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Molecular and Cellular Endocrinology Jan 2021Medullary thyroid carcinoma (MTC) is a rare neuroendocrine neoplasm of the parafollicular thyroid C cells. Although somatostatin receptors are expressed by MTCs,...
Medullary thyroid carcinoma (MTC) is a rare neuroendocrine neoplasm of the parafollicular thyroid C cells. Although somatostatin receptors are expressed by MTCs, treatment with octreotide has shown poor efficacy, whereas recently pasireotide has demonstrated antiproliferative effects in persistent postoperative MTCs. Aim of this study was to test the effects of octreotide and pasireotide on MTC cells proliferation, cell cycle proteins expression, MAPK activation, apoptosis, calcitonin secretion, migration and invasion in TT cell line as well as in primary MTC cultured cells. Our results showed that both octreotide and pasireotide reduced TT cell proliferation (-35.2 ± 12.1%, p < 0.001, and -25.3 ± 24.8%, p < 0.05, at 10 M, respectively), with concomitant inhibition of ERK phosphorylation and cyclin D1 expression. This cytostatic effect was accompanied by a proapoptotic action, with an increase of caspase3/7 activity of 1.5-fold. Moreover, both octreotide and pasireotide inhibited cell migration (-50.9 ± 11.3%, p < 0.01, and -40.5 ± 17%, p < 0.05, respectively) and invasion (-61.3 ± 35.1%, p < 0.05, and -49.7 ± 18%, p < 0.01, respectively). No effect was observed on calcitonin secretion. We then tried to extend these observations to primary cultures (n = 5). Octreotide and/or pasireotide were effective in reducing cells proliferation in 3 out of 5 tumors, and to induce cell apoptosis in 1 out of 3 MTCs. Both octreotide and pasireotide were able to reduce cell migration in all MTC tested. SST2, SST3 and SST5 were expressed in all MTC, with a tendency to increased expression of SST2 in RET mutated vs wild type MTCs. In agreement, inhibition of mutated RET in TT cells reduced SST2 expression. In conclusion, we demonstrated that octreotide and pasireotide inhibited cell proliferation and invasiveness in a subset of MTC, supporting their potential use in the control of tumor growth.
Topics: Apoptosis; Calcitonin; Carcinoma, Neuroendocrine; Cell Movement; Cell Proliferation; Humans; Mutation; Neoplasm Invasiveness; Octreotide; Proto-Oncogene Proteins c-ret; Somatostatin; Thyroid Neoplasms; Tumor Cells, Cultured
PubMed: 33248230
DOI: 10.1016/j.mce.2020.111092 -
Annals of Medicine and Surgery (2012) Sep 2022Medullary Thyroid Carcinoma (MTC) as a neuroendocrine tumor that arises from the parafollicular C-cells and shows a potentially aggressive behavior with early lymph node... (Review)
Review
INTRODUCTION
Medullary Thyroid Carcinoma (MTC) as a neuroendocrine tumor that arises from the parafollicular C-cells and shows a potentially aggressive behavior with early lymph node metastasis. MTC cells do not absorb radioactive iodine and are not sensitive to Thyroid Stimulating Hormone (TSH) suppression, and therefore surgery is the most effective option for curative therapy.
RESULTS
Medical imaging and biomarkers (calcitonin & CEA) assessment are necessary to determine the appropriate approach to lymph nodes surgery in MTC. Prophylactic central, lateral or contralateral neck dissections are recommended based on calcitonin level and volume of tumor. In general, guidelines are in agreement with prophylactic central dissection in most cases. Central and lateral dissections are recommended in all guidelines and review articles if lymphadenopathy is confirmed in preoperative examinations. Because lymph node dissection in most cases of locally advanced or metastatic MTC has no prognostic effect, dissection is done with palliative goal with maximum attention to maintaining function in these cases. In patients with an incomplete lymph node dissection, decision for reoperation can be based on calcitonin levels and the number of metastatic lymph nodes removed in previous surgery. Symptoms as well as speed of disease progression are also important in adopting the type of surgery. Consensus is in favor of reoperation in patients with recurrent regional MTC without distant metastasis.
CONCLUSION
Thyroidectomy is mandatory in patients with MTC but the type and extension of lymph node dissection are depending on the calcitonin level and tumor burden.
PubMed: 36147070
DOI: 10.1016/j.amsu.2022.104538 -
European Journal of Case Reports in... 2020Pheochromocytoma, papillary thyroid carcinoma and hyperparathyroidism have rarely been reported together. Whether this association is coincidental or results from an...
UNLABELLED
Pheochromocytoma, papillary thyroid carcinoma and hyperparathyroidism have rarely been reported together. Whether this association is coincidental or results from an unknown genetic predisposition is difficult to ascertain. We present the case of a patient who was diagnosed with pheochromocytoma, bilateral papillary thyroid carcinoma and parathyroid hyperplasia with primary hyperparathyroidism. A genetic mutation was hypothesized as the connection between these lesions. Previously described mutations were explored.
LEARNING POINTS
Parathyroid hyperplasia, primary hyperparathyroidism and papillary thyroid carcinoma individually are common conditions, but association with each other, although possibly incidental, should trigger genetic testing.Further research is needed to reliably explain the relationship between primary hyperparathyroidism and non-medullary thyroid cancer.
PubMed: 33194854
DOI: 10.12890/2020_001818 -
Frontiers in Endocrinology 2023An exceptional number of synchronous MTC/PTC in the same thyroid gland is presented. This may be the most numerous case series reported in the literature. Synchronous...
SYNOPSIS FOR TABLE OF CONTENTS
An exceptional number of synchronous MTC/PTC in the same thyroid gland is presented. This may be the most numerous case series reported in the literature. Synchronous PTC/MTC in the same thyroid gland were classified into 4 subtypes and the clinical and pathological aspects as well as the results are presented.
BACKGROUND AND OBJECTIVES
The synchronous occurrence of multiple neoplastic processes in the thyroid gland is unusual. We investigated the clinicopathological features of 30 medullary thyroid carcinomas (MTC) in association with papillary (PTC).
METHOD
Retrospective analysis of operated patients for thyroid tumors. Synchronous PTC/MTC in the same thyroid gland were classified into 4 subtypes: (type I) True mixed MTC/PTC, MTC and PTC closely intermingled. (Type II) Collision MTC/PTC, i.e. tumors that meet at the same site, invade each other and appear as a single mass in the thyroid gland, i.e. MTC and PTC merge. (Type III) Synchronous anatomically separate tumors in the same thyroid lobe, i.e. separated from each other by non-tumorous thyroid parenchyma. (Type IV) Synchronous tumors occurring in separate anatomical lobes or in the isthmus. Clinical and pathological data were reviewed. Location: Department of thyroid surgery, China-Japan Union Hospital, Jilin University. Time frame: 14 years (June 2008-November 2022).
RESULTS
Thirty patients were identified with an overall prevalence of 28621 (0.1%). 17 (56.7%) were male, 13 (43.3%) female, mean age 51.3 ± 11.0 years, mean BMI 23.6 ± 3.6kg/m. Mean duration of symptoms was 11.2 ± 18.4 months. Mean calcitonin level was 133.7 ± 196.4 pg/ml. Fine needle aspiration (FNA) was offered in 21 cases: 9 (42.9%) were suspected carcinoma, 9 (42.9%) PTC, 1 (4.8%) MTC, 2 (9.4%) MTC/PTC. Pathology revealed type I 4 (13.3%), type II 2 (6.7%), type III 14 (46.7%), type IV 10 (33.3%). The mean diameter of MTC was 1.6 ± 2.0cm, 18 (60%) were micro-MTC. The mean diameter of PTC was 0.9 ± 1.9 cm, 26 (86.7%) were micro-PTC. In 16 (53.3%) micro-PTC/-MTC occurred in synchronous sequence. Four patients had a recurrence: 2 had to be re-operated due to MTC recurrence, 2 died due to distant metastases (bone, liver).
CONCLUSION
We report an exceptional number of MTC/PTC in the same thyroid gland. This may be the most numerous case series reported in the literature. The clinical and pathological aspects as well as the results are presented.
Topics: Humans; Male; Female; Adult; Middle Aged; Thyroid Cancer, Papillary; Retrospective Studies; Carcinoma, Papillary; Thyroid Neoplasms; Carcinoma, Neuroendocrine; Neoplasms, Multiple Primary
PubMed: 37065753
DOI: 10.3389/fendo.2023.1153248 -
Frontiers in Endocrinology 2021Medullary thyroid carcinoma is a rare neuroendocrine neoplasm that originates from thyroid C cells. Surgery, with complete resection of the tumor, is the only curative... (Review)
Review
Medullary thyroid carcinoma is a rare neuroendocrine neoplasm that originates from thyroid C cells. Surgery, with complete resection of the tumor, is the only curative approach. However, in most cases, the tumor recurs at locoregional or metastatic level. In this setting, the management remains challenging. In recent years, the immune checkpoint inhibitors have provided promise for changing the cancer treatment paradigm through the application of new approaches that enhance the body's natural antitumor defenses. The aim of this review is to summarize and discuss available data on efficacy and safety of the Food and Drug Administration-approved immune checkpoint inhibitors in patients with medullary thyroid carcinoma. After an extensive search, we found 7 useful data sources (one single-case report, one short article with very preliminary data, five ongoing registered clinical trials). Despite the lack of published evidence regarding the use of immune check point inhibitors, it must be considered that all the ongoing registered clinical trials saw first light in the last three years, thus indicating a growing interest of researchers in this field. Results coming from these trials, and hopefully, in the next future, from additional trials, will help to clarify whether this class of drugs may represent a new weapon in favor of patients with medullary thyroid carcinoma.
Topics: Animals; Carcinoma, Neuroendocrine; Humans; Immune Checkpoint Inhibitors; Thyroid Neoplasms
PubMed: 33935977
DOI: 10.3389/fendo.2021.667784 -
Endocrinology, Diabetes & Metabolism... Nov 2019A 74-year-old man was referred to the Endocrinology Unit because of multinodular goiter. The dominant nodule (1.7 × 1.9 × 2.4 cm), at the medium-superior third of the...
SUMMARY
A 74-year-old man was referred to the Endocrinology Unit because of multinodular goiter. The dominant nodule (1.7 × 1.9 × 2.4 cm), at the medium-superior third of the left lobe, was inhomogeneously hypoechoic, with irregular margins, macrocalcifications and intranodular vascularization. Fine-needle aspiration biopsy (FNAB) was performed. The cytological diagnosis was TIR 2, benign, according to the 2013 Italian thyroid cytology classification system. Moderately high serum calcitonin (s-Ct) (61.5 pg/mL, n.r. 0-7.5) and normal CEA were detected. The Ct level in FNAB wash-out fluid (Ct-FNAB) was 1450 pg/mL. Based on s-Ct and Ct-FNAB levels, patient underwent total thyroidectomy. Macroscopically, a dominant circumscribed nodule of 2 ecm was described; the histological and immunohistochemical features identified medullary thyroid carcinoma (MTC) with paraganglioma (PG)-like pattern positive for Ct, CEA and chromogranin and negative for S-100 sustentacular cells (SC). Moreover, papillary carcinoma of 3 mm in the right lobe was also associated. No areas of hyperaccumulation of the tracer were documented at Ga68 PET/CT. No RET-proto-oncogene mutations were found. Post-surgery s-Ct levels were within normal range (4 pg/mL). Two years after thyroidectomy, the patient is still disease-free. We reported a case of sporadic and rare variant of MTC: this is the ninth described case of PG-like MTC. In this case, cytologically benign, the clinical suspicion arose from high Ct values at FNAB wash-out fluid. Even if clinical behavior of this variant seems indolent, additional studies are necessary to understand prognoses and predictive factors.
LEARNING POINTS
Several unusual histological variants of medullary thyroid carcinoma (MTC) have been described such as spindle cell, giant cell, clear cell, melanotic, squamous, angiosarcoma-like variants; even rarer is the paraganglioma (PG)-like pattern. We here describe a case of medullary PG-like thyroid carcinoma in a 74-year-old man. This is a rare histological variant of MTC hardly diagnosed by cytology, since immunohistochemical investigations are necessary. Measurement of calcitonin both in serum and in wash-out fluid from fine-needle aspiration could be an additional tool for an early and non-invasive identification of these variants.
PubMed: 31778356
DOI: 10.1530/EDM-19-0094 -
Frontiers in Endocrinology 2023Medullary thyroid cancer (MTC) is a rare thyroid tumour whose management in advanced stages is challenging, despite effective therapeutic options having expanded in... (Review)
Review
INTRODUCTION
Medullary thyroid cancer (MTC) is a rare thyroid tumour whose management in advanced stages is challenging, despite effective therapeutic options having expanded in recent years. Proteasome inhibitors (PrIn) have shown the ability to improve patient outcomes, including survival and quality of life, in several malignancies, due to their ability to impair cell proliferation and cause apoptosis through the inhibition of the proteasome activity. Consequently, these drugs could represent a useful tool, alone or in combination with other treatments, in MTC patients.
AIM OF THE STUDY
This review aims to summarize the available and data about the role of PrIn in MTC.
MATERIALS AND METHODS
We performed an extensive search for relevant data sources, including full-published articles in international online databases (PubMed, Web of Science, Scopus), preliminary reports in selected international meeting abstract repositories, and short articles published as supplements of international meetings, by using the following terms: medullary thyroid carcinoma, proteasome inhibitors, bortezomib, carfilzomib, ixazomib, delanzomib, marizomib, oprozomib, and MG132. Additionally, we conducted with the same keywords, an in-depth search in registered clinical trials repositories.
RESULTS
Our search revealed studies in human and murine MTC cell lines, based on the use of PrIns, both alone and in combination with other anticancer drugs, and two pertinent clinical trials.
CONCLUSION
We found a strong discrepancy between the evidence of PrIns effects in preclinical studies, and the scarcity or early interruption of clinical trials. We might speculate that difficulties in enrolling patients, as happens in other rare diseases, may have discouraged trials' implementation in favor of drugs already approved for MTC. However, given the concrete improvement in the comprehension of the molecular basis of PrIn effects in MTC, new clinical trials with accurate inclusion criteria of enrollment might be warranted, in order to ascertain whether this treatment, alone or in combination with other drugs, could indeed represent an option to enhance the therapeutic response, and to ultimately improve patients' outcome and survival.
Topics: Humans; Animals; Mice; Proteasome Inhibitors; Quality of Life; Antineoplastic Agents; Thyroid Neoplasms
PubMed: 37152939
DOI: 10.3389/fendo.2023.1145926 -
Cancers Jul 2019Several histopathological variants of colorectal carcinoma can be distinguished, some associated with specific molecular profiles. However, in routine practice,... (Review)
Review
Several histopathological variants of colorectal carcinoma can be distinguished, some associated with specific molecular profiles. However, in routine practice, ninety/ninety-five percent of all large bowel tumors are diagnosed as conventional adenocarcinoma, even though they are a heterogeneous group including rare histotypes, which are often under-recognized. Indeed, colorectal cancer exhibits differences in incidence, location of tumor, pathogenesis, molecular pathways and outcome depending on histotype. The aim is therefore to review the morphological and molecular features of these rare variants of intestinal carcinomas which may hold the key to differences in prognosis and treatment.
PubMed: 31340478
DOI: 10.3390/cancers11071036 -
Endocrinology, Diabetes & Metabolism... Sep 2021Medullary thyroid carcinoma (MTC) has a varying clinical course; distant metastases are frequently present even at diagnosis. We present two MTC cases with unusual...
SUMMARY
Medullary thyroid carcinoma (MTC) has a varying clinical course; distant metastases are frequently present even at diagnosis. We present two MTC cases with unusual metastatic sites. Two female patients are presented with slow progressive MTC. The first case developed distant metastases 23 years after diagnosis and underwent locoregional therapies. At the same time a breast mass developed representing MTC metastasis. Treatment with vandetanib led to long-term disease stabilization. The second patient is presented with metastases in the pancreas 13 years after diagnosis. Shortly, a painful mass developed in the mandible and metastasis of MTC was diagnosed. Disease progression was recorded 20 months after the initiation of local and systemic therapy. Such cases have only rarely been reported in the literature and highlight the need for prompt recognition of unexpected MTC metastases.
LEARNING POINTS
Unusual sites of metastasis may appear in patients with medullary thyroid carcinoma (MTC) years after the initial diagnosis. Although rare, unexpected MTC metastases highlight the need for prompt recognition and appropriate treatment. Local recurrences accompanied by inappropriately low calcitonin levels should prompt further investigation for possible distant metastatic disease. Systemic treatment with tyrosine kinase inhibitors may be effective even in patients with unusual metastases from MTC.
PubMed: 34551391
DOI: 10.1530/EDM-21-0063 -
Frontiers in Endocrinology 2022Medullary thyroid carcinoma (MTC) is a malignant neuroendocrine neoplasm that may spread to lymph nodes before the primary tumor is diagnosed; moreover, distant... (Review)
Review
CONTEXT
Medullary thyroid carcinoma (MTC) is a malignant neuroendocrine neoplasm that may spread to lymph nodes before the primary tumor is diagnosed; moreover, distant metastases are already present in about 10% of patients at diagnosis. Serum calcitonin (Ctn) usually reflects the spread of disease, thus orienting the extent of surgery and predicting the possibility of biochemical remission. Tumor size and vascular invasion are important prognostic factors, but little is known on the relationship between other histopathological features, such as the presence of a tumor capsule, and long term outcome of MTC.
PURPOSE
To evaluate the prevalence of encapsulated tumors among MTCs and the association of tumor capsule with a favorable outcome after surgery.
METHODS
A retrospective observational single-center study was conducted together with a narrative review of the available literature.
RESULTS
Among 44 patients (27 female, 17 male; median age: 56 years) with MTC (6 hereditary, 37 sporadic) followed up at our center in the last four years (median follow-up: 29.2 months), seven (15.9%) showed an encapsulated tumor at histology and a clinical remission after surgery. None of them had nodal metastases and median preoperative Ctn (398 pg/mL, IQR 126.5-7336) did not differ significantly from that of the 14 patients (31.8%) with persistent disease after surgery (787 pg/mL, IQR 340.5-2905.5; p=0.633), although their tumor size was significantly higher (median 33 mm versus 16 mm respectively, p=0.036). Among patients with preoperative Ctn levels above 500 pg/mL (n=11), only two (18.2%) showed undetectable Ctn levels during follow-up, both having an encapsulated MTC (OR 0.000, p=0.02). Notably, they were two similar cases of large MTC (> 3 cm) with extensive hyalinization and calcification, associated with very high Ctn levels (> 13'500 and 1'100 pg/mL, respectively) but no nodal nor distant metastases, in complete remission after surgery although one of them carried the aggressive M918T somatic mutation.
CONCLUSION
MTC rarely shows a tumor capsule, which seems to correlate with a better prognosis and absence of nodal metastases, regardless of or mutational status. Among encapsulated MTCs (E-MTC), Ctn levels and tumor size are not predictive of persistence of disease after surgery.
Topics: Carcinoma, Neuroendocrine; Female; Humans; Male; Middle Aged; Prognosis; Retrospective Studies; Thyroid Neoplasms
PubMed: 35574005
DOI: 10.3389/fendo.2022.866572