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BACKGROUND: Thymic carcinoid (TC) is a rare entity among anterior mediastinal malignancies. TCs are neuroendocrine carcinomas that constitute approximately 2%-5% of all thymic epithelial tumors. CASE SUMMARY: The study reported a rare TC with multiple bone metastases. A 77-year-old man presented with a 2-month history of lower back pain and weight loss of 5 kg. Magnetic resonance imaging scans revealed damage to the lumbar spine, sacrocaudal vertebrae and iliac crest, suggesting bone metastasis; computed tomography (CT) scan of the thorax showed a calcified anterior mediastinal mass; positron emission tomography-CT demonstrated multiple abnormal bone signals; and laboratory work-up showed no endocrine abnormalities. Fine-needle aspiration biopsy revealed predominantly single small, round to oval cells with scant cytoplasm and some loose clusters, suggesting endocrine manifestations. The pathological diagnosis was atypical carcinoid, which tend to originate from the thymus and was classified as intermediate-highly invasive. The patient underwent anlotinib-targeted therapy. Anlotinib (12 mg) was administered daily for 2 wk, after which the patient was allowed to rest for 21 d. Follow-up CT after one year demonstrated that the tumor had shrunk by approximately 29% after therapy. Treatment has a long stable disease benefit of more than 2.5 years. CONCLUSION: These findings demonstrated that anlotinib is a promising treatment regimen for patients with TC and multiple bone metastases.

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Mark Wick made a wide range of contributions to the field of mediastinal pathology. Early papers amplified the spectrum of neuroendocrine carcinomas of the thymus and brought attention to the aggressive nature of this tumor, also highlighting the occurrence of coexisting carcinoid tumor and small cell carcinoma of this organ. The controversial issue of thymoma classification was addressed in several papers and editorial comments, while also reporting a case of metastatic thymoma. A series of thymic carcinomas as well a report on the unusual clear cell variant bear his name as one of the authors. He summarized the topic of mediastinal cyst in a review published in 2005. Sarcomas arising in mediastinal germ cell tumors were also within the purview of his interests, with a publication of series of seven cases. He reviewed the topic of inflammatory myofibroblastic tumor of the heart and added a case to the existing literature. Two books dedicated to different aspect of mediastinal pathology also carry his name in the front cover in association with Drs Taazelar in one and Marchevsky in the other.

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INTRODUCTION: Endogenous Cushing's syndrome (CS) is a rare, severe disease that can cause multiple systemic involvements and behavioral problems due to excessive cortisol production. Structural changes can be noted in the brain magnetic resonance imaging (MRI) scans of these cases. CASES: A 9-year-old girl and a 13-year-old boy were admitted with hypercortisolism. In the female patient, altered consciousness was prominent along with cerebral and cerebellar brain atrophy, and findings indicating posterior reversible encephalopathy syndrome were detected in the brain MRI. Although the male patient's neurological examination was normal, significant cerebral atrophy was seen in the brain MRI. Case 1 was diagnosed as having ectopic ACTH syndrome (EAS) due to a thymic carcinoid tumor. Case 2 underwent a pulmonary lobectomy upon detection of a bronchial lesion in the Ga-68 DOTATATE PET/CT scan while being examined for EAS due to a lack of suppression in the high-dose dexamethasone suppression test. However, hypercortisolism persisted despite the removal of the bronchial lesion, and subsequently, a diagnosis of Cushing's disease was established following bilateral inferior petrosal sinus sampling. DISCUSSION: Endogenous hypercortisolism may cause brain atrophy of varying severity. The central nervous system findings can be overlooked in children with CS. More comprehensive studies are needed to better understand the behavioral changes caused by the effects on the brain and to evaluate whether these changes are reversible. In addition, identifying the source of hypercortisolism can be difficult due to a lack of experience related to the rarity of the disease in children.

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The immune-related microenvironment of thymic carcinoid has rarely been reported. We analyzed the expression of PD-L1 and VISTA, and the distribution of CD4+ T cells, CD8+ T cells and CD68+ macrophages in the thymic carcinoid by immunohistochemical staining, and showed the correlation between these markers and clinical survival, indicating the potential therapeutic prospects.

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Spindle cell thymomas are the most common spindle cell neoplasms of the anterior mediastinum. These tumors belong to the group of thymic epithelial neoplasms and are known for their wide histomorphologic spectrum. This histological heterogeneity is the reason why unequivocal diagnosis can be challenging, especially when dealing with small biopsy material. Conversely, less conventional patterns of the tumor may also pose significant diagnostic problems in resected material and the differential diagnosis often includes other spindle cell neoplasms that are known to arise in the mediastinal cavity. These can be of variable origin and may share overlapping pathological features with spindle cell thymoma. Since spindle cell thymomas are tumors that primarily affect the adult population and predominantly arise from the thymic gland in the anterior mediastinum, this review will focus on the differential diagnosis with other spindle cell neoplasms that share similar demographic characteristics and, for the most part, originate from the anterior mediastinal compartment. These include other epithelial spindle cell tumors of thymic origin (sarcomatoid thymic carcinoma and spindle cell carcinoid tumor), mesenchymal neoplasms [solitary fibrous tumor (SFT), synovial sarcoma, and dedifferentiated liposarcoma] and various other tumors with spindle cell morphology, that may occasionally involve the anterior mediastinum. The clinical, pathological, immunohistochemical and molecular hallmarks of these lesions will be discussed and useful tips for the differential diagnosis with spindle cell thymoma will be provided.

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Thymic atypical carcinoids are extremely rare tumors and have a poor prognosis owing to their aggressive clinical course. The efficacy of treatments other than complete surgical resection is unclear. We herein report a postoperative recurrent case of thymic atypical carcinoid treated with everolimus and octreotide long-acting repeatable (LAR). A 75-year-old woman was admitted to our department because a nodule was detected in the right lobe of thymus by annual computed tomography. The patient underwent thymothymectomy, and a diagnosis of thymic atypical carcinoid was made. One year and seven months after surgery, she developed multiple metastases in the lung, hilar and mediastinal lymph nodes, liver, and bone. Everolimus 10 mg/day was administered; however, the dose had to be reduced to 5 mg/day due to grade 3 hyperglycemia and grade 3 interstitial lung disease. Metastatic lesions other than liver metastasis markedly responded to everolimus, although the liver metastases gradually progressed. Three years and six months after surgery, she was administered octreotide LAR 30 mg per month in combination with everolimus. She has maintained stable disease for 8 months after the application of this combination therapy.

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Neuroendocrine tumors (NETs) are epithelial malignancies that can arise from multiple tissues. Gastrointestinal (GI) NETs are the most common; in this review of extra-abdominal carcinoid tumors, we focus our discussion on bronchial and thymic carcinoid tumors. Bronchial carcinoid tumors comprise a quarter of all NETs and less than 2% of all lung cancers. Thymic carcinoid tumors are extremely rare, accounting for 5% of thymic tumors. Both bronchial and thymic carcinoid tumors are histologically classified as either typical or atypical based on their mitotic rate (less than 2 or 2-10 mitoses per 10 high-powered fields (HPF), respectively). Both bronchial and thymic carcinoids can present with symptoms of obstruction and potentially carcinoid syndrome. The gold standard of management of bronchial and thymic carcinoid tumors is surgical resection. For patients with advanced disease, first-line systemic therapy is generally somatostatin analog monotherapy with octreotide or lanreotide. In patients with refractory disease, therapy generally involves peptide receptor radioligand therapy, everolimus, or cytotoxic chemotherapy. There are ongoing, prospective trials comparing the mainstays of systemic therapy for these patients, as well as ongoing evaluations of immune checkpoint inhibitors and multi-kinase inhibitors. Prognosis for both bronchial and thymic carcinoid tumors depends on histologic grade, local versus invasive disease, and extent of metastases. Herein we provide a summary of the pathophysiologic and clinical background, the current state of the field in diagnosis and management, and note of key ongoing prospective trials for patients with bronchial and thymic carcinoid tumors.

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Background: Thymic carcinoid is a rare highly differentiated neuroendocrine neoplasm, which can manifest as endocrine disorders caused by ectopic adrenocorticotrophic hormone (ACTH) syndrome. Although clinical manifestations such as hypertension and hypokalemia are common manifestations in patients with ectopic ACTH syndrome, clinicians should also be aware of the mental and behavioral abnormalities that may initially appear in patients. It is extremely rare for patients with ectopic ACTH syndrome caused by thymic carcinoid to concurrently exhibit abnormal mental behavior, especially as the initial clinical manifestation of the tumor. Studies have suggested that abnormal mental behavior may be related to elevated blood cortisol levels. Case Description: A patient was admitted to hospital due to abnormal mental behavior, manifesting as hyperphasia involving gibberish and illogical language, trance, and a state of suspicion. The patient had experienced persecutory delusion. Auxiliary examination revealed elevated cortisol and ACTH. Chest computed tomography (CT) showed right anterior mediastinal tumor. After discussion, the multi-disciplinary team (MDT) concluded that ectopic ACTH syndrome derived from the thymus should be considered. After excluding surgical contraindications, a thymic tumor was resected, and the postoperative pathology confirmed that it was thymic carcinoid. At 6 postoperative months, the results were as follows: cortisol at 8:00 am 196.50 nmol/L; and ACTH at 8:00 am 28.63 pg/mL. The patient's mental behavior had returned to normal, and normal communication was possible. The postoperative symptoms and signs of the patient were improved, which reiterated the presence ectopic ACTH syndrome caused by thymic carcinoid. Conclusions: Thymic carcinoid with ectopic ACTH syndrome is very rare in clinical practice, and it is easily missed and misdiagnosed. Although clinical manifestations such as hypertension and hypokalemia are common manifestations in patients with Cushing's syndrome, clinicians should be aware that patients with Cushing's syndrome may initially exhibit abnormal mental behavior. Clinically, if the patient exhibits abnormal mental behavior accompanied by symptoms such as hypokalemia, hypertension, and diabetes, blood cortisol and ACTH hormone levels should be screened without delay. If the levels are found to be significantly increased, ACTH syndrome should be highly suspected.

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BACKGROUND: Multiple endocrine neoplasia (MEN) is divided into MEN type 1 (MEN-1) and MEN type 2 (MEN-2). MEN-1 may be associated with thymic carcinoid tumors. We present a case of the surgical removal of a thymic carcinoid associated with MEN-1 via a single-incision port RATS. CASE PRESENTATION: A 39-year-old male patient with multiple endocrine neoplasia type 1 (MEN-1) who had an anterior mediastinal mass was referred to our hospital. The patient had undergone total parathyroidectomy and auto-transplantation of a partial parathyroid for hyperparathyroidism 6 years ago. Chest computed tomography revealed an isolated anterior mediastinal mass on the thymic gland with a maximum diameter measuring 22 mm. Thymic carcinoid tumor is classified as MEN-1 and has a poor prognosis, so we decided to remove the tumor. Single-incision port RATS was performed, and thymic carcinoid was confirmed in pathology. CONCLUSIONS: This report demonstrates that thymic carcinoid tumor removal is feasible and easy to perform via single-incision port RATS.

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BACKGROUND: Cardiac myxoma is the most common type of primary cardiac tumor, and thymic carcinoid is a rare neuroendocrine tumor. No previous reports have described surgical management of concomitant occurrence of these neoplasms. We report a case of simultaneous surgical resection in a patient with coexisting cardiac myxoma and atypical thymic carcinoid. CASE PRESENTATION: A 44-year-old Japanese woman underwent chest roentgenography revealing an abnormality in the mediastinum. Computed tomography revealed a 100 mm mass in the anterior mediastinum and also a 30 mm mass in the left atrium. The mediastinal tumor was diagnosed as atypical carcinoid by biopsy. Having completed resection of atypical thymic carcinoid, cardiac mass was successfully resected with careful consideration of minimizing operation time and optimizing patient safety and oncological treatment. The histopathological diagnosis of the cardiac mass was myxoma. No adjuvant chemotherapy was administered, and no recurrence was seen as of the 45 month follow-up. CONCLUSIONS: The simultaneous surgery of cardiac myxoma and atypical thymic carcinoid was feasible and effective. To the best of our knowledge, this is the first case report to describe one-stage treatment of these neoplasms.

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Here, we report a case of carbohydrate antigen (CA) 19-9-producing mediastinal neuroendocrine tumor (NET) (atypical carcinoid). A 54-year-old woman with no specific relevant medical history was referred to our hospital because of increased CA19-9 (95.3 U/ml) detected on health screening. Chest computed tomography (CT) revealed an anterior mediastinal mass without localized lymphadenopathy. Thoracic surgery was performed and the histopathological diagnosis was thymic CA19-9-positive NET. The patient developed mediastinal lymph node metastasis at 1 year (CA19-9: 413 U/ml) and multiple bone metastases 4 years (CA19-9: 2303 U/ml) after surgery. Increased CA19-9 levels paralleled the clinical courses of relapse. To our knowledge, this is the first report of CA19-9-producing thymic NET.

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Patients with the multiple endocrine neoplasia type 1 (MEN1) syndrome carry germline heterozygous loss-of-function mutations in the MEN1 gene which predisposes them to develop various endocrine and non-endocrine tumors. Over 90% of the tumors show loss of heterozygosity (LOH) at chromosome 11q13, the MEN1 locus, due to somatic loss of the wild-type MEN1 allele. Thymic neuroendocrine tumors (NETs) or thymic carcinoids are uncommon in MEN1 patients but are a major cause of mortality. LOH at the MEN1 locus has not been demonstrated in thymic tumors. The goal of this study was to investigate the molecular aspects of MEN1-associated thymic tumors including LOH at the MEN1 locus and RNA-sequencing (RNA-Seq) to identify genes associated with tumor development and potential targeted therapy. A retrospective chart review of 294 patients with MEN1 germline mutations identified 14 patients (4.8%) with thymic tumors (12 thymic NETs and 2 thymomas). LOH at the MEN1 locus was identified in 10 tumors including the 2 thymomas, demonstrating that somatic LOH at the MEN1 locus is also the mechanism for thymic tumor development. Unsupervised principal component analysis and hierarchical clustering of RNA-Seq data showed that thymic NETs formed a homogenous transcriptomic group separate from thymoma and normal thymus. KSR2 (kinase suppressor of Ras 2), that promotes Ras-mediated signaling, was abundantly expressed in thymic NETs, a potential therapeutic target. The molecular insights gained from our study about thymic tumors combined with similar data from other MEN1-associated tumors may lead to better surveillance and treatment of these rare tumors.

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This review article discusses the diagnoses and treatment of patients with multiple endocrine neoplasia type 1 (MEN 1). The most common tumors associated with MEN 1 are located in the pancreas, pituitary, and parathyroid glands. Less common tumors include neuroendocrine tumors of the lung and thymus, adrenal tumors, and cutaneous lesions. This article describes the diagnosis, clinical manifestations, treatment, and surveillance of tumors associated with patients who are diagnosed with MEN 1.

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Knowledge of ectopic Cushing's syndrome (CS) due to thymic neuroendocrine tumours (NETs) comes from short series or single cases. Our aim is to perform a systematic review using PubMed, Embase, Scopus, Ovid Medline and Biosis Previews of all cases with ectopic CS due to thymic NETs reported in the last 40 years and describe one illustrative patient attended in our institution. Search of literature: From 162 patients, 58.6% were male and mean age was 34.6 ± 13.9 years-old. Median of symptoms until diagnosis was 6 [2-24] months and 62% had aggressive CS. Imaging was positive in 93.7% (chest X-ray), 97.8% (computed tomography), 80.7% (somatostatin receptor scintigraphy) and median tumour size was 47 [25-68.5] mm. At presentation, 18% had localized disease, 26.2% locally invasive and 55.7% advanced. Eighty-eight present underwent surgery and histological subtypes were atypical (46.7%), typical (30.4%) and carcinoma (21.7%). Tumour persisted or recurred in 70.1%, 63% received radiotherapy and 45.2% chemotherapy. Follow-up median was 26.6 [14.5-57.5] months and mortality was reported in 35.8% with median survival of 38 [19-60] months. MEN-1 mutation was referred in 3.1%. Comparatively, carcinomas had aggressive CS more frequently while atypical showed advanced disease more often. In conclusion, thymic NETs causing ectopic CS are presented as aggressive hypercortisolism in the middle aged population. The disease is commonly extended at diagnosis and persists or recurs after surgery in most patients with a short term high mortality.

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Prevascular mediastinal masses include a wide range of benign and malignant entities. Localization of mediastinal masses to specific compartments together with characteristic imaging findings and demographic and clinical information allows formulation of a focused differential diagnosis. Radiologists may use these methods to distinguish between surgical and nonsurgical cases and thus inform patient management and have an impact on outcomes. Treatment of choice varies based on the pathology, ranging from no intervention or serial imaging follow-up to surgical excision, chemotherapy, and/or radiation.

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BACKGROUND: Multiple endocrine neoplasia type 1 (MEN1) is a rare inherited syndrome that concurrently involves various endocrine glands. We report a rare case of MEN1 in a 43-year-old man whose first manifestation was an asymptomatic mediastinal mass. CASE PRESENTATION: A 13-cm-sized mediastinal mass was diagnosed as an atypical thymic carcinoid by computed tomography and percutaneous needle biopsy. In addition, hypercalcemia from a left inferior parathyroid hyperplasia, and a non-functioning gastric neuroendocrine tumor seen on esophagogastroduodenoscopy were found. Therefore, the patient was clinically diagnosed with MEN1 syndrome, and underwent surgical resection of thymic carcinoid tumor after pre-operative concurrent chemoradiation therapy to decrease tumor size and volume. Parathyroid lesion and gastric neuroendocrine tumor were also removed. Finally, a MEN1 gene mutation was observed in the patient and his 7-year-old son. CONCLUSION: Despite its rare occurrence, thymic carcinoid tumor should be considered as a MEN1-associated tumor and necessitates screening of other endocrine glands. Thymic carcinoid tumor carries a poor prognosis in patients with MEN1, and thus it needs to be carefully monitored even after radical excision.

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BACKGROUND: A pigmented carcinoid is an extremely rare variant of carcinoid characterized by melanin pigmentation of the tumor, with only five cases described in the literature. In addition, thymic carcinoids are rare in elderly patients and their prognosis after resection of the carcinoid tumor is unclear. CASE PRESENTATION: An anterior mediastinal tumor was incidentally found in an 82-year-old man who had been diagnosed with acute thoracic empyema. The tumor was considered most likely to be a noninvasive thymoma or thymic carcinoma for which surgery was indicated after the resolution of the empyema. The tumor was completely resected 4 months after the empyema surgery, and the patient had an uneventful postoperative course. A cut surface of the resected specimen was extensively pigmented and appeared dark-brownish, with abundant melanin pigmentation later confirmed in the spindle-shaped tumor cells. Based on the histologic examination and immunohistochemical study, melanoma was eliminated as a differential diagnosis and the tumor was diagnosed as a pigmented atypical carcinoid of the thymus. CONCLUSIONS: This report provides additional knowledge on thymic pigmented carcinoids and thymic atypical carcinoids in elderly patients.

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BACKGROUND: Thymic carcinoid is one of an extremely rare type of malignant neuroendocrine tumor with a poor prognosis. Invasion of thymic carcinoid to other organs could lead to devastating consequences. It has been reported that thymic carcinoid mainly invaded to the pleura, lungs, liver, pancreas and bone, while rarely to the cardiac, especially to the ventricle. CASE PRESENTATION: A 53-year-old man presented with gastrointestinal symptoms and persistent pericardial effusion. Multiple imaging tools, including chest computed tomography (CT), magnetic resonance imaging (MRI), 18F-Fluorodeoxyglucose positron emission tomography/CT (18F-FDG PET/CT) showed a malignant neoplasm arising from the thymus invading into the biventricular myocardium, pericardium, and left superior pulmonary veins. The tumor was finally diagnosed as a thymic carcinoid through pathological examination. CONCLUSION: This is a rare case of thymic carcinoid invading the ventricular myocardium, which presented as subacute heart failure. The observations in this case would be useful for differential diagnosis of primary heart disease and invasion of heart due to thymic carcinoid.

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AIM: To study the clinical, biochemical characteristics, treatment results and follow-up of patients with ectopic ACTH syndrome EAS (ACTH adrenocorticotropic hormone ). MATERIALS AND METHODS: A retrospective, observational, single-center study of 130 patients with EAS. Demographic information of patients, medical history, results of laboratory and instrumental investigations at the pre- and postoperative stages and follow-up of EAS were analyzed. RESULTS: The mean age at the diagnosis ranged from 12 to 74 years (Me 40 years [28; 54]). The duration of the disease from the onset of symptoms to the verification of the diagnosis varied from 2 to 168 months (Me 17.5 months [7; 46]). Eighty-one (62,3%) patients had bronchopulmonary NET, 9 thymic carcinoid, 7 pancreatic NET, 5 pheochromocytoma, 1 cecum NET, 1 appendix carcinoid tumor, 1 medullary thyroid cancer and 25 (19.2%) had an occult source of ACTH. The median follow-up period of patients was 27 months [9.75; 61.0] with a maximum follow-up of 372 months. Currently, primary tumor was removed in 82 (63.1%) patients, bilateral adrenalectomy was performed in 23 (18%) patients, in 16 of them there was an occult source of ACTH-producing NET and in 7 patients in order to control hypercortisolism after non-successful surgical treatment. Regional and distant metastases were revealed in 25 (19.2%) patients. At the time of the last observation 59 (72%) patients were exhibited a full recovery, 12 (14.6%) had relapse of the disease and 26 (20%) died from multiple organ failure (n=18), pulmonary embolism (n=4), surgical complications (n=2), disseminated intravascular coagulation syndrome (n=1) or COVID-19 (n=1). CONCLUSION: In our cohort of patients bronchopulmonary NET are the most frequent cause of EAS (62.3%). Surgical treatment leads to remission of hypercortisolism in 72% cases; the proportion of relapse (14.6%) and fatal outcome (20%) remains frequent in EAS.

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