Microscopic Medullary Thyroid Carcinoma Research Articles

Barriers to the recognition of medullary thyroid carcinoma on FNA: Implications relevant to the new American Thyroid Association guidelines.

The 2016 American Thyroid Association guidelines recommend multiple endocrine neoplasia testing and evaluation for pheochromocytoma before thyroidectomy after a thyroid fine-needle aspiration biopsy (FNA) is positive for medullary thyroid carcinoma (MTC). In the current study, the authors examined the reasons why FNA was unable to definitively diagnose MTC preoperatively, with attention to morphologic patterns that can be misleading. Cases of MTC diagnosed on thyroid surgical resection for which there was a prior FNA and slides available for review were included (28 cases). Clinicopathologic data were collected. Slides were reviewed for numerous features blinded to the original FNA interpretation. Morphologic features were compared between concordant cases (20 cases) ("positive for MTC" or "suspicious for MTC") and discordant cases (4 cases) (any other interpretation). Three cases of microscopic MTC (measuring <1 cm) were excluded from statistical analysis, as was 1 case of sampling error (benign thyroid tissue). Nine men and 19 women were diagnosed with MTC. Four patients ultimately were diagnosed with multiple endocrine neoplasia, and 1 had bilateral pheochromocytomas. At the time of surgical excision, the mean tumor size was 2.3 cm (range, 0.1-7.5 cm). Review of morphologic features demonstrated that the discrepant cases were significantly more likely to have limiting factors (air-drying artifact/excess blood), a cohesive pattern, or to lack plasmacytoid morphology. None of the discordant cases had pseudoinclusions or amyloid (finding was not statistically significant). The majority (86%) of thyroid FNAs from patients with MTC are concordant (positive/suspicious for MTC). Patterns of failure include sampling error and limited typical morphologic features, particularly a lack of plasmacytoid morphology and cellular dyshesion. A high level of suspicion for MTC is critical to ensure patients receive appropriate preoperative testing. Cancer Cytopathol 2018;126:397-405. © 2018 American Cancer Society.

Medullary thyroid cancer in a 9-week-old infant with familial MEN 2B: Implications for timing of prophylactic thyroidectomy

BackgroundPatients with Multiple Endocrine Neoplasia type 2 (MEN 2) are at high risk of developing aggressive medullary thyroid carcinoma (MTC) in childhood, with the highest risk in those with MEN type 2B (of whom >95% have an M918T RET proto-oncogene mutation). Metastatic MTC has been reported as young as 3 months of age. Current guidelines recommend prophylactic thyroidectomy within the first year of life for MEN 2B.Patient findingsWe report a 9-week-old infant with MTC due to familial MEN 2B. A full-term male infant, born to a mother with known MEN 2B and metastatic MTC, had an M918T RET proto-oncogene mutation confirmed at 4 weeks of age. He underwent prophylactic total thyroidectomy at 9 weeks of age. Pathology showed a focal calcitonin-positive nodule (2.5 mm), consistent with microscopic MTC.SummaryThis case highlights the importance of early prophylactic thyroidectomy in MEN 2B. Although current guidelines recommend surgery up to a year of life, MTC may occur in the first few weeks of life, raising the question of how early we should intervene. In this report, we discuss the risks, benefits and barriers to performing earlier thyroidectomy, soon after the first month of life, and make suggestions to facilitate timely intervention. Prenatal anticipatory surgical scheduling could be considered in familial MEN 2B. Multidisciplinary collaboration between adult and pediatric specialists is key to the optimal management of the infant at risk.

A New Germline Point Mutation in Ret Exon 8 (Cys515Ser) in a Family with Medullary Thyroid Carcinoma

A novel Cys-Ser Ret germline point mutation in a 58-year-old woman with bilateral medullary thyroid carcinoma (MTC) prompted us to perform genetic analysis of the family and evaluate the biological consequences of such a mutation. Ret analysis by direct sequencing was performed in five family members. The biological activity and biochemical properties of the Ret- Cys515Ser mutant were analyzed in NIH-3T3 cells. The proband's son, age 35, had the Ret- Cys515Ser mutation and the L769 CTT/CTG exon 13 polymorphic variant, which was also found in his father. Clinical evaluation of the son also revealed bilateral multifocal microscopic MTC and papillary thyroid carcinoma (PTC). In vitro and in vivo analysis indicated ligand-independent activation of the Ret-Cys515Ser mutant due to aberrant disulfide homodimerization, increased mitogenic activity, and ability to induce anchorage-independent growth in NIH-3T3 cells in comparison to wild-type Ret, suggesting a possible role of Cys515Ser in tumor development. The Cys515Ser mutation adds to cysteine substitution groups that have been described in association with MTC. Our data also highlight the importance of performing a complete genetic analysis in patients who present with MTC.

Tiroidectomía profiláctica en niños y jóvenes con cáncer medular tiroideo hereditario: Experiencia chilena

With the availability of the RET proto-oncogene genetic testing, it is possible to perform prophylactic total thyroidectomy among carriers of RET mutation. To evaluate the histological findings and the effects of the prophylactic total thyroidectomy in first-degree relatives of Chilean patients with multiple endocrine neoplasia type 2 (MEN 2) based on the Ret proto-oncogene analysis. Nineteen patients belonging to 11 MEN 2 families underwent total thyroidectomy. Of these, 16 either with C cell hyperplasia (CCH) or microscopic medullary thyroid carcinoma (MTC) were selected for the final analysis. The age at the moment of thyroidectomy ranged from 3 to 24 years (median 9.5). The most common mutation was located in codon 634 (69%) followed by codon 620 (25%). Histopathology revealed MTC in 13 patients (81%, youngest 3 years, oldest ones 19 and 24 years) and CCH in 3. A significant correlation was observed between basal preoperative serum calcitonin/tumor size (r = 0.53, P < 0.05) and age/tumor size (r = 0.56, P < 0.03), but not between basal preoperative serum calcitonin and age. Stimulated preoperative calcitonin levels were confounding and not useful for differentiating CCH from MTC. None of patients in whom cervical dissection was done (9/16) presented lymph node metastases, including the oldest ones. All patients but the older ones were biochemically cured after a mean of 5 years of follow-up. Prophylactic total thyroidectomy should be done early in life because there is an age-dependent progression from HCC to MTC. MTC often precedes biochemical detection of the disease.

Can Sporadic Medullary Thyroid Carcinoma Be Biochemically Predicted? Prospective Analysis of 66 Operated Patients with Elevated Serum Calcitonin Levels

Measuring serum calcitonin (CT) in patients with thyroid diseases allows preoperative diagnoses of sporadic medullary thyroid carcinoma (MTC) and C-cell hyperplasia (CCH). The aim of this prospective study was to distinguish biochemically between CCH and MTC. Basal CT (bCT) was determined in 7276 consecutive patients referred for thyroid disease. Patients with recurrent, persistent, or familial MTC were excluded. When bCT was > 10 pg/ml a pentagastrin-stimulated CT (sCT) assay was performed. Patients were routinely operated on when bCT > 30 pg/ml or sCT > 100 pg/ml or when other indications for surgery were present. An extensive search for CCH or microscopic MTC was conducted by immunochemistry. Pathologic findings were correlated with the bCT and sCT values. In this study 66 patients were included. No morphologic alterations of C-cells were observed in 5 patients; 16 patients presented with CCH and 45 with MTC. Statistical analysis revealed a correlation of sCT and overall bCT with tumor size and staging (p <0.001). Considering cutoff values for bCT of < or = 30 pg/ml and for sCT of < or = 200 pg/ml, the positive predictive value of the test to detect MTC was 100% and the negative predictive value 63%. No patients with MTC at stage 2 to 4 had bCT <30 pg/ml or sCT <200 pg/ml. A bCT value of < or = 30 pg/ml or sCT < or = 200 pg/ml (or both) is highly predictive of MTC, requiring total thyroidectomy with lymph node dissection. Values of bCT <30 pg/ml and sCT <200 pg/ml do not distinguish between CCH and MTC at stage 1. In this case total thyroidectomy at least is recommended, and the role of nodal dissection might be discussed.

RET mutation profile and variable clinical manifestations in a family with multiple endocrine neoplasia type 2A and Hirschsprung's disease

Background. RET proto-oncogene germ line mutations are associated with the inherited multiple endocrine neoplasia type 2 syndromes (MEN 2), as well as with familial and sporadic Hirschsprung's disease (HSCR). In this study, we report a family in which the MEN 2A and the HSCR phenotypes are associated with a single point mutation in exon 10 of the RET proto-oncogene. Furthermore, we have investigated polymorphic sequence variants of the RET proto-oncogene. Methods. Family members were tested for RET proto-oncogene mutations in exons 10, 11, 13, 14, 15, and 16 by double-gradient denaturing-gradient gel electrophoresis, nucleotide sequence analysis, and restriction endonuclease digestion of polymerase chain reaction products. The status of exon 2 and 13 polymorphic sites was investigated by EagI and TaqI digestion in 12 selected patients. Results. A heterozygous C618R mutation of RET exon 10 was identified in 12 family members. Five out of 7 children with mildly elevated pentagastrin-stimulated calcitonin levels who carried the mutation underwent prophylactic thyroidectomy before the age of 12. C-cell hyperplasia (CCH) was found in 4 children and a microscopic medullary thyroid carcinoma (MTC) in an 8-year-old female. Neither CCH nor MTC was found in the only family member affected with HSCR, an 8-year-old male. This patient inherited the mutated RET allele from his mother, who had MTC but not HSCR, together with a rare allelic variant at codon 45 of RET exon 2. Conclusions. This report of a newly-described kindred with the infrequent clinical association between MEN 2A and HSCR confirms the risk of the latter phenotype among carriers of RET exon 10 cysteine codon mutations. Nevertheless, the influence of other genetic or environmental factors cannot be excluded. (Surgery 2002;131:373-81.)

Interest of routine measurement of serum calcitonin: study in a large series of thyroidectomized patients. The French Medullary Study Group.

The aim of our study was to assess the ability of routine calcitonin (CT) measurement to improve the preoperative diagnosis of medullary thyroid carcinoma (MTC) in nodular thyroid diseases. We systematically determined basal CT in 1167 patients before thyroid surgery and performed a pentagastrin (Pg) CT stimulation test in 121 of these patients whose basal CT level was normal. Sixteen MTC (1.37%) were found on histopathological examination of surgical specimens: 14 in the 34 patients (41.1%) with abnormal basal CT levels and 2 in the 1133 patients with normal basal CT levels (0.17%). An abnormal increase in Pg-stimulated CT was observed in 7 of the 121 patients tested and was related to microscopic MTC in 2 cases. Among 1167 thyroidectomized patients with nodular thyroid diseases, the prevalence of MTC was 1.37% and reached 41.1% when the basal CT level was abnormal (3% of the patients). CT evaluation detected MTC, whereas other procedures, such as fine needle aspiration cytology, failed, thus allowing early radical surgery. CT measurement should thus become a routine part of the diagnostic evaluation of nodular thyroid diseases.

Immunostaining for collagen type IV can help distinguish between C-cell hyperplasia and microscopic medullary thyroid carcinoma

Immunostaining for collagen type IV can help distinguish between C-cell hyperplasia and microscopic medullary thyroid carcinoma

The prognostic and biological significance of cellular heterogeneity in medullary thyroid carcinoma: a study of calcitonin, L-dopa decarboxylase, and histaminase.

We evaluated the cellular distribution of calcitonin (CT), L-dopa decarboxylase (DDC), and histaminase [diamine oxidase (DAO)] in 33 patients with medullary thyroid carcinoma (MTC). CT immunostaining was uniform (greater than 90% of the cells) and intense (4+) in lesions from 7 patients with C-cell hyperplasia and 6 with microscopic MTC: conversely, patchy CT staining (less than 40% of the cells) and diminished intensity (1+) were found in metastases from 8 patients who died of virulent disease. In 17 patients who underwent thyroidectomy for macroscopic cervical MTC with no evidence distant metastases, CT staining was intense (3-4+) and homogeneous (greater than 90%) in 11 subjects who were well 0.5-16 yr postoperatively. Six patients with similar clinical presentations had heterogeneous staining for CT in primary tumor (less than 40% of the cells; 1-2+ intensity); 5 died of disseminated MTC 0.5-5 yr postoperatively (P less than 0.001). Biochemical studies of distant metastases revealed an inverse relationship between the distribution of CT and that of both relationship between the distribution of CT and that of both DDC (r = 0.71; P less than 0.01) and DAO (r = 0.81; P less than 0.001). We conclude that cellular heterogeneity in MTC tissue is associated with a distinct biochemical pattern, and its presence, whether in a primary or metastatic lesion, indicates a virulent neoplasm associated with a grave prognosis.

Light-electron microscopic and cytochemical studies on the morphogenesis of familial medullary thyroid carcinoma.

Six cases of familial medullary thyroid carcinoma (MTC) were investigated by light and electron microscopy as well as by ultracytochemical methods. Light microscopic examination revealed multifocal C-cell proliferation in 5 subjects. These cells were mostly limited to thyroid follicles, but occasionally extended across the follicular capsule forming microscopic MTC. Electron microscopic examination showed that, in some follicles, the proliferating C-cells were still covered by a continuous layer of follicular cells, whereas in others the proliferation extended to the follicular center. C-cells were in direct contact with the colloid, and ultramicroinvasion of the follicular capsule was detected. These observations are consistent with the hypothesis that familial MTC seems to begin as multifocal C-cell proliferation, limited at first to thyroid follicles, between the capsule and the follicular epithelium. Later, the proliferation extends to the follicular center, and C-cells come in contact with the colloid, at which time an in situ carcinoma stage is reached. Some neoplastic cells invade the follicular capsule and, finally, multiple MTC appear and eventually conglomerate. Generally, there were no constant morphologic criteria for a dysplasia or neoplasia among the proliferating C-cells limited to thyroid follicles, when compared with normal or even malignant C-cells. For these reasons, a hyperplastic or dysplastic process preceding MTC cannot be clearly distinguished from a neoplastic process. Our study, however, shows that a light microscopic, apparently hyperplastic process may be a malignant one. Amyloid was present in the more voluminous MTC, associated with tumor cell necrosis, but it was not evident in small MTC and within the foci of C-cell proliferation. Ultracytochemical techniques revealed that the secretory granules of normal, proliferating and neoplastic C-cells contained polysaccharides and/or glycoproteins.