EFFECTS OF p53 OVEREXPRESSION ON NEOPLASTIC CELL PROLIFERATION AND APOPTOSIS IN THYMIC CARCINOMA

Objective: To investigate p53 overexpression and its correlation with neoplastic cell proliferation and apoptosis in 20 thymic carcinomas. Methods: 20 surgical samples of thymic carcinoma were collected randomly during the past 15 years in the Guangzhou area. Immunohistochemical staining was performed using LSAB method with anti-p53 monoclonal antibody (DO-7) and proliferating cell nuclear antigen (clone PC 10) as primary antibodies. The p53 index was indicated by the number of p53 positive cells among 100 carcinoma cells. More than 25 percentage of p53 positive cells found in tissue sections was recognized as p53 overexpression. Carcinoma cell proliferation activity was assayed by PCNA index (PI), and apoptosis degree was evaluated by TUNEL (TdT-mediated dUTP-X nick end labeling) index (TI) using Boehringer MannheimIn Situ Death Detection Kit. Results: P53 positive cells could be found in vast majority of thymic carcinomas (19/20) and the overexpression rate reached 35% (7/20). The median PI (40%) of 7 cases with p53 overexpression was higher than that (31%) of 13 cases without p53 overexpression, but there was no statistical significance that existed between these two data (P>0.05). The median TI (0.5/HPF) of 7 p53 overexpression cases was much lower than that (4.5/HPF) of 13 non-overexpression cases, and there was a significant difference statistically (P<0.05). Conclusion: p53 expression was a frequent finding in thymic carcinoma cells, and the p53 overexpression which might represent p53 inactivation or gene mutation was often involved in thymic carcinogenesis. The median PCNA index of p53 overexpression group was higher than that of non-overexpression group though there existed no statistical difference. This indicates that the inhibiting function of p53 on cell proliferation seemed lost in p53 overexpressed thymic carcinomas. It is worthy to be specially mentioned that the inducing function of p53 on cell apoptosis was markedly lost in p53 overexpressed thymic carcinomas. Taken together, the overexpressed p53 that could represent aberrant p53 protein had not only lost its proliferation-inhibiting but also its apoptosis-inducing function in thymic carcinomas which might play an important role in thymic carcinogenesis.

Rare solitary splenic metastasis from a thymic carcinoma detected on fluorodeoxyglucose-positron emission tomography:A case report

BACKGROUND Thymic carcinoma is a rare,aggressive tumor arising from the thymus.In less than 7%of patients with thymic carcinoma,extrathoracic metastases occur in the extrathoracic lymph nodes,liver,and bone.Isolated splenic metastasis can occur but is very uncommon.To date,only 2 cases of splenic metastases from thymic carcinoma have been reported.CASE SUMMARY A 45-year-old man presented with chronic cough,dyspnea,persistent hoarseness and unintentional weight loss 17 kgs in 6 mo.Neck magnetic resonance imaging revealed a large,lobulated,soft-tissue mass measuring 5.4 cm×6.6 cm×3.8 cm which involved the left superior mediastinum and supraclavicular fossa.Chest computed tomography(CT)revealed a confluent and lobulated soft tissue mass encased the right brachiocephalic artery,right and left carotid arteries,and left subclavian artery in the mediastinum.A fluorodeoxyglucose-positron emission tomography was arranged for malignancy survey.The image revealed intense fluorodeoxyglucose avidity in a soft tissue lobulated mass occupying the superior mediastinum,over the cystic lesion in the spleen and in few enlarged nodules over the left supraclavicular fossa.CT-guided biopsy of the thymic mass and the ultrasound-guided biopsy of the splenic lesion were consistent with a thymic carcinoma with splenic metastasis.The patient was diagnosed of thymic carcinoma,cT2N2M1b,stage IVb.CONCLUSION A fluorodeoxyglucose(FDG)-positron emission tomography(PET)scan can provide a useful diagnostic value in conjunction with pathological result in evaluating tumor staging.Our case emphasizes the utility of FDG-PET for metastasis detection in thymic carcinoma.

Bystander effect and abscopal effect in recurrent thymic carcinoma treated with carbon-ion radiation therapy:A case report

BACKGROUND Although the bystander effect and abscopal effect are familiar in medicine,they are relatively rare in clinical practice.Herein,we report the case of a patient who demonstrated an obvious bystander effect and abscopal effect response following carbon-ion irradiation for recurrent thymic carcinoma.CASE SUMMARY A 44-year-old female presented with shortness of breath.Eleven years prior,she was diagnosed with athymic tumor located in the anterosuperior mediastinum.She underwent extensive tumor resection,and the postoperative pathologic diagnosis was thymic carcinoma.She was administered 50 Gy/25 Fx of postoperative radiation.In 2019,she was diagnosed with a recurrence of thymic carcinoma,with multiple recurrent nodules and masses in the left thoracic chest and peritoneal cavity,the largest of which was in the diaphragm pleura proximal to the pericardium,with a size of 6.7 cm×5.3 cm×4.8 cm.She received carbonion radiotherapy.After carbon-ion radiotherapy treatment,the treated masses and the untreated masses were observed to have noticeably shrunk on the day of carbon-ion radiotherapy completion and on follow-up imaging.We followed the CARE Guidelines for consensus-based clinical case reporting guideline development and completed the CARE Checklist of information to report this case.CONCLUSION This report is the first of obvious abscopal and bystander effects following carbonion irradiation in a human patient,and further research is needed to better elucidate the mechanisms of bystander and abscopal effects.

Multimodality Treatment for Thymic Carcinoma: Review of 11 Cases at a Single Institute

Background: We reported our experience with thymic carcinomas and review their clinical features, treatment strategies, and prognoses. Methods: From April 1998 to November 2012, 11 patients pathologically diagnosed with thymic carcinoma and treated in our hospital were investigated. Results: There were 7 men and 4 women, with a median age of 62 years (range, 35 - 72). According to the Masaoka staging system, 3 patients had stage II, 1 stage III disease, 3 stage IVa disease and 4 stage IVb disease. Ten patients had squamous cell carcinoma, whereas 1 had large cell neuroendocrine carcinoma (LCNEC). We performed surgery or multimodality therapy including surgery as the initial therapy for 8 patients. Of the non-surgical cases, 1 patient received chemoradiotherapy and survived for over 6 years without recurrence, whereas 2 received palliative care. Three of 4 patients who underwent complete resection survived without disease recurrence, whereas only 1 patient with LCNEC survived in the incomplete resection group. Multimodality therapy with cisplatin and docetaxel was provided to 3 patients, and recurrence has not been observed in any of the cases. Conclusions: Favorable outcomes could be achieved in patients with thymic carcinoma who underwent intensive treatment. In particular, surgery combined with cisplatin and docetaxel plus thoracic irradiation may be an attractive approach for thymic carcinoma.

Clinical Analysis of 45 Patients with Thymic Carcinoma

OBJECTIVE To retrospectively evaluate the prognostic factorsfor advanced thymic carcinoma.METHODS The data from 45 patients with advanced thymiccarcinoma were retrospectively analyzed according to Masaokastage criteria. There were 29 Stage Ⅲ patients and 16 StageⅣ patients (13 Stage ⅣA patients and 3 Stage ⅣB patients).According to the World Heath Organization Histological Criteria(2004), 25 cases were identified as low-grade and 20 caseswere identified as high-grade. All diagnoses were confirmedby biopsy. Five patients underwent gross total resection, 21patients underwent subtotal resection and 19 patients underwentbiopsy alone. Forty-two patients received radiotherapy with amedian dose of 60 Gy, and 37 patients underwent conventionalradiotherapy, including local irradiation and expanded irradiation.Local irradiation volume covered the primary tumor bed andapproximately 1-2 cm^2 surrounding the tumor (according topreoperative imaging). Expanded irradiation volume coveredthe full mediastinal and pericardium areas (with or withoutprophylactic irradiation in the supraclavicular area). Five casesreceived stereotactic radiotherapy. Thirty-one patients were alsotreated with chemotherapeutics, including Cisplatin, VP-16,Endoxan, 5-FU and taxol.RESULTS The median follow-up period was 59 months. Theoverall 3-year survival rate was 57.8%, and the median survivalwas 45 months. Univariate statistical analysis showed that thehistological subtype and Masaoka stage were prognostic factors.The 3-year survival rate was 61.9% in patients treated withgross total resection and 55.0% in those who underwent biopsyonly. The 3-year survival rate was 59.5% in patients treatedwith conventional radiotherapy and 80% in those treated withstereotactic radiotherapy. The 3-year survival rate was 64.5% inpatients treated with simultaneous chemotherapy and 42.9%in patients treated without simultaneous chemotherapy (P >0.05). Chemotherapy in combination with radiation treatmentand surgery achieved better outcomes for Stage Ⅳ patients thanradiation treatment and surgery without chemotherapy (P < 0.05).CONCLUSION For patients with Stage Ⅲ and Ⅳ thymiccarcinoma, complete resection and postoperative radiotherapy orfractionated stereotactic radiotherapy constitute the best treatmentsolution. Chemotherapy can also be used in combination toimprove prognosis. For patients with Stage Ⅳ thymic carcinoma,chemotherapy is necessary.

Myasthenia gravis as a form of clinical presentation of thymic carcinoma

Thymic carcinomas are rare tumors of the thymus arising in the thymic epithelium. They represent less than 1% of thymic malignancies. They often present with an advanced disease and metastasize to regional lymph nodes and distant sites. They have a worse prognosis with a 5-year survival rate of 30%-50%, while thymomas are much less invasive and have a 5-year survival of approximately 78%. We report a rare form of clinical presentation of a thymic carcinoma in which the diagnosis of myasthenia gravis was the cornerstone of the diagnosis of cancer. Surgery is considered the salvage treatment when possible. Radiotherapy is a second choice of salvage treatment, when possible depending on its localization and relation to nearby structures such as vascular structures. Molecular target therapy is a more directed, more expensive but less toxic treatment. Further studies need to be carried out for its approval worldwide, outside clinical trials.

A Rare Case of Thymic Carcinoma

Thymic carcinomas are unusual tumors of the thymus gland. Basaloid carcinoma, an unusal epithelioid varient of a thymic carcinoma, is a rare histopathological subtype, and is not well charecterized in the literature. We present the anatomical and histogical features of a basoloid thymic carcinoma, and discuss current diagnosis and imaging strategies, as well as the operative and oncologic care of this type of thymmic carcinoma. Basaloid carcinomas of the thymus after complete surgical resection and adjuvant therapy genarally have a favorable long-term prognosis.

THYMIC CARCINOMA(REPORT OF 14 CASES)

This paper reports of 14 cases of thymic carcinoma. Most of them with symptoms of chest pain, cheststuffy and discomfort, but without combined with extrathoracic syndromes, The tumors always were largein size and frequently invaded adjacent organs, hence with low resection rate. ln this series, complete re-section of tumor only 2 cases, partial resection in 7 cases, exploratory thoracotomy in 5 cases. Thymic car-cinoma was an extremely malignant tumor with extensive invasion intrathoracally and early metastasis ex-trathoracally. The common sites of metastasis were bone, liver,lung and extrathoracic lymph nodes. Adju-vant therapy postoperatively was given to all patients. Follow-up of lbo 8 years showed 1O cases death,ofwhich 5 cases died within the first year after surgery,3 cases within the second year. Four patients werestill alive so far, in which 3 patients were within 1. 5 years postoperatively. Pathological studies revealed 9cases of squamous epithe1ial cell thymic carcinoma, 3 of lymphoepithelioma - like thymic carcinoma and 2 ofsmall cell undifferentiate thymic carcinoma.

Genetic insights into thymic carcinomas and thymic neuroendocrine neoplasms denote prognosis signatures and pathways

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.

Thymic carcinoma involving sternum： a case report

Thymic carcinoma is a malignancy of the anterior mediastinum with a poor prognosis that is thought to be derived from thymic epithelium and they represent approximately 6% of primary mediastinal tumors. Because of the lack of literature discussing the clinical and pathologic features and treatment of this tumor, thymic carcinoma has been a somewhat controversial disease up to now. Here, we report a female patient suffering from thymic carcinoma involving the sternum. The tumor was resected and the sternum was replaced with a refrigerated homograft.

Encased heart and aorta by the thymic carcinoma

Thymic carcinoma is a very rare and aggressive malignant tumor. It is indolent and invasive cancer that easily metastasis. Invasive thymoma occurs most commonly into the pleura, pericardium, lungs, and recurrent laryngeal nerve, but invasion into the intracardiac and great vessel is rare.1 We reported a rare case ofinvasive thymic carcinoma which extended into aorta, pericardium, and right ventricular outflow tract （RVOT）, causing right ventricular outflow tract flow acceleration.

Molecular pathology of thymoma and thymic carcinoma

Thymic epithelial tumors(TETs)comprise a heterogeneous group of epithelial-derived thymic neoplasms with diverse clinical behavior and underlying molecular genetic features.Owing to their rare nature,the molecular classification of TETs has only recently begun to be fully explored.The advent of advanced molecular studies,particularly the ability to sequence the DNA and RNA of tumors in a massively parallel fashion,has led to an increased understanding of the molecular underpinnings of thymic neoplasia.Thymomas,characterized by a heterogeneous group of molecular alterations,tend to have low mutational burdens and various copy number abnormalities including a characteristic loss of chromosomal material in the region of 6q25.2-p25.3,a recurrent,specific point mutation GTF2I p.L424H,and specific expression of certain microRNAs.Thymic carcinomas,in contrast,are generally characterized by increased tumor mutational burdens,multiple copy number alterations,and varied,non-recurrent,somatic mutations.Advances in molecular knowledge of TETs allow for more precise molecular classification of these tumors,and the presence of specific alterations aids in the diagnosis of borderline lesions.In the future,additional molecular studies will better delineate the molecular landscape of these tumors and may one day allow for more targeted treatment algorithms.This review aims to cover the current understanding of the molecular alterations thus far identified in thymomas and thymic carcinomas.

Thymic carcinoma:review and update

Thymic carcinoma(TC)is a rare thymic epithelial neoplasm with an aggressive clinical course.There are many recognized histologic subtypes as described by the fifth edition of the World Health Organization(WHO)Classification of Thoracic Tumors;however,given the rarity of this tumor group,diagnosis remains a challenge,especially on limited tissue samples.Additionally,rare variants of TC are continuing to be established,particularly in the era of molecular diagnostics.Herein,histologic subtypes are described as the rare subtypes of TC in the context of their immunoprofile,cytogenetic or molecular features,clinical presentation,and ensuing challenges.

A Case Report:Severe Bullous Skin Reaction Induced by Anti-PD-1 Antibody(Toripalimab)Therapy in a Patient with Thymic Carcinoma

The development of immune checkpoint inhibitors,such as those targeting programmed cell death protein 1(PD-1),represents a major breakthrough in cancer therapy.Although immune checkpoint blockade therapy has a favorable risk/benefit ratio,it causes significant immune-related adverse events(irAEs),such as cutaneous reactions,in particular,severe bullous skin reactions and toxic epidermal necrolysis.Here,we report a case of a 51-year-old woman with malignant thymoma who developed a severe bullous skin reaction(characterized by a systemic rash,bullae,epidermal desquamation,and Stevens-Johnson syndrome)as a result of treatment with the PD-1 inhibitor toripalimab.The patient was treated with high doses of glucocorticoid,intravenous immunoglobulin,and intensive care,and eventually recovered from the severe irAEs.The intravenous injection of anti-PD-1 antibodies induces cutaneous reactions,which are associated with higher mortality rates.High doses of glucocorticoid combined with intravenous immunoglobulin are effective in alleviating such irAEs.Thus,improving the level of care and preventing skin infections can effectively reduce the risk of death.

Primary Mucinous Adenocarcinoma of the Thymus: A Case Report and Literature Review

THYMIC carcinoma is a rare malignant tumor,but the most common malignant tumor of the anterior mediastinum.According to the latest World Health Organization(WHO)classification,primary thymic carcinoma has a variety of histological types,mainly including squamous cell,basaloid,mucoepidermoid,

Micronodular thymic tumor with lymphoid stroma: A case report and review of the literature

BACKGROUND Micronodular thymic tumors with lymphoid stroma include micronodular thymoma with lymphoid stroma(MNT)and micronodular thymic carcinoma with lymphoid hyperplasia(MNC),whose micromorphological features are lymphoid stromal hyperplasia and nodular arrangement of tumor epithelial cells.This type of tumor is rare;therefore,the corresponding clinical guidelines,histopathological diagnostic criteria,prognostic factors,and therapeutic regimens have not been established.CASE SUMMARY This study covers a novel presentation of MNC in a patient and summarizes the clinicopathological characteristics of this type of tumor by using pooled-analysis methods.Morphologically,this tumor type is a series of benign to malignant pedigrees.We establish the following criteria for the classification of micronodular thymic tumors with lymphoid stroma:(1)Tumor cells with moderate-to-severe dysplasia;(2)Tumor cell mitotic figures>2/10 high-power fields;(3)Appearance of neoplastic necrosis;(4)No terminal deoxynucleotidyl transferase-positive immature T lymphocytes within the tumor;(5)Tumor cells with a Ki-67 index≥10%;and(6)Tumor cells express CD5.Cases that fall into the borders of two categories in terms of morphology are attributed to atypical MNT.It is proposed that the diagnosis of MNT should be established on the diagnostic criteria mentioned above.CONCLUSION Our diagnostic algorithm can effectively distinguish malignant tumors from benign tumors and provides a potent basis for predicting a prognosis,which offers a practical reference for oncologists and pathologists.

Thyroid carcinoma showing thymus-like differentiation: Case presentation of a young man

Ectopic thymic tissue can be present in the thyroid gland and a carcinoma showing thymus-like differentiation(CASTLE) may arise from such tissue. We are reported the case of a 26-year-old man with CASTLE, with cervical subcutaneous nodules relapse, who showed a good response to treatment with surgery, chemotherapy and radiotherapy. The problematic aspect of this case was the diagnosis; only on review were we able to make a final diagnosis. CASTLE is a very rare neoplasm. It is important to differentiate this cancer from others tumors such as primary or metastatic squamous cell carcinoma of the head and neck or squamous cell thyroid carcinoma, because the therapy and prognosis are different.Diagnosis is complicated and requires careful histological analysis(CD5- and P63-positive with presence of Hassall's corpuscles); unfortunately there is no gold standard treatment so, in this case, we administered a sandwich of chemotherapy and radiotherapy.

New findings on thymic epithelial tumors:Something is changing

Thymic epithelial tumors(TETs) are uncommon neoplasms with a wide range of anatomical, clinical, histological and molecular malignant entities. To date the management of TETs within clinical practice is based on a multimodal therapeutic strategy including surgery, chemotherapy and radiotherapy with a multidisciplinary approach and prognostic evaluation is mainly based on Masaoka staging and World Health Organization classification. Therefore novel strategies are needed, especially for refractory and/or recurrent TETs and for thymic carcinomas that present a poor prognosis. Personalized approaches are currely being developed and molecular targets are emerging from recent integrated genomic analyses. Targeted therapy will represent an important treatment option for TETs with an aggressive histology. To date, data indicate that vascular endothelial growth factor molecules, insulinlike growth factor 1 receptor, cyclin-dependent kinases and mammalian target of rapamycin may be potentially useful as targeted biological therapies.

Pembrolizumab as a novel therapeutic option for patients with refractory thymic epithelial tumor:A case report

BACKGROUND Thymic epithelial carcinomas are rare and have a poor prognosis.Treatment of thymic epithelial carcinoma is multimodal and includes surgery,post-operative radiation therapy,adjuvant and neoadjuvant chemotherapy,or exclusive chemotherapy based on disease resectability.However,there is currently no standard treatment regimen for metastatic and recurrent thymic carcinoma.CASE SUMMARY A 45-year-old Caucasian male,with no past medical history,presented with hepatalgia and a cervical mass.A computed tomography(CT)scan showed multiple suspect lesions in the lungs,liver,and anterior mediastinum associated with mediastinal and cervical adenopathy.CT-guided percutaneous biopsies of the liver lesions and anterior mediastinal mass were performed,confirming the histopathology of thymic epithelial carcinoma.Management consisted of several chemotherapy regimens and radiation therapy,administered between April 2016 and December 2018.The patient achieved complete metabolic response.Fluorodeoxyglucose positron emission tomography/CT performed in June 2019 showed disease relapse,with reappearance of a large hypermetabolic hepatic mass and involvement of mediastinal and axillary lymph nodes.Intravenous pembrolizumab(200 mg,every 3 wk)was administered after two prior systemic therapies.The patient’s response to treatment was last documented on March 5,2020.CONCLUSION Pembrolizumab was successful in treatment of a patient with programmed deathligand 1-negative metastatic thymic carcinoma,pretreated with chemotherapy.

Unexpected Dramatic Response of Pretreated Invasive Thymic Malignancies on Pemetrexed-Case Report and Review of Current Treatment Modalities

Thymomas are rare and usually slowly growing tumors, originating from the epithelial layer of the thymus. Prognosis depends on the extent of invasion of adjacent tissues whereby multimodality treatment including surgery with or without adjuvant chemoradiotherapy is the preferred approach for locally advanced thymomas. For metastatic thymomas, only few chemotherapeutic options are available. We report 2 cases of patients with metastatic thymic malignancies with a dramatic response on pemetrexed treatment. The choice for this antifolate therapy is based upon a small series. Because metastatic thymic neoplasm is a rare disease, large randomised trials are not feasible. Case reports on the treatment of these malignancies are very important and can provide readers with the opportunity to deal with rare dis- eases.