Spindle Epithelial Tumor With Thymus-like Differentiation Research Articles

Abstract 937: Prioritizing treatment targets for an adolescent with metastatic processive malignancy using proteomics and personalized xenograft models within an actionable timeframe

Abstract Translation of precision oncology data into feasible precision therapies for hard-to-cure childhood, adolescent and young adult malignancies remains a significant challenge. Identifying therapeutic targets at the protein and pathway level and demonstrating treatment response in personalized models hold great promise, particularly for combination therapies, but may be considered complex and time consuming. Here, we present the case of an adolescent with metastatic, progressive spindle epithelial tumor with thymus-like differentiation (SETTLE) and evaluate how proteomics combined with rapid patient-derived models can identify treatment options not apparent at the genome or transcript level. Mass spectrometric proteome analysis of macro-dissected tumor and adjacent normal from formalin fixed paraffin embedded sections was completed within two weeks of biopsy and identified key proteins involved in one-carbon metabolism, including SHMT2 and DHFR as possible targets for single or combination therapy. Elevated SHMT2 levels were validated by immunohistochemistry and compared to levels across AYA tumors. Based on the suitability for an innovative therapy trial, we prioritized single-agent sertraline, a commercially available anti-depressant medication that inhibits SHMT2, and confirmed a positive drug response in both chicken chorioallantoic membrane (CAM) and larval zebrafish xenografts generated from the patient. Retrospective expansion in a murine xenograft enabled metabolic tracing on isolated SETTLE- patient-derived xenograft cells using 13C6-glucose confirming SHMT2 activity and response to in vitro treatment. Following failure of cytotoxic chemotherapy and second-line sorafenib treatment, a monotherapy trial of sertraline was initiated by the patient but stopped after 8 weeks after evidence of progressive disease. Possible combination therapies were evaluated further in the patient-derived models. Combining sertraline with the common antibiotic trimethoprim, resulted in enhanced growth inhibition of SETTLE cells in the larval zebrafish xenografts. Significance: Overall, we demonstrate that proteomics and personalized xenograft models may provide supportive pre-clinical data in a clinically meaningful timeframe to support medical decision-making and impact clinical practice. Citation Format: Georgina D. Barnabas, Tariq A. Bhat, Verena Goebeler, Pascal Leclair, Nadine Azzam, Nicole Melong, Jason N. Berman, Jennifer A. Chan, Donna L. Senger, Seth Parker, Christopher A. Maxwell, Gregor S. Reid, Jonathan Bush, Caron Strahlendorf, Rebecca Deyell, C James Lim, Philipp F. Lange. Prioritizing treatment targets for an adolescent with metastatic processive malignancy using proteomics and personalized xenograft models within an actionable timeframe [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 937.

Medullary thyroid carcinoma a relatively uncommon entity: A case report

Introduction: Medullary thyroid carcinoma is an uncommon primary thyroid tumour (5-10% of all thyroid malignancies) arising from parafollicular cells or C-cells. Most tumours are sporadic (75-80%) and familial syndrome multiple endocrine neoplasia; MEN-2A, MEN-2B and familial MTC in 20 to 25% cases. Case Report: We report a case of primary medullary thyroid carcinoma in a 30 years old male patient presented with complaint of midline neck swelling. On fine needle aspiration cytology diagnosis of medullary carcinoma was suggested with a differential of SETTLE (spindle epithelial tumor with thymus like differentiation). The swelling was excised and send for histopathological examination which revealed polygonal to plump spindle shaped tumor cells, arranged in lobules separated by fibrous septa, having abundant eosinophilic granular cytoplasm with round to oval nuclei, finely stippled nuclear chromatin and indistinct nucleoli and diagnosed as primary medullary thyroid carcinoma, confirmed on immunohistochemistry. Conclusion: MTC is the first human malignancy known to be associated with tumour marker and hormone calcitonin. Immunohistochemistry has definite role in confirmation of diagnosis. Keywords: Amyloid, Medullary carcinoma, Procalcitonin, Synaptophysin.

Spindle cell tumor with thymus-like differentiation masquerading as a papillary carcinoma of thyroid gland

Spindle epithelial tumor with thymus-like differentiation (SETTLE) is an indolent malignant thyroid tumor seen in children, adolescents, and young adults showing thymic or related branchial pouch differentiation. The tumors are composed of spindle cells along with focal epithelial component and glandular formations. We herein report a case of SETTLE with a follow-up period of 20 years.

Spindle Epithelial Tumor with Thymus-Like Differentiation (SETTLE): A Next-Generation Sequencing Study.

Spindle epithelial tumor with thymus-like differentiation (SETTLE) is a malignant biphasic neoplasm of the thyroid or neck with propensity for late metastasis. Unlike synovial sarcoma, its main morphologic mimic, SETTLE lacks synovial sarcoma-associated translocations. A single case of SETTLE has shown a KRAS mutation but to date no comprehensive next generation sequencing studies of this rare neoplasm have been undertaken. Herein, we subjected 5 well defined cases of SETTLE to direct sequence analysis of 592 genes and fusion gene analysis of 52 genes frequently rearranged in human cancers. We identified one case with two pathogenic variants in the KMT2D gene, one being in an intron splice site (c.674-1A>G) and the other being a frameshift variant (p.M2829fs). This same case also had a pathogenic nonsense variant in the KMT2C gene (p.R1237*). A second case of SETTLE carried a pathogenic NRAS missense variant, Q61R. No other molecular alterations, microsatellite instability, gene fusions or amplifications were identified.

Renal Involvement in Cases of Spindle Epithelial Tumor with Thymus-Like Differentiation : A Case Report and Review of the Literature

Background: Spindle epithelial tumor with thymus-like differentiation (SETTLE) is a very rare neoplasm of the thyroid first described by Chan and Rosai in 1991. Renal involvement usually occurs as part of a disseminated metastatic picture. SETTLE is believed to arise from branchial pouch or thymic remnants and shows primitive thymic differentiation. Presentation: A 41-year-old male presented with a thyroid mass in 2005. The patient underwent a total thyroidectomy followed by radiation therapy. Pathology concluded papillary thyroid cancer. In 2011, the patient was admitted with worsening cough. CT showed lung involvement, multiple mediastinal lymph nodes, and a left renal mass. A biopsy established the diagnosis of SETTLE. Four cycles of platinum chemotherapy were given. In 2014, the patient was referred to Urology with progressive flank pain and hematuria. CT showed a progression of the renal mass, and results of an U/S guided biopsy of the kidney were consistent with SETTLE. An elective radical nephrectomy was performed in late 2016 to relieve symptoms. The patient is currently being followed as an outpatient. Conclusion: Due to the rare nature of SETTLE, algorithms for the diagnosis, treatment, and outcomes are not established. Although SETTLE presents as a low-grade malignancy, this case, as well as other reported cases with a long follow-up duration, suggested that it can metastasize many years after initial diagnosis. More data is needed to elucidate the risk and prognosis of renal metastasis in SETTLE.

Spindle epithelial tumor with thymus-like differentiation (SETTLE): Case report with longest follow up & latency to metastasis

Spindle epithelial tumor with thymus-like differentiation (SETTLE) is an extremely rare, low-grade malignant spindle cell tumor of the thyroid gland with delayed metastatic potential. It occurs mainly in children, adolescents and young adults and is thought to be derived from thymic or branchial pouch remnants. Nearly 42 cases have been reported in the English literature. Metastatic disease has been described up to 22 and 25years after the initial operative intervention. SETTLE should be considered in the differential diagnosis of any spindle cell tumor in thyroid region. Pathologic diagnosis requires spindle and epithelial components and the use of immunohistochemistry. The differential diagnosis is broad and includes synovial sarcoma, spindle cell anaplastic thyroid carcinoma, spindle cell variant of medullary thyroid carcinoma, thymoma, fibrosarcoma, leiomyoma and schwannoma. Owing to delayed metastasis, close long term follow-up is mandatory. We present a case where metastatic disease appeared in the lungs 35years after the initial diagnosis, representing the longest reported latency period to metastasis, which unfortunately led to the patient's demise.

Spindle epithelial tumor with thymus-like differentiation (SETTLE): clinical-pathological features, differential pathological diagnosis and therapy.

Spindle epithelial tumor with thymus-like differentiation (SETTLE) is a very rare tumor of the thyroid gland. An algorithm for the diagnosis and treatment of SETTLE has yet to be established. The aim of this study was to identify all case reports of SETTLE and to compare the clinical-pathological features and therapy of the cases identified. We performed a PubMed search for case reports of SETTLE in English published up to November 2014 in which "SETTLE" and "Spindle epithelial tumor with thymus-like differentiation" were keywords. We identified 35 articles for a total of 42 cases. We found that SETTLE usually occurs in children and adolescents as an asymptomatic neck mass. Thyroid function tests and tumor markers are invariably within normal range in all patients, and fine needle aspiration biopsy is rarely diagnostic for SETTLE. All 42 patients had undergone thyroidectomy. After surgical resection, chemotherapy (adjuvant or first/second-line treatment) and/or radiotherapy were administered to control tumor growth in cases with metastatic involvement. Although SETTLE presents a low-grade malignancy, it can metastasize to lymph nodes, the mediastinum, lung, vertebrae, and kidney even many years after the initial diagnosis. SETTLE may have a good prognosis if appropriately treated at initial presentation and if patients undergo long-term monitoring with regular clinical and morphological evaluations.

Clinical, pathological and therapeutic course of disease in patient with initial diagnosis of metastatic settle tumor: A case report

Spindle epithelial tumor with thymus-like differentiation (SETTLE) is an extremely rare tumor of the thyroid believed to be derived from pharyngeal pouch or thymic remnants and showing primitive thymic differentiation. It was reported 41 times ending with 15 June 2015 in accordance with the available references. Herein we report a case of SETTLE in a 23-year-old male patient with a follow-up period of 24 months. We present a case focusing on the pathologic complexity and therapy of metastatic disease of this rare tumor. The present case is the first SETTLE case reported in Montenegro. At the time of setting histopathological diagnosis SETTLE tumor disease was already in metastatic stage. The primary tumor in the thyroid gland was never found.

Spindle epithelial tumor with thymus-like differentiation: A case report and comprehensive review of the literature and treatment options

Spindle epithelial tumor with thymus-like differentiation (SETTLE) is a rare cancer of thymic origin with little information available for treating clinicians. We performed a comprehensive literature search and updates were requested from all authors. We report one recent case. We present the most comprehensive review of the clinical literature for SETTLE. We identified 41 published cases. SETTLE usually presents as an asymptomatic neck mass. Most patients successfully underwent surgical resection of the primary tumor. The mean latency to develop metastasis was 10 years. SETTLE is uniformly responsive to radiotherapy and combination chemotherapy in the rare cases where response data are available. Although SETTLE is initially indolent, it has the capacity to metastasize late in its course. The malignant potential of this tumor might be underestimated because of the lack of long-term follow-up. In cases in which complete surgical resection is not possible, radiotherapy or combination chemotherapy is effective.

Recurrent Thyroid Nodule: Spindle Epithelial Tumor with Thymus-like Differentiation (SETTLE)

Thyroid nodules are uncommon in childhood and recurrent thyroid nodules even rarer. Spindle epithelial tumor with thymus-like differentiation (SETTLE), a rare and distinctive low-grade neoplasm is amongst the differential diagnosis of solitary thyroid nodule in children. We describe a boy who underwent completion thyroidectomy for SETTLE in the thyroid remnant four years after initial lobectomy was performed for the same diagnosis. Patients with SETTLE are to be closely followed as multifocality may manifest and be detected later.

Spindle epithelial tumor with thymus-like differentiation of the thyroid (SETTLE):

Spindle epithelial tumor with thymus-like differentiation (SETTLE) is a rare tumor usually localized in the thyroid gland and perithyroid tissues. It is considered to arise from ectopic thymic tissue or branchial pouch remnants. It occurs more frequently in children and adolescents. We report 2 cases of spindle epithelial tumor with thymus-like differentiation localized in the thyroid gland, and 1 of them was associated with a parathyroid adenoma. We emphasize the need for a close and long-term follow-up in these patients.

Thyroid spindle epithelial tumor with thymus-like differentiation (SETTLE): case report and review

Spindle epithelial tumor with thymus-like element (SETTLE) is a rare malignant neoplasm of the thyroid, occurring predominantly in children, adolescents, and young adults. SETTLE usually presents itself as a thyroid mass, without metastases at diagnosis. It is believed to derive from branchial pouch or thymic remnant tissue showing primitive thymic differentiation. This article reports the clinical, cytological, histological and immunohistochemical features of a SETTLE in a 3-year-old girl. Microscopic exam revealed a nodular, highly cellular neoplasm displayed in the classic biphasic pattern, with mixture of prominent spindle cell component and a minor glandular component lined by mucinous or respiratory-type epithelium. The immunohistochemical study showed strong and diffuse positivity for pan-CK, vimentin and smooth muscle actin. The present case is the first SETTLE case reported in Brazil. To date, the patient described remains without evidence of recurrence or metastasis 5 years after surgery.

Spindle epithelial tumor with thymus-like differentiation of thyroid gland: Report of two cases with follow-up

Spindle epithelial tumor with thymus-like differentiation (SETTLE) is a rare malignant thyroid tumor showing thymic or related branchial pouch differentiation. The tumors are composed predominantly of spindle cells along with focal epithelial component and ductular formations. SETTLE occurs in young patients, with indolent growth and a tendency to develop delayed blood-borne metastases. We herein report two cases of SETTLE with a follow-up period of 64 months and 30 months, respectively.

Spindle Epithelial Tumor With Thymus-like Differentiation: A Morphologic, Immunohistochemical, and Molecular Genetic Study of 11 Cases

Spindle epithelial tumor with thymus-like differentiation (SETTLE) is an extremely rare tumor of the thyroid and neck, first described by Chan and Rosai. SETTLE is a low-grade malignancy, with potential for late lung, lymph node, and other visceral metastases. The clinicopathologic features of SETTLE overlap significantly with those of synovial sarcoma. Thirteen cases previously diagnosed as "SETTLE" (11 cases) or "malignant neoplasm-SETTLE versus synovial sarcoma" (2 cases), were retrieved. Immunohistochemistry for low-molecular-weight cytokeratins, high-molecular-weight cytokeratins, cytokeratin 7, cytokeratin 20, epithelial membrane antigen, bcl-2, CD34, CD99, CD117, INI-1, and TLE1 were performed. Reverse transcriptase polymerase chain reaction for the SS18/SSX1 and SS18/SSX2 fusion genes and fluorescent in-situ hybridization for SYT rearrangement was performed. The 11 cases diagnosed, as "SETTLE" were negative for synovial sarcoma-associated fusion genes, whereas the other 2 cases were positive. SETTLE occurred in 7 females and 4 males (7 to 50 y of age, median 13.5 y) and involved the thyroid gland in 10 cases. Clinical follow-up showed 3 patients to be disease-free 7, 10, and 15 years after surgery. One patient had a lymph node metastasis at diagnosis and lung metastases 14 months after diagnosis. SETTLE infiltrated the thyroid, and consisted of a vaguely nodular admixture of fascicular, reticular, hyalinized, and microcystic areas. Spindled zones blended imperceptibly into areas showing epithelial differentiation, in the form of glomeruloid glandular structures, sertoli-like tubules, and small glands, lined by cuboidal to columnar cells. Mitotic activity was very low, necrosis was absent, and pleomorphism was not present. By immunohistochemistry, SETTLE showed extensive expression of high-molecular-weight cytokeratins in 7 of 8 cases (88%). Expression of low-molecular-weight cytokeratins and epithelial membrane antigen was limited, confined to only scattered cells in 7 of 8 (88%), and 4 of 8 (50%) of cases, respectively. Cytokeratin 7 expression was more widespread (7 of 8 cases, 88%). Cytokeratin 20 was negative. Expression of CD99 and bcl-2 was seen in 6 of 8 (75%) and 7 of 8 (88%) cases, respectively. CD117, INI-1, and TLE1 expression was seen in 6 of 8 (75%), 8 of 8 (100%), and 1 of 5 (20%) of cases, respectively. We conclude that traditional morphologic study and a limited panel of ancillary immunostains are sufficient for the distinction of SETTLE from synovial sarcoma in almost all instances. Molecular genetic study may, however, be helpful in selected cases, particularly in limited biopsies.

Cytological diagnosis of Spindle Epithelial Tumor with Thymus-like Differentiation (SETTLE)

Spindle epithelial tumor with thymus like differentiation (SETTLE) is a very rare tumor arising either from ectopic thymus or remnants of branchial pouches that retain the potential to differentiate along the thymic line.[1]; Herein is reported a case of SETTLE in a 50-year-old man who presented with dessiminated intravascular coagulopathy. The subsequent work up revealed the presence of a mediastinal mass. A presumptive clinical diagnosis of lymphoma was made, forwhich the patient received a single dose of radiation. The patient’s condition detriorated andnpatient died 5 days later. At autopsy, a thyroid mass of 10x8 cm was found with necrotic friable yellow tan color, extending into the mediastinum, obstructing the superior vena cava with extension into the right atrium and right ventricle forming a hemorrhagic mass of 12x7x6 cm. A touch preparation from the thyroid lesion demonstrated a biphasic lesion consisting of spindle and epithelial glandular components. The tissue specimen from the case demonstrated the spindle cells to stain positively for cytokeratin and vimentin but were negative for thyroglobulin and calcitonin as well as other neuroendocrine markers confirming the diagnosis of SETTLE.

Spindle Epithelial Tumor With Thymus-Like Differentiation of the Thyroid

Spindle epithelial tumor with thymus-like differentiation (SETTLE) of the thyroid is a rare tumor that occurs habitually in children and young adults. To date, about 20 cases of SETTLE have been reported in the English medical literature. It is considered to be a tumor of low malignancy with a favorable outcome, but delayed blood-borne metastases have been reported (sometimes over 20 years after initial treatment). In the current report, the authors describe an interesting case of SETTLE in a young woman. Double phase Tc-99m tetrofosmin scintigraphy showed accumulation of the tracer in the thyroid mass.

Unusual Spindle Cell Tumor of Thyroid (SETTLE)

Spindle epithelial tumor with thymus-like differentiation (SETTLE) is a rare tumor seen mostly in children and adolescents. It is presumed that it arises from ectopic thymus or remnants of branchial pouches that differentiate along the thymic line. Unusual spindle cell-predominant histology makes this entity difficult to recognize. The clinical course is not exactly known due to the small number of reported cases but metastasis has been documented during initial presentation. We report a case of SETTLE in the neck where preoperative clinical and radiological impression was that of a mass in the left submandibular gland area. However, during the operation it was felt by the surgeon that the mass was in continuity with the left thyroid lobe.

Fine‐needle aspiration biopsy of monophasic variant of spindle epithelial tumor with thymus‐like differentiation of the thyroid: Report of one case and review of the literature

Spindle epithelial tumor with thymus-like differentiation (SETTLE) is a rare biphasic tumor of the thyroid with approximately 20 well-documented cases reported in the English literature. Although a monophasic variant of SETTLE is conceivable, the majority of the reported cases were truly biphasic tumors. A minimal amount of epithelial component was present in the reported cases of so-called spindle-cell predominant SETTLE. Here, we report an apparently monophasic case of SETTLE in a 16-yr-old girl, in which no epithelial cells were identified in either fine-needle aspiration biopsy (FNAB) or the subsequent hemithyroidectomy specimen. The FNAB smears were moderately cellular and composed of single and loosely grouped spindle cells with homogenous metachromatic material, which could be mistaken as amyloid, erroneously suggesting medullary thyroid carcinoma. The compact nodules of uniform spindle cells in histology sections raised the possibility of monophasic synovial sarcoma. The spindle cells stained positive for both cytokeratin and vimentin, but were negative for thyroglobulin and calcitonin as well as neuroendocrine markers, confirming the diagnosis of SETTLE.

Spindle epithelial tumor with thymus‐like differentiation (SETTLE): Youngest reported patient

Spindle epithelial tumor with thymus-like differentiation (SETTLE) is a very rare thyroid tumor. It is one of a family of tumors arising either from ectopic thymus or remnants of branchial pouches that retain the potential to differentiate along the thymic line. Herein is reported a case of SETTLE in a 2-year-old girl. The patient underwent right thyroid lobectomy for a tumor of the right thyroid lobe. The resected specimen of this tumor revealed a whitish and solid mass. On microscopy, the tumor exhibited an area of spindle cells, glandular epithelium, and mucinous cystic lesions. The following findings were obtained on immunohistochemistry: the spindle cell area was diffusely positive for cytokeratin AE1/3 and vimentin, and partially positive for alpha-smooth muscle-specific actin. The glandular structures consisted of columnar cells and the cystic area was also positive for cytokeratin AE1/3. All three components of the tumor were negative for thyroglobulin, thyroid transcription factor-1, S-100 protein, carcinoembryonic antigen, somatostatin, synaptophysin, and chromogranin A. On the basis of the aforementioned findings, SETTLE was diagnosed. The patient remains disease free to date, 2 years after surgery with no additional treatment. To the best of the authors' knowledge the present SETTLE patient is the youngest yet reported.

An enlarged thyroid in a 20-year-old woman. Thyroid spindle epithelial tumor with thymuslike differentiation.

We report a case of spindle epithelial tumor with thymuslike differentiation (SETTLE) of the thyroid in a 20-year-old woman. The tumor located at the right lobe was well circumscribed by fibrous capsule. Microscopically, the highly cellular spindle cell neoplasm was arranged in intersecting fascicles separated by fibrous bands and was intermingled with small tubulopapillary epithelial foci. Immunohistochemically, most of the tumor cells were strong for pancytokeratin and focally positive for smooth muscle actin and vimentin. The cells were negative for EMA, thyroglobulin, S100 protein, and the diagnosis of thyroid spindle thymuslike differentiation was made.