{"title":"Hereditary Medullary Thyroid Cancer: Genotype-Phenotype Correlation.","authors":"Karin Frank-Raue, Friedhelm Raue","doi":"10.1007/978-3-031-80396-3_7","DOIUrl":"10.1007/978-3-031-80396-3_7","url":null,"abstract":"<p><p>Multiple endocrine neoplasia type 2 (MEN2) is an autosomal dominant hereditary cancer syndrome caused by germline variants in the REarranged during Transfection (RET) proto-oncogene. MEN2 is caused by autosomal dominant gain-of-function mutations in the RET proto-oncogene. There are two clinically distinct types of MEN2 syndrome, termed MEN2A and MEN2B. MEN2A is associated with medullary thyroid carcinoma (MTC) and the less frequent occurrence of pheochromocytoma, primary hyperparathyroidism, or both, rarely with cutaneous lichen amyloidosis or Hirschsprung's disease. MEN2B is associated with MTC, pheochromocytoma, and other noncancerous abnormalities, such as Marfanoid habitus and ganglioneuromas of the intestines. Specific RET mutations suggest a predilection toward a particular phenotype and clinical course with strong genotype-phenotype correlation. Based upon these genotype-phenotype correlations, RET mutations are stratified into three risk levels, i.e., highest, high, and moderate risk, based on the age of onset and the penetrance of the MTC. Children in the highest risk category develop MTC within the first year of life and should undergo thyroidectomy in their first year, perhaps even in their first months of life. In children in the high-risk category, ultrasound of the neck and calcitonin (Ctn) measurement should be performed prior to thyroidectomy. Thyroidectomy should typically be performed at 5 years of age or earlier, depending on the presence of elevated serum Ctn levels. However, heterogeneity in disease expression and progression within these groups varies considerably. To personalize disease management, the decision regarding the age of prophylactic thyroidectomy is no longer based upon genotype alone but is currently driven by additional clinical data, the most important being serum Ctn levels. In the moderate-risk group, the timing of thyroidectomy is particularly dependent on the Ctn level. Personalized management also includes decisions about the best age to begin biochemical screening for pheochromocytoma and primary hyperparathyroidism.</p>","PeriodicalId":39880,"journal":{"name":"Recent Results in Cancer Research","volume":"223 ","pages":"183-209"},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143659081","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
José Manuel Cameselle-Teijeiro, Manuel Sobrinho-Simões
{"title":"Histopathology of C Cells and Medullary Thyroid Carcinoma.","authors":"José Manuel Cameselle-Teijeiro, Manuel Sobrinho-Simões","doi":"10.1007/978-3-031-80396-3_2","DOIUrl":"10.1007/978-3-031-80396-3_2","url":null,"abstract":"<p><p>C cells are the neuroendocrine cell component of the thyroid gland that embryologically arise from the pharyngeal endoderm. Normal C cells are concentrated in the upper two-thirds of both lateral lobes, appear singly or in small groups dispersed in, among or peripherally to the follicles, and are involved in the production of calcitonin. Reactive C-cell hyperplasia should be differentiated from proliferation of atypical C cells (neoplastic C-cell hyperplasia) which is considered an intraepithelial neoplasia of C cells/medullary carcinoma in situ, a precursor lesion associated to familial medullary thyroid carcinoma (MTC). MTC typically exhibits a lobular and/or trabecular growth pattern with amyloid deposits; however, due to its great histological variability, immunohistochemical positivity for calcitonin, carcinoembryonic antigen, calcitonin-gene-related peptide, insulinoma-associated protein 1, and/or other markers is necessary to confirm diagnosis. Investigation of germline RET proto-oncogene mutation is mandatory to identify familial MTC. Somatic RET mutations or fusions as well as RAS mutations in cytological and/or biopsy samples may represent therapeutic targets. Mixed medullary and follicular-derived cell carcinoma is a heterogeneous group of tumors which needs to be distinguished from collision tumors.</p>","PeriodicalId":39880,"journal":{"name":"Recent Results in Cancer Research","volume":"223 ","pages":"9-50"},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143659085","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Primary Hyperparathyroidism in MEN2 Syndromes.","authors":"Katerina Saltiki, Maria Alevizaki","doi":"10.1007/978-3-031-80396-3_9","DOIUrl":"10.1007/978-3-031-80396-3_9","url":null,"abstract":"<p><p>One of the components of the classical form of MEN2 syndromes is primary hyperparathyroidism (PHP). It occurs in 20-30% of the typical MEN2A syndrome. Recently, the prevalence in ret gene carriers is rarer possibly due to the increased recognition of cases who have familial MTC only. PHP is diagnosed more frequently in association with the exon 11, 634 mutation of the ret gene-so there is phenotype/genotype correlation. The clinical manifestations of PHP in MEN2 are usually mild and the peak age of diagnosis is after the third decade. The treatment is surgical excision of the enlarged gland(s). Although there can be multigland disease in the parathyroids, it is frequently the case that both hyperplasia and adenoma may coexist, or even a single adenoma may be found during the investigation and finally during the operation. Patients with MEN2 syndromes should be screened for PHP with serum calcium measurements. The intensity of the screening should be higher in those carrying the ret mutations most frequently associated with this manifestation.</p>","PeriodicalId":39880,"journal":{"name":"Recent Results in Cancer Research","volume":"223 ","pages":"237-246"},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143659097","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"What Is New in Diagnostics and Management of Medullary Thyroid Carcinoma.","authors":"Friedhelm Raue, Karin Frank-Raue","doi":"10.1007/978-3-031-80396-3_1","DOIUrl":"10.1007/978-3-031-80396-3_1","url":null,"abstract":"<p><p>Medullary thyroid carcinoma (MTC) is a rare neoplasm originating from parafollicular C cells. It secretes calcitonin (Ctn), a highly sensitive and specific tumor marker, which allows for early diagnosis and defines postoperative cure or persistence/recurrence of MTC. Germline mutations in the RET proto-oncogene are responsible for the development of MTC in MEN2. Somatic RET mutations modify the behavior of MTC and are a target for systemic therapy with selective RET inhibitors. Recent advances in preoperative immunohistochemistry and molecular diagnostics in biopsies achieved by fine needle aspiration significantly improves diagnosis and allows classification in low and high risk MTC with important implications for treatment and prognosis. This personalized approach enables a less aggressive surgery in low risk MTC patients, reduces the incidence of complications and improves quality of life. Risk stratification in MEN2 patients based on genotype-phenotype correlation of the different RET mutations allows cure by personalized thyroidectomy. Postoperative imaging in patients with persistent or recurrent MTC with PET/CT using different radiopharmaceuticals proved to be sensitive and accurate in detecting MTC recurrences/metastases and assesses their biological and clinical aggressiveness. Molecular genetic classification of tumors enables personalized systemic therapies with multikinase inhibitors or selective RET inhibitors in patients with advanced metastasized and progressive disease. Despite the recent progress in diagnosis and treatment, confirmation of these new procedures and standardization of these approaches in MTC are required.</p>","PeriodicalId":39880,"journal":{"name":"Recent Results in Cancer Research","volume":"223 ","pages":"1-8"},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143659111","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Calcitonin as Biomarker for the Medullary Thyroid Carcinoma.","authors":"Yoon Ju Bae, Michael Schaab, Jüergen Kratzsch","doi":"10.1007/978-3-031-80396-3_6","DOIUrl":"10.1007/978-3-031-80396-3_6","url":null,"abstract":"<p><p>Calcitonin (CTN) is a polypeptide hormone consisting of 32 amino acids with a disulfide bridge between position 1 and 7 that is mainly produced by the C-cells of thyroid gland. The measurement of CTN concentrations in blood reflects C-cell activity and is performed in general by immunoassay methods. However, there are analytical, physiological, pharmacological, and pathological factors that can influence results of serum CTN values. Due to the influence of these factors there is a high variability in assay-dependent cutoffs used to discriminate between MTC, C-cell hyperplasia (CCH) and the absence of the pathological impairment of C cells. There is a lot of evidence that the measurement of serum CTN concentrations in patients with thyroid nodules can lead to an earlier diagnosis of MTC or CCH than the exclusive use of imaging procedures and/or fine needle aspiration cytology. Basal CTN concentrations higher than 60-100 pg/mL are highly indicative for the diagnosis MTC. In the range between cutoff and 60 pg/mL CTN, both MTC and HCC may be a relevant diagnosis. Procalcitonin (PCT) and CTN appear to have a comparable diagnostic capability to diagnose MTCs. However, \"positive\" PCT values more than 50 pg/mL may be reached also in subclinical infections and will lead, therefore, to an overdiagnosis of the tumor. Calcium-stimulated serum CTN concentrations higher than cutoff values could improve diagnostics of MTC but a lack of replicable cutoff values in different studies favors the use of only basal values, currently.</p>","PeriodicalId":39880,"journal":{"name":"Recent Results in Cancer Research","volume":"223 ","pages":"155-182"},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143659074","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Rozita Bagheri-Yarmand, Elizabeth G Grubbs, Marie-Claude Hofmann
{"title":"Thyroid C-Cell Biology and Oncogenic Transformation.","authors":"Rozita Bagheri-Yarmand, Elizabeth G Grubbs, Marie-Claude Hofmann","doi":"10.1007/978-3-031-80396-3_3","DOIUrl":"10.1007/978-3-031-80396-3_3","url":null,"abstract":"<p><p>The thyroid parafollicular cell, or commonly named \"C-cell,\" functions in serum calcium homeostasis. Elevations in serum calcium trigger release of calcitonin from the C-cell, which in turn functions to inhibit absorption of calcium by the intestine, resorption of bone by the osteoclast, and reabsorption of calcium by renal tubular cells. Oncogenic transformation of the thyroid C-cell is thought to progress through a hyperplastic process prior to malignancy with increasing levels of serum calcitonin serving as a biomarker for tumor burden. The discovery that Multiple Endocrine Neoplasia, type 2 is caused by activating mutations of the RET gene serves to highlight the RET-RAS-MAPK signaling pathway in both initiation and progression of medullary thyroid carcinoma. Thyroid C-cells are known to express RET at high levels relative to most cell types, therefore aberrant activation of this receptor is targeted primarily to the C-cell, providing one possible cause of tissue-specific oncogenesis. The role of RET signaling in normal C-cell function is unknown though calcitonin gene transcription appears to be sensitive to RET activation. Beyond RET the modeling of oncogenesis in animals and screening of human tumors for candidate gene mutations has uncovered mutation of RAS family members and inactivation of RB1 regulatory pathway as potential mediators of C-cell transformation. More recently, the integration of multiple biological layers of omics studies has uncovered new pathways of oncogenesis. A growing understanding of how RET interacts with these pathways, both in normal C-cell function and during oncogenic transformation, will help in the development of novel molecular targeted therapies.</p>","PeriodicalId":39880,"journal":{"name":"Recent Results in Cancer Research","volume":"223 ","pages":"51-91"},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13063308/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143659109","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Surgical Treatment of Medullary Thyroid Cancer.","authors":"Andreas Machens, Henning Dralle","doi":"10.1007/978-3-031-80396-3_10","DOIUrl":"10.1007/978-3-031-80396-3_10","url":null,"abstract":"<p><p>Medullary thyroid cancer (MTC) is an infrequent calcitonin-secreting thyroid malignancy that can vary a great deal in tumor biology and progression. The most important determinant of distant metastases, which represents the single greatest risk factor of poor cancer-specific survival, is lymph node metastasis in the neck and mediastinum. In patients with node-positive MTC, systematic compartment-oriented dissection of central and lateral neck nodes at the initial operation promotes biochemical cure and decreases the risk of locoregional recurrence in previously dissected lymph node compartments. Routine calcitonin screening in nodular thyroid disease and genomic screening, flanked by advances in ultrasound and functional imaging modalities, have been pivotal in making the diagnosis early and enabling risk-reducing surgical interventions in patients with sporadic and hereditary MTC, without compromising clinical outcome. To assess a RET carrier's risk of medullary thyroid cancer, all that is needed is patient age, underlying RET mutation, and biomarker levels. Recently, risk-reducing surgery, consisting in hemithyroidectomy with or without diagnostic ipsilateral central lymph node dissection, has been advocated for sporadic MTC clinically confined to one thyroid lobe that is desmoplasia negative on intraoperative frozen sectioning. These recent developments reflect the current shift from reactive to increasingly preemptive, risk-reducing surgery for MTC.</p>","PeriodicalId":39880,"journal":{"name":"Recent Results in Cancer Research","volume":"223 ","pages":"247-266"},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143659101","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Stefan Delorme, Friedhelm Raue, Bettina Beuthien-Baumann
{"title":"Medullary Thyroid Carcinoma: Imaging.","authors":"Stefan Delorme, Friedhelm Raue, Bettina Beuthien-Baumann","doi":"10.1007/978-3-031-80396-3_5","DOIUrl":"10.1007/978-3-031-80396-3_5","url":null,"abstract":"<p><p>Imaging plays an important role in the early detection and staging of medullary thyroid carcinoma (MTC), as well as in follow-up to locate early recurrence. MTC is a rare, calcitonin-secreting thyroid malignancy that is often diagnosed by ultrasound and calcitonin screening as part of the routine evaluation of any thyroid nodule. If serum calcitonin is elevated, imaging studies are needed for preoperative staging to guide surgical management. This may include ultrasound of the neck and abdomen. CT or MRI studies for more distant disease are performed preoperatively when calcitonin levels are greater than 500 pg/mL. Neither FDG-PET/CT nor F-DOPA-PET/CT is routinely being used for preoperative staging, but may be helpful in individual cases of doubt. Postoperative elevated calcitonin is associated with persistence or recurrence of MTC. Imaging studies to localize tumor tissue in postoperative follow-up include ultrasound, CT, MRI, and PET scans. However, they should be used judiciously, as the impact of treatment is often limited. In addition, even patients with persistent disease may survive long enough to accumulate significant radiation doses from CT or PET scans. Imaging studies are also useful in diagnosing associated components of hereditary MTC, such as pheochromocytoma and primary hyperparathyroidism.</p>","PeriodicalId":39880,"journal":{"name":"Recent Results in Cancer Research","volume":"223 ","pages":"129-153"},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143659090","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Systemic Treatment for Cholangiocarcinoma.","authors":"Aumkhae Sookprasert, Kosin Wirasorn, Jarin Chindaprasirt, Piyakarn Watcharenwong, Thanachai Sanlung, Siraphong Putraveephong","doi":"10.1007/978-3-031-35166-2_8","DOIUrl":"https://doi.org/10.1007/978-3-031-35166-2_8","url":null,"abstract":"<p><p>Cholangiocarcinoma (CCA) is a diverse group of epithelial cancers that affect the biliary tree. The incidence of CCA is low in Western countries but significantly higher in endemic regions such as China and Thailand. Various risk factors contribute to the development of CCA. Recent studies have revealed molecular alterations in biliary tract cancers, providing insights into cholangiocarcinogenesis and potential targeted therapies. Surgical resection is the primary curative treatment for CCA. Adjuvant chemotherapy has been extensively studied, and some regimens have proven to be beneficial. Neoadjuvant chemotherapy has shown potential benefits in select cases, but its role remains controversial. In advanced stages, chemotherapy is the standard of care, and molecular profiling has identified potential targets such as FGFR, IDH1, HER2, and other tumor-agnostic therapies. Immunotherapy has demonstrated limited benefit in advanced CCA. This chapter provides an overview of the current evidence and ongoing research evaluating various chemotherapy regimens, targeted therapies, and immunotherapies across different stages of CCA.</p>","PeriodicalId":39880,"journal":{"name":"Recent Results in Cancer Research","volume":"219 ","pages":"223-244"},"PeriodicalIF":0.0,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10148828","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Narong Khuntikeo, Bandit Thinkhamrop, Thomas Crellen, Chatanun Eamudomkarn, Trevor N Petney, Ross H Andrews, Paiboon Sithithaworn
{"title":"Epidemiology and Control of Opisthorchis viverrini Infection: Implications for Cholangiocarcinoma Prevention.","authors":"Narong Khuntikeo, Bandit Thinkhamrop, Thomas Crellen, Chatanun Eamudomkarn, Trevor N Petney, Ross H Andrews, Paiboon Sithithaworn","doi":"10.1007/978-3-031-35166-2_3","DOIUrl":"https://doi.org/10.1007/978-3-031-35166-2_3","url":null,"abstract":"<p><p>It is known that Opisthorchis viverrini (OV) is the most significant risk factor for the development of cholangiocarcinoma (CCA); hence, it is also known as carcinogenic parasite. Effective control and elimination of OV infection should significantly reduce O. viverrini-related CCA. This chapter includes details of the three recently developed innovative tools, namely the Isan cohort database software, an OV-RDT for screening of O. viverrini, and an ultrasound telecommunication system. Past and current control programs, i.e., education, medication, and sanitation were discussed and stressed the need for a comprehensive control program which encompasses primary, secondary, and tertiary patient care programs for confirmation and management of suspected CCA cases. The approach of mathematical modeling for control of OV and CCA was also briefly described. Additionally, we highlighted the current progress toward control of OV and CCA in Thailand and potential for expansion into nearby countries in Southeast Asia.</p>","PeriodicalId":39880,"journal":{"name":"Recent Results in Cancer Research","volume":"219 ","pages":"27-52"},"PeriodicalIF":0.0,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10154155","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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