Sporadic and Familial Medullary Thyroid Carcinoma: A Retrospective Single Center Study on Presentation and Outcome.

BACKGROUND: Medullary Thyroid Carcinoma (MTC) is a neuroendocrine tumor that arises from the thyroid C-cells. Most cases are sporadic (sMTC) while, approximately 25%, are hereditary (hMTC) due to germline mutations of REarranged during Transfection (RET) gene mutations and manifest in the framework of multiple endocrine neoplasia (MEN) 2A or 2B, or as pure familial MTC syndrome (FMTC). OBJECTIVE: The aim of this study is to evaluate the clinical, histopathological, biochemical and outcome differences between sMTC and hMTC. METHODS: Retrospective analysis of a consecutive series of 102 patients with histologically proven MTC diagnosed in the period between 2000 and 2022. For the analysis patients with MTC diagnosed during screening through genetic test were excluded. RESULTS: Patients with hMTC had higher incidence of multifocal and bilateral MTC and younger age at diagnosis. We did not found differences on tumor stage at diagnosis between sMTC and hMTC, such as time to progression and rate of persistent and recurrent disease. At univariate analysis, factors associated with persistent and recurrent disease during follow-up in patients with sMTC were tumor size, extrathyroidal extension, presence of lymph node metastases at diagnosis, pre- and post-operative calcitonin, post-operative CEA; in patients with hMTC, features associated with persistent and recurrent disease were lymph node metastases, post-operative calcitonin and pre- and post-operative CEA values. CONCLUSION: Patients with hMTC and sMTC had similar histopathological characteristics and clinical outcome.

Molecular targets of tyrosine kinase inhibitors in thyroid cancer.

Thyroid cancer (TC) is the eighth most frequently diagnosed cancer worldwide with a rising incidence in the past 20 years. Surgery is the primary strategy of therapy for patients with medullary TC (MTC) and differentiated TC (DTC). In DTC patients, radioactive iodine (RAI) is administered after thyroidectomy. Neck ultrasound, basal and thyroid-stimulating hormone-stimulated thyroglobulin are generally performed every three to six months for the first year, with subsequent intervals depending on initial risk assessment, for the detection of possible persistent/recurrent disease during the follow up. Distant metastases are present at the diagnosis in ∼5 % of DTC patients; up to 15 % of patients have recurrences during the follow up, with a survival reduction (70 %-50 %) at 10-year. During tumor progression, the iodide uptake capability of DTC cancer cells can be lost, making them refractory to RAI, with a negative impact on the prognosis. Significant advances have been done recently in our understanding of the molecular pathways implicated in the progression of TCs. Several drugs have been developed, which inhibit signaling kinases or oncogenic kinases (BRAFV600E, RET/PTC), such as those associated with Platelet-Derived Growth Factor Receptor and Vascular Endothelial Growth Factor Receptor. Tyrosine kinase receptors are involved in cancer cell proliferation, angiogenesis, and lymphangiogenesis. Several tyrosine kinase inhibitors (TKIs) are emerging as new treatments for DTC, MTC and anaplastic TC (ATC), and can induce a clinical response and stabilize the disease. Lenvatinib and sorafenib reached the approval for RAI-refractory DTC, whereas cabozantinib and vandetanib for MTC. These TKIs extend median progression-free survival, but do not increase the overall survival. Severe side effects and drug resistance can develop in TC patients treated with TKIs. Additional studies are needed to identify a potential effective targeted therapy for aggressive TCs, according to their molecular characterization.

Renal Medullary Carcinoma: A Surveillance, Epidemiology, and End Results (SEER) Analysis.

INTRODUCTION: Renal medullary carcinoma (RMC) is an aggressive and rare renal malignancy that predominantly affects Black patients but is also found in individuals of other ethnicities. To date, only a few hundred cases have been reported in the urologic literature. Due to this extreme rarity, the exact pathophysiology and optimal treatment have yet to be well described. This study aims to determine the predictors of mortality and overall survival outcomes in patients with RMC. METHODS: We utilized the Surveillance, Epidemiology, and End Results Program (SEER) database 18 registries to retrieve demographic and clinical information on patients with RMC between 1996 and 2018. A multivariate analysis was performed to determine predictors of mortality in the study population. Kaplan-Meier survival curves were then created to display the differences in overall survival of Black versus non-Black patients diagnosed with renal medullary carcinoma during the study period. RESULTS: We identified 100 patients diagnosed with renal medullary carcinoma using the SEER Database in the study period. The mean age was 28.0 ± 12.0 (95% confidence interval [CI] 25.7-30.4). Among the patients, 76% were male and 24% were female. Most RMC patients were Black (83%) with only 17% identifying as White. The mean survival in months was 13.8 ± 3.0 (95% CI 7.9-19.7). The majority (70%) of patients in this study presented with distant, metastatic disease at the time of diagnosis. Black patients with RMC were less likely to receive surgery and five times more likely to die in comparison to their White counterparts OR = 5.4 (95% CI 1.09-26.9, P = 0.04). Not only did Black patients have a lower survival rate at 12 mo compared to White patients, but they also continued to experience a sharp decline in survival to 10.2% at 24 mo (P < 0.05) and 7.6% at 48 mo (P < 0.05) following diagnosis of renal medullary carcinoma. CONCLUSIONS: These data confirm that RMC is a rare disease that disproportionately affects Black patients. The prognosis appears to be substantially worse for Black subjects diagnosed with this cancer than non-Black patients. The worse outcomes seen in Black subjects are of an unclear etiology and are yet to be investigated.

Diagnostic challenges of renal medullary carcinoma and the role for cytologic assessment: Case report and literature review.

BACKGROUND: Renal medullary carcinoma (RMC) is a diagnostically challenging, aggressive primary renal malignancy associated with abysmal survival. Delays in diagnosis contribute to most patients having diffusely metastatic disease at the time of initial presentation. METHODS: We present the case of a 13-year-old African American male with sickle cell trait who presented with a renal mass and hematuria. Evaluation included imaging, fluid cultures, and cytologic assessment. RESULTS: Patient was diagnosed with RMC based on cytologic assessment of sub-centimeter fluid collections aspirated from the left kidney at the time of cortical biopsy for suspected renal mass. The additional fluid aspiration in conjunction with renal biopsy was an atypical but crucial step in early diagnosis. CONCLUSION: Cytomorphologic evaluation of fluid biospecimens is not currently part of the standard work-up for patients with renal masses but, when available, can provide crucial information that reduces time to diagnosis. Prompt symptom recognition and treatment initiation may improve patient outcomes.

Diagnostic Utility of Procalcitonin for Sporadic Medullary Thyroid Carcinoma in Patients with Nodular Disease and Mild or Moderate Hypercalcitoninemia.

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.

Is medullary carcinoma of the colon underdiagnosed? An audit of poorly differentiated colorectal carcinomas in a large national health service teaching hospital.

AIMS: Medullary carcinoma is an uncommon colorectal tumour which appears poorly differentiated histologically. Consequently, it may be confused with poorly differentiated adenocarcinoma not otherwise specified (NOS). The principal aim of this study was to review a large series of poorly differentiated colorectal cancers resected at a large National Health Service (NHS) Teaching Hospital to determine how often medullary carcinomas were misclassified . Secondary aims were to investigate how often neuroendocrine differentiation or metastatic tumours were considered in the differential diagnosis, and compare clinico-pathological features between medullary and poorly differentiated adenocarcinoma NOS. METHODS AND RESULTS: Histology slides from 302 colorectal cancer resections originally reported as poorly differentiated adenocarcinoma were reviewed and cases fulfilling World Health Organisation (WHO) criteria for medullary carcinoma identified. The original pathology report was examined for any mention of medullary phenotype, consideration of neuroendocrine differentiation or consideration of metastasis from another site. Clinico-pathological features were compared to poorly differentiated adenocarcinoma NOS. Only one-third of medullary carcinomas were correctly identified between 1997 and 2018. The other two-thirds were reported as poorly differentiated adenocarcinoma NOS. The possibility of an extracolonic origin or neuroendocrine carcinoma was considered in 21 and 27% of reports. Most medullary carcinomas exhibited mismatch repair deficiency, were located in ascending colon and caecum and had a lower rate of vascular channel invasion and lymph node metastasis compared to poorly differentiated adenocarcinoma. CONCLUSIONS: Medullary carcinoma of the colon is often mistaken for poorly differentiated adenocarcinoma NOS and occasionally for neuroendocrine or metastatic carcinoma. Greater familiarity with morphological criteria and use of mismatch repair protein staining should improve diagnosis.

A case report of simultaneous medullary and papillary carcinoma of thyroid.

Objective. Medullary (MTC) and papillary (PTC) thyroid carcinoma are two different types of thyroid carcinoma with significant differences in origin. Their co-occurrence in a patient is a rare phenomenon. We report a patient with simultaneous presentation of both MTC and PTC. Case presentation. A 62-year-old euthyroid woman with a cervical mass was evaluated, underwent total thyroidectomy, and neck dissection. The examination revealed a MTC large nodule as well as a small nodule of the tall cell variant of PTC, along with the concomitant cervical lymph node metastases. Subsequently, the genetic analysis showed BRAF mutations. Adjuvant treatments including radioiodine and thyroid hormone replacement therapies were performed for the patient. Conclusions. The cooccurrence of MTC and PTC in the same patient is a rare phenomenon. The clinical manifestations and biological behavior of these cancers are completely different. Since the therapeutic strategy and prognosis are very different in these patients, accurate diagnosis of this coexistence is very important.

An encapsulated oncoytic neoplasm of follicular origin of thyroid, expressing neuroendocrine markers. A case report and literature review.

A case is reported of an oncocytic tumor of the thyroid expressing simultaneously follicular and neuroendocrine markers, but not calcitonin. The data reported in the literature and the possible relationships of these lesions with the calcintonin-negative medullary carcinomas were examined.

Basal and pentagastrin-stimulated calcitonin cut-off values in diagnosis of preoperative medullary thyroid cancer

Background/aim: Medullary thyroid cancer (MTC) originates from parafollicular cells (C cell) and produces calcitonin (CT). Basal serum CT was used in the diagnosis and treatment of MTC. If basal CT level is 100 pg/mL or higher, it is likely to have MTC, but if basal CT level is below 10 pg/mL, the probability of developing thyroid disease is low. In cases with basal CT level between 10­100 pg/mL, pentagastrin-stimulated (PS) CT level is studied to evaluate MTC and C cell hyperplasia (CHH). This study aimed to determine cut-off value for basal and PS peak CT level for diagnosis of MTC. Materials and methods: We retrospectively reviewed files of patients presented to endocrine outpatient clinic of Ege University, Medicine School, between 2010 and 2019; 176 patients with basal CT level of 10­100 pg/mL and patients with PS test were included to the study. Results: The receiver operating characteristic curve (ROC) analysis was used to determine cut-off value for basal CT that can discriminate cases with MTC and those with nodular goiter. Cut-off value for basal CT was calculated as 46.5 pg/mL (specificity; 100 %, sensitivity; 74 %). In the ROC analysis for peak PS CT, cut-off value was calculated as 285 pg/mL (specificity:100 %; sensitivity:82 %). When peak CT level was > 290 pg/mL in PS test, both specificity and sensitivity for MTC were determined as 100 %. The PS peak CT level > 285 pg/ mL was significant for MTC diagnosis while range of 117­274 pg/mL was significant for CHH. Conclusion: In this study, cut-off value was calculated as 46.5 pg/mL for basal CT, whereas 285 pg/mL for PS peak CT in the diagnosis of preoperative MTC.

Calcitonin testing for detection of medullary thyroid cancer in people with thyroid nodules.

BACKGROUND: Thyroid nodules are very common in general medical practice, but rarely turn out to be a medullary thyroid carcinoma (MTC). Calcitonin is a sensitive tumour marker for the detection of MTC (basal calcitonin). Sometimes a stimulation test is used to improve specificity (stimulated calcitonin). Although the European Thyroid Association's guideline advocates calcitonin determination in people with thyroid nodules, the role of routine calcitonin testing in individuals with thyroid nodules is still questionable. OBJECTIVES: The objective of this review was to determine the diagnostic accuracy of basal and/or stimulated calcitonin as a triage or add-on test for detection of MTC in people with thyroid nodules. SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase and Web of Science from inception to June 2018. SELECTION CRITERIA: We included all retrospective and prospective cohort studies in which all participants with thyroid nodules had undergone determination of basal calcitonin levels (and stimulated calcitonin, if performed). DATA COLLECTION AND ANALYSIS: Two review authors independently scanned all retrieved records. We extracted data using a standard data extraction form. We assessed risk of bias and applicability using the QUADAS-2 tool. Using the hierarchical summary receiver operating characteristic (HSROC) model, we estimated summary curves across different thresholds and also obtained summary estimates of sensitivity and specificity at a common threshold when possible. MAIN RESULTS: In 16 studies, we identified 72,368 participants with nodular thyroid disease in whom routinely calcitonin testing was performed. All included studies performed the calcitonin test as a triage test. Median prevalence of MTC was 0.32%. Sensitivity in these studies ranged between 83% and 100% and specificity ranged between 94% and 100%. An important limitation in 15 of the 16 studies (94%) was the absence of adequate reference standards and follow-up in calcitonin-negative participants. This resulted in a high risk of bias with regard to flow and timing in the methodological quality assessment. At the median specificity of 96.6% from the included studies, the estimated sensitivity (95% confidence interval (CI)) from the summary curve was 99.7% ( 68.8% to 100%). For the median prevalence of MTC of 0.23%, the positive predictive value (PPV) for basal calcitonin testing at a threshold of 10 pg/mL was 7.7% (4.9% to 12.1%). Summary estimates of sensitivity and specificity for the threshold of 10 pg/mL of basal calcitonin testing was 100% (95% CI 99.7 to 100) and 97.2% (95% CI 95.9 to 98.6), respectively. For combined basal and stimulated calcitonin testing, sensitivity ranged between 82% and 100% with specificity between 99% and 100%. The median specificity was 99.8% with an estimated sensitivity of 98.8% (95% CI 65.8 to 100) . AUTHORS' CONCLUSIONS: Both basal and combined basal and stimulated calcitonin testing have a high sensitivity and specificity. However, this may be an overestimation due to high risk of bias in the use and choice of reference standard The value of routine testing in patients with thyroid nodules remains questionable, due to the low prevalence, which results in a low PPV of basal calcitonin testing. Whether routine calcitonin testing improves prognosis in MTC patients remains unclear.

Renal medullary carcinoma masquerading as renal infection: a case report.

BACKGROUND: Renal medullary carcinoma is a rare and aggressive tumor and often seen in young adults with sickle cell hemoglobinopathies. CASE PRESENTATION: We report a case of renal medullary carcinoma in a 29-year old male patient with an occupying renal lesion who presented with fever, flank pain and hematuria. The patient received intensive antibiotics treatment, but no improvement was seen. The symptoms disappeared after laparoscopic radical left nephrectomy. Postoperative pathological study showed that the mass was renal medullary carcinoma. CONCLUSIONS: Our case suggests that renal medullary carcinoma should be considered in differential diagnoses of patients with occupying renal lesions who have fever of unknown origin.

Renal Medullary Carcinoma: a Report of the Current Literature.

PURPOSE OF THE REVIEW: We present an updated report of renal medullary carcinoma (RMC), a rare and aggressive condition. RECENT FINDINGS: There is a majority of male patients, of African descent, in the second or third decade of life. In differential diagnosis, other tumors, such as malignant rhabdoid tumor (MRT), vinculin-anaplastic lymphoma kinase (VCL-ALK) translocation renal cell carcinoma, and collecting duct carcinoma, may present difficulties. Abnormalities of tumor suppressor gene SMARCB1 have been found in RMC. Reported symptoms were hematuria, pain, weight loss, respiratory distress, palpable mass, cough, and fever. Most patients present with metastases at diagnosis. There is no definite recommended treatment, and protocols are extrapolated from other malignancies, with nephrectomy and systemic therapies being most frequently used. Response to treatment and prognosis remain very poor. RMC is a rare and aggressive tumor. Definitive diagnosis requires histological assessment and the presence of sickle-cell hemoglobinopathies.

Racial/ethnic differences in thyroid cancer incidence in the United States, 2007-2014.

BACKGROUND: Small tumor diagnostic tools including ultrasound-guided fine needle aspiration (FNA) and computed tomography (CT) could be causing rising and racially/ethnically different thyroid cancer incidence rates due to variable overdiagnosis of indolent tumors. Papillary tumors and <40 mm tumors are most likely to be overdiagnosed as indolent tumors by FNA and CT. METHODS: Age-adjusted incidence rates (AAIRs) for the years 2007-2014 were calculated for race/ethnicity (white, Hispanic, Asian, African American, Native American) by patient/tumor characteristics for microscopically confirmed malignant thyroid cancer cases in the Surveillance, Epidemiology, and End Results Program 18 database (SEER 18; N = 93,607). Multivariate analysis determined cancer patients' odds ratios of diagnosis with papillary thyroid carcinoma (vs other histologies) and tumors <40 mm (vs ≥40 mm). RESULTS: For both males and females, there were statistically significant differences in incidence rates between race/ethnicity, with whites having the highest AAIRs and African Americans the lowest AAIRs. Among thyroid cancer patients, tumor size and histology differed significantly by race and insurance coverage after controlling for age, sex, stage, and tumor sequence. Non-whites with thyroid cancer (vs whites) were less associated with small tumors (odds ratio [OR], 0.51-0.79; P < .0001). Medicaid and uninsured patients with thyroid cancer were less associated with tumors <40 mm (OR, 0.55-0.71; 95% confidence interval [CI], 0.49-0.76) and papillary carcinoma (OR, 0.86; 95% CI, 0.80-0.93). CONCLUSION: The diagnosis of small tumors is occurring at greater rates in whites (vs non-whites) and insured (vs Medicaid and uninsured) patients; consequently, these groups may be vulnerable to unnecessary tests and treatments or potentially aided by early detection. Guidelines that define postdetection interventions may be needed to limit the overtreatment of indolent and small papillary carcinomas. Cancer 2018;124:1483-91. © 2018 American Cancer Society.

Multiple endocrine neoplasia 2 in Cyprus: evidence for a founder effect.

PURPOSE: Multiple endocrine neoplasia type 2 (MEN2) affects patients with RET proto-oncogene mutations. This cohort study refers to patients who were diagnosed with familial medullary thyroid carcinoma (MTC) and underwent RET genetic testing in Cyprus between years 2002 and 2017. METHODS AND PATIENTS: Forty patients underwent RET testing by Sanger sequencing of exons 10-11 and 13-16. Genotyping with STR genetic markers flanking the RET gene along with Y-chromosome genotyping and haplogroup assignment was also performed. RESULTS: RET mutations were identified in 40 patients from 11 apparently unrelated Cypriot families and two non-familial sporadic cases. Nine probands (69.2%) were heterozygous for p.Cys618Arg, one (7.7%) for p.Cys634Phe, one (7.7%) for the somatic delE632-L633 and two (15.4%) for p.Met918Thr mutations. The mean age at MTC diagnosis of patients carrying p.Cys618Arg was 36.8 ± 14.2 years. The age of pheo diagnosis ranged from 26 to 43 years and appeared simultaneously with MTC in 5/36 (13.9%) cases. The high frequency of the p.Cys618Arg mutation suggested a possible ancestral mutational event. Haplotype analysis was performed in families with and without p.Cys618Arg. Six microsatellite markers covering the RET gene and neighboring regions identified one core haplotype associated with all patients carrying p.Cys618Arg mutation. CONCLUSIONS: The mutation p.Cys618Arg is by far the most prevalent mutation in Cyprus followed by other reported mutations of variable clinical significance. The provided molecular evidence speculates p.Cys618Arg mutation as an ancestral mutation that has spread in Cyprus due to a possible founder effect.

Morphology combined with ancillary techniques: An algorithm approach for thyroid nodules.

INTRODUCTION: Several authors have underlined the limits of morphological analysis mostly in the diagnosis of follicular neoplasms (FN). The application of ancillary techniques, including immunocytochemistry (ICC) and molecular testing, contributes to a better definition of the risk of malignancy (ROM) and management of FN. According to literature, the application of models, including the evaluation of ICC, somatic mutations (ie, BRAFV600E ), micro RNA analysis is proposed for FNs. This study discusses the validation of a diagnostic algorithm in FN with a special focus on the role of morphology then followed by ancillary techniques. METHODS: From June 2014 to January 2016, we enrolled 37 FNs with histological follow-up. In the same reference period, 20 benign nodules and 20 positive for malignancy were selected as control. ICC, BRAFV600E mutation and miR-375 were carried out on LBC. RESULTS: The 37 FNs included 14 atypia of undetermined significance/follicular lesion of undetermined significance and 23 FN. Specifically, atypia of undetermined significance/follicular lesion of undetermined significance resulted in three goitres, 10 follicular adenomas and one NIFTP whereas FN/suspicious for FN by seven follicular adenomas and 16 malignancies (nine non-invasive follicular thyroid neoplasms with papillary-like nuclear features, two invasive follicular variant of papillary thyroid carcinoma [PTC] and five PTC). The 20 positive for malignancy samples included two invasive follicular variant of PTC, 16 PTCs and two medullary carcinomas. The morphological features of BRAFV600E mutation (nuclear features of PTC and moderate/abundant eosinophilic cytoplasms) were associated with 100% ROM. In the wild type cases, ROM was 83.3% in presence of a concordant positive ICC panel whilst significantly lower (10.5%) in a negative concordant ICC. High expression values of MirR-375 provided 100% ROM. CONCLUSIONS: The adoption of an algorithm might represent the best choice for the correct diagnosis of FNs. The morphological detection of BRAFV600E represents the first step for the identification of malignant FNs. A significant reduction of unnecessary thyroidectomies is the goal of this application.

Advances and controversies in the management of medullary thyroid carcinoma.

PURPOSE OF REVIEW: Medullary thyroid carcinoma (MTC) comprises approximately 4% of all malignant thyroid neoplasms. Although the majority of patients have a good prognosis, a subgroup of patients develops progressive disease and requires systemic therapy. Here, we focused on the current MTC therapeutic approaches and discussed the advantages and disadvantages of molecular targeted therapies. RECENT FINDINGS: Targeted molecular therapies that inhibit RET and other tyrosine kinase receptors involved in angiogenesis have been shown to improve progression-free survival in patients with advanced MTC. Two drugs, vandetanib and cabozantinib, have been approved for the treatment of progressive or symptomatic MTC, and several others have exhibited variable efficacy. No tyrosine kinase inhibitor has been shown to improve survival. Although no definitive recommendation can currently be made, cumulative data indicate that knowledge of the tumor mutational profile may facilitate improvements in targeted therapy for MTC. SUMMARY: Tyrosine kinase inhibitors are effective therapeutic agents for the treatment of progressive MTC. Nevertheless, it is not clear who will benefit the most from therapy, and the decision regarding when and how to initiate the treatment should be made based on the patient's medical history and tumor behavior. Hopefully, in the near future, molecular profiling of MTC can be used to determine the most effective molecular therapeutic target.

Medullary carcinoma of the small bowel.

AIMS: Medullary carcinoma of the large bowel occurs mainly right-sided in elderly females. The tumour is almost invariably microsatellite instable and has been associated with favourable outcome. Our study aimed to present three cases of medullary carcinoma originating from the small bowel. METHODS AND RESULTS: We describe three cases of small bowel medullary carcinoma. Two patients had coeliac disease, diagnosed at the ages of 79 and 71 years, respectively. The tumours showed the characteristic syncytial growth pattern with marked intratumoral lymphocytic inflammation. Loss of MutL homologue 1 (MLH1) [and postmeiotic segregation increased 2 (S. cerevisiae) PMS2] expression was observed in all cases, consistent with high-level microsatellite instability. All tumours were negative for Epstein-Barr virus. Follow-up information was available for one patient, who is recurrence-free 6 years after resection. DISCUSSION: Medullary carcinoma of the small bowel is exceedingly rare. Our data and a review of the literature suggest that this tumour type is characteristic for coeliac disease and may be the histological type underlying small bowel cancers with high-level microsatellite instability in patients with coeliac disease.

Comparative assessment of calcitonin stimulation test using calcium gluconate and pentagastrin and the usefulness of procalcitonin basic and post-stimulation concentrations in the diagnosis of patients after surgery for medullary.

OBJECTIVES: The aim of the study was to compare the calcitonin (CT) stimulation tests with tests of calcium gluconate (CaG) and pentagastrin (PG), their tolerance and usefulness of PCT in the patients' diagnosis with active Medullary thyroid cancer (MCT) after thyroidectomy. METHODS: CT was marked in serum by the immunosorbent sandwich test. PCT was marked by the immunosorbent sandwich test, with the final reading of fluorenscence. PG was given intravenously at a dose of 0.5 mg/kg body weight for 10 seconds. CaG was also given by intravenous injection at a dose of 2.5 mg of elemental Ca/kg body weight at a rate of 5ml/min, for minimum 3 minutes. Blood was taken at the 0 minute, the 3 and 5 minute after getting the stimulating substances. RESULTS: The post-stimulation CT concentration in the 3 and 5 minute of the CaG test vs PG is significantly higher compared to the baseline. The maximal stimulation of the CT is in the 3 minute, but higher concentrations occurred using the CaG. CONCLUSION: The results of the study suggest a similar diagnostic value of the tests with CaG compared to the PG as stimulants. In the present study we noticed a trend of basic and post-stimulation concentrations of PCT to increase in the tests with PG and CaG which correspond with the elevated concentrations of CT.

Twenty years of lesson learning: how does the RET genetic screening test impact the clinical management of medullary thyroid cancer?

OBJECTIVE: Medullary thyroid carcinoma (MTC) is a rare disease that can be inherited or sporadic; its pathogenesis is related to activating mutations in the RET gene. DESIGN: This study describes our 20-year experience regarding RET genetic screening in MTC. PATIENTS AND METHODS: We performed RET genetic screening in 1556 subjects, 1007 with an apparently sporadic MTC, 95 with a familial form and 454 relatives of RET-positive patients with MTC. RESULTS: A germline RET mutation was found in 68 of 1007 (6·7%) patients with sporadic MTC, while 939 patients with MTC were negative for germline RET mutations. We then identified a total of 137 gene carriers (GC). These subjects initiated a clinical evaluation for the diagnosis of MEN 2. A total of 139 MEN 2 families have been followed: 94 FMTC, 33 MEN 2A and 12 MEN 2B. Thirty-three different germline RET mutations were identified. Codon 804 was the most frequently altered codon particularly in FMTC (32/94, 34%), while codon 634 was the most frequently altered codon in MEN 2A (31/33, 94%); MEN 2B cases were exclusively associated with an M918T mutation at exon 16. CONCLUSIONS: Our 20-year study demonstrated that RET genetic screening is highly specific and sensitive, and it allows the reclassification as hereditary of apparently sporadic cases and the identification of GC who require an adequate follow-up. We confirmed that FMTC is the most prevalent MEN 2 syndrome and that it is strongly correlated with noncysteine RET mutations. According to these findings, a new paradigm of follow-up of hereditary MTC cases might be considered in the next future.

RET gene mutations (genotype and phenotype) of multiple endocrine neoplasia type 2 and familial medullary thyroid carcinoma.

The rapid technical advances in molecular biology and accelerating improvements in genomic and proteomic diagnostics have led to increasingly personalized strategies for cancer therapy. Such an approach integrates the genomic, proteomic, and molecular information unique to the individual to provide an accurate genetic diagnosis, molecular risk assessment, informed family counseling, therapeutic profiling, and early preventative management that best fits the particular needs of each patient. The discovery of mutations in the RET proto-oncogene resulting in variable onset and severity of multiple endocrine neoplasia type 2 (MEN2) was the first step in developing direct genetic testing for at-risk individuals. Patients with germline RET mutations may undergo risk assessment and appropriate intervention based on specific mutations. Moreover, family members of affected individuals receive counseling based on understanding of the genetic transmission of the disease. Increasingly, clinicians are able to make therapeutic choices guided by an informative biomarker code. Improvements in detection and management of patients with MEN2 resulting from understanding of the RET proto-oncogene are evidence of the benefits of personalized cancer medicine. This review describes the discovery of the RET proto-oncogene, the association between genotype and phenotype, and the role of mutation analysis on diagnosis and treatment of MEN2.