Classification, histopathology and molecular pathology of thymic epithelial tumors: a review.

Thymic epithelial tumors represent 0.2-1.5% among all malignant neoplasms. They are slow-growing tumors with an overall recurrence rate around 10% and 90% of them are located in the anterior mediastinum. In this review we focused on the classification, histopathology, molecular pathology and prognosis of thymic epithelial tumors, mainly thymoma and thymic carcinoma.

Recent advances and conceptual changes in the classification of neuroendocrine tumors of the thymus.

Neuroendocrine tumors of the thymus (TNET) are exceedingly rare neoplasms. Their histomorphology is identical to neuroendocrine tumors elsewhere in the body (in particular the lungs) and bears no similarity with thymomas and thymic carcinomas. Recent molecular findings have profoundly changed our perception of these tumors and may impact future histological classification systems.

The role of needle core biopsies in the evaluation of thymic epithelial neoplasms.

Thymic epithelial neoplasms are rare tumors derived from thymic epithelium that most often present as large anterior mediastinal masses. The vast majority of thymic epithelial neoplasms fall under the diagnostic category of thymoma, with a smaller percentage qualifying for a diagnosis of thymic carcinoma. The ability to render a definitive diagnosis on these tumors is generally hampered by their deep location and close proximity to vital structures, which makes biopsy sampling for histopathologic evaluation difficult. In recent years, the trend in medicine has been to opt for the least invasive procedure to obtain tissue samples that, by definition, implies also obtaining smaller and smaller biopsies, resulting in lesser amounts of tissue available for examination. In the mediastinum, the most common modalities for procuring biopsy samples from mass lesions include fine-needle aspiration, percutaneous core needle biopsy and video-assisted thoracoscopic biopsy. In this review, we will deal only with the role and limitations of percutaneous core biopsies in the interpretation of thymic epithelial neoplasms.

Atypical Type A Thymoma Variant Manifesting Polymyalgia Rheumatica.

We report a case of atypical type A thymoma variant manifesting polymyalgia rheumatica. A 68-year-old man underwent extended thymectomy with concomitant resection of the pericardium and right lung for an anterior mediastinal tumor. He was diagnosed with atypical type A thymoma variant with pericardial invasion. He developed pain in his extremities 1 year and 2 months after surgery. Detailed examinations resulted in a diagnosis of polymyalgia rheumatica and bone metastasis of thymoma. He was treated with oral prednisolone for polymyalgia rheumatica. His symptoms and bone lesion have been stable up to the present time of 3.5 years post-surgery.

[Interpretation of the fourth edition of WHO pathological classification of the thyroid tumors in 2017].

In recent years, the incidence of thyroid carcinoma gradually increased in China. The pathology diagnosis and classification was based on WHO classification of Tumors of Endocrine Organs, the third edition which published in 2004. The fourth edition, WHO classification of Tumors of Endocrine Organs was published in July 2017. Compared with the third, some important aspects (or points) were revised: the ICD-O code of hyalinizing trabecular tumor was changed from 0 to 1; three other encapsulated follicular-patterned thyroid tumors were added; the variants of well differentiation thyroid carcinoma (including papillary carcinoma and follicular carcinoma ) which was originated from thyroid epithelial cells were updated; oncocytic cell tumors were separated from follicular tumors; the ICD-O code of ectopic thymoma was changed from 1 to 3. Refinement and standardization part of the concepts and diagnostic criterias were done which can solve practical problems in pathology diagnosis.

Diagnosis of thymic epithelial tumor subtypes by a quantitative proteomic approach.

The histological typing of thymic epithelial tumours (TETs) still remains a challenge for surgical pathologists, especially when encountering borderline cases mainly focused on spindle cell types (including type A, atypical type A (aA), AB, and B3). A systematic proteomics analysis of TETs was performed using isobaric tags for relative and absolute quantification (iTRAQ) labeling coupled with two-dimensional liquid chromatography-tandem mass spectrometry (2D-LC-MS/MS). In total, 6479 and 6305 proteins were identified and quantified, respectively. After Gene Ontology (GO) annotation and Ingenuity Pathway Analysis (IPA), six differentially expressed proteins were validated by tissue microarray or multiple reaction monitoring (MRM) quantification. ABCE1 and CLIC2 are promising to be diagnostic candidate biomarkers in thymic carcinomas (TCs). CHD1L was up-regulated in type AB and type B thymomas compared with type A thymoma. Both CLIC2 and MAP7 were negatively detected in type B1 and B2 thymomas. SMAD4 was overexpressed in type aA thymomas and TCs. CDC42 was significantly down-regulated in type B2 thymomas compared with other subtypes. Six novel candidate biomarkers were found to be useful in differentiating subtypes of TETs. SMAD4 may play a specific role in tumorigenesis and the development of aA thymomas and thymic carcinomas.

Ectopic Hamartomatous Thymoma: A Review Of The Literature With Report Of New Cases And Proposal Of A New Name: Biphenotypic Branchioma.

Ectopic hamartomatous thymoma (EHT) is a rare benign neoplasm of the lower neck suggesting branchial origin. Despite use of the term thymoma in the nomenclature, there is no evidence of thymic origin or differentiation. It affects middle-aged adults with a remarkable male predominance. To date less than 80 cases have been reported in the English literature. We present here two additional cases of EHT. The first is a benign case in a 31-year-old man, showing typical histological features. The second is a malignant case in a 70-year-old woman, showing intraductal carcinoma arising in intimate association with an EHT. These cases are presented in the context of a review of cases reported in the English literature. The exact origin has not been identified, but is considered to be of branchial apparatus, creating a quandary about the best terminology. Recently, the designation "branchial anlage mixed tumor" or "thymic anlage tumor" were proposed, but do not quite reflect the true nature of the neoplasm. To avoid taxonomic confusion, international consensus on terminology is desired. As this entity is a neoplasm that shows dual mesoderm and endoderm derivation/differentiation, we propose a new name "biphenotypic branchioma."

Thymoma: a clinicopathological correlation of 1470 cases.

We present 1470 surgical resections for thymoma identified in the pathology files of 14 institutions from 11 countries with the purpose of determining and correlating a simplified histological classification of thymoma and pathological staging with clinical outcome. The study population was composed of 720 men and 750 women between the ages of 12 and 86 years (average, 54.8 years). Clinically, 137 patients (17%) had a history of myasthenia gravis, 31 patients (3.8%) of other autoimmune disease, and 55 (6.8%) patients of another neoplastic process. Surgical resection was performed in all patients. Histologically, 1284 (87.13%) cases were thymomas (World Health Organization types A, B1, and B2, and mixed histologies), and 186 (12.7%) were atypical thymomas (World Health Organization type B3). Of the entire group, 630 (42.9%) were encapsulated thymomas, and 840 (57.9%) were invasive thymomas in different stages. Follow-up information was obtained in 1339 (91%) patients, who subsequently were analyzed by univariate and multivariate statistical analysis. Follow-up ranging from 1 to 384 months was obtained (mean, 69.2 months) showing tumor recurrence in 136 patients (10.1%), whereas 227 died: 64 (28.2%) due to tumor and 163 (71.8%) due to other causes. Statistical analysis shows that separation of these tumors into thymoma and atypical thymoma is statistically significant (P = .001), whereas tumor staging into categories of encapsulated, minimally invasive, and invasion into adjacent organs offers a meaningful clinical assessment with a P = .038. Our findings suggest that our simplified histological schema and pathological staging system are excellent predictors of clinical outcome.

Nephrotic Syndrome and a Retroperitoneal Mass: A Case Report of a Patient with Recurrent Invasive Thymoma.

A 68-year-old man was admitted to our hospital to undergo an examination for nephrotic syndrome while concurrently complicated with recurrent thymoma in the parietal pleura and retroperitoneum. He had been diagnosed with invasive thymoma and had undergone thymo-thymectomy seven years previously. Based on the renal biopsy findings, his nephrotic syndrome was ascribed to minimal change disease. He was treated with corticosteroid monotherapy, which resulted in complete remission six months later, despite the fact that the recurrent thymoma remained. The role of thymoma in the pathogenesis of paraneoplastic glomerulopathy and the therapeutic concerns that emerged in this case are also discussed.

Vascular architecture as a diagnostic marker for differentiation of World Health Organization thymoma subtypes and thymic carcinoma.

AIMS: Thymomas and thymic squamous cell carcinomas (TSQCCs) are rare thymic epithelial tumours. Data on angiogenesis and vascular phenotype in these tumours are limited, and no study has taken histological World Health Organization (WHO) subtypes into account. The aim of this study was to compare vascularization, pericytes coverage and expression of angiogenic growth factors in different WHO-defined subtypes of thymoma METHODS AND RESULTS: Vascular density, diameter and architecture and expression of α-smooth muscle actin (SMA), platelet-derived growth factor (PDGF) receptor-ß (PDGFRß), vascular endothelial growth factor (VEGF) receptor 1 (VEGFR1) and VEGF receptor 2 (VEGFR2) were investigated in WHO type A, AB, B1, B2 and B3 thymomas and TSQCCs, by the use of immunostaining, quantitative morphometry, and tumour vessel isolation by trypsin digestion. Expression levels of angiopoietin 1 (Ang-1), angiopoietin 2 (Ang-2), VEGF-A, PDGF-B and Hif-1α were examined by quantitative reverse transcription polymerase chain reaction. A and AB thymomas were characterized by a dense network of capillary-like vessels with tight pericyte coverage, whereas B thymomas showed a loose vascular network with increasing vascular diameters and increasing expression of SMA and PDGFRß from B1 to B3 thymomas and TSQCCs. VEGFR1 and VEGFR2 were expressed in vessels of all analysed tumour entities, and at higher levels in epithelial cells of A and B3 thymomas and TSQCCs. mRNA of Ang-2, but not of Ang-1, was significantly up-regulated in all thymoma subtypes, with the highest levels being found in A thymomas. In TSQCCs, Ang-1 and VEGF were the predominantly up-regulated growth factors. Hif-1α was only up-regulated in B3 thymomas and TSQCCs. CONCLUSION: Thymomas and TSQCCs differ significantly in their vascular architecture and expression of key angiogenic growth factors. The findings could help to improve the differential diagnosis of difficult-to-classify thymic epithelial tumours, and indicate different mechanisms of tumour angiogenesis and functional differences of tumour vessels of major thymoma subtypes and TSQCCs.

[Thymomas]. / Thymome.

Thymomas are rare tumors but are one of the most common mediastinal neoplasms in adults and exhibit an enormous variability in histological, biological and genetic features. The morphological spectrum within a given entity is enormous and some tumors with histological patterns of more than one entity are more common than pure histological subtypes. Due to a lack of subtype-specific markers classification of thymomas often requires complex diagnostic algorithms. The refined presentation including the definition of obligatory and optional features and of diagnostic immunohistochemical profiles, is the focus of the new World Health Organization (WHO) classification of thymomas, aiming at improving diagnostic reproducibility. This review highlights novel aspects of the WHO classification of thymomas and addresses typical differential diagnostic challenges with a focus on diagnostic pitfalls.

[Thymic carcinomas]. / Thymuskarzinome.

Thymic carcinomas (TC) are approximately 10 times less prevalent than thymomas but of high clinical relevance because they are more aggressive, less frequently resectable than thymomas and usually refractory to classical and targeted long-term treatment approaches. Furthermore, in children and adolescents TC are more frequent than thymomas and particularly in this age group, germ cell tumors need to be a differential diagnostic consideration. In diagnostic terms pathologists face two challenges: a), the distinction between thymic carcinomas and thymomas with a similar appearance and b), the distinction between TC and histologically similar metastases and tumor extensions from other primary tumors. Overcoming these diagnostic challenges is the focus of the new WHO classification of thymic epithelial tumors. The objectives of this review are to highlight novel aspects of the WHO classification of thymic carcinomas and to address therapeutically relevant diagnostic pitfalls.

Sunitinib in patients with advanced thymic malignancies: Cohort from the French RYTHMIC network.

BACKGROUND: Sunitinib is a potent oral tyrosine kinase inhibitor of VEGFRs, KIT, and PDGFRs. In a single arm phase II trial, sunitinib has demonstrated its potential activity in refractory thymic carcinoma (TC) and thymoma (T). Taking advantage of the French RYTHMIC network prospective database, we investigated the off-label efficacy of sunitinib in previously-treated thymic epithelial tumors (TETs) patients not included in a clinical trial. METHODS: RYTHMIC database started in 2012, and prospectively collects clinical, imaging, treatment, and follow-up data of all patients diagnosed with TET, for whom management is discussed at a national multidisciplinary tumor board. All patients who received sunitinib were selected for this analysis. RESULTS: 28 patients from 7 institutions were identified, including 20 TC and 8T; 32% of patients were females, and median age was 50 years. Fifteen patients (54%) received sunitinib as ≥4th line treatment. The initial daily dose of sunitinib was 50mg in 11 patients, 37.5mg in 16 patients and 25mg in 1 patient. Sunitinib adverse events were all manageable and tolerable; 8 patients had to stop sunitinib due to toxicity after a median duration of treatment of 2.7 months. In the overall population, disease control rate was of 63% (86% for T, and 55% for TC); overall response rate was 22% (29% for T, and 20% for TC). Median PFS in the whole population was 3.7 months (5.4 months for T, and 3.3 months for TC, p=0.097). The median overall survival in the whole population was 15.4 months: survival was not reached for T, and was 12.3 months for TC patients (p=0.043). CONCLUSION: Sunitinib is an active treatment in TETs irrespective of histological subtype, supporting the use of tyrosine kinase inhibitors with anti-angiogenic activity as alternative treatment options in refractory disease.

Comparison of outcomes between neuroendocrine thymic tumours and other subtypes of thymic carcinomas: a joint analysis of the European Society of Thoracic Surgeons and the International Thymic Malignancy Interest Group.

OBJECTIVES: The latest World Health Organization (WHO) histological classification divides thymic epithelial tumours in thymomas and thymic carcinomas (TCs), the latter also including the neuroendocrine thymic tumours (NETTs). NETTs and other TC histotypes have been described to have a significantly lower survival than thymomas, but these two groups of tumours have rarely been compared directly. Using the European Society of Thoracic Surgeons and the International Thymic Malignancy Interest Group datasets, we wanted to study this issue. METHODS: This is a retrospective multicentre cohort study of patients operated for TC. Outcome measures were overall survival (OS) and recurrence-free survival (RFS). OS was analysed using the Kaplan-Meier method and RFS was assessed using competing risk analysis. The association with clinical and prognostic factors for OS and RFS was evaluated with log-rank test and Gray's test, respectively. RESULTS: A total of 1247 tumours (1042 TCs) were collected between 1984 and 2012. A R0 resection was performed in 363 TCs and in 52 NETTs. The median follow-up was 4.4 years for TCs and 4.1 years for NETTs. Owing to the missing values for survival information, a total of 728 TC patients and 132 NETTs were included in the OS analysis. Among them, 262 TC and 39 NETT patients died. The median OS was 6.6 years for TC and 7.5 years for NETTs. The overall 5-year survival rates were 60% for TC and 68% for NETTs; 10-year survival rates were 40% for TCs and 39% for NETTs (P = 0.19). Five-year RFS was 0.35 and 0.34 for TCs and NETTs (P = 0.36). On multivariate analysis, histology did not influence either OS (P = 0.79) or RFS (P = 0.59). CONCLUSIONS: This represents the largest clinical series of TCs and NETTs collected. Despite the biological aggressiveness of these rare neoplasms, the 5-year survival rate after resection is over 60% and TCs and NETT showed a similar rate of survival and recurrences after surgery.

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).

Lymph Node Dissection in Thymic Malignancies: Implication of the ITMIG Lymph Node Map, TNM Stage Classification, and Recommendations.

OBJECTIVES: The aim of this study is to investigate the pattern of lymphatic metastasis and suggest a lymph node dissection (LND) strategy for thymic malignancies. METHODS: We retrospectively reviewed 131 thymic malignancy patients who had undergone LND. The recently introduced nodal map of the International Thymic Malignancy Interest Group/International Association for the Study of Lung Cancer and the TNM (tumor, node, metastasis) stage classification were used for grouping and staging the lymph nodes. The pattern of lymphatic metastasis and factors in lymphatic metastasis were investigated. RESULTS: Node metastasis was detected in 13 patients (N1 in six and N2 in seven). Six N2 patients (86%) had right paratracheal node (RPN) metastases. The rates of node metastasis were 1% at T1 and 37.5% at T2/3 (p < 0.001). The rates of node metastasis were 8% in the M0 and 43% in the M1 (p = 0.03). The rate was higher for thymic carcinoma (25%) than for thymoma (5.1%, p = 0.01), and the rates also differed between the subtypes of thymoma. There was no node metastasis of the A, AB, or B1 types. Tumor size was also a significant factor in node metastasis. The optimal cutoff value for the node metastasis was 6 cm and the specificity was 62%. Only 16% of the patients had received a preoperative histologic diagnosis. All patients with node metastasis had TNM stage II or higher thymic malignancy. The freedom from recurrence rate of the pN1/2 was significantly worse than that of the pN0 (5-year rate 38.5% versus 87.9%, p < 0.001). CONCLUSION: A status of stage II or higher was the most specific predictor of node metastasis, and the RPN was a crucial station for lymphatic metastasis in thymic malignancies. Thus, LND including RPN is recommended in stage II or higher thymic malignancies.

Surgical treatment of thymoma: an 11-year experience with 761 patients.

OBJECTIVES: Thymomas are rare, and information regarding their surgical outcomes and possible prognostic factors is limited. In this study, we aimed to determine the clinicopathological characteristics of thymoma and estimate independent predictors of both overall and disease-free survival in thymoma patients. METHODS: We carried out a retrospective review of the clinicopathological characteristics and prognostic factors in 761 consecutive patients with pathologically confirmed thymoma treated in Shanghai Chest Hospital between January 2001 and December 2011. Survival was calculated using the Kaplan-Meier method and evaluated with log-rank tests. Multivariable analysis was performed using the Cox regression model. RESULTS: Complete follow-up information was available for 544 patients. The overall survival rate was 92.8% at 5 years and 90.5% at 10 years. The 5- and 10-year disease-free survival was 87.9 and 82.1%, respectively. On multiple Cox regression analysis, the Masaoka-Koga clinical stage [odds ratio (OR), 2.057; 95% confidence interval (CI), 1.454-2.911; P < 0.01] and sex (OR, 2.244; 95% CI, 1.115-4.519; P = 0.02) were found to be independent predictors of overall survival. The Masaoka-Koga clinical stage (OR, 2.127; 95% CI, 1.487-3.042; P < 0.01) and completeness of resection (OR, 2.935; 95% CI, 1.410-6.109; P < 0.01) predicted disease-free survival. CONCLUSIONS: The four-tiered Masaoka-Koga clinical stage is the most important prognostic factor, predicting not only overall survival but also disease-free survival after thymoma resection. Completeness of resection predicts disease-free survival, and the World Health Organization histological classification may not have significant prognostic implications.

The major prognostic factors of thymomas: about a Tunisian study of 100 cases.

AIM: Thymomas are characterised by their rarity, histologic variability and peculiar patterns of recurrence. Herein, we present the experience of a single institution and aim to highlight the major prognostic factors of these tumours. MATERIALS AND METHODS: We present a retrospective study on 100 thymomas diagnosed between 1994 and 2011. Statistical analyses were performed using version 18.0 SPSS. The Kaplan Meier method was used to estimate survival, and survival curves were compared using the Log-Rank test. A p < 0.05 was considered statistically significant. RESULTS: 50 men and 50 women underwent surgical resection for thymoma. Radiologic findings highlighted a diagnosis of thymoma in 51% of cases. The thymomas were classified as stage I in 25 cases, stage II in 47 cases, stage III in 25 cases and stage IV in 3 cases. According to the WHO classification, tumours were classified as type A in 14 cases, type AB in 24 cases, type B1 in 17 cases, type B2 in 20 cases, type B3 in 8 cases, B1/B2 in 8 cases and B2/B3 in 9 cases. The mean survival of patients was 136 months. Age, sex, tumour size, WHO classification and Masaoka stage were evaluated as prognostic factors. Univariate analysis showed that the major prognostic factors were WHO classification (p = 0.019) and Masaoka Stage (p = 0.0001). CONCLUSION: Our results place emphasis on the prognostic value of WHO classification and Masaoka stage in thymomas; in addition, the necessity of improving reproducibility of microscopic classification to avoid discrepancies among prognostic groups is highlighted.

The 2015 World Health Organization Classification of Tumors of the Thymus: Continuity and Changes.

This overview of the 4th edition of the World Health Organization (WHO) Classification of thymic tumors has two aims. First, to comprehensively list the established and new tumor entities and variants that are described in the new WHO Classification of thymic epithelial tumors, germ cell tumors, lymphomas, dendritic cell and myeloid neoplasms, and soft-tissue tumors of the thymus and mediastinum; second, to highlight major differences in the new WHO Classification that result from the progress that has been made since the 3rd edition in 2004 at immunohistochemical, genetic and conceptual levels. Refined diagnostic criteria for type A, AB, B1-B3 thymomas and thymic squamous cell carcinoma are given, and it is hoped that these criteria will improve the reproducibility of the classification and its clinical relevance. The clinical perspective of the classification has been strengthened by involving experts from radiology, thoracic surgery, and oncology; by incorporating state-of-the-art positron emission tomography/computed tomography images; and by depicting prototypic cytological specimens. This makes the thymus section of the new WHO Classification of Tumours of the Lung, Pleura, Thymus and Heart a valuable tool for pathologists, cytologists, and clinicians alike. The impact of the new WHO Classification on therapeutic decisions is exemplified in this overview for thymic epithelial tumors and mediastinal lymphomas, and future perspectives and challenges are discussed.