásicos Imunológicos/farmacologia , Antineoplásicos Imunológicos/uso terapêutico , Biomarcadores , Carcinoma de Célula de Merkel/tratamento farmacológico , Neoplasias Palpebrais/tratamento farmacológico , Evolução Fatal , Humanos , Imuno-Histoquímica , Imageamento por Ressonância Magnética , Masculino , Nivolumabe/farmacologia , Nivolumabe/uso terapêutico , Tomografia Computadorizada por Raios XAssuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Lenalidomida , Mieloma Múltiplo/tratamento farmacológico , Mielofibrose Primária/tratamento farmacológico , Trombocitemia Essencial/complicações , Idoso , Aspirina/uso terapêutico , Medula Óssea/patologia , Calreticulina/genética , Dexametasona/administração & dosagem , Humanos , Hidroxiureia/efeitos adversos , Hidroxiureia/uso terapêutico , Lenalidomida/administração & dosagem , Masculino , Gamopatia Monoclonal de Significância Indeterminada/complicações , Gamopatia Monoclonal de Significância Indeterminada/diagnóstico , Gamopatia Monoclonal de Significância Indeterminada/patologia , Mieloma Múltiplo/complicações , Mieloma Múltiplo/diagnóstico , Osteólise/etiologia , Mielofibrose Primária/diagnóstico , Mielofibrose Primária/etiologia , Indução de Remissão , Fatores de Risco , Deleção de Sequência , Estomatite Aftosa/induzido quimicamenteAssuntos
Suscetibilidade a Doenças , Subunidade beta 1 de Receptor de Interleucina-12/deficiência , Infecções por Mycobacterium não Tuberculosas/diagnóstico , Infecções por Mycobacterium não Tuberculosas/etiologia , Mycobacterium xenopi , Adulto , Predisposição Genética para Doença , Humanos , Mycobacterium xenopi/imunologiaAssuntos
Cromossomos Humanos/genética , Leucemia de Mastócitos , Mutação , Transtornos Mieloproliferativos , Proteínas de Neoplasias , Idoso , Humanos , Leucemia de Mastócitos/sangue , Leucemia de Mastócitos/genética , Leucemia de Mastócitos/patologia , Leucemia de Mastócitos/terapia , Masculino , Transtornos Mieloproliferativos/sangue , Transtornos Mieloproliferativos/genética , Transtornos Mieloproliferativos/patologia , Transtornos Mieloproliferativos/terapia , Proteínas de Neoplasias/sangue , Proteínas de Neoplasias/genéticaAssuntos
Transformação Celular Viral , Infecções por Vírus Epstein-Barr/complicações , Infecções por Vírus Epstein-Barr/virologia , Herpesvirus Humano 4 , Linfoma Folicular/diagnóstico , Linfoma Folicular/etiologia , Linfoma Difuso de Grandes Células B/diagnóstico , Linfoma Difuso de Grandes Células B/etiologia , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores , Progressão da Doença , Infecções por Vírus Epstein-Barr/diagnóstico , Evolução Fatal , Feminino , Testes Genéticos , Humanos , Imuno-Histoquímica , Linfoma Folicular/terapia , Linfoma Difuso de Grandes Células B/terapia , Masculino , Resultado do TratamentoRESUMO
An 88-year-old patient underwent pacemaker generator replacement. Shortly after the replacement, the pacemaker pocket became swollen and, assuming a hematoma, underwent percutaneous drainage. However, the swelling was due to an aggressive lymphoma located in the pocket. This is the first described case of T-cell lymphoma in a pacemaker pocket.
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BACKGROUND: Polycythemia vera (PV) is one of the Philadelphia-negative myeloproliferative neoplasms (MPN), characterized by a pan-myelosis with an erythroid-predominant proliferation mainly driven by somatic JAK2V617F gain-of-function mutation. Hairy cell leukemia (HCL) is a rare B-cell lineage lymphoproliferative disease (LPD) with a typic immunophenotypic profile. BRAFV600E, leading to constitutive activation of the RAF/MEK/ERK signalling pathway and increased cell proliferation, is identified as the driver mutation in almost all cases. Although the risk of developing an LPD is significantly increased in patients with MPN compared with the general population, few cases of co-occurring PV and HCL are reported to date. BRAF is one of the most frequently mutated oncogenes in human cancer and some point mutations were identified in multiple neoplasms in addition to HCL, including follicular and papillary thyroid adenoma and carcinoma. CASE PRESENTATION: Here we report a molecular diagnostic challenge in a woman with a concomitant diagnosis of JAK2V617F PV, BRAFV600E HCL, and HRASQ61K thyroid follicular adenoma. CONCLUSION: In the age of molecular and precision medicine, this case underlines the importance of integrating molecular results with clinical, radiologic, cytologic, and histopathologic investigations.
Assuntos
Leucemia de Células Pilosas/patologia , Mutação , Policitemia Vera/patologia , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas p21(ras)/genética , Neoplasias da Glândula Tireoide/patologia , Feminino , Humanos , Leucemia de Células Pilosas/complicações , Leucemia de Células Pilosas/tratamento farmacológico , Leucemia de Células Pilosas/genética , Pessoa de Meia-Idade , Policitemia Vera/complicações , Policitemia Vera/tratamento farmacológico , Policitemia Vera/genética , Prognóstico , Inibidores de Proteínas Quinases/uso terapêutico , Neoplasias da Glândula Tireoide/complicações , Neoplasias da Glândula Tireoide/tratamento farmacológico , Neoplasias da Glândula Tireoide/genéticaRESUMO
ALK-negative anaplastic large cell lymphoma is a rare T-cell neoplasm with an aggressive course requiring prompt diagnostic work-up and treatment. Few cases of concomitant multiple myeloma and T-cell neoplasm are described in the literature, mainly regarding primary cutaneous anaplastic large cell lymphoma. We present the case of a 65-year-old man, simultaneously diagnosed with ALK-negative anaplastic large cell lymphoma with extranodal localization in the gastrocnemius muscle (stage 1AE) and IgG lambda multiple myeloma (ISS 2, Durie-Salmon stage 3A). Both diseases required therapeutic intervention due to the high proliferative index of lymphoma and the presence of bone lesions attributable to myeloma. The therapeutic program initially included chemotherapy (cyclophosphamide, doxorubicin, vincristine, etoposide, and prednisone; CHOEP), radiotherapy on the leg, bortezomib, and then consolidation with autologous hematopoietic stem cell transplantation. Despite being on bortezomib treatment and waiting for transplantation, the patient experienced an early myeloma progression that turned out to be refractory to second-line lenalidomide-based treatment. To our knowledge, this is the first case of concurrent diagnosis of extranodal ALK-negative anaplastic large cell lymphoma of the muscle and multiple myeloma. Simultaneous onset can be challenging for clinicians as both diseases may have an aggressive course requiring multiple treatments with increased risk of toxicity and complicated management.
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The incidence of endometrial cancer (EC) is increasing in developed countries. The most frequent is the endometrioid subtype with usually good prognosis; nevertheless, some cases escape this paradigm and may have recurrence. A recent study from The Cancer Genome Atlas suggested to implement the EC analysis by molecular profile for improving diagnosis, prognosis, and therapeutic treatment. The present preliminary study was performed on 15 G3 endometrioid endometrial cancers (G3 EEC) for the identification of somatic mutations in a panel of specific exons in selected genes as ARID1A, CTNNB1, KRAS, PIK3CA, POLE, PTEN, and TP53. The combined procedure, based on the Sanger sequencing and PCR-high-resolution melting analysis, allowed the identification of variations of the selected gene panel in most of patients (93%) of our cohort. The overall evaluation of mutational load exhibited that the most frequent mutated genes were PTEN (93%), followed by PIK3CA (47%) suggesting a deep involvement of PI3K pathway alteration in G3 EEC. Mutations in TP53 (27%), ARID1A (27%), POLE (13%), and at the lower level in KRAS and CTNNB1 (7%) were also observed (exclusively in FIGO III stage patients). The evaluation of the mutations of our proposed panel (ARID1A, CTNNB1, KRAS, PIK3CA, POLE, PTEN, TP53) is suitable to improve the characterization of G3 EEC and could suggest targetable pathways for development of personalized treatments.
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Carcinoma Endometrioide/diagnóstico , Carcinoma Endometrioide/genética , Neoplasias do Endométrio/diagnóstico , Neoplasias do Endométrio/genética , Biomarcadores Tumorais/genética , Feminino , Humanos , Mutação , Projetos Piloto , Polimorfismo de Nucleotídeo Único , PrognósticoRESUMO
This error was caused due to the author's oversight and this does not change the views or the results presented in the manuscript.
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The precise B cell of origin and molecular pathogenesis of nodal marginal zone lymphoma (NMZL) remain poorly defined. To date, due to the rarity of NMZL, the vast majority of already-published studies have been conducted on a limited number of samples and the technical approach to analyze the immunoglobulin genes was of amplifying rearranged variable region genes with the classical direct sequencing of the PCR products followed by cloning. Here, we studied the B cell Ig heavy-chain repertoires by next-generation sequencing (NGS) in 30 NMZL cases. Most of the cases were mutated (20/28; 71.5%) with homologies to the respective germ line genes ranging from 85 to 97, 83%, whereas 8/28 (28.5%) were unmutated. In addition, our results show that NMZL cases have a biased usage of specific immunoglobulin heavy-chain variable (IGHV) region genes. Moreover, we documented intraclonal diversity in all (100%) of the mutated cases and ongoing somatic hypermutations (SHM) have been confirmed by hundreds of reads. We analyzed the mutational pattern to detect and quantify antigen selection pressure and we found a positive selection in 4 cases, whereas in the remaining cases there was an unspecific stimulation. Finally, the disease-specific survival and the progression-free survival were significantly different between cases with mutated and unmutated IGHV genes, pointing out mutational status as a possible new biomarker in NMZL.
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Cadeias Pesadas de Imunoglobulinas/genética , Região Variável de Imunoglobulina/genética , Linfoma de Zona Marginal Tipo Células B/patologia , Mutação/genética , Neoplasias Esplênicas/patologia , Idoso , Idoso de 80 Anos ou mais , Linfócitos B/patologia , Feminino , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Humanos , Linfoma de Zona Marginal Tipo Células B/genética , Masculino , Prognóstico , Neoplasias Esplênicas/genética , Neoplasias Esplênicas/imunologiaRESUMO
PURPOSE: Early response to ABVD, assessed with interim FDG-PET (iPET), is prognostic for classical Hodgkin lymphoma (cHL) and supports the use of response adapted therapy. The aim of this study was to identify a gene-expression profile on diagnostic biopsy to predict iPET positivity (iPET+). EXPERIMENTAL DESIGN: Consecutive untreated patients with stage I-IV cHL who underwent iPET after two cycles of ABVD were identified. Expression of 770 immune-related genes was analyzed by digital expression profiling (NanoString Technology). iPET was centrally reviewed according to the five-point Deauville scale (DS 1-5). An iPET+ predictive model was derived by multivariate regression analysis and assessed in a validation set identified using the same inclusion criteria. RESULTS: A training set of 121 and a validation set of 117 patients were identified, with 23 iPET+ cases in each group. Sixty-three (52.1%), 19 (15.7%), and 39 (32.2%) patients had stage I-II, III, and IV, respectively. Diagnostic biopsy of iPET+ cHLs showed transcriptional profile distinct from iPET-. Thirteen genes were stringently associated with iPET+. This signature comprises two functionally stromal-related nodes. Lymphocytes/monocytes ratio (LMR) was also associated to iPET+. In the training cohort a 5-gene/LMR integrated score predicted iPET+ [AUC, 0.88; 95% confidence interval (CI), 0.80-0.96]. The score achieved a 100% sensitivity to identify DS5 cases. Model performance was confirmed in the validation set (AUC, 0.68; 95% CI, 0.52-0.84). Finally, iPET score was higher in patients with event versus those without. CONCLUSIONS: In cHL, iPET is associated with a genetic signature and can be predicted by applying an integrated gene-based model on the diagnostic biopsy.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores Tumorais/genética , Fluordesoxiglucose F18/metabolismo , Doença de Hodgkin/metabolismo , Tomografia por Emissão de Pósitrons/métodos , Transcriptoma , Adulto , Biomarcadores Tumorais/metabolismo , Bleomicina/administração & dosagem , Estudos de Coortes , Dacarbazina/administração & dosagem , Doxorrubicina/administração & dosagem , Feminino , Doença de Hodgkin/diagnóstico por imagem , Doença de Hodgkin/tratamento farmacológico , Doença de Hodgkin/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Curva ROC , Compostos Radiofarmacêuticos/metabolismo , Vimblastina/administração & dosagemRESUMO
Splenomegaly is a key clinical manifestation of myelofibrosis, and splenectomy is currently indicated in patients with drug refractory, symptomatic splenomegaly or with the aim of improving refractory cytopenias. Transformation to acute myeloid leukemia occurs in up to 20% of patients with myelofibrosis, while cases of myeloid sarcoma have been reported very unfrequently. In this manuscript, we report the case of a 60-year-old man with a history of primary myelofibrosis who underwent splenectomy because of drug-refractory massive splenomegaly, systemic symptoms and anemia. At the opening of the peritoneal cavity, the spleen resulted massively enlarged and tenaciously entrapped by a pervasive neoplastic-like tissue. The extensive involvement of the abdomen fatally complicated the surgical procedure. At postmortem examination, the spleen showed a diffuse infiltration of immature cells that were also found in the peritoneum, bowel, liver, lungs and myocardium. After immunohistochemical, cytogenetic, flow cytometric and molecular characterization of neoplastic population, a diagnosis of disseminated myeloid sarcoma of the spleen was made. This case report highlights a very unusual case of myeloid sarcoma originating from the spleen in a patient with myelofibrosis who had no evidence of bone marrow or peripheral blood involvement by leukemic cells. Molecular characterization showed that leukemic cells originated from the founding clone of the chronic phase. The sarcoma could not be suspected based on clinical findings and was diagnosed only at the time of surgical procedure and autopsy. This case suggests that leukemic transformation of myelofibrosis can originate outside the bone marrow and, presumably rarely, present as a granulocytic sarcoma.
Assuntos
Mielofibrose Primária/patologia , Sarcoma Mieloide/patologia , Esplenomegalia/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Mielofibrose Primária/tratamento farmacológico , Sarcoma Mieloide/etiologia , Esplenomegalia/etiologia , Esplenomegalia/cirurgiaRESUMO
PURPOSE: The phosphatidylinositol 3'-kinase (PI3K)/AKT/molecular target of rapamycin (mTOR) pathway is involved in the development of tumor resistance to endocrine therapy in breast cancer cell lines and represents an attractive target for pharmacologic intervention. However, the effects of endocrine therapy with aromatase inhibitors on in vivo expression of this signaling cascade, and its relation to tumor response and patient outcome, is unknown. EXPERIMENTAL DESIGN: PI3K, phospho-AKT (pAKT) and phospho-mTOR were assessed by immunohistochemistry on tumor specimens collected at baseline and after 6 months of treatment in 113 elderly breast cancer patients consecutively enrolled in a randomized phase II trial of primary letrozole therapy and letrozole associated with metronomic cyclophosphamide. RESULTS: Basal expression of the pathway was not significantly correlated with response or patient outcome. Both letrozole alone and letrozole with cyclophosphamide resulted in a significant reduction of PI3K expression (P = 0.02 and P < 0.005, respectively) and phospho-mTOR expression (P = 0.0001 and P = 0.0001, respectively). pAKT showed no change in the letrozole arm, whereas it was significantly decreased in the letrozole plus cyclophosphamide arm (P < 0.005). pAKT expression reduction was associated with a greater response rate (P = 0.05) and greater reduction in Ki67 expression (P = 0.05). Phospho-mTOR expression reduction was associated with a significantly longer disease-free survival in a multivariate analysis (P = 0.02). CONCLUSIONS: Letrozole inhibits key molecules in the PI3K pathway that are important targets of new drugs being developed to overcome resistance. Changes in these molecules may have prognostic significance. These results should be taken into account when planning prospective trials testing up-front aromatase inhibitor with drugs targeting the PI3K/AKT/mTOR signaling pathway.