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1.
Anticancer Drugs ; 35(7): 653-657, 2024 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-38696710

RESUMO

Selective RET inhibitors have shown promise in thyroid cancer (TC) and nonsmall cell lung cancer (NSCLC) harboring RET fusions on next-generation sequencing (NGS), although rarity of the rearrangement has led to limited data for certain tumor types, such as carcinoma of unknown primary. We present a 65-year-old female with no history of malignancy, smoking or radiation exposure, who was found to have an anterior mediastinum malignancy of unknown primary, with metastases to supraclavicular lymph nodes. Core biopsy of the mediastinum revealed poorly differentiated carcinoma, while a biopsy of the thyroid revealed atypia of indeterminate significance (Bethesda III). PD-L1 immunohistochemistry was positive (90%), and liquid NGS revealed mutations in TP53 and the TERT promoter (c.-124C>T), as well as a CCDC6-RET fusion. This genetic profile resembled an anaplastic TC vs. NSCLC primary, although thymic primary and poorly differentiated TC remained on the differential. The patient was initiated on selpercatinib, which was held after 3 weeks due to thrombocytopenia and hypertension. At a reduced dosage, patient developed transaminitis, and selpercatinib was switched to pralsetinib. Brain MRI showed a nonenhancing temporal lobe signal abnormality, which on biopsy proved to be glioblastoma (GBM) with TERT promoter c.-124C>T mutation and FGFR3-TACC3 fusion by NGS. Pralsetinib was held during adjuvant chemoradiation for the GBM, and again for 4 weeks due to pneumonitis that resolved with steroids, and pralsetinib was restarted at a reduced dose. The patient has since demonstrated a stable reduction of the mediastinal mass for >15 months with RET inhibition therapy, despite several treatment interruptions.


Assuntos
Neoplasias do Mediastino , Neoplasias Primárias Desconhecidas , Proteínas Proto-Oncogênicas c-ret , Humanos , Feminino , Proteínas Proto-Oncogênicas c-ret/genética , Proteínas Proto-Oncogênicas c-ret/antagonistas & inibidores , Idoso , Neoplasias do Mediastino/tratamento farmacológico , Neoplasias do Mediastino/genética , Neoplasias Primárias Desconhecidas/tratamento farmacológico , Neoplasias Primárias Desconhecidas/genética , Neoplasias Primárias Desconhecidas/patologia , Pirazóis/uso terapêutico , Piridinas/uso terapêutico , Piridinas/farmacologia , Proteínas de Fusão Oncogênica/genética
2.
Hum Pathol ; 148: 41-50, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38697270

RESUMO

Extragonadal germ cell tumors (EGCTs) are rare, representing <5% of all germ cell tumors (GCTs). Whilst EGCTs share morphological and immunohistochemical features with their gonadal counterparts, they tend to be more aggressive and are frequently associated with secondary somatic malignancies. The aim of our study was to evaluate the clinical, morphological and immunohistochemical features, and to analyze tumors for chromosomal abnormalities of 12p, in addition to any novel genetic alterations, in a series of EGCTs. Seventy-seven EGCTs were included. Anterior mediastinum was the most common anatomic site, followed by central nervous system, retroperitoneum, sacroccygeal area, and neck. Whole genome SNP array identified isochromosome 12p in 26% of tumors. Additional cytogenetic abnormalities included the presence of gain of chr 21 in 37% of tumors. Somatic-type malignancies were identified in 8% of patients. Disease progression (metastasis and/or recurrence) was documented in 8 patients, most of whom died from their relapse. Three patients who died of disease had somatic-type malignancies. Mediastinal seminomas had a significantly better overall survival when compared to mediastinal non-seminomatous GCTs. Our study demonstrates that EGCTs share similar histologic features, but diverse clinical outcomes compared to their gonadal counterparts. Outcomes vary according to anatomic location and histologic subtypes. Our data corroborate that somatic-type malignancies are frequently encountered in mediastinal EGCTs and that their presence portends a poorer prognosis.


Assuntos
Neoplasias Embrionárias de Células Germinativas , Humanos , Neoplasias Embrionárias de Células Germinativas/patologia , Neoplasias Embrionárias de Células Germinativas/genética , Masculino , Adulto , Feminino , Adulto Jovem , Adolescente , Pessoa de Meia-Idade , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/análise , Criança , Segunda Neoplasia Primária/patologia , Segunda Neoplasia Primária/genética , Neoplasias do Mediastino/patologia , Neoplasias do Mediastino/genética , Neoplasias do Mediastino/mortalidade , Imuno-Histoquímica , Cromossomos Humanos Par 12/genética , Idoso , Recidiva Local de Neoplasia/patologia , Progressão da Doença , Polimorfismo de Nucleotídeo Único , Aberrações Cromossômicas , Predisposição Genética para Doença , Neoplasias Testiculares
3.
J Exp Clin Cancer Res ; 43(1): 148, 2024 May 22.
Artigo em Inglês | MEDLINE | ID: mdl-38773631

RESUMO

BACKGROUND: Primary mediastinal B-cell lymphoma (PMBL) and classical Hodgkin lymphoma (cHL) are distinct hematological malignancies of B-cell origin that share many biological, molecular, and clinical characteristics. In particular, the JAK/STAT signaling pathway is a driver of tumor development due to multiple recurrent mutations, particularly in STAT6. Furthermore, the XPO1 gene that encodes exportin 1 (XPO1) shows a frequent point mutation (E571K) resulting in an altered export of hundreds of cargo proteins, which may impact the success of future therapies in PMBL and cHL. Therefore, targeted therapies have been envisioned for these signaling pathways and mutations. METHODS: To identify novel molecular targets that could overcome the treatment resistance that occurs in PMBL and cHL patients, we have explored the efficacy of a first-in-class HSP110 inhibitor (iHSP110-33) alone and in combination with selinexor, a XPO1 specific inhibitor, both in vitro and in vivo. RESULTS: We show that iHSP110-33 decreased the survival of several PMBL and cHL cell lines and the size of tumor xenografts. We demonstrate that HSP110 is a cargo of XPO1wt as well as of XPO1E571K. Using immunoprecipitation, proximity ligation, thermophoresis and kinase assays, we showed that HSP110 directly interacts with STAT6 and favors its phosphorylation. The combination of iHSP110-33 and selinexor induces a synergistic reduction of STAT6 phosphorylation and of lymphoma cell growth in vitro and in vivo. In biopsies from PMBL patients, we show a correlation between HSP110 and STAT6 phosphorylation levels. CONCLUSIONS: These findings suggest that HSP110 could be proposed as a novel target in PMBL and cHL therapy.


Assuntos
Proteína Exportina 1 , Doença de Hodgkin , Carioferinas , Receptores Citoplasmáticos e Nucleares , Humanos , Carioferinas/antagonistas & inibidores , Carioferinas/metabolismo , Receptores Citoplasmáticos e Nucleares/metabolismo , Receptores Citoplasmáticos e Nucleares/antagonistas & inibidores , Animais , Camundongos , Doença de Hodgkin/tratamento farmacológico , Doença de Hodgkin/patologia , Doença de Hodgkin/metabolismo , Doença de Hodgkin/genética , Linfoma de Células B/tratamento farmacológico , Linfoma de Células B/metabolismo , Linfoma de Células B/patologia , Linfoma de Células B/genética , Proteínas de Choque Térmico HSP110/metabolismo , Proteínas de Choque Térmico HSP110/genética , Linhagem Celular Tumoral , Neoplasias do Mediastino/tratamento farmacológico , Neoplasias do Mediastino/metabolismo , Neoplasias do Mediastino/patologia , Neoplasias do Mediastino/genética , Ensaios Antitumorais Modelo de Xenoenxerto , Triazóis/farmacologia , Triazóis/uso terapêutico , Hidrazinas/farmacologia , Hidrazinas/uso terapêutico , Feminino , Fator de Transcrição STAT6/metabolismo , Terapia de Alvo Molecular
4.
Diagn Pathol ; 18(1): 127, 2023 Nov 29.
Artigo em Inglês | MEDLINE | ID: mdl-38031161

RESUMO

Neuroblastoma is rare in the adult population, especially in thoracic or mediastinal locations, with only 25 previously reported cases. We report an additional example of primary thymic neuroblastoma in a previously asymptomatic 71-year-old man with an anterior mediastinal mass who underwent robotic excision with pericardium and adjacent lung. The tumor was a 5.2 cm partially encapsulated, white-tan and rubbery mass with grossly identifiable areas of necrosis (25%) and hemorrhage. Histologically, the specimen showed a rim of adipose tissue and residual thymic tissue with areas of cystic thymic epithelium and prominent lymphoid tissue containing Hassall's corpuscles. The tumor was composed of uniform, round cells with scant cytoplasm and small nuclei with inconspicuous nucleoli set within a background of conspicuous neuropil. Mitotic figures were easily found. By immunohistochemistry, the tumor cells expressed synaptophysin, chromogranin, NKX2.2 (diffuse, nuclear), GFAP (patchy), SMI31 (neurofilament) (focal, cytoplasmic), and TdT (diffuse, nuclear), while lacking expression of CD99, TTF-1, CK 20, MCPyV, PHOX2B, Olig2, OCT3/4, CD45, CD3 and PAX5. S100 protein was negative in the neuroblastic cells, with scattered positive cells in a vague sustentacular-like pattern. Fluorescence in situ hybridization for isochromosome 12p and EWSR1 gene rearrangement were negative. As thymic neuroblastoma is extremely rare in adults, a neuroblastic tumor of germ cell origin (either primary or metastatic) or spread from a sinonasal tract tumor should be excluded because of differing treatments and prognoses. The properties of these rare neoplasms appear similar to olfactory neuroblastoma rather than pediatric-type neuroblastoma.


Assuntos
Neoplasias do Mediastino , Neuroblastoma , Adulto , Idoso , Humanos , Masculino , Biomarcadores Tumorais/genética , Imuno-Histoquímica , Hibridização in Situ Fluorescente , Neoplasias do Mediastino/genética , Neoplasias do Mediastino/química , Mediastino/patologia , Neuroblastoma/patologia
5.
Virchows Arch ; 482(5): 923-927, 2023 May.
Artigo em Inglês | MEDLINE | ID: mdl-36943470

RESUMO

Vasculogenic mesenchymal tumor (VMT), a primitive mesenchymal neoplasm enriched by various-sized atypical vessels, is a new entity that develops in mediastinal germ cell tumors (GCTs) with yolk sac tumor (YST) components after chemotherapy. Notably, patients with VMT in the residual GCT have increased risk of developing sarcomas or hematopoietic malignancies. Here, we report a late-teenage male patient with residual teratoma and high-grade VMT after chemotherapy for a mediastinal mixed GCT, including YST. Whole-exome sequencing revealed biallelic inactivation of TP53 and extensive copy number alterations that suggested whole-genome doubling. The biopsy tissue of the mixed GCT before chemotherapy exhibited overlapping genetic alterations to those in the VMT. Immunohistochemical analyses of the VMT showed that the abnormal vessels were positive for cytokeratin, glypican 3, EZH2, and IMP3. The findings that VMT inherits the genetic alterations of pre-existing mixed GCT and exhibits a partly YST-like immunophenotype might contribute to its clinical aggressiveness.


Assuntos
Tumor do Seio Endodérmico , Neoplasias do Mediastino , Neoplasias Embrionárias de Células Germinativas , Teratoma , Neoplasias Testiculares , Adolescente , Humanos , Masculino , Mediastino/patologia , Sequenciamento do Exoma , Teratoma/genética , Teratoma/patologia , Neoplasias do Mediastino/genética , Tumor do Seio Endodérmico/patologia , Neoplasias Testiculares/patologia
6.
Am J Surg Pathol ; 47(1): 81-90, 2023 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-36001451

RESUMO

Classic Hodgkin lymphoma (CHL) patients may infrequently present with a prior or recurrent disease with discordant histology resembling non-Hodgkin lymphomas. These include primary mediastinal large B-cell lymphoma (PMBL), diffuse large B-cell lymphoma (DLBCL), or mediastinal gray-zone lymphoma (MGZL). Such patients are often refractory to standard therapy and their diagnosis is hampered by significant morphologic and immunophenotypic overlap and insufficient molecular data. Among 509 CHL patients seen at an academic medical center, 6 patients had a prior or subsequent diagnosis different from CHL. Paired tissue samples were evaluated by targeted mutational analysis using a 164-gene panel. Our findings show multiple shared variants indicative of a clonal relationship between the CHL and the PMBL, DLBCL, or MGZL diagnoses. Most frequent mutated genes included TNFAIP3 (4 of 6, 66.7%), STAT6 (3 or 6, 50%), ARID1A (3 of 6, 50%), and XPO1 (3 of 5, 60%). Three patients showed the same oncogenic variant within the XPO1 gene (E571K), and mutations in TNFAIP3 and B2M were observed in 2 of the 5 patients with shared variants. In addition, differences in the mutation profile between the lymphoma pairs were also observed, which could represent clonal evolution. Mutational profiling could be of benefit in patients with recurrent/refractory disease with discordant histology, where the clonal relationship could be helpful to inform and guide therapeutic decisions. These findings provide further evidence of a true biological continuum surrounding CHL, PMBL, DLBCL, and MGZL and shed light on underlying genetic events and their clinical impact.


Assuntos
Doença de Hodgkin , Linfoma Difuso de Grandes Células B , Neoplasias do Mediastino , Humanos , Neoplasias do Mediastino/genética , Neoplasias do Mediastino/terapia , Neoplasias do Mediastino/diagnóstico , Doença de Hodgkin/diagnóstico , Linfoma Difuso de Grandes Células B/patologia , Imunofenotipagem , Mutação
7.
Oncologist ; 27(11): e912-e915, 2022 11 03.
Artigo em Inglês | MEDLINE | ID: mdl-36166584

RESUMO

BACKGROUND: Primary mediastinal nonseminoma germ cell tumors (PMNSGCT) are a subgroup of nonseminoma germ cell tumors (GCT) with poor prognosis. In this study, PMNSGCT-specific genomic landscape was analyzed and correlated with clinical outcomes. METHODS: DNA was extracted and sequenced from 28 archival tumor tissue of patients with mediastinal GCT (3 seminoma and 25 nonseminoma). Overall survival (OS) and association with gene alterations were estimated using the Kaplan-Meier and univariate Cox regression methods. RESULTS: Three patients (11%) had a karyotype XXY, 17/28 (61%) tumor samples presented chromosome 12p amplification. Somatic mutations were detected in 19/28 (68%) samples. The most frequently mutated genes were: TP53 (13/28; 46%), KIT (5/28; 18%), and KRAS (5/28; 18%). Deleterious TP53 alterations were associated with significantly reduced overall survival (HR: 7.16; P = .012). CONCLUSIONS: TP53 alterations are common in PMNSGCT and are associated with reduced overall survival, potentially underlying the poor sensitivity to chemotherapy observed in these patients.


Assuntos
Neoplasias do Mediastino , Neoplasias Embrionárias de Células Germinativas , Seminoma , Neoplasias Testiculares , Masculino , Humanos , Neoplasias Embrionárias de Células Germinativas/genética , Neoplasias Testiculares/genética , Neoplasias Testiculares/patologia , Seminoma/patologia , Neoplasias do Mediastino/genética , Neoplasias do Mediastino/patologia , Prognóstico , Proteína Supressora de Tumor p53/genética
8.
Mod Pathol ; 35(11): 1636-1643, 2022 11.
Artigo em Inglês | MEDLINE | ID: mdl-35660795

RESUMO

Neoplastic cartilage is a common component of teratomas in type II germ cell tumors. Although IDH1/2 mutations have been well-described in somatic cartilaginous tumors, ranging from benign enchondromas to highly aggressive dedifferentiated chondrosarcomas, the presence of IDH1/2 mutations in cartilaginous neoplasms arising from germ cell tumors has not been previously investigated. To better understand the relationship between these tumors and their bone/soft tissue counterpart, we studied the IDH1/2 mutational status of 20 cases of primary mediastinal mixed germ cell tumors with areas of readily identifiable cartilaginous differentiation. Our study found that cartilaginous lesions arising in germ cell tumors have a different frequency and distribution of IDH1/2 mutations compared to those at somatic sites. We identified IDH1/2 mutations in only 15% (3/20) of cases, compared to a frequency in the literature among differentiated chondroid tumors of bone and soft tissue of 54%, a highly significant decreased frequency (p = 0.0011; chi-square test). Furthermore, they were exclusively IDH2 R172 mutations that occurred at a non-significant, increased frequency in the germ cell tumor group compared to conventional chondrosarcoma (15% vs. 5%, respectively, p > 0.05, chi-square test). The unexpected finding, therefore, was entirely attributable to the absence of IDH1 R132 mutation in chondroid neoplasia of germ cell origin (p < 0.00001, Fisher exact test). Our results suggest that a subset of cartilaginous lesions arising within type II germ cell tumors have a similar oncogenic mechanism to their bone/soft tissue counterpart but that the majority form using different oncogenic mechanisms compared to their somatic counterparts.


Assuntos
Neoplasias Ósseas , Condrossarcoma , Neoplasias do Mediastino , Neoplasias Embrionárias de Células Germinativas , Humanos , Isocitrato Desidrogenase/genética , Neoplasias do Mediastino/genética , Mutação , Condrossarcoma/genética , Condrossarcoma/patologia , Neoplasias Ósseas/genética , Neoplasias Ósseas/patologia , Cartilagem/patologia , Neoplasias Embrionárias de Células Germinativas/genética
9.
Genes Chromosomes Cancer ; 61(10): 603-615, 2022 10.
Artigo em Inglês | MEDLINE | ID: mdl-35611992

RESUMO

Development of primary mediastinal B-cell lymphoma (PMBL) is driven by cumulative genomic aberrations. We discovered a unique copy-neutral loss of heterozygosity (CN-LOH) landscape of PMBL which distinguishes this tumor from other B-cell malignancies, including the biologically related diffuse large B-cell lymphoma. Using single nucleotide polymorphism array analysis we identified large-scale CN-LOH lesions in 91% (30/33) of diagnostic PMBLs and both investigated PMBL-derived cell lines. Altogether, the cohort showed 157 extra-large (25.3-248.4 Mb) CN-LOH lesions affecting up to 14 chromosomes per case (mean of 4.4) and resulting in a reduction of heterozygosity an average of 9.9% (range 1.3-51%) of the genome. Predominant involvement of terminal chromosomal segments suggests the implication of B-cell specific crossover events in the pathogenesis of PMBL. Notably, CN-LOH stretches non-randomly clustered on 6p (60%), 15 (37.2%), and 17q (40%), and frequently co-occurred with homozygous mutations in the MHC I (6p21), B2M (15q15), and GNA13 (17q23) genes, respectively, as shown by preliminary whole-exome/genome sequencing data. Altogether, our findings implicate CN-LOH as a novel and distinct mutational process contributing to the molecular pathogenesis of PMBL. The aberration acting as "second hit" in the Knudson hypothesis, ranks as the major mechanism converting to homozygosity the PMBL-related driver genes. Screening of the cohort of 199 B cell leukemia/lymphoma whole-genomes revealed significant differences in the CN-LOH landscape of PMBL and other B-cell malignancies, including the biologically related diffuse large B-cell lymphoma.


Assuntos
Linfoma Difuso de Grandes Células B , Neoplasias do Mediastino , Genômica , Humanos , Perda de Heterozigosidade , Linfoma Difuso de Grandes Células B/diagnóstico , Neoplasias do Mediastino/genética , Mutação
10.
Cancer Biol Ther ; 23(1): 393-400, 2022 12 31.
Artigo em Inglês | MEDLINE | ID: mdl-35576916

RESUMO

Mediastinal yolk sac tumors (YSTs) are highly aggressive germ cell tumors with an extremely poor prognosis. Radiotherapy plays an important role in the treatment of mediastinal YSTs. To maximize benefit from radiotherapy in patients with mediastinal YSTs, exploring functionally relevant biomarkers is essential. Previous studies have demonstrated that mutations in DNA-damage repair (DDR) genes, including BRCA1/2, potentially enhance sensitivity to radiotherapy in solid tumors. However, DDR-gene mutations, as possible predictive biomarkers for radiotherapy in primary mediastinal YSTs, have not yet been reported. Herein, we report a 29-year-old male patient with a refractory metastatic primary YST involving a germline frameshift mutation in the BRCA2 gene (NM_000059.3: exon11: c.4563_4564delAT: L1522fs). During treatment alternation, the patient was found to respond poorly to chemotherapy with or without an immune checkpoint inhibitor but well to radiotherapy. Finally, the patient achieved approximately 17 months of overall survival. To the best of our knowledge, this case report is the first to describe a remarkable response to local radiotherapy in a patient with a refractory metastatic mediastinal YST involving a DDR-gene mutation (germline BRCA2 frameshift variation). This case report provides insightful clues for precision radiotherapy in clinical practice.


Assuntos
Tumor do Seio Endodérmico , Neoplasias do Mediastino , Adulto , Proteína BRCA2/genética , Biomarcadores , Tumor do Seio Endodérmico/genética , Tumor do Seio Endodérmico/patologia , Tumor do Seio Endodérmico/radioterapia , Mutação da Fase de Leitura , Mutação em Linhagem Germinativa , Humanos , Masculino , Neoplasias do Mediastino/genética , Neoplasias do Mediastino/patologia , Neoplasias do Mediastino/radioterapia
11.
Ann Diagn Pathol ; 59: 151951, 2022 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-35489185

RESUMO

The development of clonally related hematologic neoplasms in the setting of primary mediastinal germ cell tumors (PMGCTs) has been recognized previously and is associated with a dismal prognosis. However, the presentation of hematologic neoplasms as chronic myelomonocytic leukemia (CMML) and hemophagocytic lymphohistiocytosis (HLH) has been rarely reported. Here we report two patients with PMGCTs and hematologic neoplasms. The PMGCT was composed mostly of yolk sac tumor whereas the hematologic neoplasms had morphologic features that resembled CMML and HLH. The hematologic neoplasms from both patients harbored isochromosome 12p [i(12p)] and TP53 mutations, supporting a clonal relationship between these tumors. This association represents a unique clinical syndrome that likely contributes to the poor clinical outcome of these patients.


Assuntos
Neoplasias Hematológicas , Isocromossomos , Neoplasias do Mediastino , Neoplasias Embrionárias de Células Germinativas , Neoplasias Testiculares , Neoplasias Hematológicas/genética , Humanos , Masculino , Neoplasias do Mediastino/genética , Neoplasias do Mediastino/patologia , Mutação , Neoplasias Embrionárias de Células Germinativas/genética , Proteína Supressora de Tumor p53/genética
12.
Hum Pathol ; 123: 113-122, 2022 05.
Artigo em Inglês | MEDLINE | ID: mdl-35181378

RESUMO

Cardiac undifferentiated pleomorphic sarcoma (UPS) is a rare malignancy. Several studies have revealed frequent MDM2, CDK4, PDFGRA, and KIT amplifications and CDKN2A and CDKN2B deletions. Cases lacking the above copy number alterations may harbor alternative driver mutations; however, little is known about such occurrences. This study was conducted to gain further insights into the molecular features of cardiac UPS using targeted sequencing of 560 cancer-related genes, and fluorescence in situ hybridization and immunohistochemistry of MDM2, CDK4, CDKN2A, TP53, and RB1 in 9 cardiac UPS cases. TP53 mutation or CDKN2A deletion was found in cases lacking MDM2 amplification. Further, p53 overexpression was detected in the case with TP53 mutation, while p16 expression was completely lost in the case with CDKN2A homozygous deletion. p16 overexpression was found in cases with MDM2 and CDK4 amplification but without CDKN2A deletion. Immunohistochemistry of MDM2, CDK4, p53, and p16 is expected to be preliminarily used for gene status analysis. As cardiac UPS and intimal sarcomas are merging into a single spectrum, mutation data for 3 cardiac UPS and 9 intimal sarcomas from the literature, as well as data for 5 cardiac UPS in our study were evaluated, and known recurrently mutated cancer driver genes, including PDGFRB, TP53, ALK, PTCH1, RET, ERBB4, JAK3, GATA1, PIK3CG, and RARA, were identified. Several new potentially actionable mutations, including those in RARA, ALK, PTCH1, RET, ROS1, ABL1, and MET, were also found. These findings improve the molecular understanding of this rare malignancy and are expected to provide a basis for developing precision therapeutics for cardiac UPS and intimal sarcomas.


Assuntos
Neoplasias Cardíacas , Histiocitoma Fibroso Maligno , Neoplasias do Mediastino , Sarcoma , Neoplasias de Tecidos Moles , Neoplasias Cardíacas/genética , Neoplasias Cardíacas/patologia , Histiocitoma Fibroso Maligno/genética , Homozigoto , Humanos , Hibridização in Situ Fluorescente , Neoplasias do Mediastino/genética , Mutação , Proteínas Tirosina Quinases/genética , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas c-mdm2/genética , Receptores Proteína Tirosina Quinases/genética , Sarcoma/genética , Sarcoma/patologia , Deleção de Sequência , Neoplasias de Tecidos Moles/genética , Proteína Supressora de Tumor p53/genética
14.
Leuk Lymphoma ; 63(4): 834-844, 2022 04.
Artigo em Inglês | MEDLINE | ID: mdl-35075971

RESUMO

Few data exist concerning circulating tumor DNA (ctDNA) relevance in primary mediastinal B-cell lymphoma (PMBL). To explore this topic, we applied a 9-gene next-generation sequencing pipeline to samples from forty-four PMBL patients (median age 36.5 years). The primary endpoint was a similarity between paired biopsy/plasma mutational profiles. We detected at least one variant in 32 plasma samples (80%). The similarity between the biopsy and ctDNA genetic profiles for the 30 patients with paired mutated biopsy/plasma samples was greater than or equal to 80% in 19 patients (63.3%). We then compared PMBL ctDNA features with those of a cohort of Hodgkin lymphoma patients (n = 60). The top three mutated genes were SOCS1, TNFAIP3, and B2M in both lymphoma types. PMBL displayed more alterations in TNFAIP3 (71.9% vs. 46.3%, p = 0.029) and GNA13 (46.9% vs. 17.1%, p = 0.013) than cHL. Our 9-gene set may delineate tumor genotypes using ctDNA samples from both lymphoma types.


Assuntos
DNA Tumoral Circulante , Doença de Hodgkin , Linfoma de Células B , Linfoma Difuso de Grandes Células B , Neoplasias do Mediastino , Adulto , DNA Tumoral Circulante/genética , Doença de Hodgkin/diagnóstico , Doença de Hodgkin/genética , Doença de Hodgkin/patologia , Humanos , Linfoma de Células B/genética , Linfoma Difuso de Grandes Células B/diagnóstico , Linfoma Difuso de Grandes Células B/genética , Linfoma Difuso de Grandes Células B/patologia , Neoplasias do Mediastino/diagnóstico , Neoplasias do Mediastino/genética , Neoplasias do Mediastino/patologia , Estudos Retrospectivos
15.
Blood ; 140(9): 955-970, 2022 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-34496020

RESUMO

Primary mediastinal large B-cell lymphoma (PMBCL) is a separate entity in the World Health Organization's classification, based on clinicopathologic features and a distinct molecular signature that overlaps with nodular sclerosis classic Hodgkin lymphoma (cHL). Molecular classifiers can distinguish PMBCL from diffuse large B-cell lymphoma (DLBCL) using ribonucleic acid derived from paraffin-embedded tissue and are integral to future studies. However, given that ∼5% of DLBCL can have a molecular PMBCL phenotype in the absence of mediastinal involvement, clinical information remains critical for diagnosis. Studies during the past 10 to 20 years have elucidated the biologic hallmarks of PMBCL that are reminiscent of cHL, including the importance of the JAK-STAT and NF-κB signaling pathways, as well as an immune evasion phenotype through multiple converging genetic aberrations. The outcome of PMBCL has improved in the modern rituximab era; however, whether there is a single standard treatment for all patients and when to integrate radiotherapy remains controversial. Regardless of the frontline therapy, refractory disease can occur in up to 10% of patients and correlates with poor outcome. With emerging data supporting the high efficacy of PD1 inhibitors in PMBCL, studies are underway that integrate them into the up-front setting.


Assuntos
Doença de Hodgkin , Linfoma Difuso de Grandes Células B , Neoplasias do Mediastino , Doença de Hodgkin/patologia , Humanos , Linfoma Difuso de Grandes Células B/diagnóstico , Linfoma Difuso de Grandes Células B/genética , Linfoma Difuso de Grandes Células B/terapia , Neoplasias do Mediastino/diagnóstico , Neoplasias do Mediastino/genética , Neoplasias do Mediastino/terapia , Mediastino/patologia , Rituximab/uso terapêutico
16.
Int J Mol Sci ; 22(21)2021 Oct 29.
Artigo em Inglês | MEDLINE | ID: mdl-34769213

RESUMO

Germ cell tumors (GCTs) are considered to be highly curable; however, there are major differences in the outcomes related to histology and anatomical localization. GCTs originating from the testis are, overall, sensitive to platinum-based chemotherapy, whereas GCTs originating from the mediastinum show a worse response, which remains largely unexplained. Here, we address the differences among GCTs from two different anatomical locations (testicular versus mediastinal/extragonadal), with a specific focus on the role of the P53 pathway. It was recently shown that GCTs with TP53 mutations most often localize to the mediastinum. To elucidate the underlying mechanism, TP53 knock-out lines were generated in cisplatin-sensitive and -resistant clones of the representative 2102Ep cell line (wild-type TP53 testicular GCT) and NCCIT cell line (hemizygously mutated TP53, mutant TP53 mediastinal GCT). The full knock-out of TP53 in 2102Ep and resistant NCCIT resulted in an increase in cisplatin resistance, suggesting a contributing role for P53, even in NCCIT, in which P53 had been reported to be non-functional. In conclusion, these results suggest that TP53 mutations contribute to the cisplatin-resistant phenotype of mediastinal GCTs and, therefore, are a potential candidate for targeted treatment. This knowledge provides a novel model system to elucidate the underlying mechanism of clinical behavior and possible alternative treatment of the TP53 mutant and mediastinal GCTs.


Assuntos
Antineoplásicos/farmacologia , Cisplatino/farmacologia , Neoplasias do Mediastino/genética , Neoplasias Embrionárias de Células Germinativas/genética , Neoplasias Testiculares/genética , Proteína Supressora de Tumor p53/genética , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Masculino , Neoplasias do Mediastino/tratamento farmacológico , Mutação/efeitos dos fármacos , Neoplasias Embrionárias de Células Germinativas/tratamento farmacológico , Neoplasias Testiculares/tratamento farmacológico
17.
Zhonghua Bing Li Xue Za Zhi ; 50(10): 1139-1144, 2021 Oct 08.
Artigo em Chinês | MEDLINE | ID: mdl-34619867

RESUMO

Objective: To investigate the clinicopathological features and prognostic factors of primary mediastinal large B-cell lymphoma (PMBL). Methods: The clinical data of 60 patients with PMBL including 44 biopsy cases and 16 consultation cases from September 2000 to November 2019 in the Department of Pathology, China-Japan Friendship Hospital (14 cases) and Peking Union Medical College Hospital (46 cases) were enrolled. Pathologic features, immunophenotype, immunoglobulin (Ig) gene rearrangement and microRNA expression profile were retrospectively studied. Results: Of the 60 patients, 23 were males and 37 were females, age ranged from 15 to 64 years (median 28 years). Immunohistochemical staining showed that the tumor cells were positive for pan-B cell antigens, CD30 (77.4%, 24/31), CD23 (73.1%, 19/26), MUM1 (45.8%, 11/24), Ki-67 index ≥70 % (90.6%, 29/32). EBER in situ hybridization was analyzed in 21 PMBL, only one case (4.8%) was positive. Ig gene rearrangement was performed in 20 cases, and seven were positive (35.0%). MicroRNA gene expression profiles were analyzed in seven cases of PMBL and nine cases of diffuse large B-cell lymphoma, and there were 33 microRNAs with significant difference (P<0.05). Univariate analysis indicated that the poor prognostic factors included serum lactate dehydrogenase (LDH) level,International Prognostic Index (IPI) score ≥3, stages Ⅲ-Ⅳ, chemotherapy not combined with rituximab and MUM1 positivity (P<0.05). Multivariate analysis showed that the treatment combined with rituximab was independently related to prognosis (P<0.05). Conclusions: PMBL is different from diffuse large B-cell lymphoma in clinicopathologic features, immunophenotypic presentation and molecular features. The prognostic factors, molecular genetics and immunological characteristics reveal that this study has enriched our understanding of the biology of PMBL, thus providing evidence and strategies for treatment.


Assuntos
Linfoma Difuso de Grandes Células B , Neoplasias do Mediastino , MicroRNAs , Adolescente , Adulto , Feminino , Humanos , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Linfoma Difuso de Grandes Células B/genética , Masculino , Neoplasias do Mediastino/tratamento farmacológico , Neoplasias do Mediastino/genética , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Adulto Jovem
18.
Int J Mol Sci ; 22(17)2021 Aug 27.
Artigo em Inglês | MEDLINE | ID: mdl-34502216

RESUMO

Background and case: An adolescent male presented with a second mediastinal tumor 1.5 years after treatment of a proven malignant germ-cell tumor in that location. The differential diagnosis included a recurrent germ-cell tumor or a non-germ cell malignancy. Serum tumor markers alpha-fetoprotein (AFP) and human chorionic gonadotrophin (HCG) were negative. The first biopsy was not informative, and the second biopsy gave a broad differential diagnosis including secondary non-germ cell malignancy using histology and immunohistochemistry. DNA methylation profiling, RNA sequencing, and targeted microRNA371a-3p profiling was subsequently performed, without a supportive result. After resection of the tumor the definitive diagnosis yielded two secondary non-germ cell malignancies in the form of a leiomyosarcoma and a solitary neuro endocrine carcinoma (NEC). In spite of the differences between the molecular profiles of the initial germ-cell tumor, the leiomyosarcoma and large-cell NEC are clonally related, as determined by the presence of identical chromosomal breakpoints. The copy number profiles suggest an initial polyploidization step, followed by various independent chromosomal gains and losses. This case demonstrates that germ-cell tumors must be evaluated carefully, including molecularly, in which the non-germ cell malignancy is negative for miR-371a-3p, both in tissue as well as in serum, in contrast to the primary tumor. We conclude that the patient presented with a primary type II mediastinal GCT and, a year and a half later, followed by a leiomyosarcoma and a large-cell NEC presenting as two secondary somatic-type malignancies clonally related to the original GCT. Conclusions: Malignant germ-cell tumors are known to recur as a somatic-type malignancy in very rare cases. This case report illustrates the challenges faced in defining the nature and clonality of the secondary somatic-type malignancies.


Assuntos
Biomarcadores Tumorais/genética , Neoplasias do Mediastino/patologia , Recidiva Local de Neoplasia/patologia , Neoplasias Embrionárias de Células Germinativas/patologia , Adolescente , Humanos , Masculino , Neoplasias do Mediastino/genética , Neoplasias do Mediastino/terapia , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/terapia , Neoplasias Embrionárias de Células Germinativas/genética , Neoplasias Embrionárias de Células Germinativas/terapia , Prognóstico
20.
Ital J Pediatr ; 47(1): 134, 2021 Jun 09.
Artigo em Inglês | MEDLINE | ID: mdl-34108028

RESUMO

BACKGROUND: Neuroblastoma (NB) is the most common extracranial solid tumor in children. It is known for high heterogeneity and concealed onset. In recent years, the mechanism of its occurrence and development has been gradually revealed. The purpose of this study is to summarize the clinical characteristics of children with NB and abnormal chromosome 10, and to investigate the relationship between the number and structure of chromosome 10 abnormalities and NB prognosis. METHODS: Chromosome G-banding was used at the time of diagnosis to evaluate the genetics of chromosomes in patients with NB and track their clinical characteristics and prognosis. All participants were diagnosed with NB in the Medical Oncology Department of the Beijing Children's Hospital from May 2015 to December 2018 and were followed up with for at least 1 year. RESULTS: Of all 150 patients with bone marrow metastases, 42 were clearly diagnosed with chromosomal abnormalities. Thirteen patients showed abnormalities in chromosome 10, and chromosome 10 was the most commonly missing chromosome. These 13 patients had higher LDH and lower OS and EFS than children with chromosomal abnormalities who did not have an abnormality in chromosome 10. Eight patients had both MYCN amplification and 1p36 deletion. Two patients had optic nerve damage and no vision, and one patient had left supraorbital metastases 5 months after treatment. CONCLUSIONS: The results indicated that chromosome 10 might be a new prognostic marker for NB. MYCN amplification and 1p36 deletion may be related to chromosome 10 abnormalities in NB. Additionally, NB patients with abnormal chromosome 10 were prone to orbital metastases.


Assuntos
Neoplasias da Medula Óssea/secundário , Aberrações Cromossômicas , Cromossomos Humanos Par 10 , Neuroblastoma/genética , Neuroblastoma/patologia , Neoplasias das Glândulas Suprarrenais/genética , Neoplasias das Glândulas Suprarrenais/patologia , Neoplasias da Medula Óssea/genética , Pré-Escolar , Cromossomos Humanos Par 1 , Feminino , Humanos , Lactente , Masculino , Neoplasias do Mediastino/genética , Neoplasias do Mediastino/patologia , Proteína Proto-Oncogênica N-Myc/genética , Neoplasias Orbitárias/genética , Neoplasias Orbitárias/secundário , Prognóstico , Neoplasias Retroperitoneais/genética , Neoplasias Retroperitoneais/patologia
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