ABSTRACT
Pendred syndrome is an autosomal recessive familial disorder, defined as a sensorineural deafness coinciding with a goiter related to an iodine organification defect. It constitutes 4 to 10 % of all causes of familial congenital hearing loss. It is now well established that this condition was caused by mutations in the SLC26A4 gene which codes for pendrin, a protein involved in the transport of anions (I-, Cl, HCO3-), particularly in apical iodine efflux in thyroid cells and chloride (Cl-|HCO3-) at the cochlear level. A current issue is to determine factors that distinguish Pendred syndrome from other varieties of isolated deafness also including enlargement of the vestibular aqueduct, but without evidence of thyroid expression. A prospective investigation of these 2 situations, conducted in Lille, leads us to redefine diagnostic criteria and assessment methods, and to discuss genetic or environmental factors contributing to the phenotypes.
Subject(s)
Deafness/diagnosis , Goiter, Nodular/diagnosis , Hearing Loss, Sensorineural/diagnosis , Adolescent , Adult , Child , Child, Preschool , DNA Mutational Analysis , Deafness/genetics , Diagnosis, Differential , Female , Goiter, Nodular/genetics , Hearing Loss, Sensorineural/genetics , Humans , Male , Middle Aged , Thyroid Gland/pathology , Vestibular Aqueduct/pathology , Young AdultABSTRACT
BACKGROUND: Laparoscopic adrenalectomy (LA) is the standard treatment for benign adrenal lesions. The laparoscopic approach has also been increasingly accepted for adrenal metastases but remains controversial for adrenocortical carcinoma (ACC). In a retrospective cohort study we compared the outcome of LA versus open adrenalectomy (OA) in the treatment of stage I and II ACC. METHODS: This was a double cohort study comparing the outcome of patients with stage I/II ACC and a tumor size <10 cm submitted to LA or OA at Lille University Hospital referral center from 1985 to 2011. Main outcomes analyzed were: postoperative morbidity, overall survival, and disease-free survival. RESULTS: Among 111 consecutive patients operated on for ACC, 34 met the inclusion criteria. LA and OA were performed in 13 and 21 patients, respectively. Baseline patient characteristics (gender, age, tumor size, hormonal secretion) were similar between groups. There was no difference in postoperative morbidity, but patients in LA group were discharged earlier (p < 0.02). After a similar follow-up (66 ± 52 for LA and 51 ± 43 months for OA), Kaplan-Meier estimates of disease-specific survival and disease-free survival were identical in both groups (p = 0.65, p = 0.96, respectively). CONCLUSIONS: LA was associated with a shorter length of stay and did not compromise the long-term oncological outcome of patients operated on for stage I/II ACC ≤ 10 cm ACC. Our results suggest that LA can be safely proposed to patients with potentially malignant adrenal lesions smaller than 10 cm and without evidence of extra-adrenal extension.
Subject(s)
Adrenal Cortex Neoplasms/mortality , Adrenalectomy/mortality , Adrenocortical Carcinoma/mortality , Laparoscopy , Neoplasm Recurrence, Local/mortality , Postoperative Complications , Adrenal Cortex Neoplasms/pathology , Adrenal Cortex Neoplasms/surgery , Adrenocortical Carcinoma/pathology , Adrenocortical Carcinoma/surgery , Adult , Aged , Female , Follow-Up Studies , Humans , Male , Middle Aged , Neoplasm Recurrence, Local/pathology , Neoplasm Recurrence, Local/surgery , Neoplasm Staging , Prognosis , Retrospective Studies , Survival Rate , Time FactorsABSTRACT
AIMS: To investigate the performance of two proposed methods for assessing the prognosis of poorly differentiated thyroid carcinomas (PDTC): the Turin proposal and Hiltzik's histological grade (HHG). This was done using a series of 82 thyroid carcinomas of follicular origin. RESULTS: The two methods were able to classify patients accurately into two different prognosis groups. Although the Turin proposal and HHG displayed discrepant cases, they provided similar prognostic information. The Turin proposal gave accurate numbers and thresholds of PTDC criteria (loss of follicular architecture and mitoses, necrosis or convoluted nuclei). One Turin criterion, convoluted nuclei, failed to provide any prognostic value. Hiltzik's histological grade was also a simple and reliable method, allowing detection of tumours with high-grade features (mitosis and/or tumour necrosis), notably some papillary carcinomas that displayed an intermediate prognosis. We show that Ki67 labelling (≥ 4%) was an independent factor and predictor of cause-specific survival. CONCLUSION: With similar performances in predicting prognosis, the Turin proposal and HHG provided complementary results in identifying a larger group of 'intermediate prognosis' thyroid carcinomas, which require adequate treatment and follow-up.
Subject(s)
Adenocarcinoma, Follicular/pathology , Thyroid Gland/pathology , Thyroid Neoplasms/pathology , Adult , Aged , Female , Humans , Male , Middle Aged , Mitosis , Necrosis/pathology , Neoplasm Grading , PrognosisSubject(s)
Hypothyroidism/immunology , Hypothyroidism/metabolism , Receptors, Thyrotropin/immunology , Adult , Aged , Autoantibodies/immunology , Female , Humans , Immunoglobulins, Thyroid-Stimulating/immunology , Iodide Peroxidase/immunology , Male , Middle Aged , Receptors, Thyrotropin/analysis , Receptors, Thyrotropin/metabolism , Thyrotropin/immunologyABSTRACT
Autoimmune thyroiditis are common and benign disorders, affecting preferentially women, at any age of life. They may occur singly or integrated as a part of familial predisposition to autoimmune thyroid disease or autoimmune polyendocrinopathies. Clinical presentation is variable: goiter or thyroid atrophy, euthyroid or temporary or permanent hypothyroidism, rarely transient thyrotoxicosis. Commune features are the presence of antithyroperoxydase antibodies and lymphoplasmocytic infiltrate of the thyroid parenchyma. It is important to distinguish the cases in which thyroid dysfunction is transient and requires only monitoring and those in which hypothyroidism is permanent and justifies thyroid hormone replacement. In the forms with goiter, clinical and ultrasonic control of the thyroid is justified.
Subject(s)
Thyroiditis, Autoimmune/diagnosis , Autoantibodies/blood , Hormone Replacement Therapy , Humans , Hypothyroidism/drug therapy , Hypothyroidism/etiology , Immunologic Factors/therapeutic use , Interferon-alpha/therapeutic use , Interferon-beta/therapeutic use , Thyroid Gland/diagnostic imaging , Thyroiditis, Autoimmune/blood , Thyroiditis, Autoimmune/drug therapy , Thyrotropin/therapeutic use , UltrasonographyABSTRACT
BACKGROUND: APECED syndrome is a rare disease caused by biallelic mutations of the AIRE gene, usually presenting with the triad "hypoparathyroidism-adrenal failure-chronic mucocutaneous candidiasis (CMC)" and non-endocrine manifestations. The aim of this study was to determine the molecular profile of the AIRE gene, the prevalence of rare manifestations and to characterize immunological disturbances in a French cohort. PATIENTS AND METHODS: A national, multicenter prospective observational study to collect genetic, clinical, biological and immunological data (NCT03751683). RESULTS: 25 patients (23 families) were enrolled. Eleven distinct AIRE variants were identified, two of which were not previously reported: an intronic variant, c.653-70G > A, and a c.1066del (p.Arg356GlyfsX22) variant (exon 9). The most common was the Finnish variant c.769C > T (16 alleles), followed by the variant c.967_979del13 (15 alleles), which seemed associated with a less severe phenotype. 17/25 patients were homozygote. The median number of clinical manifestations was seven; 19/25 patients presented with the hypoparathyroidism-adrenal failure-CMC triad, 8/13 showed pulmonary involvement, 20/25 had ectodermal dystrophy, 8/25 had malabsorption, and 6/23 had asplenia. Fifteen out of 19 patients had NK cell lymphopenia with an increase in CD4+ and CD8+ T lymphocytes and an age-dependent alteration of B lymphocyte homeostasis compared with matched controls (p < 0.001), related to the severity of the disease. All tested sera (n = 18) were positive for anti-interferon-α, 15/18 for anti-interleukin-22 antibodies, and 13/18 for anti-interleukin-17F antibodies, without clear phenotypic correlation other than with CMC. CONCLUSION: This first prospective cohort showed a high AIRE genotype variability, with two new gene variants. The prevalence of potentially life-threatening non-endocrine manifestations, was higher with systematic screening. These manifestations could, along with age-dependent B-cell lymphopenia, contribute to disease severity. Systematic screening for all the manifestations of the syndrome would allow earlier diagnosis, supporting vaccination, and targeted therapeutic approaches.
ABSTRACT
Nineteen patients with autoimmune polyendocrine syndrome type 1 were identified in a longitudinal study conducted in northern France (Nord-Picardie-Normandie region, 9 million inhabitants), giving a prevalence of 1/500 000 inhabitants. This survey confirmed the usual onset in childhood, and the high frequency of candidiasis, adrenal insufficiency, alopecia and hypoparathyroidism. Broad phenotypic variability was observed, even within a given family. The AIRE gene mutations identified in these patients were closer to those observed in the United Kingdom than in Finland. Preliminary results of an ongoing nationwide survey suggest that the prevalence tends to be higher in the north.
Subject(s)
Polyendocrinopathies, Autoimmune/diagnosis , Polyendocrinopathies, Autoimmune/epidemiology , Adolescent , Adult , Aged , Child , Data Collection , Disease Progression , Female , France/epidemiology , Genetic Predisposition to Disease , Humans , Male , Middle Aged , Polyendocrinopathies, Autoimmune/etiology , Young AdultABSTRACT
EXPLORATION AND MANAGEMENT OF THYROID NODULES. Most thyroid nodules are benign (95%) and can benefit from clinical and ultrasound monitoring. Cancers (approximately 5% of nodules) could be suspected, particularly in subjects whose neck was irradiated, in cases of a hard, irregular, evolving nodule, or with very high serum calcitonin (> 100 pg/ml). It is crucial to recognize cancers when nodules exceed the supracentimeter stage. Thyroid ultrasonography is the most common, handy, safe, and cost-effective tool to image thyroid nodules. It classifies thyroid nodules according to the EU-TIRADS score, which comprises 5 categories associated with an increasing risk of malignancy. An ultrasound-guided fine needle aspiration (FNA) biopsy is performed only in nodules staged EU-TIRADS classes 5, 4, and 3 over 1, 1.5, and 2 cm, respectively. Cytologic analysis of FNA material classifies thyroid nodules according to the Bethesda system into 6 classes, each with its own prognostic value. The difficulties in cytological evaluation are related to the uninterpretable (Bethesda I) and indeterminate (especially III and IV) results, for which have to be discussed opportunities of reassessment and follow-up by scintiscans and cytological molecular markers. Management is imperfectly codifiable: from surveillance in the absence of suspicious elements initially to total thyroidectomy in their presence.
EXPLORATION ET PRISE EN CHARGE DES NODULES THYROÏDIENS. La plupart des nodules thyroïdiens sont bénins (95 %) et peuvent bénéficier d'une surveillance clinique et échographique. La malignité (5 % des nodules environ) est à suspecter, particulièrement chez les sujets dont le cou a été irradié, en cas de nodule dur, irrégulier, évolutif, avec une calcitoninémie très élevée (supérieure à 100 pg/mL). C'est au stade de nodule supracentimétrique qu'il importe de reconnaître les cancers. L'échographie est l'examen d'imagerie de référence ; elle permet de classer les nodules selon le score EU-TIRADS, composé de cinq catégories associées à un risque croissant de malignité. Les ponctions échoguidées en vue de l'analyse cytologique sont réservées aux catégories EU-TIRADS 5, 4 et 3 de plus de 1, 1,5 et 2 cm respectivement. Les caractéristiques cytologiques sont présentées selon la nomenclature de Bethesda en six classes dont chacune quantifie aussi le risque de malignité, en complément des données échographiques. Les difficultés de l'évaluation cytologique sont liées aux résultats ininterprétables (Bethesda I) et indéterminés (surtout Bethesda III et IV) pour lesquels se discutent l'opportunité de la réévaluation et de la surveillance, des scintigraphies dites de seconde intention, et également des marqueurs moléculaires sur le produit de cytoponction. La prise en charge est imparfaitement codifiable : de la surveillance en l'absence d'éléments suspects initialement à la thyroïdectomie totale en leur présence.
Subject(s)
Thyroid Neoplasms , Thyroid Nodule , Humans , Thyroid Nodule/diagnosis , Thyroid Nodule/therapy , Thyroid Nodule/pathology , Thyroid Neoplasms/pathology , Retrospective Studies , Ultrasonography , Biopsy, Fine-Needle/methodsABSTRACT
BACKGROUND: Levothyroxine sodium marketed in France was reformulated following a French National Agency for Medicines and Health Products Safety request for a more stringent potency specification. Despite previously established purity and bioequivalence of the new and old formulations, reports of adverse events substantially increased following reformulation. This analysis evaluated the nature and relevance of the medically confirmed safety reports. METHODS: Spontaneous and solicited individual case safety reports in France were retrieved from 26 March 2015 to 30 June 2016 (old formulation) and 26 March 2017 to 30 June 2018 (new formulation). Rates of reports and adverse events were calculated for the overall patient population and for at-risk subgroups. Adverse events delineated by thyroid-stimulating hormone levels were evaluated. RESULTS: A total of 295 and 42 775 reports for the old formulation and new formulation, respectively, were retrieved, with 149 and 5503 medically confirmed. The most common medically confirmed adverse events were consistent with the known safety profile of levothyroxine, with generally comparable rates between both formulations (range of differences, 1.8-4.1%). Most cases were not serious (old formulation, 65.8%; new formulation, 78.7%). Reporting rates were similar or higher for the old formulation within subgroups of at-risk patients. Nature/distributions of adverse events by thyroid-stimulating hormone levels as determined by both the marketing authorization holder of levothyroxine and the French National Agency for Medicines and Health Products Safety were similar. CONCLUSIONS: The new formulation safety profile aligns with the established profile of the old formulation of levothyroxine. The benefit-risk profile is unchanged, such that the benefits of using the new formulation in the approved indications outweigh the risks associated with the treatment.
Subject(s)
Drug Compounding/statistics & numerical data , Drug-Related Side Effects and Adverse Reactions/epidemiology , Thyroxine/adverse effects , France/epidemiology , Humans , Retrospective Studies , Therapeutic EquivalencyABSTRACT
BACKGROUND: The aim of this study was to evaluate the role of dual isotope 123Iodine/99mTc-MIBI thyroid scintigraphy (IMS) in discriminating between malignant and benign lesions in indeterminate nodules using quantitative analysis methods. METHODS: Thirty-five consecutive patients with thyroid nodules of indeterminate or non-diagnostic cytology and cold on 123Iodine scintigraphy (10 Bethesda I, 24 Bethesda III-IV, 1 in which cytology was impossible) underwent IMS between 2017 and 2019 with uptake quantification at two time points ahead of thyroidectomy: early and late. Images were analyzed by two blinded physicians. RESULTS: Twelve nodules were malignant and 23 benign on histopathology. Mean uptake values were lower in benign than in malignant nodules at both time points: early, 8.7±4.1 versus 12.9±3.5 (P=0.005); and late, 5.3±2.7 versus 7.7±1.1 (P=0.008). Interobserver reproducibility was excellent. The intraclass correlation coefficient was 0.86 in benign and 0.92 in malignant lesions for early uptake result (ER) and 0.94 and 0.85 respectively for late uptake result (LR). The optimal LR cut-off to exclude a diagnosis of malignancy was set at 5.9 . The sensitivity, specificity, positive predictive value, negative predictive value and accuracy of this cut-off were, respectively, 100%, 65.2%, 60%, 100% and 77.1%. CONCLUSION: Despite some study limitations, quantitative analysis of 99mTc-MIBI thyroid scintigraphy had a good reproducibility, which could help to rule out malignancy in non-diagnostic or indeterminate thyroid nodules and thereby reducing the number of patients undergoing unnecessary surgery when LR is below 5.9.
Subject(s)
Iodine Radioisotopes , Radionuclide Imaging/methods , Technetium Tc 99m Sestamibi , Thyroid Neoplasms/diagnostic imaging , Thyroid Nodule/diagnostic imaging , Adult , Aged , Biopsy, Fine-Needle , Diagnosis, Differential , Female , Humans , Male , Middle Aged , Reproducibility of Results , Retrospective Studies , Sensitivity and Specificity , Thyroid Neoplasms/pathology , Thyroid Neoplasms/surgery , Thyroid Nodule/pathology , Thyroid Nodule/surgery , UltrasonographySubject(s)
Drugs, Generic/therapeutic use , Hypothyroidism/drug therapy , Thyroxine/therapeutic use , Cardiovascular Diseases/etiology , Cardiovascular Diseases/metabolism , Drugs, Generic/adverse effects , Drugs, Generic/pharmacokinetics , Female , Humans , Hypothyroidism/metabolism , Intestinal Absorption , Pregnancy , Pregnancy Complications/metabolism , Thyrotropin/metabolism , Thyroxine/adverse effects , Thyroxine/pharmacokineticsABSTRACT
OBJECTIVE: It is unknown why some patients with biochemical evidence of primary aldosteronism (PA) do not develop hypertension. We aimed to compare clinical and biochemical characteristics of normotensive and hypertensive patients with PA. DESIGN AND PATIENTS: Retrospective comparison of 10 normotensive and 168 hypertensive patients with PA for office or ambulatory blood pressure, serum potassium, plasma aldosterone and renin concentrations; the aldosterone:renin ratio, and tumour size. Comparison of initial hormonal pattern and drop in blood pressure following adrenalectomy in five normotensive and nine hypertensive patients matched for age, sex and body mass index. RESULTS: The 10 normotensive patients were women and presented with hypokalemia or an adrenal mass. Age, plasma aldosterone and renin concentrations were similar in normotensive and hypertensive cases, but kalemia and body mass index were significantly lower in the normotensive patients. Mean tumour diameter was larger in the normotensive patients than in the hypertensive matched patients with an adenoma (P < 0.01). In normotensive patients, diastolic blood pressure and upright aldosterone correlated negatively with kalemia. Blood pressure was lowered similarly after adrenalectomy in five normotensive PA patients and in their matched hypertensive counterparts. Aldosterone synthase expression was detected in four out of five adrenal tumours. CONCLUSIONS: Blood pressure may be normal in patients with well-documented PA. The occurrence of hypokalemia, despite a normal blood pressure profile, suggests that protective mechanisms against hypertension are present in normotensive patients.
Subject(s)
Biomarkers/analysis , Blood Pressure/physiology , Hyperaldosteronism/physiopathology , Hypertension/complications , Adrenal Gland Neoplasms/complications , Adrenal Gland Neoplasms/genetics , Adrenal Gland Neoplasms/metabolism , Adrenalectomy , Adrenocortical Adenoma/complications , Adrenocortical Adenoma/genetics , Adrenocortical Adenoma/metabolism , Adult , Biomarkers/metabolism , Case-Control Studies , Cytochrome P-450 CYP11B2/genetics , Cytochrome P-450 CYP11B2/metabolism , Female , Follow-Up Studies , Humans , Hyperaldosteronism/complications , Hyperaldosteronism/etiology , Hyperaldosteronism/genetics , Hypertension/genetics , Hypertension/metabolism , Male , Middle Aged , Retrospective Studies , Steroid 11-beta-Hydroxylase/genetics , Steroid 11-beta-Hydroxylase/metabolism , Treatment OutcomeABSTRACT
Morphologic examination is the gold standard for diagnosing papillary thyroid carcinoma (PTC). This diagnosis, especially for the follicular variant, may be variable even among experts. Our objective was to analyze the frequency of PTC microscopic criteria in a series of thyroid tumors including follicular adenoma (FA) and PTC to build a score which could constitute a novel way for microscopic analysis of such thyroid tumors. Sixty-six PTC and 66 FA were matched for age, sex, and thyroiditis. Two independent observers delineated the classical PTC microscopic criteria. PTC microscopic criteria were variably expressed in individual tumors. Under univariate analysis, all criteria were significantly more frequent in PTC than in FA (p<0.05). Under multivariate analysis, the most important criteria were: dark staining colloid >25%, nuclear grooves, enlarged nuclei, ovoid nuclei >5% of tumor cells, and lack of polarization. Using linear discriminant analysis, these five criteria allowed us to build a scaled score. The score proposed did not allow the making of a definite distinction between FA and PTC in routine practice. It represents the variety of microscopic presentations of FA and PTC on the basis of a statistical analysis and could help in further evaluation of immunohistochemical or molecular markers.
Subject(s)
Carcinoma, Papillary/pathology , Thyroid Gland/pathology , Thyroid Neoplasms/pathology , Adult , Aged , Diagnosis, Differential , Female , Histocytochemistry , Humans , Male , Middle Aged , Severity of Illness IndexABSTRACT
Graves' disease is the most frequent cause of hyperthyroidism. Many questions remain about the choice of diagnostic evaluations and treatment strategy according to clinical context (age, gender, pregnancy, etc.) and about the best management of the main extrathyroidal complication that is Graves orbitopathy. The exact pathogenic mechanisms are not fully clear. They associate genetic factors, interactions between endogenous and environmental factors, and immune system dysregulation. Graves' orbitopathy is one of the consequences of this partial understanding. Iatrogenic Graves' disease induced by the new targeted therapies are described and could help to better understand the molecular pathways involved in the disease and to develop new therapeutic approaches.
Subject(s)
Environment , Graves Disease/diagnosis , Graves Disease/epidemiology , Graves Disease/etiology , Age of Onset , Disease Susceptibility/complications , Disease Susceptibility/epidemiology , Disease Susceptibility/immunology , Drug-Related Side Effects and Adverse Reactions/complications , Drug-Related Side Effects and Adverse Reactions/epidemiology , Gene-Environment Interaction , Genetic Predisposition to Disease , Humans , Iatrogenic Disease/epidemiology , Immune System Phenomena/physiology , Infections/complications , Infections/epidemiologyABSTRACT
Autoimmune polyendocrinopathy candidiasis ectodermal dystrophy (APECED) is an autosomal recessive disease caused by mutations in the autoimmune regulator (AIRE) gene, characterized by the clinical triad of chronic mucocutaneous candidiasis (CMC), hypoparathyroidism, and adrenal insufficiency. CMC can be complicated by systemic candidiasis or oral squamous cell carcinoma (SCC), and may lead to death. The role of chronic Candida infection in the etiopathogenesis of oral SCC is unclear. Long-term use of fluconazole has led to the emergence of Candida albicans strains with decreased susceptibility to azoles. CMC is associated with an impaired Th17 cell response; however, it remains unclear whether decreased serum IL-17 and IL-22 levels are related to a defect in cytokine production or to neutralizing autoantibodies resulting from mutations in the AIRE gene.
Subject(s)
Candida albicans/physiology , Candidiasis, Chronic Mucocutaneous/immunology , Carcinoma, Squamous Cell/immunology , Mouth Neoplasms/immunology , Mutation/genetics , Polyendocrinopathies, Autoimmune/immunology , Th17 Cells/immunology , Transcription Factors/genetics , Adrenal Insufficiency , Animals , Autoantibodies/metabolism , Fluconazole/therapeutic use , Humans , Hypoparathyroidism , Polyendocrinopathies, Autoimmune/drug therapy , AIRE ProteinABSTRACT
Lymph node involvement (LNI) is one of the most important prognostic factors for poor survival in medullary thyroid carcinoma (MTC). At diagnosis, LNI is found in over 50% of sporadic MTCs, and especially in large tumours. Cervical lymph node dissection is therefore mandatory during MTC surgery. However, some large tumours (responsible for high preoperative basal calcitonin levels) are found to lack LNI, and can be cured definitely. Preoperative detection of these particular tumours might spare patients from undergoing extensive cervical dissection. The objective of the present retrospective study of a series of large sporadic MTCs was to identify clinical, biological and pathological factors that were predictive of LNI. Consecutive cases of large, sporadic MTCs (measuring at least 1 cm in diameter) were retrieved and reviewed. The levels of several mature microRNAs (miRs) in paraffin-embedded samples were assessed using qPCR. Of the 54 MTCs, 26 had LNI and 28 were pN0. Relative to pN0 patients, patients with LNI had a significant higher preoperative basal calcitonin level (p = 0.0074) and a greater prevalence of infiltrative margins (p < 0.0001), lymphovascular invasion (p = 0.0004), extrathyroidal extension (p < 0.0001), a higher pT stage (p = 0.0003) and more abundant desmoplastic stroma (p = 0.0006). Tumour expression levels of miR-21 (p = 0.0008) and miR-183 (p = 0.0096) were higher in the LNI group. The abundance of desmoplastic stroma (p = 0.007) and the miR-21 expression level (p = 0.0026) were independent prognostic factors for LNI. The abundance of desmoplastic stroma and high levels of miR-21 expression were strong indicators of LNI, and may thus help the surgeon to choose the extent of cervical lymph node dissection for large, sporadic MTCs with no preoperatively obvious LNI.