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Background: Currently, the incidence rate of Medullary Thyroid Microcarcinoma (micro-MTC) has an increasing trend, but the incidence of LNM and prognosis were still ambiguous. We analyzed the status of neck LNM of micro-MTC patients and created a prognostic nomogram to predict the probability of lateral lymph node metastasis (LLNM) for clinical practice. Methods: This is a retrospective study included patients with micro-MTC from SEER database for the period from 2004 to 2017 and patients from our medical center for the period from 2011 to 2019. A nomogram was constructed and the accuracy and clinical practicability were separately tested by Harrell's C-indexes, calibration plots, Receiver operating characteristic curve (ROC) and decision curve analyses (DCA). Results: A total of 413 patients with micro-MTC from SEER database and 64 patients with micro-MTC from our department enrolled in the study. There were 16.0% and 9.4% cases in SEER database and 39.1% and 25.0% cases in our department appeared LNM and LLNM, respectively. Besides, a nomogram was constructed to assess the incidence of LLNM with good C-index, which was 0.850 in training cohort and 0.856 in validation cohort. The results of the area under the curve (AUC) were 0.830 in training cohort, 0.801 in validation cohort and 0.832 in external testing cohort, respectively. Conclusion: A relatively high rate of LLNM than expected was found, which should be emphasized. The prediction model could facilitate clinicians to assess the probability of LLNM and make a personalized treatment strategy. [ABSTRACT FROM AUTHOR]

Papillary thyroid and medullary thyroid cancers are two distinct types of thyroid neoplasms. Co-occurrence of these cancers is rare, especially in mixed tumours with lymph node metastases. A 66-year-old man presented with a thyroid tumour. Thyroid ultrasonography revealed three separate nodules in the thyroid, suspected to be associated with lymph node metastasis. Although preoperative thyroid function was normal, calcitonin and carcinoembryonic antigen levels were elevated. The patient underwent a total cervical thyroidectomy with bilateral radical dissection. Histological and immunohistochemical analyses identified mixed medullary and papillary thyroid carcinoma (MMPTC) in the nodules in the left lobe of the thyroid and the isthmus. Mixed metastatic spread was observed in several lymph nodes from the neck dissection specimen. Accurate diagnosis of the rare co-occurrences of papillary and medullary thyroid carcinomas is crucial. TSH suppression can be effective for treating papillary thyroid carcinoma, whereas radical surgery is the preferred treatment for medullary thyroid carcinoma. Identifying lymph node metastasis before surgery is a key surgical strategy. [ABSTRACT FROM AUTHOR]

Background: "Spinal ganglioneuroma" is a rare entity of neuroblastic tumors, frequent among children, that has been sparsely reported in articles involving both the pediatric and adult populations. These tumors mostly arise from the sympathetic ganglia located in the paravertebral region, near the intervertebral foramina of the spine. This makes their extension into the spinal canal possible but quite rare, in a dumbbell fashion, producing radicular or medullary symptoms. We provide an extensive review of the pediatric cases found in the literature; while reporting a challenging case we have recently got to treat at the CHRU de Brabois in Nancy, France. Methods: We searched PubMed's database for articles and abstracts related to "spinal ganglioneuromas," from inception until June 1, 2024. We combined every case among patients under 18 years of age and divided them between the different spinal areas. We excluded those that originated from outside of the spine. We particularly focused our attention on the thoraco-lumbar region, which involved our case report, since the surgical management is completely different from other regions of the spine. Results: As per June 1, 2024, 21 patients aged between 3 and 17 years were identified with "spinal ganglioneuromas," with a predominance of females (81%). The thoracic region of the spine seems to be the area of predilection for these tumors (42.85%), although some have been found in the cervical (9.5%), cervico-thoracic (4.76%), thoraco-lumbar (19.04%), lumbar (19.04%), and sacral (4.76%) regions. Discussion: Our specific case included long-date abdominal pain and recent progressive paraparesis as the main symptoms, with radiological manifestations of renal atrophy and hydronephrosis, due to the compression and complete displacement of the kidney, as well as scoliosis. To our knowledge, this combination of symptoms has never been seen with spinal ganglioneuromas before in the pediatric population, given the gigantic size of the tumor, and its significant extension to both the spinal canal and the retroperitoneal space, which is quite uncommon. Conclusion: Spinal ganglioneuromas are very rare, benign lesions, that should be included in the differential diagnosis of dumbbell tumors that can cause in the pediatric population, alongside neurological symptoms in the limbs and back pain, thoracic, abdominal, and even urinary symptoms. [ABSTRACT FROM AUTHOR]

Pancreatic cancer is one of the deadliest malignancies in humans and it is expected to play a bigger part in cancer burden in the years to come. Pancreatic ductal adenocarcinoma (PDAC) represents 85% of all primary pancreatic malignancies. Recently, much attention has been given to PDAC, with significant advances in the understanding of the mechanisms underpinning disease initiation and progression, along with noticeable improvements in overall survival in both localized and metastatic settings. However, given their rarity, rare histological subtypes of pancreatic cancer have been underappreciated and are frequently treated as PDAC, even though they might present non-overlapping molecular alterations and clinical behavior. While some of these rare histological subtypes are true variants of PDAC that should be treated likewise, others represent separate clinicopathological entities, warranting a different therapeutic approach. In this review, we highlight clinical, pathological, and molecular aspects of rare histological types of pancreatic cancer, along with the currently available data to guide treatment decisions. Plain language summary: Should rare subtypes of pancreatic cancer be treated as its most common variant (ductal adenocarcinoma)? The most common type of pancreatic cancer is ductal adenocarcinoma. While much attention has been given to the molecular aspects and treatment aspects of this disease, rare variants of pancreatic cancer have been underappreciated. Some of them present unique molecular features that suggest different treatment approaches could lead to better outcomes. In this review, we summarize information on the clinical, pathological, and molecular features of rare subtypes of pancreatic cancer, along with subtype-specific data on treatment. [ABSTRACT FROM AUTHOR]

When considering placing dental implants in atrophic edentulous sites, there may be inadequate site width and little or no vertical bone loss. Any of several surgical procedures can augment these sites. Extracortical augmentation is done by applying graft material against the cortical bone. This technique expects progenitor cells to migrate outside the bony ridge's confines and form new bone. Another method entails ridge splitting and expansion to create space for osteogenesis and, when possible, implant placement. This may be a better method for horizontal ridge augmentation. The ridge is split, separating the facial and lingual cortices for a complete bone fracture. The patient's osseous cells can then migrate into the created space from the exposed medullary bone to form bone. The technique can be preferably performed flapless so the intact periosteum maintains a blood supply to ensure appropriate healing. [ABSTRACT FROM AUTHOR]

Introduction: Medullary thyroid carcinoma (MTC) is a rare neuroendocrine tumor from parafollicular cells that produce calcitonin (Ct). Despite several existing guidelines for the surgical management of sporadic MTC (sMTC), optimal initial surgical management of the thyroid, the central and the lateral neck remains a matter of debate. Methods: A systematic review in PubMed and Scopus for current guidelines addressing the surgical management of sMTC and its referenced citations was conducted as per the PRISMA guidelines. Results: Two‐hundred and one articles were identified, of which 7 met the inclusion criteria. Overall, guidelines vary significantly in their recommendations for the surgical management of sMTC. Only one guideline recommended partial thyroidectomy for limited disease, but the possibility to avoid completion thyroidectomy in selected cases is acknowledged in 42% (3/7) of the remaining guidelines. The majority of guidelines (71.4%; 5/7) recommended prophylactic central neck dissection (CND) for all patients while the remaining two guidelines recommended CND based on Ct level and tumor size. The role of prophylactic lateral neck dissection based on preoperative Ct levels was recommended by 42% (3/7) of guidelines. Overall, these guidelines are based on low‐quality evidence, mostly single‐center retrospective series, some of which are over 20 years old. Conclusion: Current surgical management guidelines of sMTC should be revised, and ought to be based on updated data challenging current recommendations, which are based on historic, low‐quality evidence. Partial thyroidectomy may become a viable option for small, limited tumors. Prospective, multi‐center studies may be useful to conclude whether prophylactic ND is necessary in all sMTC patients. [ABSTRACT FROM AUTHOR]

Context. Parathyroid carcinomas (PC) are rare. Imaging and laboratory tests can suggest a diagnosis of PC, but pathological examination is ultimately required to confirm the diagnosis. Objective. The clinicopathologic data, diagnosis, and treatment of a case of PC diagnosed in our hospital in 2022 are retrospectively summarized in this case report to improve the understanding, diagnosis, and differential diagnosis of this disease. Design. Case report. Subjects and Methods. Herein, we present the case of a 35-year-old man who presented with imaging and laboratory findings suggestive of a parathyroid neoplasm. Results. The patient underwent radical resection of the tumor, which was histopathologically diagnosed as PC. Conclusion. In this case, the clinical manifestations of PC were insidious, and the histological features had to be differentiated from tumors, such as parathyroid adenoma, clear cell renal cell carcinoma, and medullary thyroid carcinoma; thus, its diagnosis was challenging. [ABSTRACT FROM AUTHOR]

We herein report a case of developmental venous anomaly (DVA) with venous congestion caused by stenosis of the collecting vein that presented with intracerebral hemorrhage (ICH). A 74-year-old woman was referred to our hospital a few days after the onset of motor aphasia. Computed tomography (CT) and magnetic resonance imaging (MRI) showed ICH in the left frontal lobe. Angiography revealed DVA in the left frontal lobe in the late venous phase. Stenosis of the collecting vein of DVA at the entrance to the superior sagittal sinus was detected and accompanied by cavernous malformation (CM) beside DVA. Cone-beam CT revealed the absence of the left septal vein and hypoplastic transverse caudate veins. The patient was treated by blood pressure management and no additional neurological symptoms were detected. DVA develops to compensate for the absence of pial or deep venous systems, and generally benign and clinically asymptomatic. However, the outflow restriction of DVA causes chronic venous hypertension and the formation of CM. These abnormalities are considered to occur during post-natal life and may result in ICH. The risk of hemorrhage needs to be considered in cases of DVA with restricted venous outflow or CM. [ABSTRACT FROM AUTHOR]

Multiple endocrine neoplasia type 2B (MEN 2B) is a rare genetic syndrome with an estimated prevalence of 0.9 to 1.6 per million individuals and an annual incidence of 1.4 to 2.6 per million live births. It is caused by a mutation in the RET proto-oncogene and is characterized by the presence of medullary thyroid carcinoma (MTC) in 100% of cases, pheochromocytoma in up to 50%, and extraendocrine features such as a marfanoid phenotype, musculoskeletal and dental abnormalities, mucosal neuromas, alacrimia, and diffuse intestinal ganglioneuromatosis with symptoms of esophageal and gastrointestinal dysmotility. This syndrome is associated with a diminished quality of life and poor survival, primarily due to the aggressiveness of MTC, which often presents at an early or metastatic stage. Diagnosis is often delayed, resulting in a delayed comprehensive approach that includes genetic profiling, early surgical management of MTC, and specific therapies such as tyrosine kinase inhibitors (TKIs) for advanced MTC. Surgery remains the mainstay and the only potential cure, although the advent of targeted therapies appears to improve progression-free survival in advanced cases.

Background: Patients with metastatic medullary thyroid cancer (MTC) who progressed under tyrosine kinase inhibitors can benefit from an alkylating agent such as dacarbazine or temozolomide. Patient Findings: We describe two patients with metastatic MTC who developed a hypermutant phenotype after alkylating agent treatment. This phenotype was characterized by a high tumor mutational burden (TMB) and a mutational signature indicative of alkylating agent mutagenesis (single-base substitution 11). Both patients received immune checkpoint inhibitors, with partial morphological responses, clinical benefit, and progression-free survival of 6 and 9 months, respectively. Summary and Conclusions: Based on the described observations, we suggest that a hypermutant phenotype may be induced after alkylating agent treatment for MTC and the sequential use of immunotherapy should be further explored as a treatment option for MTC patients with increased TMB. [ABSTRACT FROM AUTHOR]

Purpose: Concurrence of medullary and papillary thyroid carcinoma (MTC and PTC) represents less than 1% of all thyroid malignancies. We aimed to reveal the demographic and clinical characteristics of this rare pathology and to evaluate the effect of the same or contralateral lobular localization of these two malignancies in clinical and laboratory features. Evaluation of progression-free survival (PFS) in current pathology is one of the important features of our study. Methods: All patients diagnosed with simultaneous MTC and PTC after thyroidectomy were evaluated retrospectively. Data on the following variables were recorded: age, gender, tumor localization (ipsilateral lobe located MTC and PTC-Group I, contralateral lobe located MTC and PTC-Group II), tumor size, cervical lymph node metastasis, distant metastasis, tumor stage, postoperative basal calcitonin, carcinoembryonic antigen, thyroglobulin (Tg), and anti-Tg values. In all our cases, since MTC progressed before PTC, progression was accepted as serum calcitonin values exceeded 150 pg/mL. Results: Groups were formed as follows: Group I, four cases where MTC and PTC were localized in different foci in the same lobe; Group II, nine cases where they were localized in different lobes. There was only one case in which two tumors were located in the same focus. The case with dual differentiation was included in Group I (35. 7%). When the PFS of the two groups were compared, no statistically significant difference was found (P = 0.87). Conclusions: As a result of this analysis, the location of the simultaneously detected PTC in the same or different lobes with the MTC does not make a significant difference in clinical and laboratory features. [ABSTRACT FROM AUTHOR]

Recently, selpercatinib, a highly selective inhibitor of RET receptor tyrosine kinase, has been used for RET-altered thyroid cancer. We present four cases of patients with advanced thyroid cancer who were treated with selpercatinib. The first patient was a 63-year-old male with advanced medullary thyroid cancer (MTC) treated with vandetanib. Six months ago, he had an intracranial hemorrhage and swallowing difficulty. He started selpercatinib with percutaneous endoscopic gastrostomy (PEG). For 11 months, a partial response (PR) was observed stably with PEG administration without any more cardiovascular events. The second patient was a 67-year-old female with advanced MTC treated with vandetatib. After selpercatinib treatment, a PR was observed for most metastatic sites, including choroidal metastasis. The third patient was a 32-year-old female with advanced papillary thyroid cancer (PTC) without history of systematic treatment. For six months, a PR was observed at her metastatic site with manageable adverse events. The last patient was a 59-year-old female with advanced PTC treated with lenvatinib. She suffered from a panic disorder and pleural pain due to metastasis during lenvatinib treatment. After selpercatinib treatment, her pain and panic symptoms were improved. Facing varying clinical obstacles of the real world, selpercatinib safely proved remarkable therapeutic efficacy regardless of previous treatment or metastatic site.

Brain metastases (BM) in patients with thyroid cancer (TC) are rare with an incidence of 1% for papillary and follicular, 3% for medullary and up to 10% for anaplastic TC (PTC, FTC, MTC and ATC). Little is known about the characteristics and management of BM from TC. Thus, we retrospectively analyzed patients with histologically verified TC and radiologically verified BM identified from the Vienna Brain Metastasis Registry. A total of 20/6074 patients included in the database since 1986 had BM from TC and 13/20 were female. Ten patients had FTC, 8 PTC, one MTC and one ATC. The median age at diagnosis of BM was 68 years. All but one had symptomatic BM and 13/20 patients had a singular BM. Synchronous BM at primary diagnosis were found in 6 patients, while the median time to BM diagnosis was 13 years for PTC (range 1.9–24), 4 years for FTC (range 2.1–41) and 22 years for the MTC patient. The overall survival from diagnosis of BM was 13 months for PTC (range 1.8–57), 26 months for FTC (range 3.9–188), 12 years for the MTC and 3 months for the ATC patient. In conclusion, development of BM from TC is exceedingly rare and the most common presentation is a symptomatic single lesion. While BM generally constitute a poor prognostic factor, individual patients experience long-term survival following local therapy. [ABSTRACT FROM AUTHOR]

Non-clear cell renal cell carcinoma (nccRCC) is an entity comprised of a heterogeneous constellation of RCC subtypes. Genomic profiling has broadened our understanding of molecular pathogenic mechanisms unique to individual nccRCC subtypes. To date, clinical trials evaluating the use of immunotherapies and targeted therapies have predominantly been conducted in patients with clear cell histology. A comprehensive review of the literature has been undertaken in order to describe molecular pathogenic mechanisms pertaining to each nccRCC subtype, and concisely summarise findings from therapeutic trials conducted in the nccRCC space.

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Simple Summary: Recently, selpercatinib, a highly selective inhibitor of RET receptor tyrosine kinase, has been used for RET-altered thyroid cancer. However, real-world data of its effectiveness and safety in various clinical situations are lacking. We present four cases of patients with advanced thyroid cancer who were treated with selpercatinib with variable clinical situations. Selpercatinib showed good efficacy in all four patients without significant side effects. Despite facing varying clinical obstacles of the real world, selpercatinib safely proved remarkable therapeutic efficacy, although drug safety and durability through long-term use should be further validated. Recently, selpercatinib, a highly selective inhibitor of RET receptor tyrosine kinase, has been used for RET-altered thyroid cancer. We present four cases of patients with advanced thyroid cancer who were treated with selpercatinib. The first patient was a 63-year-old male with advanced medullary thyroid cancer (MTC) treated with vandetanib. Six months ago, he had an intracranial hemorrhage and swallowing difficulty. He started selpercatinib with percutaneous endoscopic gastrostomy (PEG). For 11 months, a partial response (PR) was observed stably with PEG administration without any more cardiovascular events. The second patient was a 67-year-old female with advanced MTC treated with vandetatib. After selpercatinib treatment, a PR was observed for most metastatic sites, including choroidal metastasis. The third patient was a 32-year-old female with advanced papillary thyroid cancer (PTC) without history of systematic treatment. For six months, a PR was observed at her metastatic site with manageable adverse events. The last patient was a 59-year-old female with advanced PTC treated with lenvatinib. She suffered from a panic disorder and pleural pain due to metastasis during lenvatinib treatment. After selpercatinib treatment, her pain and panic symptoms were improved. Facing varying clinical obstacles of the real world, selpercatinib safely proved remarkable therapeutic efficacy regardless of previous treatment or metastatic site. [ABSTRACT FROM AUTHOR]

Non-clear cell renal cell carcinoma (nccRCC) is an entity comprised of a heterogeneous constellation of RCC subtypes. Genomic profiling has broadened our understanding of molecular pathogenic mechanisms unique to individual nccRCC subtypes. To date, clinical trials evaluating the use of immunotherapies and targeted therapies have predominantly been conducted in patients with clear cell histology. A comprehensive review of the literature has been undertaken in order to describe molecular pathogenic mechanisms pertaining to each nccRCC subtype, and concisely summarise findings from therapeutic trials conducted in the nccRCC space. [ABSTRACT FROM AUTHOR]

Little is known about nationwide practice patterns for the management medullary thyroid cancer (MTC) in relation to the 2015 American Thyroid Association guidelines and their impact on survival. Using the Surveillance, Epidemiology, and End Results Program database (2000-2018), MTC treatment patterns were evaluated in terms of adherence to the 2015 American Thyroid Association guidelines across three time periods (2000-2009, 2010-2015, and 2016-2018). Outcomes of interest were guideline concordance, treatment utilization trends, disease-specific survival (DSS), and overall survival (OS). A total of 3332 patients with MTC were identified. Of which, 53.8%, 33.2%, and 11.4% of patients had localized, regional, and distant disease, respectively. In patients with locoregional disease, the rate of guideline-concordant surgery improved over time from 63.0% in 2000-2009 to 76.0% in 2016-2018 (P < 0.001). Guideline-concordant care was associated with increased OS (HR = 1.85, 95% CI: 1.42-2.43, P < 0.001) in patients with localized disease and increased DSS (HR = 1.65, 95% CI: 1.01-2.54, P < 0.001) and OS (HR = 1.89, 95% CI: 1.35-2.58, P < 0.001) in patients with regional disease. The median OS and DSS in patients with distant disease were 31 and 55 mo, respectively, and the rate of chemotherapy use rose from 21.6% to 39.2% (P = 0.003). The rate of guideline-concordant surgery for locoregional MTC increased after guideline publication in 2015, with an observed prolongment in OS and DSS. Chemotherapy use among patients with distant disease has increased over time, but their prognosis remains variable. [ABSTRACT FROM AUTHOR]

Purpose: Vandetanib is well-tolerated in patients with advanced medullary thyroid carcinoma (MTC). Long-term outcomes and mechanisms of MTC progression have not been reported previously.Experimental Design: We monitored toxicities and disease status in patients taking vandetanib for hereditary, advanced MTC. Tumor samples were analyzed for molecular mechanisms of disease progression.Results: Seventeen patients [8 male, age 13 (9-17)* years] enrolled; 16 had a RET p.Met918Thr germline mutation. The duration of vandetanib therapy was 6.1 (0.1-9.7+)* years with treatment ongoing in 9 patients. Best response was partial response in 10, stable disease in 6, and progressive disease in one patient. Duration of response was 7.4 (0.6-8.7+)* and 4.9 (0.6-7.8+)* years in patients with PR and SD, respectively. Six patients died 2.0 (0.4-5.7)* years after progression. Median progression-free survival (PFS) was 6.7 years [95% confidence interval (CI): 2.3 years-undefined] and 5-year overall survival (OS) was 88.2% (95% CI: 60.6%-96.9%). Of 16 patients with a RET p.Met918Thr mutation, progression-free survival was 6.7 years (95% CI: 3.1-undefined) and 5-year overall survival was 93.8% (95% CI: 63.2%-99.1%). No patients terminated treatment because of toxicity. DNA sequencing of tissue samples (n = 11) identified an increase in copy number alterations across the genome as a potential mechanism of drug resistance [*median (range)].Conclusions: This study demonstrates that vandetanib is safe and results in sustained responses in children and adolescents with hereditary MTC. Our preliminary molecular data suggest that an increase in copy number abnormalities may be associated with tumor progression in hereditary MTC patients treated with vandetanib. Clin Cancer Res; 24(4); 753-65. ©2017 AACR.

BACKGROUND: Medullary thyroid carcinoma is a rare tumor and represents less than 5% of all thyroid cancers. Tumor size and the presence of possible metastases are strictly related to serum calcitonin level, which also suggests prognosis. A serum calcitonin level above the normal range is highly suspicious for medullary cancer. This tumor has no characteristic patterns on ultrasound and fine-needle aspiration, so serum calcitonin level is the only significant element for diagnosis. The literature contains 47 cases of serum calcitonin-negative medullary thyroid cancer with heterogeneous behavior, ranging from non-aggressive to aggressive form. CASE REPORT: We report a rare case of a young man with negative serum calcitonin but with lateral cervical node metastases from medullary thyroid carcinoma. At the beginning, diagnosis was not achieved due to normal range of serum calcitonin and a negative thyroid ultrasonography for large nodules. Nevertheless, in another medical center he underwent a neck biopsy of the lateral cervical mass. The histologic findings showed metastases of medullary thyroid cancer. Therefore, a total thyroidectomy plus cervical lymphadenectomy was performed. During the follow-up, due to unusefulness of serum markers, and as CEA levels were negative pre- and post-operatively, an ¹⁸F-DOPA PET scan was performed. In 3 years of follow-up, there is still no evidence of disease relapse. CONCLUSIONS: Our case shows how a normal serum level of calcitonin cannot exclude medullary thyroid cancer. Early diagnosis is crucial because it influences appropriate surgical therapy and patient outcome. The current lack of an optimal strategy for the diagnosis and postoperative follow-up for patients with negative serum calcitonin tumor presents a diagnostic challenge for physicians. [ABSTRACT FROM AUTHOR]

Gastric carcinomas consist of a heterogeneous group of neoplasms with broad cytological and architectural variations. Gastric carcinomas with lymphoid stroma show poor correlation between their histomorphology and biological behavior. This contrast causes a need for more detailed analysis and molecular exploration of lymphoid stroma-rich gastric carcinomas with medullary like features and lack of glandular differentiation. In this study, we performed a detailed retrospective analysis of 53 gastric carcinomas among 654 gastric tumors from surgical resection specimens, all of which had no prominent glandular differentiation. Morphological and clinical data were compared with immunohistochemistry (MLH1, PMS2, MSH2 and MSH6 for mismatch repair mechanism deficiency; CD2, CD8 and CD163 for immune infiltration; and PD-1, PD-L1, LMP-1, ERBB2 and ki-67) besides EBER in situ hybridization and molecular studies (PCR based microsatellite instability and BRAF V600E mutation analysis). Morphological, immunohistochemical and molecular findings lead us to classify lymphoid stroma–rich advanced gastric carcinomas (n = 40/53) into two distinct entities originating from two different pathogenetic pathway: one is gastric carcinomas revealing predominantly medullary type morphology with defective DNA mismatch repair mechanism (n = 30/53) and the other is EBV associated carcinomas (n = 10/53). In addition, we suggest that biomarker based classification algorithms besides morphological evaluation are necessary to identify these two entities. Distinguishing these entities is crucial to apply different treatment strategies, including alternative treatments such as immunotherapy. [ABSTRACT FROM AUTHOR]

Sporadic or hereditary medullary thyroid carcinoma (MTC) is an uncommon thyroid malignancy arising from calcitonin secreting parafollicular C cells. Interestingly, MTC and calcitonin were distinct entities that were discovered independently yet concurrently, and their association was unknown. This review aims to present a historical review of the evolution of our understanding of MTC and its tumor marker calcitonin to highlight the prominent individuals that influenced and shaped our knowledge of this uncommon thyroid cancer type up to the dawn of the 21st century. An overview of all published reports of novel research and work summarizing important findings for MTC and calcitonin was carried out. Surgery remains the cornerstone of treatment for localized MTC. However, several new treatment options are either available or in development for advanced or metastatic MTC, including several novel small molecules targeting oncogenic RET and peptide receptor radionuclide therapy, immunotherapy, radioimmunotherapy, and radiofrequency ablation. In the near future, these novel treatments hold promise for therapy of this very distinct thyroid cancer type. [ABSTRACT FROM AUTHOR]

Medullary thyroid carcinoma (MTC) is a rare neuroendocrine tumor originating from the parafollicular cells. The diagnostic and therapeutic strategies for the condition are different from those used for well-differentiated thyroid cancer. Since the 2015 American Thyroid Association guidelines for the diagnosis and treatment of MTC, the latest, including the National Comprehensive Cancer Network and European Association for Medical Oncology guidelines have been updated to reflect several recent advances in the management of MTC. Advances in molecular diagnosis and postoperative risk stratification systems have led to individualized treatment and follow-up strategies. Multi-kinase inhibitors, such as vandetanib and cabozantinib, can prolong disease progression-free survival with favorable adverse effects. In addition, potent selective rearranged during transfection (RET) inhibitors (selpercatinib and pralsetinib) have shown a promising efficacy in recent clinical trials. This review summarizes the management of MTC in recent guidelines focused on sporadic MTC.

BackgroundPrimary analysis of the double-blind, phase III Efficacy of XL184 (Cabozantinib) in Advanced Medullary Thyroid Cancer (EXAM) trial demonstrated significant improvement in progression-free survival with cabozantinib versus placebo in patients with progressive medullary thyroid cancer (MTC). Final analysis of overall survival (OS), a key secondary endpoint, was carried out after long-term follow-up.Patients and methodsEXAM compared cabozantinib with placebo in 330 patients with documented radiographic progression of metastatic MTC. Patients were randomized (2:1) to cabozantinib (140 mg/day) or placebo. Final OS and updated safety data are reported.ResultsMinimum follow-up was 42 months. Kaplan-Meier analysis showed a 5.5-month increase in median OS with cabozantinib versus placebo (26.6 versus 21.1 months) although the difference did not reach statistical significance [stratified hazard ratio (HR), 0.85; 95% confidence interval (CI), 0.64-1.12; P = 0.24]. In an exploratory assessment of OS, progression-free survival, and objective response rate, cabozantinib appeared to have a larger treatment effect in patients with RET M918T mutation-positive tumors compared with patients not harboring this mutation. For patients with RET M918T-positive disease, median OS was 44.3 months for cabozantinib versus 18.9 months for placebo [HR, 0.60; 95% CI, 0.38-0.94; P = 0.03 (not adjusted for multiple subgroup analyses)], with corresponding values of 20.2 versus 21.5 months (HR, 1.12; 95% CI, 0.70-1.82; P = 0.63) in the RET M918T-negative subgroup. Median treatment duration was 10.8 months with cabozantinib and 3.4 months with placebo. The safety profile for cabozantinib remained consistent with that of the primary analysis.ConclusionThe secondary end point was not met in this final OS analysis from the trial of cabozantinib in patients with metastatic, radiographically progressive MTC. A statistically nonsignificant increase in OS was observed for cabozantinib compared with placebo. Exploratory analyses suggest that patients with RET M918T-positive tumors may experience a greater treatment benefit with cabozantinib.Trial registration numberNCT00704730.

BackgroundMultiple endocrine neoplasia type 2 is an autosomal dominant inherited syndrome caused by activating mutations in the RET proto-oncogene. The RETK666N DNA variant was previously reported in two isolated medullary thyroid carcinoma (MTC) cases, but no family studies are available, and its oncogenic significance remains unknown.MethodsThe clinical features, genetic data, and family information of eight index MTC patients with a germline RETK666N variant were assessed.ResultsFour probands presented with MTC and extensive nodal metastasis, one with biopsy-confirmed distant metastasis. Two additional probands presented with localized disease. However, nodal status was not available. Of the final two probands, one had an incidental 1.5 mm MTC and C-cell hyperplasia uncovered after surgery for papillary thyroid carcinoma, and one had two foci of MTC (largest dimension 2.3 cm) detected after surgery for dysphagia. Genetic screening identified 16 additional family members carrying the K666N variant (aged 5-90 years), 11 of whom have documented evaluation for MTC. Of these, only two were found to have elevated basal serum calcitonin upon screening, and the remaining patients had calcitonin levels within the reference range. One patient who elected to have a thyroidectomy at 70 years of age was confirmed to have MTC. The other subject, 57 years old, elected surveillance. Four prophylactic thyroidectomies were performed, with one case of C-cell hyperplasia at 20 years and three cases that revealed normal pathology at ages 21, 30, and 30 years. None of the K666N DNA variant carriers had evidence of primary hyperparathyroidism or pheochromocytoma.ConclusionsFrom this case series, the largest such experience to date, it is concluded that the RETK666N variant is likely pathogenic and associated with low penetrance of MTC. However, the findings are insufficient to define its pathogenicity clearly and make firm recommendations for screening and treatment. Given the potential benefit associated with early detection of aberrant C-cell growth, and the noninvasive nature of genetic testing, "at risk" individuals should be screened, and if the K666N variant is identified, they should be managed using a personalized screening approach for detection of MTC.

Many authors recommend the measurement of serum calcitonin (Ctn) to screen for sporadic medullary thyroid carcinoma (MTC) in patients with thyroid nodules. In this situation, procalcitonin (pro-Ctn) would have greater utility in patients with hypercalcitoninemia<100 pg/ml. The aim of this study was to evaluate the utility of pro-Ctn in patients with thyroid nodules and without a suspicion of familial MTC or type 2 multiple endocrine neoplasia who had mild or moderate hypercalcitoninemia without an apparent cause. Consecutive patients with nodular thyroid disease assessed routinely by Ctn measurement were selected. Sixty patients with basal Ctn>10 pg/ml but<100 pg/ml were included. Nine patients (15%) had MTC, with cytology being diagnostic in only four. Among the 51 patients without MTC, pro-Ctn was<0.1 ng/ml in 46 (90.2%). All patients with MTC had pro-Ctn>0.1 ng/ml. Basal Ctn was>24.6 pg/ml in all patients with MTC and in 42 patients (82.3%) without MTC. It is noteworthy that among patients with basal Ctn>24.6 pg/ml (n=18) pro-Ctn>0.1 ng/ml identified all patients with MTC and 64.2% of subjects with these pro-Ctn concentrations had this tumor. In conclusion, we did not find superiority of pro-Ctn over Ctn for the diagnosis of sporadic MTC in patients with nodular disease and mild or moderate hypercalcitoninemia. However, in the case of patients with hypercalcitoninemia in the gray zone, pro-Ctn has an excellent negative predictive value while the data regarding its positive predictive value are not uniform. [ABSTRACT FROM AUTHOR]

Background Thyroid cancer is becoming increasingly common worldwide, but little is known about the epidemiology of medullary thyroid carcinoma (MTC). This study investigated the current status of the incidence and treatment of MTC using Korean National Health Insurance Service (NHIS) data for the entire Korean population from 2004 to 2016. Methods This study included 1,790 MTC patients identified from the NHIS database. Results The age-standardized incidence rate showed a slightly decreasing or stationary trend during the period, from 0.25 per 100,000 persons in 2004 to 0.19 in 2016. The average proportion of MTC among all thyroid cancers was 0.5%. For initial surgical treatment, 65.4% of patients underwent total thyroidectomy. After surgery, external-beam radiation therapy (EBRT) was performed in 10% of patients, a proportion that increased from 6.7% in 2004 to 11.0% in 2016. Reoperations were performed in 2.7% of patients (n=49) at a median of 1.9 years of follow-up (interquartile range, 1.2 to 3.4). Since November 2015, 25 (1.4%) patients with MTC were prescribed vandetanib by December 2016. Conclusion The incidence of MTC decreased slightly with time, and the proportion of patients who underwent total thyroidectomy was about 65%. EBRT, reoperation, and tyrosine kinase inhibitor therapy are additional treatments after initial surgery for advanced MTC in Korea.

Myeloid sarcoma (MS) in the setting of concomitant medullary AML is relatively well described, while much less is known about patients presenting with MS with <20% bone marrow blasts. We conducted a retrospective analysis of 56 patients with MS with <20% marrow blasts seen at MD Anderson between 2005 and 2020. The prevalence of MS without medullary AML was 1.4% among all newly diagnosed AML patients. The majority (75%) of patients had a single known anatomic site involved, with the skin (34%) being the most frequent. The most common histologic subtype was monocytic, and 11% of patients had a known history of an antecedent hematologic disorder. The majority of patients (70%) received frontline intensive chemotherapy induction, with 75% of those evaluable attaining complete or partial responses. The median overall survival (OS) and event-free survival (EFS) were 3.41 and 3.07 years, respectively. Patients with bone marrow blasts of ≥5% or medullary relapse had inferior outcomes, while age (>60 years) was not associated with outcomes. There was a suggestion that patients with isolated leukemia cutis may have had better outcomes compared to patients with other organ involvement, but this did not reach statistical significance. Most patients who had cytogenetic analysis had a diploid karyotype within their MS and bone marrow. RAS pathway mutations were enriched in MS at diagnosis, and at time of medullary relapse. Our study provides a large dataset summarizing the clinical and molecular analysis of patients with MS with <20% BM blasts and suggests that monitoring for medullary leukemia is important for early detection of relapse. [ABSTRACT FROM AUTHOR]

Medullary thyroid carcinoma (MTC) is a rare neuroendocrine tumor of parafollicular C cells. The majority of MTCs occur sporadically, but about 30% of the cases are associated with multiple endocrine neoplasia type 2 (MEN2) syndrome or familial MTC. Generally, MTCs have no clinical manifestation, but infrequently the patients develop symptoms of hypercortisolism by secreting adrenocorticotropic hormone (ACTH) or corticotropin-releasing hormone (CRH). Although ectopic Cushing syndrome is only found in 0.7% of MTC patients, it can lead to fatal consequences if left untreated. Over 50 cases of MTC-related Cushing syndrome have been reported, and few autopsy cases exist in the literature. In those cases, the tumor cells are positive for calcitonin, but mostly display negative immunostaining for ACTH or CRH. The authors report an autopsy case of a 22-year-old woman who was found dead with no medical history whose cause of death was diabetic ketoacidosis associated with MTC, which showed poor calcitonin stainability. [ABSTRACT FROM AUTHOR]

Abstract Medullary thyroid carcinoma (MTC) accounts up to 10% of all thyroid cancers, but is responsible for a disproportionate number of deaths. While surgery is the only curative treatment for MTC, indications for lateral neck lymph node (LLN) dissection are controversial. We performed a retrospective review to describe clinical outcomes in 93 MTC patients from July 1995 to March 2015. We analyzed their clinicopathologic factors, and cut‐off values of tumor size and calcitonin levels were calculated using a receiver operating characteristic curve. Using the instances of lymph node metastases, the tumor size cut‐off value was 0.95 cm (area under curve, AUC = 0.697) in patients with ipsilateral central lymph node (CLN) metastases, 2.25 cm (AUC = 0.793) in contralateral CLN metastases, and 1.75 cm (AUC = 0.753) in ipsilateral LLN metastases. The cut‐off values of preoperative calcitonin levels were 226.6 pg/mL (AUC = 0.746) in ipsilateral CLN, 755.0 pg/mL (AUC = 0.840) in contralateral CLN metastases, and 237.0 pg/mL (AUC = 0.775) in ipsilateral LLN metastases. This study supports the notion that ipsilateral LLN metastases occur before contralateral CLN metastases. Therefore, ipsilateral LLN dissection should be considered in patients with contralateral CLN metastases. The extent of surgery should be based on the status of LN metastases, preoperative basal calcitonin level, and tumor size to help individualize the extent of surgery.

Medullary thyroid cancer (MTC) is a relatively rare thyroid malignancy, constituting a small percentage of all thyroid cancer cases. Even more rare is the occurrence of mixed MTC and papillary thyroid cancer (PTC), found in a very small fraction of MTC cases. These cancers originate from different cell types with distinct developmental origins. The coexistence of MTC and PTC in the same patient raises questions about whether this occurrence is merely coincidental or if there is an underlying genetic link. We present the case of a woman with metastatic mixed MTC and PTC. A 61-year-old woman with a history of Hashimoto's disease was found to have bilateral thyroid nodules; the largest (1.7 cm) was in the right lobe. This nodule met fine needle aspiration (FNA) biopsy criteria and was found to have a follicular neoplasm of undetermined significance. The patient elected to pursue total thyroidectomy instead of lobectomy given the presence of bilateral nodules. Postoperative pathology showed mixed medullary carcinoma (pT3b) and follicular variant papillary thyroid microcarcinoma (pT1a) involving the right lobe with positive anterior and posterior margins and lymphovascular invasion. Preoperative calcitonin was not checked. However, post-thyroidectomy calcitonin was 1599 pg/mL. She underwent central and right lateral neck dissection which showed 27 out of 35 lymph nodes were positive for malignancy. Postoperative calcitonin dropped to 38.7 pg/mL. She then established care in our endocrine clinic. Screening for pheochromocytoma and primary hyperparathyroidism was normal. She underwent external beam radiation of the neck. A year after her initial surgery, her neck ultrasound and computed tomography (CT) studies show no signs of local or distant anatomic recurrence. Her thyroglobulin level remains undetectable, carcinoembryonic antigen (CEA) within normal range, and calcitonin stable at about 20 pg/mL. She is on levothyroxine 100 mcg daily with thyroid-stimulating hormone (TSH) at a suppression goal of <0.1 mIU/L. Mixed PTC and MTC is poorly studied due to its rarity. The origin of these mixed tumors is unclear, but some suggest that they arise from neoplastic changes of remnant multipotent cells in the thyroid. While patients with PTC often have a favorable prognosis following surgical therapy, MTC has a more aggressive course. We suggest monitoring patients like ours for both MTC and PTC, as if present in isolation. Our case highlights the clinical aspects of this condition and our current knowledge of its pathophysiology., Competing Interests: Human subjects: Consent was obtained or waived by all participants in this study. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Alshaakh Mohd Mari et al.)

Multiple endocrine neoplasia (MEN) syndromes are rare autosomal dominant diseases that are associated with a mixture of both endocrine and non-endocrine tumors. Traditionally, there are 2 types of MEN that have unique clinical associations: MEN 1 (parathyroid hyperplasia, pancreatic neuroendocrine tumors, and pituitary tumors) and MEN 2 (medullary thyroid carcinoma and pheochromocytoma), which is further classified into MEN 2A (adds parathyroid adenomas) and 2B (adds ganglioneuromas and marfanoid habitus). Many of the endocrine tumors are resected surgically, and the pre, intra, and postoperative management strategies used must take into account the high recurrence rates asscioated with MEN tumors., Competing Interests: Disclosure C.C. Frye reports that he and his wife own equity in Neurocrine Biosciences and OpComm Solutions, Inc and that he serves as a Director for OpComm Solutions, Inc (neither of these companies are related to this project). The remaining authors report no disclosures., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Objective: To determine the rate of nodal metastasis in dogs with thyroid cancer and evaluate whether immunohistochemistry (IHC) identifies additional metastases beyond evaluation with H&E., Animals: 70 prospectively enrolled client-owned dogs with thyroid cancer managed with thyroidectomy., Methods: Dogs underwent thyroidectomy with concurrent elective bilateral medial retropharyngeal (MRP) ± deep cervical lymphadenectomy. Thyroid tumors and associated lymph nodes were reviewed by a single board-certified pathologist. Immunohistochemistry was used for all primary tumors (thyroid transcription factor-1 and calcitonin) to support a diagnosis of follicular or medullary carcinoma. Lymph nodes without evidence of metastasis after H&E review were labeled with the antibody associated with the wider uptake in the primary tumor., Results: 77 thyroid cancers were resected from the 70 dogs enrolled, including 61 (79.2%) follicular, 8 (10.7%) medullary, and 7 (9.3%) mixed follicular/medullary carcinomas, with 1 (1.3%) carcinosarcoma. Twelve dogs had evidence of nodal metastasis following H&E review. Occult micrometastasis was identified in 1 dog following nodal IHC, resulting in documented metastasis in 13 of 70 (18.6%) dogs. Metastasis was more common with medullary (5/8) and follicular/medullary carcinoma (3/7) than follicular carcinoma (5/61). All MRP metastases were ipsilateral (7/77 [9.1%]), without contralateral MRP metastases (0/62). Fourteen of 41 (34.1%) deep cervical lymph nodes were metastatic., Clinical Relevance: Nodal metastasis was uncommon for follicular carcinoma but was seen in > 50% of dogs with thyroid cancer involving a medullary component. Routine nodal IHC appears to be low yield for thyroid carcinoma. Extirpation of ipsilateral MRP and identifiable deep cervical lymph nodes is recommended with thyroidectomy until detailed preoperative risk stratification becomes available.

Purpose: Ultrasound (US) is the most important imaging in the preoperative diagnosis of medullary thyroid carcinoma (MTC). MTC are easy to be misdiagnosed due to lacking typical malignant US features. This study investigated US features, clinical characteristics, prognosis, and detection methods, aimed to explore the association between US features and biological behavior, and improve early diagnosis of MTC. Methods: A total of 189 MTC patients were enrolled in the study. Based on US features, 29 MTC were categorized as "indeterminate" (i-MTC) and 160 MTC were categorized as "malignant" (m-MTC) according to Thyroid Imaging, Reporting and Data System published by America College of Radiology (ACR TI-RADS). We compared US features, clinical characteristics and prognosis between both groups. We analyzed cytological categories of fine needle aspiration (FNA) within each i-MTC and m-MTC group according to the 2017 Bethesda System for Reporting Thyroid Cytopathology (TBSRTC). We assessed the positive rate of FNA, frozen pathological examination, and preoperative serum calcitonin (Ctn) level in i-MTC and m-MTC groups. Results: Preoperative US features were significantly different in shape, margin, composition, echogenicity, and calcifications between i-MTC and m-MTC (p < 0.05). I-MTC showed a hypoechoic solid or solid-cystic nodule lacking malignant US features. While m-MTC was presented as a solid nodule with obviously malignant US features. There were significant differences in lymph node dissection, extent of tumor, lymph node metastasis, and TNM stage and prognosis between i-MTC and m-MTC (p < 0.05). Compared to m-MTC, i-MTC underwent central neck dissection more frequently rather than lateral neck dissection at the time of the initial operation; i-MTC had less extrathyroidal invasion and lymph node metastasis, earlier stage, higher rate of biochemical cure, and lower rate of structural persistence/recurrence (p < 0.05). The 2017 TBSRTC of i-MTC and m-MTC was significantly different (p < 0.05). Preoperative serum Ctn level had a higher diagnostic sensitivity for both i-MTC and m-MTC when comparing to FNA and frozen pathological examination (p < 0.05). Conclusions: US features were associated with biological characteristics and prognosis of MTC. I-MTC lack malignant US features, preformed less aggressiveness, and better prognosis. TBSRTC according to FNA combined with serum Ctn were helpful for the detection of i-MTC. [ABSTRACT FROM AUTHOR]

Thyroid imaging reporting and data systems (TIRADS) are used to stratify the malignancy risk of thyroid nodule by ultrasound (US) examination. We conducted a meta-analysis to evaluate the pooled cancer prevalence and the relative prevalence of papillary, medullary, follicular thyroid cancer (PTC, MTC, and FTC) and other malignancies among nodules included in studies evaluating their performance. Four databases were searched until February 2020. Original articles with at least 1000 nodules, evaluating the performance of at least one TIRADS among AACE/ACE/AME, ACR-TIRADS, ATA, EU-TIRADS, or K-TIRADS, and reporting data on the histological diagnosis of malignant lesions were included. The number of malignant nodules, PTC, FTC, MTC and other malignancies in each study was extracted. For statistical pooling of data, a random-effects model was used. Nine studies were included, evaluating 19,494 thyroid nodules. The overall prevalence of malignancy was 34% (95%CI 21 to 49). Among 6162 histologically proven malignancies, the prevalence of PTC, FTC, MTC and other malignancies was 95%, 2%, 1%, and 1%, respectively. A high heterogeneity was found for all the outcomes. A limited number of studies generally conducted using a retrospective design was found, with possible selection bias. Acknowledging this limitation, TIRADSs should be regarded as accurate tools to diagnose PTC only. Proposed patterns and/or cut-offs should be revised and other strategies considered to improve their performance in the assessment of FTC, MTC and other malignancies. [ABSTRACT FROM AUTHOR]