Genetic insights into thymic carcinomas and thymic neuroendocrine neoplasms denote prognosis signatures and pathways / 中华医学杂志(英文版)

BACKGROUND@#Thymic carcinomas (TCs) and thymic neuroendocrine neoplasms (TNENs) are two aggressive subtypes of thymic malignancy. Traditional therapy for advanced TCs and TNENs has limited outcome. New genomic profiling of TCs and TNENs might provide insights that contribute to the development of new treatment approaches.@*METHODS@#We used gene panel sequencing technologies to investigate the genetic aberrations of 32 TC patients and 15 TNEN patients who underwent surgery at Shanghai Chest Hospital between 2015 and 2017. Patient samples were sequenced using a 324-gene platform with licensed technologies. In this study, we focused on clinically relevant genomic alterations (CRGAs), which are previously proven to be pathogenic alterations, to identify the pathology-specific mutational patterns, prognostic signatures of TCs and TNENs.@*RESULTS@#The mutational profiles between TCs and TNENs were diverse. The genetic alterations that ranked highest in TCs were in CDKN2A, TP53, ASXL1, CDKN2B, PIK3C2G, PTCH1, and ROS1 , while those in TNENs were in MEN1, MLL2, APC, RB1 , and TSC2 . Prognostic analysis showed that mutations of ROS1, CDKN2A, CDKN2B, BRAF, and BAP1 were significantly associated with worse outcomes in TC patients, and that mutation of ERBB2 indicated shortened disease-free survival (DFS) and overall survival (OS) in TNEN patients. Further investigation found that the prognosis-related genes were focused on signal pathways of cell cycle control, chromatin remodeling/DNA methylation, phosphoinositide 3-kinases (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR), and receptor tyrosine kinase (RTK)/RAS/mitogen-activated protein kinase (MAPK) signaling.@*CONCLUSION@#We profiled the mutational features of 47 Chinese patients with thymic malignancy of diverse pathologic phenotypes to uncover the integrated genomic landscape of these rare tumors, and identified the pathology-specific mutational patterns, prognostic signatures, and potential therapeutic targets for TCs and TNENs.

Síndrome de Klinefelter diagnosticado en un adulto a raíz del estudio de infección respiratoria recurrente y masa mediastínica: caso clínico / Thymoma in a patient with klinefelter syndrome: case report

Klinefelter syndrome (47, XXY in most cases) is a frequently underdiagnosed chromosomal anomaly associated with multiple comorbidities in adult life. Patients with Klinefelter syndrome have a higher risk of cancer. Specifically, these patients have a higher risk for mediastinal germ cell tumors. It is estimated that 8% of male patients with mediastinal tumors have Klinefelter. We report a 42-years-old male who suffered recurrent respiratory infections. During the study, a mediastinal mass was found, whose pathological study disclosed a type B thymoma. The patient had a history of infertility, high stature, gynecomastia, obesity with gynecoid distribution of body fat and testicular atrophy. A karyotype was requested (47, XXY), confirming the diagnosis of Klinefelter syndrome.

Chemotherapy and prognosis in advanced thymic carcinoma patients

OBJECTIVE: The role of chemotherapy in treating advanced thymic carcinoma is unclear. The purpose of the current study was to investigate the efficacy of chemotherapy and the prognostic factors for patients with advanced thymic carcinoma. METHODS: A retrospective review of the medical records of 86 patients treated with chemotherapy for advanced thymic carcinoma was conducted between 2000 and 2012 at our institution. The clinical characteristics, chemotherapy regimens and prognostic factors were analyzed. Survival curves were plotted using the Kaplan-Meier method and the Cox proportional hazard model was used for multivariate analysis. RESULTS: Of the 86 patients, 56 were male and 30 were female. The median survival time was 24.5 months. For the first-line chemotherapy treatment, the objective response rate was 47.7% and the disease control rate was 80.2%. The median progression-free survival for all patients was 6.5 months for first-line chemotherapy. No significant differences in progression-free survival were observed among the different chemotherapy regimens. Multivariate analyses revealed that the prognostic factors for overall survival included performance status (p=0.043), histology grade (p=0.048), and liver metastasis (p=0.047). CONCLUSION: Our results suggest that there is no difference in efficacy between multiagent and doublet regimens. The prognosis of patients with advanced thymic carcinoma can be predicted based on histological grade, liver metastasis and performance status.

Síntomas de miastenia grave en un paciente con antecedente de timectomía por timoma invasor / Symptoms of myasthenia gravis in a patient with a history of thymectomy for invasive thymoma

Introducción. La miastenia grave es una enfermedad autoinmunitaria mediada por anticuerpos. Entre 10 y 15 % de quienes la padecen tienen timoma y su presencia se asocia con una mayor gravedad de los síntomas, crisis miasténicas y fracaso del tratamiento de primera línea. La timectomía se recomienda en pacientes jóvenes con miastenia grave generalizada y en todos los pacientes con timoma. Caso clínico. Se presenta el caso de una mujer de 43 años que, en el 2005, presentó una primera crisis miasténica asociada con un timoma invasor que se trató con timectomía y radioterapia. Durante los siguientes tres años, presentó síntomas graves y dos crisis más, que obligaron a suministrarle respiración mecánica asistida e inmunoglobulina. Al cabo del tratamiento, no se evidenciaron signos de recurrencia en las tomografías de tórax con contraste. Entre el 2009 y el 2012, la gravedad de los síntomas fue menor. En el 2013, estos se exacerbaron y una resonancia magnética de tórax con contraste reveló una lesión en el mediastino anterior, ya observada en el 2011, sugestiva de tejido residual o fibrosis. Se inició el tratamiento usual con inmunoglobulina y se hizo una tomografía por emisión de positrones cuyos resultados no fueron concluyentes, por lo que se llevó a cabo una nueva resección y se constató que no había recurrencia del tumor. Conclusiones. Los pacientes con miastenia grave y aquellos con timoma asociado, deben someterse a la timectomía como parte del tratamiento. Sin embargo, la exacerbación de los síntomas o su reaparición después del procedimiento no necesariamente implica una nueva alteración en el timo.

Introduction: Myasthenia gravis is an antibody-mediated autoimmune disease. Approximately 10-15% of patients present with a thymoma, the presence of which is associated with greater severity of symptoms, myasthenic crisis, and irresponsiveness to front-line therapy. A thymectomy is recommended in young patients with generalized myasthenia gravis and in all patients presenting with thymoma. Clinical case: The patient was a 43-year-old woman, who first showed symptoms of myasthenic crisis in 2005 and presented with invasive thymoma managed with thymectomy and radiotherapy. In the subsequent three years, the patient presented with severe symptoms and two myasthenic crises that required mechanical ventilation and immunoglobulin treatment. Contrast chest computed tomography examinations showed no recurrence. Between 2009 and 2012, the patient experienced decreased symptom severity. In 2013, the patient presented with an exacerbation of symptoms; a contrast chest magnetic resonance scan showed a lesion in the anterior mediastinum, previously observed in 2011, suggestive of residual tissue as opposed to fibrosis. Regular management was started with immunoglobulins; a positron emission tomography scan was inconclusive, requiring a new resection, which showed no evidence of tumor recurrence. Conclusions: Patients with myasthenia gravis and those with myasthenia-related thymoma both share thymectomy as an element of treatment. However, following the procedure, exacerbation or reappearance of symptoms does not necessarily represent new alterations in the thymus.

Masa intraauricular derecha en paciente chagásico con marcapasos definitivo / A mass inside the lright atrium in a patient with chagas disease and a pacemaker

Se presenta un paciente de 60 años, chagásico crónico y usuario de marcapasos definitivo con masa en aurícula derecha asociada a Síndrome de Vena Cava Superior y baja de peso.

A 69 year old man, with Chagas Disease and an implanted pacemaker develop a superior vena cava syndrome and weight loss.

Metastatic Thymic Carcinoid: Does Surgeon Have a Primary Role.

Thymic carcinoids are rare mediastinal tumours. These are aggressive tumours that often present late and have poor prognosis. Primary surgical treatment is recommended even in metastatic tumours since the role of adjuvant therapy is not well established. We present a case of metastatic thymic carcinoid managed with surgical excision.

Thymoma: First large Indian experience.

BACKGROUND: Thymoma is the most common tumor of the anterior mediastinum. Surgery is mainstay of treatment, with adjuvant radiation recommended for invasive thymoma. Because of rarity, prospective randomized trials may not be feasible even in multicentric settings hence the best possible evidence can be large series. Till date Thymoma has not been studied in Indian settings. MATERIALS AND METHODS: All patients presenting to Thoracic disease management group at our Centre during 2006‑2011 were screened. Sixty two patients’ with histo‑pathological confirmation of thymoma medical records could be retrieved and are presented in this study. Mosaoka staging and WHO classification was used. The clinical, therapeutic factors and follow up parameters were recorded and survival was calculated. Effects of prognostic factors were compared. RESULTS: Sixty two patients were identified (36M, 26F; age 22‑84, median 51.5 years) and majorities (57%) of thymoma were stage I‑II. WHO pathological subtype B was most common 30 (49%). Mean tumor size was smaller in patients with myasthenia (5.3cm) than the entire group (7.6cm). Neoadjuvant therapy was offered to five unresectable stages III or IV a patient’s with 40% resectability rates. Median overall survival was 60 months (Inter quartile‑range 3‑44 months) with overall survival rate (OS) at three year being 90%. Resectable tumors had better outcomes (94%) than non resectable (81%) at three years. Mosaoka Stage was the only significant (P = 0.03) prognostic factor on multivariate analysis. CONCLUSION: This is first thymoma series from India with large number of patients where staging is an important prognostic factor and surgery is the mainstay of therapy. In Indian context aggressive multimodality treatment should be offered to advanced stage patients and which yields good survival rates and comparable.

Thymic atypical carcinoid.

Only 2% of carcinoids originate from the thymus with an estimated incidence of 1.5 to 3 per 10,000,000 persons per year. We present the case of a 30-year-old female patient in whom the diagnosis was confirmed by a fine needle aspiration cytology of a large mediastinal mass.

Invasive thymoma with intraorbital metastases.

Thymomas are epithelial neoplasm of thymus and most common primary neoplasm of anterior and superior mediastinum affecting males and females equally. It occurs usually in the fifth to seventh decade. Approximately one-third of thymomas are invasive. Metastases to distant extrathoracic sites such as the liver, lung, lymph node, kidneys, ovary and brain occur infrequently. This is more common with invasive thymomas. Although brain has been shown to be a site of infrequent metastases, intraorbital metastases has not yet been reported. Here we report one such case of invasive thymoma of anterior superior mediastinum, which later metastasized to orbit as well as the brain.

Carcinoma da tireóide com diferenciação semelhante a timo (CASTLE): relato de caso e revisão da literatura / Thyroid carcinoma with thymus-like differentiation (CASTLE): case report and review of the literature

O carcinoma com diferenciação semelhante a timo (CASTLE) é uma neoplasia epitelial maligna rara, que surge nos tecidos moles do pescoço ou na glândula tireóide. O diagnóstico diferencial deve ser estabelecido com carcinoma pavimento-celular primário ou secundário da cabeça e do pescoço ou da tireóide, visto que têm prognósticos distintos. A imunorreatividade para CD5 pode ser útil no diagnóstico de CASTLE. O CASTLE possui elevada taxa de recidiva local, apesar de o seu curso clínico indolente, ao contrário das neoplasias previamente referidas, que têm um prognóstico muito reservado, dada a elevada taxa de disseminação sistêmica. O tratamento inclui excisão cirúrgica e radioterapia. A quimioterapia também tem sido realizada, apesar de até a presente data não existir evidência clara da sua eficácia. Relata-se caso de doente de sexo masculino, com 52 anos, que surge com tosse seca, disfonia e massa da tireóide, que foi submetido à tireoidectomia. O exame anatomopatológico da peça operatória permitiu o diagnóstico de CASTLE. O doente efetuou radioterapia e quimioterapia e obteve resposta mínima. Pretende-se discutir o diagnóstico anatomopatológico diferencial e a abordagem terapêutica mais adequada de uma patologia com prognóstico favorável, mas de natureza recidivante, que exige seguimento rigoroso a longo prazo.

Carcinoma with thymus-like differentiation (CASTLE) is a rare malignant epithelial tumor wich arises on soft tissue of the neck or thyroid gland. It is important to differentiate CASTLE from primary or metastatic squamous cell carcinoma of head and neck, and from squamous cell thyroid carcinoma, because it has a different prognosis. CD5 immunoreactivity might be helpful in CASTLE diagnosis. CASTLE behaves generally in an indolent fashion, even though it has a high relapse rate, while the other have a dismal prognosis due its high dissemination rate. Treatment includes surgical excision and radiotherapy. Chemotherapy can be offered, although its efficacy is not clear. Authors present a case of a 52 year-old male that complaints with cough, disphony, asthenia, and thyroid mass. Thyroidectomy was performed and the pathology revealed a CASTLE. After radiotherapy and chemotherapy, minimal response was obtained. The authors intend to discuss the differential pathologic diagnosis and the best therapy of this indolent but recurrent neoplasm, that demands strict long term follow-up.

La citometría de flujo en el estudio de tumores mediastinales ricos en elementos linfoides / Flow cytometry for the study of mediastinal tumors with abundant lymphoid elements

El mediastino anterior es un sitio frecuente de localización de tumores ricos en elementos linfoides. La identificación correcta de cada entidad es de importancia en el tratamiento de los pacientes. En ocasiones puede plantearse el diagnóstico diferencial entre timoma y linfoma linfoblástico con fenotipo de precursor T (LLB-T). La Citometría de Flujo (CF) es una técnica complementaria útil para estos tumores de la cual se obtiene información cualitativa y cuantitativa. Revisamos 38 tumores mediastinales que tenían estudio de CF. Además comparamos los resultados de CF de timomas y tejido tímico normal con 42 casos de LLB-T de otras localizaciones anatómicas. De los 38 tumores mediastinales 6 eran lesiones benignas, 9 linfomas difusos de células grandes con fenotipo B (LDCG-B), 10 linfomas de Hodgkin (LH), 11 timomas y 2 LLB-T. En 24 casos la CF aportó información positiva, definiendo el inmunofenotipo de las células linfoides neoplásicas, o los linfocitos característicos que acompañan a los timomas. La CF en los 10 casos de LH y en 4 lesiones benignas permitió descartar otros tipos de linfoma (LDCG-B, LLB-T, etc.). Las marcaciones para CD3, CD4 y CD8 fueron las más útiles para el diagnóstico diferencial entre timomas y LLB-T. En conclusión, la CF es una técnica complementaria de utilidad que aporta información en lesiones mediastinales de manera rápida, requiriendo cantidades pequeñas de material, tanto para el diagnóstico inicial como para el monitoreo de estas enfermedades.

The anterior mediastinum is a common site of tumors with abundant lymphoid elements. Flow cytometry is a useful complementary technique to analyze this type of tumors, which provides qualitative and quantitative information. A differential diagnosis can be sometimes made between thymoma and precursor T-lymphoblastic lymphoma (T-LBL). Correct identification is of utmost importance for patient treatment. A total of 38 mediastinal tumors were analyzed, and samples were separated for flow cytometry. Flow cytometry data from thymomas and normal thymic tissue were compared with 42 cases of T-LBL from other anatomical locations. Among 38 mediastinal tumors, we found 6 benign lesions, 9 diffuse large B-cell lymphomas (DLBCL), 10 Hodgkin lymphomas (HL), 11 thymomas and 2 T-LL. Flow cytometry provided positive information in 24 cases, and defined lymphoid neoplastic cells immunophenotype or the typical lymphocytes accompanying thymomas. Flow cytometry helped differentiate 10 cases of HL and 4 benign lesions from other lymphomas (DLBCL, T-LBL, etc.). CD3, CD4 and CD8 expressions were most useful for the differential diagnosis of thymomas and T-LL. To conclude, flow cytometry is a valid complementary technique, which promptly provides information on mediastinal lesions, requiring small quantities of tissue for both early diagnosis and follow up of these diseases.

Quiste multiloculado de timo / Multiloculated thymic cyst

Los quistes de timo son lesiones de mediastino extremadamente raros y generalmente asintomáticos. Pueden ser divididos en dos tipos:quistes tímicos uniloculares, considerados como malformaciones del desarrollo, originados en remanentes embrionarios del conductotimofaríngeo y los quistes tímicos multiloculares, considerados de naturaleza reactiva como resultado de inflamación de las estructurasderivadas del epitelio ductal medular tímico. Habitualmente son descubiertos por Rx de control, en muy pocos casos se manifiestan portos, disnea u otro síntoma inespecífico. Radiológicamente se presentan como una tumoración redondeada de bordes lisos; con la TAC selogra precisar su naturaleza quística, de pared fina, y el contenido con densidad acuosa. Se presenta este caso de quiste multiloculado, quesimuló radiológicamente otros tumores mediastínicos...

Thymic cysts of the mediastinum are extremely rare lesions that are usually asymptomatic. They can be divided into two types: unilocular thymic cysts which are considered as developmental malformations arising from embryonic duct remnants; thymopharingeal and multilocular thymic cysts which are considered of reactive nature as a result of inflammation of the structures derived from thymic medullary ductal epithelium. They are usually detected by Rx control; rarely do they manifest themselves by cough, dyspnea or other symptoms. Radiologically the tumor presents itself with smooth rounded edges; by TAC the thin walled cystic nature, density and water content can be established. We present this case of a multilocular cyst which prior to surgical treatment, radiologically simulated various medastinal tumors.

Thymolipoma--a case report.

A 28 year old male presented with a 8 months history of chest pain, cough and breathlessness. CT scan revealed a large mass in right anterior mediastinum showing fat and soft tissue attenuation. Histopathology of the resected mass revealed a tumour showing extensive areas of mature fat and relatively less interspersed thymic tissue confirming thymolipoma. Because of its rarity, we are presenting this case with a brief review of literature.

Thymoma: a pathological study of 50 cases.

BACKGROUND: A combination of epithelial cells and lymphocytes results in a varied histomorphology of thymomas and consequent varied classification systems. AIM: To correlate the Marino and Muller-Hermelink (MMH) classification with the invasive behaviour of thymomas. SETTING AND DESIGN: Retrospective analysis. MATERIALS AND METHOD: Thymomas encountered in the past 21 years were re-classified with the MMH classification and correlated with Masaoka's staging and clinical presentation. RESULTS: The thymomas formed 91% of the primary thymic epithelial tumours. Predominantly cortical thymomas (n=21) and cortical thymomas (n=22) were the common subtypes and 60% and 77% of these, respectively, were in stages II or III. Cystic change, necrosis or haemorrhage played no role in predicting invasive behaviour. Cortical epithelium correlated well with the presence of para-thymic syndromes, especially myasthenia gravis. CONCLUSION: MMH classification is easy to apply. Cortical thymomas in stage I should be followed up for possible recurrence.

Pure red cell aplasia--report of 11 cases from eastern Nepal.

There were eleven cases of pure red cell aplasia diagnosed over a period of 2 years (January 2000-December 2001). All the patients had anemia with pallor and weakness being the presenting complaints. Hematological profile depicted normocytic normochromic anemia, reticulocytopenia and marked paucity of erythroid precursors on bone marrow aspiration and biopsy studies. In the present study, one case was of congenital pure red cell aplasia, in one other case of pyrexia of unknown origin, no definitive diagnosis could be made. Other associated diseases seen with pure red cell aplasia were thymoma, septicemia, protein energy malnutrition, non-Hodgkin's lymphoma, juvenile rheumatoid arthritis, acute myeloid leukemia, tuberculosis and hepatitis C. The association of pure red cell aplasia with haematologic malignancies is rare. There are very few case reports on pure red cell aplasia with hepatitis C.

Thymoma with Pseudosarcomatous Stroma

Thymoma with psuedosarcomatous stroma is a recently described, rare variant of thymomas that are characterized by having a biphasic histologic pattern which consists of both an epithelial and a spindle cell stromal component. So far only 11 cases having similar histologic findings have been reported world wide. At this time we report a case of this rare variant of thymoma which occurred in a 53-year-old Korean man. This previously healthy patient presented with coughing and an anterior mediastinal mass was then detected radiographically. Mediastinal exploration revealed a 9 x 8 x 8 cm-sized well- encapsulated, ovoid, cystic mass. Histological examination showed a biphasic neoplasm composed of anastomosing nests of epithelial cells and somewhat cellular stromal spindle cells that had advanced degenerative changes. Immunohistochemical staining using the antibodies for cytokeratins, EMA, e-cadherin, and p75NGFR showed a strong expression of these markers in the epithelial component but no expression in the spindle stromal cells. The epithelial tumor cells showed no reactivity to CD5 and L26 and a high proportion of the infiltrated lymphocytes were the cortical type that expressed CD99 and terminal deoxynucleotidyl transferase. Ultrastructural examinations revealed tonofilaments in the spindle cells. Follow up has been done for 5 years after the surgical excision and the patient has been free of disease during that period. Similar to previous reports, this patient had a benign clinical course that was unassociated with myasthenia gravis which appears to be a characteristic of this histologic variant of thymoma. However, our case also showed advanced degenerative features and we could demonstrate ultrastructural evidence of epithelial differentiation in the stromal spindle cells that were not mentioned in the previously reported cases. Based on the results of our studies, we suggest this entity is a distinct type of organotypic thymoma that shows cortical differentiation and abundant cellular stroma.