Thymoma metastatic to liver and pancreas: case report and review of the literature

A 71-year-old man presented with a thymic mass involving the superior vena cava. A mediastinoscopical biopsy initially suggested a diagnosis of type A thymoma. After neoadjuvant chemotherapy, the patient underwent en-bloc thymectomy and vascular resection for a pathology-confirmed type B3 thymoma involving the superior vena cava, the left brachiocephalic vein and the distal part of the right brachiocephalic vein. Adjuvant radiotherapy was administered. Two years after the primary surgery, abdominal computed tomography (CT) and whole body fluorodeoxyglucose (18-FDG) positron emission tomography (PET) scans showed a single hepatic lesion that was treated with wedge liver resection. Pathological examination confirmed metastatic type B3 thymoma. Almost 4 years later, abdominal CT and 18-FDG PET revealed a 2.9-cm solid mass involving the body of the pancreas. Distal pancreatectomy with lymph node dissection was performed. Pathological examination showed a pancreatic metastasis from a type B3 thymoma, without lymph node involvement. The patient is alive and free of disease 6 months after the pancreatectomy (68 months after the initial thymectomy surgery). Intra-abdominal recurrence and pancreatic metastases are very uncommon manifestations of thymoma, but this event should be kept in mind when an abdominal mass is seen during follow-up

Tumours of the thymus: a cohort study of prognostic factors from the European Society of Thoracic Surgeons database

OBJECTIVES A retrospective database was developed by the European Society of Thoracic Surgeons, collecting patients submitted to surgery for thymic tumours to analyse clinico-pathological prognostic predictors. METHODS A total of 2151 incident cases from 35 institutions were collected from 1990 to 2010. Clinical-pathological characteristics were analysed, including age, gender, associated myasthenia gravis stage (Masaoka), World Health Organization histology, type of thymic tumour [thymoma, thymic carcinoma (TC), neuroendocrine thymic tumour (NETT)], type of resection (complete/incomplete), tumour size, adjuvant therapy and recurrence. Primary outcome was overall survival (OS); secondary outcomes were the proportion of incomplete resections, disease-free survival and the cumulative incidence of recurrence (CIR). RESULTS A total of 2030 patients were analysed for OS (1798 thymomas, 191 TCs and 41 NETTs). Ten-year OS was 0.73 (95% confidence interval 0.69-0.75). Complete resection (R0) was achieved in 88% of the patients. Ten-year CIR was 0.12 (0.10-0.15). Predictors of shorter OS were increased age (P < 0-001), stage [III vs I HR 2.66, 1.80-3.92; IV vs I hazard ratio (HR) 4.41, 2.67-7.26], TC (HR 2.39, 1.68-3.40) and NETT (HR 2.59, 1.35-4.99) vs thymomas and incomplete resection (HR 1.74, 1.18-2.57). Risk of recurrence increased with tumour size (P = 0.003), stage (III vs I HR 5.67, 2.80-11.45; IV vs I HR 13.08, 5.70-30.03) and NETT (HR 7.18, 3.48-14.82). Analysis using a propensity score indicates that the administration of adjuvant therapy was beneficial in increasing OS (HR 0.69, 0.49-0.97) in R0 resections. CONCLUSIONS Masaoka stages III-IV, incomplete resection and non-thymoma histology showed a significant impact in increasing recurrence and in worsening survival. The administration of adjuvant therapy after complete resection is associated with improved surviva

Long-term disease-free survival of patients with radically resected thymomas: relevance of cell-cycle protein expression

BACKGROUND. Despite radical Surgical resection, thymomas often recur. The objective of the current retrospective Study was to investigate the prognostic relevance of the expression of cell-cycle proteins in these neoplasms to formulate a possible therapeutic Surveillance strategy for the prevention of recurrence. METHODS. The authors retrospectively reviewed the main clinicopathologic factors, including the World Health Organization (WHO) classification, of patients with thymoma who had undergone radical surgical resection. Specimens were studied using immunohistochemistry and the expression of cell-cycle proteins (i.e., p21, p27, and p53) was assessed. Univariate and multivariate analysis of predicting survival prognostic factors were performed. RESULTS. The authors analyzed 88 patients with thymoma who underwent radical surgical resection at the study institution. According to the Masaoka staging system, 41 patients had Stage I disease, 31 patients had Stage II disease, and 16 patients had Stage III disease. There were 24 tumor recurrences (27.3%), 4 of which were local, 16 of which were distant intrathoracic, and 4 of which were extrathoracic. The second radical resection provided a disease-free Survival rate that was similar to the first. Only Masaoka stage (P=0.001), WHO classification (P=0.001), high expression of p53 (P=0.03), and low expression of p21 (P=0.02) and p27 (P=0.001) were found to he correlated with a reduced disease-free survival. Low p27 expression was found to be the most significant predictive factor of a short disease-free Survival (P=0.001), especially when associated with low p21 expression and high p53 expression (P=0.0001). CONCLUSIONS. Long-term disease-free survival in thymoma patients treated with radical surgical resection Was found to be correlated with Masaoka stage, WHO classification, and expression of cell-cycle proteins, with the latter found to be the most significant predictive factor. Functional cooperation between cell-cycle proteins might constitute another level of regulation in tumor growth. More careful surveillance should be adopted whenever there is negative cell-cycle protein expression. (c) 2005 American Cancer Society

A djuvant treatment in patients at high risk of recurrence of thymoma: Efficacy and safety of a three-dimensional conformal radiation therapy regimen

The clinical benefits of postoperative radiation therapy (PORT) for patients with thymoma are still controversial. In the absence of defined guidelines, prognostic factors such as stage, status of surgical margins, and histology are often considered to guide the choice of adjuvant treatment (radiotherapy and/or chemotherapy). In this study, we describe our single-institution experience of three-dimensional conformal PORT administered as adjuvant treatment to patients with thymoma. METHODS: Twenty-two consecutive thymoma patients (eleven male and eleven female) with a median age of 52 years and treated at our institution by PORT were analyzed. The patients were considered at high risk of recurrence, having at least one of the following features: stage IIB or III, involved resection margins, or thymic carcinoma histology. Three-dimensional conformal PORT with a median total dose on clinical target volume of 50 (range 44-60) Gy was delivered to the tumor bed by 6-20 MV X-ray of the linear accelerator. Follow-up after radiotherapy was done by computed tomography scan every 6 months for 2 years and yearly thereafter. RESULTS: Two of the 22 patients developed local recurrence and four developed distant metastases. Median overall survival was 100 months, and the 3-year and 5-year survival rates were 83% and 74%, respectively. Median disease-free survival was 90 months, and the 5-year recurrence rate was 32%. On univariate analysis, pathologic stage III and presence of positive surgical margins had a significant impact on patient prognosis. Radiation toxicity was mild in most patients and no severe toxicity was registered. CONCLUSION: Adjuvant radiotherapy achieved good local control and showed an acceptable toxicity profile in patients with high-risk thymoma

MALIGNANCIES OF THE THYMUS

Abstract: The role of radiotherapy in the treatment of thymoma and thymic carcinoma has been evaluated by many investigators over the past two decades. The low incidence of these neoplasms has limited most published studies to small series spanning long time intervals or population-based studies. The exact indications and protocols for the use of radiotherapy as a part of the multidisciplinary approach to thymoma and thymic carcinoma are still unclear. However, a review of recent literature shows potential benefits for certain patients based on stage and grade of disease as well as the extent of surgical resection

A large microRNA cluster on chromosome 19 is a transcriptional hallmark of WHO type A and AB thymomas

BACKGROUND: Thymomas are one of the most rarely diagnosed malignancies. To better understand its biology and to identify therapeutic targets, we performed next-generation RNA sequencing. METHODS: The RNA was sequenced from 13 thymic malignancies and 3 normal thymus glands. Validation of microRNA expression was performed on a separate set of 35 thymic malignancies. For cell-based studies, a thymoma cell line was used. RESULTS: Hierarchical clustering revealed 100% concordance between gene expression clusters and WHO subtype. A substantial differentiator was a large microRNA cluster on chr19q13.42 that was significantly overexpressed in all A and AB tumours and whose expression was virtually absent in the other thymomas and normal tissues. Overexpression of this microRNA cluster activates the PI3K/AKT/mTOR pathway. Treatment of a thymoma AB cell line with a panel of PI3K/AKT/mTOR inhibitors resulted in marked reduction of cell viability. CONCLUSIONS: A large microRNA cluster on chr19q13.42 is a transcriptional hallmark of type A and AB thymomas. Furthermore, this cluster activates the PI3K pathway, suggesting the possible exploration of PI3K inhibitors in patients with these subtypes of tumour. This work has led to the initiation of a phase II clinical trial of PI3K inhibition in relapsed or refractory thymomas (http://clinicaltrials.gov/ct2/show/NCT02220855)

Thymic Epithelial Tumors: Model of rare tumors for the identification of new biomarkers and novel therapeutic opportunities

In this thesis, I discuss the identification of new insights and the evaluation of novel treatment opportunities in thymic epithelial tumors, which are widely recognized as rare cancers. Rare cancers are a heterogeneous group of diseases, which share similar problems: uncertainty of diagnosis, lack of therapies, poor research opportunities, difficulties in clinical trials, lack of expertise and of centres of reference. Despite their low incidence, not greater than 6 cases per 100000 in habitants, in Europe a considerable fraction of all cancers is represented by rare cancers (24%),making their clinical relevance far from being insignificant. Indeed, most of rare malignancies require complex surgical treatment, thus a multidisciplinary approach is essential and treatment should be provided in centres of expertise and/or in networks including expert centres. This research focuses on a peculiar model of rare cancer, thymic epithelial tumors which are characterized by: the platinum-sensitivity in the majority of cases; the lack of effective treatments in case of platinum-resistance cases; the lack of novel, reproducible and minim-invasive biomarkers and the dramatic survival variations depending on the oncological expertise. Actually, an opportunity to improve knowledge and outcomes of rare tumors and reduce disparities, is provided by the centralization of their diagnosis and management in reference centres and the cooperation with recognized expert Networks for these diseases. Thus, the main aim of this thesis is to describe the most updated scientific findings concerning diagnosis, molecular characterization and treatment of thymic epithelial tumors, in relation to my research activity in both expert reference centre and national and international expert networks. Thymic epithelial tumors are rare thoracic cancers, characterized by unpredictable oncological outcomes and unique association with immunological dysregulations. Here, I report the last researches that I carried out, focused on: the identification of new biomarkers using the emerging approach of liquid biopsy; the evaluation of novel systemic treatments in progressing/relapsing platinum-resistant tumors and the immunological characterization of patients with both autoimmunity and immunodeficiency. The work I have presented, therefore, has shown that, despite the several problems due to the rarity of these malignancies, the achievement of new molecular insights and novel treatment opportunities is feasible. The centralization of diagnosis and management in expert reference centers, as well as the cooperation with international dedicated networks is mandatory

Risk factors correlated to lymph node metastasis in thymic epithelial tumors and the prognostic significance of lymph node dissection for thymic carcinomas and thymic neuroendocrine tumors

Thymustumore werden im Allgemeinen als wenig maligne Tumore, mit geringer Wahrscheinlichkeit einer Lymphknotenmetastasierung (LNM) angesehen. Diese Studie zielt darauf ab, die Faktoren, die mit einer möglichen LNM bei Thymusepithelialtumoren (TETs) stehen zusammenhängen , zu analysieren und den Einfluss der Lymphknotendissektionen (LND) bei pathologisch gesicherten Hochrisikotypen (Thymuskarzinomen, TCs und Nuroendokrinen Tumoren des Thymus, TNETs) auf die Prognose zu untersuchen. Diese Studie analysierte systematisch die klinisch-pathologischen Informationen von Pat. mit Thymus Malignomen in der Surveillance, Epidemiology, and End Results Datenbank. Zunächst wurde die Inzidenz von diesen Tumoren zusammengefasst, dann wurden die relevanten klinisch-pathologischen Faktoren von Pat. mit Thymomen (A-B3), Thymuskarzinomen (TCs) und Thymus neuroendokrinen Tumoren (TNETs), die operiert und bei denen Lymphknoten exsipiert wurde, gesammelt. Außerdem wurden unabhängig von der LNM in Beziehung stehende Variablen mittels Logistik-Regression bestimmt. Schließlich wurden Pat., bei denen die diagnostizierten TCs und TNETs chirurgisch behandelt wurden, gesammelt und die Prognose bei unterschiedlichem Lymphknotenstatus analysiert. Die Cox-Analyse wurde verwendet, um die Variablen im Zusammenhang mit der Prognose des Gesamtüberlebens (OS) und des krebsspezifischen Überlebens (CSS) zu analysieren. Propensity Score Matching (PSM) wurde für die Subgruppenanalyse von Pat. mit unterschiedlichem Lymphknotenstatus verwendet. Insgesamt wurden 5934 Pat. mit pathologisch gesicherten Thymus-Malignomen eingeschlossen am häufigsten waren Thzmome gefolgt von TCs und TNETS. Insgesamt wurden 1048 TETs Pat. operiert und erhielten eine LND. Der Gesamtanteil der TETs Pat.. mit LNM betrug 1,1%. Die LNM-Rate bei Thymomen, TCs und TNETs betrug 6,8%, 30,2% bzw. 61,1%. Histologietyp sowie T-Stadium waren unabhängige Faktoren, die mit LNM in der multivariaten Logistikanalyse korrelierten. Es gab 812 Pat. mit TCs und TNETs, die sich einer chirurgischen Behandlung unterzogen hatten, darunter waren 76,7% TCs und 11,6% TNETs. Etwa 398 Pat. erhielten eine LND und von diesen hatten 36,2% eine LNM. In der multivariaten Cox-Analyse von OS und CSS war die Prognose von LND- Pat. signifikant schlechter als die von N0 Pat.. Der prognostische Unterschied zwischen N+ und LND- Pat. war nicht statistisch signifikant. Nach PSM ist in der univariaten Analyse und in der multivariaten Subgruppenanalyse von OS und CSS das Überleben von N0 Pat. immer noch besser als das von LND- und N+ Gruppen, jedoch zeigte der Prognoseunterschied zwischen LND- und N+ Pat. keine statistische Signifikanz in der multivariaten Analyse (P >0.05). Lymphknotenbeteiligung ist bei TETs nicht ungewöhnlich. Hauptfaktoren im Zusammenhang mit LNM in TETs sind der Histologietyp sowie das T-Stadium. LND in TCs und TNETs kann dabei helfen einen genaueren Lymphknotenstatus, sowie die Langzeitprognose von Patienten besser zu beurteilen.Thymic tumors are generally considered with low degree of malignancy, and the probability of lymph node metastasis (LNM) is low. This study aims to further comprehensively analyze the related factors of LNM in thymic epithelial tumors (TETs) and investigate the impact of lymph node dissection (LND) in high-risk pathological types (thymic carcinomas, TCs and thymic neuroendocrine tumors, TNETs) on the prognosis. The present research systematically analyzed the clinicopathological information of patients with thymic malignancies in the Surveillance, Epidemiology, and End Results (SEER) database. The overall incidence of tumors was firstly analyzed. Furtherly, the relevant clinicopathological factors of thymoma (A-B3), thymic carcinomas (TCs), and thymic neuroendocrine tumors (TNETs) who had surgical treatment and underwent ≥1 lymph node examined were collected, and variables independently related to LNM were determined via Logistics regression. Finally, the patients diagnosed TCs and TNETs undergoing operative treatment were collected, and the differences in the prognosis of patients with different lymph node status were analyzed. Univariate and multivariate Cox analysis was used to analyze the variables related to the prognosis of overall survival (OS) and cancer-specific survival (CSS). Propensity score matching (PSM) was used for subgroup analysis of patients with different lymph node status. An overall of 5934 patients was involved with pathologically confirmed thymic malignancies (1975-2016), of which the highest proportion was thymoma (63.3%), followed by TCs (18.5%) and TNETs (5.6%). A total of 1048 TETs individuals underwent surgery and LND. The overall proportion of TETs patients with LNM was 19.1%. The rate of LNM in thymoma, TCs, and TNETs was 6.8%, 30.2%, and 61.1%, respectively. Histology type and T stage were independent factors correlated with LNM in the multivariate Logistics analysis. There were 812 patients with TCs and TNETs underwent surgical treatment, including 76.7% cases of TCs and 11.6% cases of TNETs. About 398 patients underwent LND and 36.2% of patients among them had LNM. In the multivariate Cox analysis of OS and CSS, the prognosis of LND- patients was significantly worse than that of N0 patients (OS: P =0.019; CSS: P =0.012), and the prognostic difference between N+ and LND- patients was not statistically significant (OS: P =0.561, CSS: P =0.759). After PSM, in the univariate analysis and multivariate subgroup analysis of OS and CSS, the survival of N0 patients is still better than that of LND- and N+ groups, however, the prognosis (OS and CSS) difference between LND- and N+ patients did not show statistical significance in multivariable analysis (P >0.05). Nodal involvement was not uncommon in TETs. Main factors related to LNM in TETs were histology type and T stage. LND in TCs and TNETs can achieve a clearer lymph node status and assess the long-period prognosis of patients with more accuracy