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Frontiers in Endocrinology 2022Immunotherapy has changed the treatment of patients with advanced cancer, with different phase III trials showing durable responses across different histologies. This... (Review)
Review
Immunotherapy has changed the treatment of patients with advanced cancer, with different phase III trials showing durable responses across different histologies. This review focuses on the preclinical and clinical evidence of potential predictive biomarkers of response and efficacy of immunotherapy in thyroid neoplasms. Programmed death-ligand 1 (PD-L1) staining by immunohistochemistry has shown higher expression in anaplastic thyroid cancer (ATC) compared to other subtypes. The tumor mutational burden in thyroid neoplasms is low but seems to be higher in ATC. Immune infiltrates in the tumor microenvironment (TME) differ between the different thyroid neoplasm subtypes. In general, differentiated thyroid cancer (DTC) has a higher number of tumor-associated lymphocytes and regulatory T cells (Tregs), while ATC and medullary thyroid cancer (MTC) display a high density of tumor-associated macrophages (TAMs). Nevertheless, results from clinical trials with immunotherapy as monotherapy or combinations have shown limited efficacy. Further investigation into new strategies aside from anti-cytotoxic T-lymphocyte antigen 4 (CTLA-4)/programmed death 1 (PD-1)/PD-L1 antibodies, validation of predictive biomarkers, and better population selection for clinical trials in thyroid neoplasms is more than needed in the near future.
Topics: B7-H1 Antigen; Humans; Immunotherapy; Thyroid Carcinoma, Anaplastic; Thyroid Neoplasms; Tumor Microenvironment
PubMed: 35992118
DOI: 10.3389/fendo.2022.929091 -
Familial Cancer Jul 2021The data from the Indian subcontinent on Medullary thyroid carcinoma (MTC) and associated endocrinopathies in hereditary MTC (HMTC) syndromes are limited. Hence, we...
The data from the Indian subcontinent on Medullary thyroid carcinoma (MTC) and associated endocrinopathies in hereditary MTC (HMTC) syndromes are limited. Hence, we analyzed clinical and biochemical characteristics, management, and outcomes of HMTC and other associated endocrinopathies [Pheochromocytoma (PCC) and Primary hyperparathyroidism (PHPT)] and compared with apparently sporadic MTC. The records of 97 (51 sporadic and 46 hereditary) consecutive MTC patients were retrospectively analyzed. RET mutation was available in 38 HMTC patients. HMTC group was subclassified into Multiple endocrine neoplasia (MEN) 2A index (n = 25), MEN2B index (n = 8), and MEN2A detected by familial screening (n = 12). Patients with HMTC and MEN2B index were younger at presentation than sporadic MTC. MEN2A patients detected by familial screening, but not MEN2A index and MEN2B index patients, had significantly lower serum calcitonin, smaller thyroid nodule size, more frequent early stage presentation (AJCC Stage ≤ II), and higher cure rate than sporadic MTC, which emphasizes the need for early diagnosis. RET (REarranged during Transfection) 634 mutations were the most common cause of HMTC and more frequently associated with PCC (overall 54% and 100% in those aged ≥ 35 years). Patients in ATA-Highest (HST) group had a universal presentation in stage IV with no cure. In contrast, the cure rate and postoperative disease progression (calcitonin doubling time) were similar between ATA-High (H) and ATA- Moderate (MOD) groups, suggesting the need for similar follow-up strategies for the latter two groups. Increased awareness of endocrine (PCC/PHPT) and non endocrine components may facilitate early diagnosis and management.
Topics: Adrenal Gland Neoplasms; Adult; Calcitonin; Carcinoma, Medullary; Female; Humans; Hyperparathyroidism, Primary; India; Male; Multiple Endocrine Neoplasia Type 2a; Multiple Endocrine Neoplasia Type 2b; Mutation; Pheochromocytoma; Proto-Oncogene Proteins c-ret; ROC Curve; Retrospective Studies; Syndrome; Thyroid Neoplasms; Young Adult
PubMed: 33392850
DOI: 10.1007/s10689-020-00219-9 -
Endocrinologia, Diabetes Y Nutricion Apr 2022Familial non-medullary thyroid carcinoma (FNMTC) is defined by the presence of 2 or more first-degree family members with differentiated thyroid carcinoma (DTC). The aim...
INTRODUCTION
Familial non-medullary thyroid carcinoma (FNMTC) is defined by the presence of 2 or more first-degree family members with differentiated thyroid carcinoma (DTC). The aim of this study is to compare clinicopathological features and prognosis of FNMTC and sporadic carcinoma (SC).
MATERIALS AND METHODS
Retrospective study of DTC included in the hospital database during the period 1990-2018.
RESULTS
A total of 927 patients were analyzed, 61 of them were FNMTC, with a mean follow-up of 9.7 ± 6.5 years. The prevalence of FNMTC was 6.6%, with a lower TNM staging presentation (P = 0.003) consequence of a higher proportion of tumors smaller than 2 cm (P = 0.003), combined with a greater multifocality (P = 0.034) and papillary histologic subtype (P = 0.022) compared to SC. No significant differences in age at diagnosis (P = 0.347), gender (P = 0.406), neither in other aggressiveness markers (bilaterality, extrathyroidal extension, lymph node involvement and metástasis) were detected. Rate of persistence/recurrence (P = 0.656), disease-free survival (P = 0.929) and mortality caused by the tumor itself (P = 0.666) were comparable. Families with ≥3 affected relatives, had smaller tumors (P = 0.005), more multifocality (P = 0.040) and bilaterality (P = 0.002), as well as a higher proportion of males (P = 0.020). Second generation patients present earlier FNMTC compared to those of the first generation (P = 0.001).
CONCLUSION
In our study FNMTC presents a lower TNM staging, higher multifocality and papillary variant, with similar aggressiveness and prognosis compared to SC.
Topics: Carcinoma; Carcinoma, Papillary; Humans; Male; Prognosis; Retrospective Studies; Thyroid Cancer, Papillary; Thyroid Neoplasms
PubMed: 35353680
DOI: 10.1016/j.endien.2022.03.003 -
Endocrine Pathology Mar 2023Medullary thyroid carcinoma (MTC) is a C-cell-derived epithelial neuroendocrine neoplasm. With the exception of rare examples, most are well-differentiated epithelial... (Review)
Review
Medullary thyroid carcinoma (MTC) is a C-cell-derived epithelial neuroendocrine neoplasm. With the exception of rare examples, most are well-differentiated epithelial neuroendocrine neoplasms (also known as neuroendocrine tumors in the taxonomy of the International Agency for Research on Cancer [IARC] of the World Health Organization [WHO]). This review provides an overview and recent evidence-based data on the molecular genetics, disease risk stratification based on clinicopathologic variables including molecular profiling and histopathologic variables, and targeted molecular therapies in patients with advanced MTC. While MTC is not the only neuroendocrine neoplasm in the thyroid gland, other neuroendocrine neoplasms in the thyroid include intrathyroidal thymic neuroendocrine neoplasms, intrathyroidal parathyroid neoplasms, and primary thyroid paragangliomas as well as metastatic neuroendocrine neoplasms. Therefore, the first responsibility of a pathologist is to distinguish MTC from other mimics using appropriate biomarkers. The second responsibility includes meticulous assessment of the status of angioinvasion (defined as tumor cells invading through a vessel wall and forming tumor-fibrin complexes, or intravascular tumor cells admixed with fibrin/thrombus), tumor necrosis, proliferative rate (mitotic count and Ki67 labeling index), and tumor grade (low- or high-grade) along with the tumor stage and the resection margins. Given the morphologic and proliferative heterogeneity in these neoplasms, an exhaustive sampling is strongly recommended. Routine molecular testing for pathogenic germline RET variants is typically performed in all patients with a diagnosis of MTC; however, multifocal C-cell hyperplasia in association with at least a single focus of MTC and/or multifocal C-cell neoplasia are morphological harbingers of germline RET alterations. It is of interest to assess the status of pathogenic molecular alterations involving genes other than RET like the MET variants in MTC families with no pathogenic germline RET variants. Furthermore, the status of somatic RET alterations should be determined in all advanced/progressive or metastatic diseases, especially when selective RET inhibitor therapy (e.g., selpercatinib or pralsetinib) is considered. While the role of routine SSTR2/5 immunohistochemistry remains to be further clarified, evidence suggests that patients with somatostatin receptor (SSTR)-avid metastatic disease may also benefit from the option of Lu-DOTATATE peptide radionuclide receptor therapy. Finally, the authors of this review make a call to support the nomenclature change of MTC to C-cell neuroendocrine neoplasm to align this entity with the IARC/WHO taxonomy since MTCs represent epithelial neuroendocrine neoplasms of endoderm-derived C-cells.
Topics: Humans; Prognosis; Thyroid Neoplasms; Carcinoma, Neuroendocrine; Neuroendocrine Tumors
PubMed: 36890425
DOI: 10.1007/s12022-023-09753-5 -
Annals of Diagnostic Pathology Jun 2023Medullary thyroid carcinoma (MTC) is a rare type of thyroid malignancy. Recently, a two-tier grading system (GS) for MTC has been suggested. We conducted this study to...
OBJECTIVE
Medullary thyroid carcinoma (MTC) is a rare type of thyroid malignancy. Recently, a two-tier grading system (GS) for MTC has been suggested. We conducted this study to evaluate the generalizability, as well as application of recently proposed GS to our cohort of Medullary thyroid carcinoma (MTC) cases.
METHODS
We assigned grades to MTC cases and divided them into two groups by using morphologic criteria only as suggested by recent studies: low-grade (LG, <5 mitosis per 2 mm, and no necrosis) and high-grade (HG, ≥5 mitosis per 2mm or necrosis).
RESULTS
A total of 59 MTC cases were evaluated and of those 52 (88 %) were LG and 7 (12 %) were HG. Vascular invasion (VI) (p = 0.017), distant metastasis (DM) (p < 0.0001), nuclear pleomorphism (NP) (p = 0.017) and prominent nucleoli (p = 0.03) were prominently noted in the HG group. After controlling for demographics using multivariate cox regression, tumor grade and necrosis remained significantly associated with the overall survival (HR = 22.7, p < 0.01 and HR = 11.1, p = 0.008, respectively). Upon comparing the cases with and without nodal disease, we found that nodal disease is more strongly associated with NP (p = 0.029), tumor fibrosis (p = 0.0001), VI (p = 0.001) and DM (p = 0.005).
CONCLUSIONS
We applied the two-tier GS for MTC to our cohort of cases and found statistically significant differences in the overall survival among the two groups. Adding the grading to the pathology report communicates additional information regarding risk stratification in MTC.
Topics: Humans; Thyroid Neoplasms; Carcinoma, Neuroendocrine; Prognosis
PubMed: 36736129
DOI: 10.1016/j.anndiagpath.2023.152112 -
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 -
Surgery Sep 2021Unlike medullary thyroid carcinoma in adults, the vast majority of pediatric medullary thyroid carcinoma is hereditary. Pediatric medullary thyroid carcinoma is known to...
BACKGROUND
Unlike medullary thyroid carcinoma in adults, the vast majority of pediatric medullary thyroid carcinoma is hereditary. Pediatric medullary thyroid carcinoma is known to have different genetic alterations driving tumorigenesis, but it is not known if pediatric medullary thyroid carcinoma has different clinicopathologic features. This study aims to identify which pediatric medullary thyroid carcinoma patients might warrant elective neck dissection.
METHODS
We selected all patients ages 0 to 19 diagnosed with clinically evident medullary thyroid carcinoma in the National Cancer Database between 2004 to 2016. Clinicopathologic factors, treatments, and outcomes were analyzed and compared between this cohort and adults (ages ≥20) with medullary thyroid carcinoma.
RESULTS
One hundred twenty-five pediatric medullary thyroid carcinoma (median age: 13) and 5,086 adult medullary thyroid carcinoma (median age: 57) patients were identified. Pediatric patients had smaller tumors (median diameter: 1.2 cm vs 2.0 cm; P < .001), lower rates of nodal metastases (n = 31, 36.9% vs 1,689, 50.4%; P = .02) but double the incidence of multifocal tumors (n = 70, 59.3%, vs 1,412, 29.9%; P < .001) compared with adults. Multifocal tumors conferred a significantly increased risk of nodal metastases in adult medullary thyroid carcinoma (64.4% vs 43.2%; P < .001) but not pediatric medullary thyroid carcinoma (37.7% vs 35.7%; P = .85). Nodal metastases were more frequent among older children (0-5 years: 0.0%, 6-12: 40.7%, 13-19: 41.7%; P = .04). However, rates of occult nodal metastases were similar between older children (6-19 years: n = 12, 21.4%) and adults (557, 25.8% P = .56).
CONCLUSION
Pediatric medullary thyroid carcinoma has lower rates of lymph node metastases compared with adults. The risk of nodal disease was low among the youngest children, but older children ages 6 to 19 were at considerable risk for occult metastases. These findings could guide clinicians in selecting pediatric patients considered for elective lymph node dissection.
Topics: Adolescent; Adult; Aged; Aged, 80 and over; Carcinoma, Neuroendocrine; Child; Child, Preschool; Female; Follow-Up Studies; Humans; Incidence; Infant; Infant, Newborn; Lymph Nodes; Lymphatic Metastasis; Male; Middle Aged; Neck Dissection; Retrospective Studies; Thyroid Neoplasms; Thyroidectomy; United States; Young Adult
PubMed: 33838880
DOI: 10.1016/j.surg.2021.03.001 -
World Journal of Surgery Feb 2023The basic nature of cancer includes unlimited growth, invasion, and metastasis. The TNM staging system is very simple and popular. It indicates the degree of the...
INTRODUCTION
The basic nature of cancer includes unlimited growth, invasion, and metastasis. The TNM staging system is very simple and popular. It indicates the degree of the anatomical spread of the disease but does not include tumor growth. Collins reported that human tumors grow exponentially, which can be expressed in doubling time.
PATIENTS AND METHODS
We found that in patients with medullary thyroid carcinoma (MTC) and papillary thyroid carcinoma (PTC) serum calcitonin and thyroglobulin levels changed exponentially over time, respectively, and that doubling times of these values were very strong prognostic factors. Doubling time has two major limitations. Doubling rate resolves these limitations. Using doubling rate, we performed kinetic analyses on tumor volume during active surveillance of micro-PTC.
RESULTS
Our kinetic studies on patients with biochemically persistent disease revealed that 17% of MTC and 51% of PTC showed decrease in serum tumor marker levels over time. During active surveillance of micro-PTC, 17% of the patients showed clear decrease in their tumor volume. The evidences currently available are limited. However, our data indicate the following: Growth slowdown and regression are very common phenomena in the natural history of micro-PTC, clinical PTC in young and middle-aged patients, and hereditary MTC. The biologic characteristics of cancers of the same name, such as PTC, are diverse and vary widely with age.
CONCLUSIONS
Doubling time and doubling rate are very powerful tools to provide the most appropriate management for the patients with thyroid cancers. Knowing the natural history of thyroid cancer is essential for the best disease management of thyroid cancer.
Topics: Middle Aged; Humans; Kinetics; Carcinoma, Papillary; Thyroid Neoplasms; Thyroid Cancer, Papillary; Retrospective Studies
PubMed: 36153411
DOI: 10.1007/s00268-022-06741-4 -
International Journal of Surgical... Sep 2021Insulinoma-associated protein 1 (INSM1) is shown to be an excellent marker for neuroendocrine differentiation. However, the diagnostic utility of INSM1 in medullary...
Insulinoma-associated protein 1 (INSM1) is shown to be an excellent marker for neuroendocrine differentiation. However, the diagnostic utility of INSM1 in medullary thyroid carcinoma (MTC) has not yet been extensively investigated. INSM1 staining was performed on 21 MTCs, 7 MTC mimickers (including 3 papillary carcinomas, 2 poorly differentiated carcinomas, 1 follicular adenoma, and 1 nodular plasma cell hyperplasia), and 3 cases of C-cell hyperplasia. INSM1 staining of these cases was compared with the traditional MTC markers including calcitonin (CT), monoclonal carcinoembryonic antigen (mCEA), chromogranin A (CgA), and synaptophysin (Syn). The -score was generated using the QuPath program, an open-source image analysis software. All 21 MTC cases and 3 C-cell hyperplasia cases were positive for all markers. The MTC mimickers were entirely negative for INSM1. INSM1 and Syn displayed, more consistently, high expression with minimal variability than CgA that showed a wide range of expression with significant variability. mCEA and CT exhibited mostly a high expression with some variability. Being a nuclear stain, interpretation was easier with INSM1 compared to other cytoplasmic markers. INSM1 is an excellent marker for neuroendocrine differentiation, entirely applicable in the diagnosis of MTC and C-cell hyperplasia with high sensitivity and specificity. In comparison with the traditional MTC markers, INSM1 is unique in the crisp nuclear staining pattern with a consistent, diffuse, and strong expression. INSM1 can be potentially combined with CT or mCEA as a dual stain, especially when the lesional tissue is limited for a panel of immunostains.
Topics: Adult; Aged; Aged, 80 and over; Biomarkers, Tumor; Carcinoma, Neuroendocrine; Diagnosis, Differential; Feasibility Studies; Female; Humans; Male; Middle Aged; Repressor Proteins; Synaptophysin; Thyroid Gland; Thyroid Neoplasms; Young Adult
PubMed: 33650906
DOI: 10.1177/1066896921995935 -
Thyroid : Official Journal of the... Feb 2021Medullary thyroid carcinomas (MTC) are rare neoplasms derived from calcitonin-secreting cells of the thyroid. They can occur sporadically or as part of the multiple... (Review)
Review
Medullary thyroid carcinomas (MTC) are rare neoplasms derived from calcitonin-secreting cells of the thyroid. They can occur sporadically or as part of the multiple endocrine neoplasia type 2 syndromes. Overall, successful management of MTC patients heavily relies on the patient's conditions, tumor stage, genetic background, and the medical team's experience. Over the past 10 years, many consensus or near consensus of expert panels have been published for the treatment and follow-up of MTC (e.g., American Thyroid Association [ATA] 2009, ATA 2015, European Society of Medical Oncology [ESMO] 2019, European Association of Nuclear Medicine [EANM] 2020). The recent 2020 EANM guidelines recommend in particular to carry out F-FDOPA (6-18F-fluoro-L-3,4-dihydroxyphenylalanine) positron emission tomography/computed tomography scan (PET/CT scan) in MTC patients with persistent disease; however, this recommendation was not made in the 2015 ATA revised version. 18F-flurodeoxy glucose PET/CT scan is limited to aggressive forms, and PET imaging using Ga-somatostatin analogs appears suboptimal. This special article focuses on the clinical value of PET imaging in three common clinical scenarios (before initial thyroidectomy, before cervical reoperations for persistent/recurrent disease, and in the follow-up of metastatic cases).
Topics: Carcinoma, Neuroendocrine; Dihydroxyphenylalanine; Humans; Neoplasm Recurrence, Local; Neoplasm Staging; Positron Emission Tomography Computed Tomography; Predictive Value of Tests; Radiopharmaceuticals; Thyroid Neoplasms; Thyroidectomy; Treatment Outcome
PubMed: 33191866
DOI: 10.1089/thy.2020.0674