Atypical Thymic Carcinoid Research Articles

Superior Vena Cava Syndrome in Men with Thymic Atypical Carcinoid (Neuroendocrine Tumor Grade 2)

Introduction: Cases of neuroendocrine tumors (NET) can occur in various organs, generally in the form of gastroenteropancreatic (GEP-NET) and pulmonary tract (PNET). The incidence of thymic neuroendocrine tumors (TNET) is rare, accounting for less than 5% of thymic and mediastinal malignancies, and 0.4% of all neuroendocrine tumors. Case presentation: A 57-year-old man came to RSUP Dr. Mohammad Hoesin Palembang with complaints of coughing, bluish and curved blood vessels in the chest, and shortness of breath during activities that have been getting worse for six months. CT scan showed a tumor measuring 18.6 x 11.7 x 11 cm in the anterior mediastinum and pressing on the superior vena cava and abdominal aorta. TTNA and core biopsy with CT guidance showed NET Grade 2, mitoses 6/2 mm2, positive tumor cells with immunohistochemistry for synaptophysin, chromogranin, CD 56, AE1/AE3, and Ki67 9%. The patient received paclitaxel and carboplatin chemotherapy for 6 cycles. Conclusion: The prognosis for atypical carcinoid patients is 20-80% for a 5-year survival rate. Appropriate patient management is needed to improve the outcome of patients with primary thymic atypical carcinoid (NET, grade 2).

Atypical thymic carcinoid associated with rapidly progressive symptoms of Cushing's syndrome in a child

Atypical thymic carcinoid in children is rare and its prognosis principally depends on the completeness of the surgical resection. We report a case of atypical thymic carcinoid with lymph node metastasis that had not been identified prior to surgery. An 8-year-old boy was referred because of Cushing's syndrome and a worsening of his symptom, which included facial edema, fatigue, and headache, over 3 weeks. Blood testing revealed high plasma cortisol and adrenocorticotropic hormone (ACTH), and chest computed tomography demonstrated two tumors in his anterior mediastinum, but no findings suggestive of lymph node metastasis. We suspected the presence of an ACTH-producing thymic carcinoid tumor; therefore, the patient underwent total thymectomy and dissection of his anterior mediastinal and bilateral deep cervical lymph nodes. Histopathological examination revealed an atypical carcinoid tumor and left cervical lymph node metastasis. The patients' plasma cortisol and ACTH concentrations decreased after surgery, and he was further treated with radiotherapy and combination chemotherapy. Thus, it is possible that the development of symptoms may indicate more rapid progression of atypical thymic carcinoid, and deep cervical lymphadenectomy is necessary for its complete resection.

Insulinoma-associated-1 (INSM1) expression in thymic squamous cell carcinoma.

Thymic squamous cell carcinoma (TSC) presents distinct immunohistochemical features with its expression of CD5 and CD117, both of which are rarely expressed in squamous cell carcinoma in other organs. We found insulinoma-associated-1 (INSM1) expression in some TSCs; thus, a series of thymic tumors were examined retrospectively. Using surgically resected thymic tumors (TSC, n = 35; thymic atypical carcinoid [TAC], n = 4; and thymoma, n = 112) and non-neoplastic thymic tissue (n = 26), we evaluated immunohistochemically the expressions of INSM1, ASCL1, SOX2, NE markers (synaptophysin, chromogranin A, and CD56), and conventional TSC markers (CD5 and CD117). INSM1 was expressed in 22 TSCs (63%), whereas the positive frequencies of synaptophysin, chromogranin A, and CD56 were limited to 13, 10, and 1 cases, respectively. The discordance was highly contrasted with concordantly positive TACs. INSM1 and NE makers were rarely expressed in thymomas. INSM1 expression in TSCs was also associated with CD5 expression, which was significantly less frequent in INSM1-negative TSCs. INSM1, ASCL1, and SOX2 expressions were correlated with one another, but none of the single transcription factors or their combinations is associated with NE expression. The non-neoplastic medullary thymic epithelium was dispersedly positive for INSM1, particularly around Hassall's corpuscles. Despite positive INSM1, a significant decrease in the frequency of NE maker expression may present as a diagnostic pitfall in TSCs. Furthermore, the discordance, which was inherent in the non-neoplastic thymic epithelium, might be a characteristic feature in TSCs.

Treatment of Thymic Oligometastastic or Oligoprogressive Lesions with Hypofractionated Radiation Therapy or Stereotactic Body Radiation Therapy

<h3>Purpose/Objective(s)</h3> Recent large clinical trials have demonstrated an improvement in local failure-free survival (LFFS) and progression free survival (PFS) with hypofractionated radiation therapy (HFRT) and stereotactic body radiation therapy (SBRT) in select patients with oligometastatic (OM) and oligoprogressive (OP) disease. However, little is known about the outcomes of HFRT and SBRT in patients with OM or OP disease from thymic malignancies. Therefore, the purpose of this analysis was to characterize the outcomes of such patients treated at our institution. <h3>Materials/Methods</h3> We retrospectively reviewed patients with OM or OP thymic malignancies treated with HFRT or SBRT between 2009-2021. We defined OM as 5 or fewer sites of metastatic disease at the time of RT and OP as 5 or fewer sites of metastatic disease increasing in radiological size. Patients treated with 20 or fewer fractions of radiation were included. Survival outcomes were defined from the end of RT. Analyses were done using the <i>lifelines</i> module in Python. <h3>Results</h3> We analyzed 48 patients treated to 81 lesions. The median age was 54 years old (range: 24-82 years), 63% were male and 79% were white. Patients had thymoma (54%), thymic carcinoma (38%), or atypical thymic carcinoid (8%). At the time of initial diagnosis, patients were stage I-II (21%), III (12.5%), IVA (23%) or IVB (42%). The majority of patients (65%) received systemic therapy prior to radiation therapy. Of the 81 lesions treated, 67 (83%) were OM lesions and 14 (17%) were polymetastatic, but OP lesions. Treatment sites included bone (37%), pleura (25%), lymph nodes (20%), lung (10%), brain (5%) and other (4%). Most patients were treated in 3 fractions (N=31; 8-10 Gy x 3 fractions), 5 fractions (N=28; 5-7 Gy x 5 fractions (N=20) or 8-10 Gy x 5 fractions (N=8)), or 15 fractions (N=11; 2.5-4 Gy x 15 fractions). The median biological effective dose (BED) was 51.3 Gy. Median follow up was 16 months. The 2-year/5-year rates of LFFS and PFS were 83%/76% and 32%/17%, respectively. The 2-year/5-year/10-year rates of overall survival (OS) were 92%/80%/61%. Patients with thymic carcinoma or atypical carcinoid had similar LFFS vs. those with thymoma (2-year LFFS: 85% vs. 82%, p=0.31), but they had shorter PFS (2-year PFS: 5% vs. 39%, p=0.01), and OS was not significantly different (2-year OS: 86% vs. 96%, p=0.25). Patients (N=14 patients treated to 19 lesions) treated with a BED > 60 Gy did not experience any local failure at 2 years (2-yr LFFS=100%). <h3>Conclusion</h3> Patients with OM or OP thymic malignancies treated with HFRT or SBRT had high rates of LFFS, PFS and OS. Despite having a more aggressive disease, patients with thymic carcinoma still experienced favorable LFFS with HFRT or SBRT. Patients treated with regimens with BED greater than 60 Gy had excellent LFFS. These results suggest that with long OS and PFS times, consideration should be given to SBRT/HFRT regimens to maximize local control in these patients with favorable prognoses.

Interim results of an ongoing phase 1/2a study of HPN328, a tri-specific, half-life extended, DLL3-targeting, T-cell engager, in patients with small cell lung cancer and other neuroendocrine cancers.

8566 Background: HPN328 is a delta like canonical Notch ligand 3 (DLL3)-targeting T-cell engager (TCE) derived from the TriTAC platform, designed to minimize off-target toxicities. HPN328 contains 3 binding domains, engineered to redirect T cells to kill DLL3-expressing cancer cells: anti-DLL3 for target engagement, anti-CD3 for T-cell engagement, and anti-albumin for half-life extension. Methods: This ongoing Ph1/2a study is evaluating HPN328 in patients (pts) with metastatic small cell lung cancer (SCLC) and other neuroendocrine (NE) cancers associated with DLL3 expression. Eligible pts must have disease that is relapsed/refractory to standard systemic therapy. Primary endpoints are safety, tolerability, and determination of MTD/RP2D. Secondary objectives are pharmacokinetics (PK), pharmacodynamics, immunogenicity, and preliminary anti-tumor activity (RECIST 1.1). HPN328 is administered IV, once weekly. AEs are graded by CTCAE 5.0, and ASTCT for cytokine release syndrome (CRS). Results: As of Feb 3rd, 2022, 16 pts were enrolled in 8 dose-escalation cohorts at doses from 0.015mg to 12.0mg (SCLC n = 10 (62.5%); NE prostate cancer (NEPC) n = 2 (12.5%); other NE neoplasms (NEN) n = 4 (25%)). Median pt age was 61 (43-73) yrs. Pts received a median of 3 (1-5) prior treatments; 75% received a PD-1 blocker. At baseline, 6 pts (37.5%) had treated brain metastases and 8 (50%) had liver metastases. Median treatment duration was 10.6 (3.3-31.3 plus) weeks. Treatment is ongoing in 7 pts (44%; median 16.5 weeks). CRS was reported in 5 pts (31%); events were grade 1 or 2, occurred within 24 hrs of the 1st or 2nd dose and did not recur with rechallenge. No ≥ Grade-3 CRS occurred. No dose-limiting toxicities were observed, and no AEs led to discontinuation. HPN328 exhibited linear PK, with dose-proportional increases in exposure and a median half-life of 71 hrs. Small, transient increases in select cytokines and chemokines were observed up to 24 hrs post dose. T-cell activation and margination were observed, consistent with target engagement. DLL3 expression was confirmed on IHC analysis of most baseline biopsies. 15 pts were efficacy evaluable. 6 of 15 (40%) had decrease in sum of target lesion diameters (4 SCLC, 1 NEPC, 1 NEN). 3 of 9 (33%) SCLC pts across all doses had &gt; 30% decrease (weeks on treatment: 17.2, 16.9 [ongoing], and 25.1 [ongoing, confirmed PR]). At doses ≥1.215mg, 2 of 4 (50%) SCLC pts had &gt; 30% decrease and 1 had &gt; 20% decrease. 4 pts (25%) had stable disease: 2 SCLC, 1 NEPC, 1 NEN (Thymic atypical carcinoid). Conclusions: HPN328 is a novel half-life extended DLL3-targeting TCE that is well tolerated and clinically active. AEs have been transient, manageable, and consistent with class. No ≥ Grade-3 CRS occurred. Tumor shrinkage has been observed, including 1 confirmed PR. Dose escalation is ongoing; updated data will be presented. Clinical trial information: NCT04471727.

Simultaneous surgical resection of cardiac myxoma and atypical thymic carcinoid: a case report

BackgroundCardiac 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 presentationA 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.ConclusionsThe 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.

Primary thymic atypical carcinoid with rare multiple bone metastasis: A case report and literature review.

Primary thymic atypical carcinoid (TAC) is a type of extremely rare neuroendocrine tumor. Approximately one-third of patients with TAC tumors are asymptomatic, and no treatments of TAC have been rigorously tested in multicenter clinical trials. To date, there has been no previous case report of TACs with multiple skull metastases. The present report describes a case of a 56-year-old male patient with a primary TAC and multiple axial skeleton metastases, including multiple bilateral metastases to the parietal bones, outer wall of the orbital cavities, and the petrous apex, as well as metastases to the suprasellar region and the clivus. The histological examination confirmed the diagnosis of TAC. Single-photon emission computed tomography, computed tomography and magnetic resonance imaging scans revealed multiple bone metastases. The patient refused chemotherapy and radiotherapy and only accepted alleviative treatment, and died 89 days after diagnosis. This type of cancer is highly malignant with an extremely short natural course and high disease-related mortality. In addition, a review of the literature was performed to provide a reference for proper diagnosis and treatment of TACs.

A rare case of multiple endocrine neoplasia type 1 initially presenting as an asymptomatic, huge mediastinal mass: case report

BackgroundMultiple 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 presentationA 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.ConclusionDespite 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.

Pigmented spindle cell variant of a thymic atypical carcinoid in an octogenarian

BackgroundA 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 presentationAn 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.ConclusionsThis report provides additional knowledge on thymic pigmented carcinoids and thymic atypical carcinoids in elderly patients.

A Resected Case of Atypical Thymic Carcinoid

A Resected Case of Atypical Thymic Carcinoid

Insulinoma-associated protein 1 immunostaining for various types of neuroendocrine tumors on FNA smears.

Insulinoma-associated protein 1 (INSM1) has recently emerged as a reliable nuclear immunostaining marker for detecting neuroendocrine tumors (NETs) in paraffin-embedded surgical samples and cytologic cell blocks, but the reliability of INSM1 staining on cytologic smears is understudied. This study investigated the performance of INSM1 staining on cytologic smears for the detection of various NETs in comparison with chromogranin (CG) and synaptophysin (SYN). INSM1, CG, and SYN were stained on cytologic smears of 70 NETs, including 20 pancreatic NETs, 10 lung carcinoid tumors, 11 small cell lung carcinomas (SCLCs), 10 medullary thyroid carcinomas, 10 Merkel cell carcinomas, 4 thymic atypical carcinoid tumors, and 5 olfactory neuroblastomas. The detection rate, the percentage of positive cells, and the staining intensity were recorded. The overall detection rate of INSM1 (94%) was higher than the rates of CG (79%) and SYN (89%). The detection rate of INSM1 was higher than the rates of CG and SYN in SCLC, Merkel cell carcinoma, and olfactory neuroblastoma; higher than the rate of CG and equal to the rate of SYN in pancreatic NETs and medullary thyroid carcinoma; equal to the rate of CG and higher than the rate of SYN in thymic atypical carcinoid tumors; and equal to the rate of CG and lower than the rate of SYN in lung carcinoid tumors. INSM1 staining was easier to interpret than CG and SYN staining, especially in high-grade NETs. INSM1 can be reliably stained on cytologic smears and outperforms CG and SYN in the verification of clinically or radiologically suspected NETs.

Anti-L-shaped mini-sternotomy combined with video-assisted thoracoscopy for resection of atypical thymic carcinoid: A case report

Anti-L-shaped mini-sternotomy combined with video-assisted thoracoscopy for resection of atypical thymic carcinoid: A case report

Familial Multiple Endocrine Neoplasia Type 1-associated Pulmonary Typical Carcinoid and Thymic Atypical Carcinoid—Report of a Surgical Case—

Familial Multiple Endocrine Neoplasia Type 1-associated Pulmonary Typical Carcinoid and Thymic Atypical Carcinoid—Report of a Surgical Case—

Capecitabine and Temozolomide as a Promising Therapy for Advanced Thymic Atypical Carcinoid.

Thymic atypical carcinoid (TAC) is a rare thymic neuroendocrine tumor that originates in the neuroendocrine system and lacks a standardized treatment. The combination of capecitabine (CAP) and temozolomide (TEM) is associated with an extremely high and long-lasting response rate in patients with metastatic pancreatic neuroendocrine tumors. However, there is little evidence showing that the CAPTEM regimen is effective for TAC. For patients with unresectable or metastatic atypical carcinoid of the thymus, few treatment options are available, and the treatment efficacy is not satisfactory. To explore the efficacy and safety of the CAPTEM regimen against TAC, we conducted a retrospective review. A total of nine patients with advanced atypical carcinoid of the thymus in the China-Japan Friendship Hospital were treated with capecitabine (750 mg/m2 twice daily, days 1-14) and temozolomide (200 mg/m2 once daily, days 10-14) every 28 days between 2014 and 2018. The disease control rate (DCR), progression-free survival (PFS), and adverse effects after treatment were analyzed. The DCR was calculated by RECIST version 1.1. Progression-free survival was calculated by the Kaplan-Meier survival method. A total of nine patients (six male and three female) were included. The median age at CAPTEM initiation was 50 years (range, 26-58). The median number of CAPTEM cycles was 8 (range, 3-23). The DCR was 89% (8/9), with eight patients achieving stable disease. Only one patient (11%) showed progressive disease. The median PFS was 8 months. Because we applied vitamin B6 and ondansetron before administering the drugs, the side effects of this regimen were very small. Adverse reactions were all below grade 3 and included myelosuppression and digestive tract reaction. Our results suggest that the CAPTEM regimen may be effective and well tolerated for the treatment of TAC. More evidence is needed to validate the effectiveness of this regimen. Capecitabine and temozolomide regimen is effective and well tolerated in patients with advanced thymic atypical carcinoid.

The Value of Postoperative Radiation Therapy in Atypical Thymic Carcinoid Remains Unclear: A Population-Based Study

The Value of Postoperative Radiation Therapy in Atypical Thymic Carcinoid Remains Unclear: A Population-Based Study

Clinical implication of MEN1 mutation in surgically resected thymic carcinoid patients

Thymic carcinoid is a rare but very aggressive neuroendocrine tumour derived from the neuroendocrine system. Here we report a male patient with thymic atypical carcinoid. Though thymic carcinoid is relatively common, the gene sequencing profile was performed and the gene sequencing result indicated germline multiple endocrine neoplasia type 1 (MEN1) mutation and two somatic mutations on MEN1 gene and no copy number variation or fusion events were detected. It is well-known that the mutation of MEN1 is the typical manifestation of MEN1 syndrome, which is an autosome dominant disease that includes varying combinations of more than 20 endocrine and non-endocrine tumors. In the English literature, 7 cases of solitary thymic carcinoid harboring somatic variants in MEN1 are reported in the absence of other organs involvement as MEN1 syndrome presents. We summarized the clinical features and prognosis of this rare thymic tumor.

A case report of metastatic atypical thymic carcinoid with ectopic ACTH production: locoregional control after adaptive radiation treatment.

Thymic carcinoid is an extremely rare malignancy. This tumor is often associated with endocrine disorders such as Cushing's syndrome, multiple endocrine neoplasia type 1 and superior vena cava syndrome. We describe the case of a 44-year-old Italian woman with metastatic atypical thymic carcinoid secreting ectopic adrenocorticotropic hormone who was treated with adaptive radiation therapy with a curative dose schedule for a symptomatic mediastinal tumor. After 22 months, the patient was in good clinical condition, presenting stable disease without any evidence of local or systemic progression. To our knowledge there are no previously reported data regarding radical radiotherapy in the treatment of thymic carcinoids.

Use of DOTATATE PET/CT Scan in the Diagnosis and Staging of Thymic Atypical Carcinoid Tumor in a Patient with Secondary ACTH-dependent Cushing Syndrome: Look Twice and Cut Once

Use of DOTATATE PET/CT Scan in the Diagnosis and Staging of Thymic Atypical Carcinoid Tumor in a Patient with Secondary ACTH-dependent Cushing Syndrome: Look Twice and Cut Once

A Case of Distal Pancreatectomy for Pancreatic Metastasis of Thymic Atypical Carcinoid

Background: Thymic atypical carcinoid(AC) tends to have a more aggressive clinical course than typical carcinoid(TC). About 20%-30% of patients with thymic AC experience local recurrence or distant metastasis. Pancreatic metastasis of thymic AC is extremely infrequent. We experienced a case of pancreatic metastasis of thymic atypical carcinoid, in which a distal pancreatectomy was performed. Case presentation: A 50-year-old man underwent thoracoscopic resection of a mediastinal tumor in June 2009. The diagnosis was thymic AC. He also underwent an extended thymectomy in October 2011, thoracoscopic resection in October 2012, and tumor resection of the chest wall in March 2013 for recurrences. During follow up in April 2014, computed tomography (CT) revealed lymph node swelling on the ventral side of the brachiocephalic vein, around the left gastric vein, and on the left side of the celiac artery. Dynamic CT revealed a pancreatic tumor 10 mm in diameter with low enhancement. EUS-guided fine-needle aspiration (EUS-FNA) biopsy revealed the pancreatic tumor was compatible with metastasis of thymic AC. The patient underwent abdominal lymph node resection and distal pancreatectomy in June 2014. Because the lymph node on the ventral side of the branchiocephalic vein was judged as unresectable, 60-Gy radiation therapy was given in September 2014. Per pathological examination and immunohistochemistry, the final diagnosis was pancreatic metastasis of thymic AC. With several chemotherapy courses for recurrences, the patient has remained alive for eight years after the first surgery. Conclusion: AC metastasis to the pancreas is extremely rare. EUS-FNA is useful for diagnosis. Definitive determination of whether the treatment provides a survival benefit awaits further studies.

Investigation on Computed Tomography Features of Primary Thymic Atypical Carcinoid Tumors.

The thymic atypical carcinoid tumors (aTCs) are rare. The computed tomography (CT) features of aTC were poorly studied, and researches under this topic with large samples are in a small quantity in the literature. Our aim was to investigate the CT features of aTC. Eleven cases of aTC (7 men and 4 women; mean age, 56 ± 16 years) proved by pathology were retrospectively analyzed. All the patients underwent contrast-enhanced CT scans with dual phase (25-30 and 60-70 seconds) after contrast agent injection. Two experienced radiologists analyzed the imaging findings. The observing indexes of CT features were based on standard CT reporting terms of mediastinal masses suspicious for thymic malignancy, particularly on the findings of marginal cystic/necrotic component (MCC) sign and hypervascular sign in tumors. All the tumors were located in the anterior and/or middle mediastinum and heterogeneous parenchyma, with moderate to marked enhancement, and had multiple cystic/necrotic components. The maximum diameter of lesions ranged from 5 to 24 cm. Among the 11 patients involved in this study, 6 patients had distant metastases, all of which were identified as skeletal metastases; 9 cases showed MCC sign only at the margin (3 cases) or at both marginal and central margins (6 cases), and 5 cases showed hypervascular sign. Our results suggested that the MCC and hypervascular signs should be included as characterization in addition to the standard features for the diagnosis of aTC.