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Surgery Jan 2023Recent advancements in 3-dimensional patient-derived organoid models have revolutionized the field of cancer biology. There is an urgent need for development of...
BACKGROUND
Recent advancements in 3-dimensional patient-derived organoid models have revolutionized the field of cancer biology. There is an urgent need for development of endocrine tumor organoid models for medullary thyroid carcinoma, adrenocortical carcinoma, papillary thyroid carcinoma, and a spectrum of benign hyperfunctioning parathyroid and adrenal neoplasms. We aimed to engineer functionally intact 3-dimensional endocrine patient-derived organoids to expand the in vitro and translational applications for the advancement of endocrine research.
METHODS
Using our recently developed fine needle aspiration-based methodology, we established patient-derived 3-dimensional endocrine organoid models using prospectively collected human papillary thyroid carcinoma (n = 6), medullary thyroid carcinoma (n = 3), adrenocortical carcinoma (n = 3), and parathyroid (n = 5). and adrenal (n = 5) neoplasms. Multiplatform analyses of endocrine patient-derived organoids and applications in oncoimmunology, near-infrared autofluorescence, and radiosensitization studies under 3-dimensional in vitro conditions were performed.
RESULTS
We have successfully modeled and analyzed the complex endocrine microenvironment for a spectrum of endocrine neoplasms in 3-dimensional culture. The endocrine patient-derived organoids recapitulated complex tumor microenvironment of endocrine neoplasms morphologically and functionally and maintained cytokine production and near-infrared autofluorescence properties.
CONCLUSION
Our novel engineered endocrine patient-derived organoid models of thyroid, parathyroid and adrenal neoplasms represent an exciting and elegant alternative to current limited 2-dimensional systems and afford future broad multiplatform in vitro and translational applications, including in endocrine oncoimmunology.
Topics: Humans; Organoids; Tumor Microenvironment; Thyroid Neoplasms; Adrenal Gland Neoplasms
PubMed: 36400581
DOI: 10.1016/j.surg.2022.09.027 -
World Journal of Surgery Aug 2021The purpose of the article was to evaluate the existence of significant clinical, pathological and prognostic differences between familial and sporadic form of pediatric...
BACKGROUND
The purpose of the article was to evaluate the existence of significant clinical, pathological and prognostic differences between familial and sporadic form of pediatric non-medullary thyroid carcinoma, in order to tailor the therapeutic strategy to be adopted for patients with family history.
METHODS
We analyzed the records of 76 pediatric patients that underwent surgery for differentiated thyroid cancer from 2014 to 2019 at the Surgical Pathology Department of the University of Pisa, Italy. Among these, 20 (26,3%) had positive family history (familial non-medullary thyroid carcinoma-FNMTC group) while 56 (73.7%) were affected by sporadic forms (sporadic non-medullary thyroid carcinoma-SNMTC group).
RESULTS
In our study, the correlation between the FNMTC and the SNMTC group showed no difference in terms of tumor features like multifocality, bilaterality, capsular/extracapsular invasion and the presence of vascular emboli. A statistical significance, on the other hand, was revealed by observation of clinical outcomes, such as distant metastasis (p = 0,022), persistence of disease (p = 0,054) and necessity of radioiodine sessions (p = 0,005).
CONCLUSIONS
These findings suggest that family history may have an independent role on the outcome, expressing its action through an intrinsic more aggressive biological behavior. Therefore, familial non-medullary thyroid carcinoma in children represents a nosological entity that requires an accurate pre-operative evaluation, an adequate surgical strategy and a careful follow up.
Topics: Child; Humans; Iodine Radioisotopes; Retrospective Studies; Thyroid Cancer, Papillary; Thyroid Neoplasms; Thyroidectomy
PubMed: 33891138
DOI: 10.1007/s00268-021-06104-5 -
Cancers Jul 2023Renal medullary carcinoma (RMC) is one of most aggressive renal cell carcinomas and novel therapeutic strategies are therefore needed. Recent comprehensive molecular and...
BACKGROUND
Renal medullary carcinoma (RMC) is one of most aggressive renal cell carcinomas and novel therapeutic strategies are therefore needed. Recent comprehensive molecular and immune profiling of RMC tissues revealed a highly inflamed phenotype, suggesting the potential therapeutic role for immune checkpoint therapies. We present the first prospective evaluation of an immune checkpoint inhibitor in a cohort of patients with RMC.
METHODS
A cohort of patients with locally advanced or metastatic RMC was treated with pembrolizumab 200 mg intravenously every 21 days in a phase II basket trial (ClinicalTrials.gov: NCT02721732). Responses were assessed by irRECIST. Tumor tissues were evaluated for PD-L1 expression and for tumor-infiltrating lymphocyte (TIL) levels. Somatic mutations were assessed by targeted next-generation sequencing.
RESULTS
A total of five patients were treated. All patients had advanced disease, with the majority of patients (60%) having metastatic disease at diagnosis. All patients had rapid disease progression despite pembrolizumab treatment, with a median time to progression of 8.7 weeks. One patient (patient 5) experienced sudden clinical progression immediately after treatment initiation and was thus taken off trial less than one week after receiving pembrolizumab.
CONCLUSIONS
This prospective evaluation showed no evidence of clinical activity for pembrolizumab in patients with RMC, irrespective of PD-L1 or TIL levels.
PubMed: 37568622
DOI: 10.3390/cancers15153806 -
Head & Neck Feb 2021Medullary thyroid carcinoma (MTC) is a rare malignancy with high incidence of cervical lymph node (CLN) metastasis. We investigated the impact of nodal disease burden on...
BACKGROUND
Medullary thyroid carcinoma (MTC) is a rare malignancy with high incidence of cervical lymph node (CLN) metastasis. We investigated the impact of nodal disease burden on survival.
METHODS
We searched the National Cancer Database for MTC patients treated surgically. Impact of nodal metastasis on survival was analyzed using Cox univariable and multivariable regression.
RESULTS
We identified 2627 patients from 2004 to 2015. Positive CLNs were identified in 1433 (54.5%), and 542 (20.6%) had >10 CLN+. Overall survival was 94.5% and 89.6% at 3 and 5 years. Patients with 11 to 20 CLN+ had significantly worse survival than patients with 1 to 10 CLN+ in univariable and multivariable analyses (HR = 3.56 (2.31-5.50) vs 2.26 (1.60-3.20); P < .0001). The ratio of positive to dissected CLN was associated with overall survival.
CONCLUSIONS
Higher burden of nodal disease is associated with worse survival in MTC. The number of positive nodes could be a valuable prognosticator in addition to the current staging system.
Topics: Carcinoma, Neuroendocrine; Cost of Illness; Humans; Lymph Nodes; Lymphatic Metastasis; Neoplasm Staging; Prognosis; Thyroid Neoplasms
PubMed: 33107153
DOI: 10.1002/hed.26511 -
Endocrinology, Diabetes & Metabolism... Jun 2020We report a rare case of concurrent medullary thyroid cancer (MTC) and papillary thyroid cancer (PTC) with intermixed disease in several of the lymph node (LN)...
SUMMARY
We report a rare case of concurrent medullary thyroid cancer (MTC) and papillary thyroid cancer (PTC) with intermixed disease in several of the lymph node (LN) metastases in a patient who was subsequently diagnosed with clear cell renal cell carcinoma (RCC). A 56 year old female presented with dysphagia and was found to have a left thyroid nodule and left superior cervical LN with suspicious sonographic features. Fine needle aspiration biopsy (FNAB) demonstrated PTC in the left thyroid nodule and MTC in the left cervical LN. Histopathology demonstrated multifocal PTC with 3/21 LNs positive for metastatic PTC. One LN in the left lateral neck dissection exhibited features of both MTC and PTC within the same node. In the right lobe, a 0.3 cm focus of MTC with extra-thyroidal extension was noted. Given persistent calcitonin elevation, a follow-up ultrasound displayed an abnormal left level 4 LN. FNAB showed features of both PTC and MTC on the cytopathology itself. The patient underwent repeat central and left radical neck dissection with 3/6 LNs positive for PTC in the central neck and 2/6 LNs positive for intermixed PTC and MTC in the left neck. There was no evidence of distant metastases on computed tomography and whole body scintigraphy, however a 1.9 x 2.5 cm enhancing mass within the right inter-polar kidney was discovered. This lesion was highly suspicious for RCC. Surgical pathology revealed a 2.5 cm clear cell RCC, Fuhrman grade 2/4, with negative surgical margins. She continues to be observed with stable imaging of her triple malignancies.
LEARNING POINTS
Mixed medullary-papillary thyroid neoplasm is characterized by the presence of morphological and immunohistochemical features of both medullary and papillary thyroid cancers within the same lesion. Simultaneous occurrence of these carcinomas has been previously reported, but a mixed disease within the same lymph node is an infrequent phenomenon. Prognosis of mixed medullary-papillary thyroid carcinomas is determined by the medullary component. Therefore, when PTC and MTC occur concurrently, the priority should be given to the management of MTC, which involves total thyroidectomy and central lymph node dissection. Patients with thyroid cancer, predominantly PTC, have shown higher than expected rates of RCC. To our knowledge, this is the first report describing the combination of MTC, PTC, and RCC in a single patient.
PubMed: 32538376
DOI: 10.1530/EDM-20-0025 -
Turk Patoloji Dergisi 2022Our study investigated the morphological and immunohistochemical characteristics of invasive breast carcinoma of no special type (IBC-NST) with medullary pattern to...
OBJECTIVE
Our study investigated the morphological and immunohistochemical characteristics of invasive breast carcinoma of no special type (IBC-NST) with medullary pattern to explore the inconsistencies between the structural and clinical traits of this category of tumor.
MATERIAL AND METHOD
The breast carcinoma samples (n = 26) with medullary pattern (defined according to established criteria) were subjected to immunohistochemical assays of the following receptors: ER, PR, HER2/neu, Ki-67, p53, Bcl-2, VEGF, MMP1, E-cadherin, EGFR, Hsp70, Hsp90, CD20, CD3, CD4, CD8, CD68, CD163, CD56, CD138, MPO, S100, IgG, IgM, and PD-L1.
RESULTS
IBC-NST with medullary pattern was found to have negative expression of ER, PR, and HER2/neu; strong positive expression of Kі-67, mutant р53, Bcl-2, E-cadherin, EGFR, and PD-L1; moderate positive expression of Hsp70 and Hsp90; and low or negative expression of VEGF and MMP1. Furthermore, there was pronounced variability in the qualitative composition of tumor immune infiltrates with regards to T-lymphocytes, B-lymphocytes, macrophages, plasmocytes, and granulocytes.
CONCLUSION
IBC-NST with medullary pattern has many unfavourable morphological and immunohistochemical prognostic characteristics, which are balanced against the pronounced protective properties of the tumor cells and the qualitative characteristics of the tumor microenvironment. These can lead to a favourable disease course despite the relatively adverse features of the carcinoma cells.
Topics: B7-H1 Antigen; Biomarkers, Tumor; Breast Neoplasms; Cadherins; Female; Humans; Ki-67 Antigen; Matrix Metalloproteinase 1; Prognosis; Proto-Oncogene Proteins c-bcl-2; Receptor, ErbB-2; Tumor Microenvironment; Vascular Endothelial Growth Factor A
PubMed: 34636027
DOI: 10.5146/tjpath.2021.01559 -
Romanian Journal of Morphology and... 2020Medullary thyroid cancer (MTC) is an infrequent neuroendocrine tumor, which amounts to 3-5% of all thyroid malignancies. Approximately 75-80% of MTCs are sporadic... (Review)
Review
Medullary thyroid cancer (MTC) is an infrequent neuroendocrine tumor, which amounts to 3-5% of all thyroid malignancies. Approximately 75-80% of MTCs are sporadic neoplasms. The rest of 20-25% are familial cases that belong to multiple endocrine neoplasia (MEN) syndromes, specifically MEN2 and MEN3. These cases of familial MTC are attributed to an activating germline mutation of a tyrosine kinase receptor gene, the rearranged during transfection (RET) proto-oncogene, located on chromosome 10q11.21. These mutations are also found in some cases of sporadic MTC. This review sets forth in summary the accepted guidelines and approaches regarding diagnosis, management, and treatment of MTC. Surgical resection is the standard care, and an early, prophylactic intervention is performed in genetic cases. Further investigation and understanding of the molecular pathways involved in the growth and advancement of MTC is required in order to provide efficient therapy in cases of progressive disease.
Topics: Carcinoma, Neuroendocrine; Humans; Multiple Endocrine Neoplasia Type 2a; Mutation; Proto-Oncogene Mas; Proto-Oncogene Proteins c-ret; Thyroid Neoplasms
PubMed: 33817709
DOI: 10.47162/RJME.61.3.06 -
Cancers Apr 2023We provide an update on calcitonin (Ctn) screening for the early detection of medullary thyroid carcinoma (MTC) and present the results of a large single-center analysis...
BACKGROUND
We provide an update on calcitonin (Ctn) screening for the early detection of medullary thyroid carcinoma (MTC) and present the results of a large single-center analysis evaluating sex-specific cut-off-levels and long-term courses.
METHODS
A total of 12,984 consecutive adult patients (20.1% male and 79.9% female) with thyroid nodules who had undergone routine Ctn measurement were retrospectively analyzed. Patients with confirmed suspicious Ctn values were referred for surgery.
RESULTS
Ctn measurements were elevated in 207 (1.6%) patients, with values below twice the sex-specific reference limit in 82% of these cases. Further clarification was possible in 124/207 cases, of which MTC could be ruled out in 108 cases. Histopathological assessment confirmed MTC in 16/12,984 patients.
CONCLUSIONS
Our extrapolated MTC prevalence of 0.14% is significantly lower than that described in early international screening studies. The stimulation test can usually be dispensable when using a decision-making concept based on sex-specific basal Ctn cut-off values. Ctn screening is recommended even in patients with very small thyroid nodules. High quality standards in pre-analytics, laboratory measurements, and the interpretation of data must be ensured, as well as close interdisciplinary cooperation between medical disciplines.
PubMed: 37190260
DOI: 10.3390/cancers15082333 -
AME Case Reports 2022Papillary thyroid carcinoma is the most common type of thyroid carcinoma, making up 85-90% of all thyroid carcinomas. Medullary thyroid carcinoma is the third most...
BACKGROUND
Papillary thyroid carcinoma is the most common type of thyroid carcinoma, making up 85-90% of all thyroid carcinomas. Medullary thyroid carcinoma is the third most common type of thyroid carcinoma, making up less than 5% of all thyroid carcinomas. However, synchronous papillary-medullary thyroid carcinoma is exceedingly rare and has not been well described historically. There have been fewer than 40 cases reported in the current literature.
CASE DESCRIPTION
In this case report we present a 65-year-old man with synchronous papillary-medullary thyroid carcinoma. A 65-year-old man presented with a symptomatic multinodular thyroid goiter. Ultrasound (US) confirmed bilateral thyroid nodules, and he was initially managed nonoperatively. Fine needle aspiration (FNA) biopsy of the left dominant nodule revealed atypia of undetermined significance (AUS) (Bethesda class III). Further assessment of the FNA specimen with ThyGeNEXT (mutation panel) revealed no mutations and the ThyraMIR (microRNA risk classifier) was negative, which classified the results as very highly likely to be benign. Due to worsening local compressive symptoms, a total thyroidectomy was performed. Final surgical pathology revealed incidental multicentric, multifocal micropapillary carcinoma foci from (0.1 to 0.5 cm), and a 0.3 cm medullary carcinoma in the left thyroid lobe on the background of nodular hyperplasia.
CONCLUSIONS
Synchronous papillary-medullary thyroid carcinoma is a rare finding that should be considered in patients with symptomatic multinodular thyroid goiters. It is important to report this case to increase awareness and improve our understanding and management of these unusual carcinomas in the future.
PubMed: 35928582
DOI: 10.21037/acr-22-13 -
Cancers Aug 2023Medullary thyroid carcinoma (MTC) is a malignant tumor that arises from parafollicular C cells, which are responsible for producing calcitonin. The majority (75%) of MTC... (Review)
Review
Medullary thyroid carcinoma (MTC) is a malignant tumor that arises from parafollicular C cells, which are responsible for producing calcitonin. The majority (75%) of MTC cases are sporadic forms, while the remaining (25%) have a hereditary component. In these hereditary cases, MTC can occur in conjunction with other endocrine disorders (i.e., pheochromocytoma) or as an isolated condition known as familial medullary thyroid carcinoma. The primary genetic mutation associated with the development of MTC, regardless of its hereditary or sporadic nature, is a point mutation in the RET gene. Evaluation of serum calcitonin levels represents the most reliable and sensitive marker for both the initial diagnosis and the postsurgical monitoring of MTC. Unfortunately, most patients do not achieve normalization of postsurgical serum calcitonin (CT) levels after surgery. Therefore, there is a need to find new biomarkers to be used with serum CT in order to increase test sensitivity and specificity. In this review, we summarize the literature from 2010 to 2023 to review the role of circulating tumor cells, cell-free DNA, and miRNA and their application in diagnosis, outcome of MTC, and response to treatments.
PubMed: 37568824
DOI: 10.3390/cancers15154009