Diagnosis Of Medullary Thyroid Cancer Research Articles

Ultrasonography Should Not Guide the Timing of Thyroidectomy in Pediatric Patients Diagnosed with Multiple Endocrine Neoplasia Syndrome 2A through Genetic Screening

American Thyroid Association (ATA) guidelines suggest that thyroidectomy can be delayed in some children with multiple endocrine neoplasia syndrome 2A (MEN2A) if serum calcitonin (Ct) and neck ultrasonography (US) are normal. We hypothesized that normal US would not exclude a final pathology diagnosis of medullary thyroid cancer (MTC). We retrospectively queried a MEN2A database for patients aged<18 years, diagnosed through genetic screening, who underwent preoperative US and thyroidectomy at our institution, comparing preoperative US and Ct results with pathologic findings. 35 eligible patients underwent surgery at median age of 6.3 (range 3.0-13.8) years. Mean MTC size was 2.9 (range 0.5-6.0) mm. The sensitivity of a US lesion≥5 mm in predicting MTC was 13% [95% confidence interval (CI) 2%, 40%], and the specificity was 95% [95% CI 75%, 100%]. Elevated Ct predicted MTC in 13/15 patients (sensitivity 87% [95% CI 60%, 98%], specificity 35% [95% CI 15%, 59%]). The area under the receiver operating characteristic curve (AUC) for using US lesion of any size to predict MTC was 0.50 [95% CI 0.33, 0.66], suggesting that US size has poor ability to discriminate MTC from non-MTC cases. The AUC for Ct level at 0.65 [95% CI 0.46, 0.85] was better than that of US but not age [AUC 0.62, 95% CI 0.42, 0.82]. In asymptomatic children with MEN2A diagnosed by genetic screening, preoperative thyroid US was not sensitive in identifying MTC of any size and, when determining the age for surgery, should not be used to predict microscopic MTC.

Approach to the patients with medullary thyroid cancer

Medullary thyroid cancer (MTC) is characterized hy the secretion of calcitonin that is derived from parafollicular cells.20％-25％ of MTC are hereditary.Compared with other types of thyroid cancer,MTC is prone to recurrence,metastasis,and younger onset age.RET gene germline mutation accounts for the hereditary MTC,and somatic mutation is responsible for part of sporadic cases.A good correlation between phenotype and genotype is reported.We present in this article a case of medullary thyroid cancer patient with genetic diagnosis and treatment as well as postoperative follow-up together with RET gene screening results in her family members in order to call attention to the diagnosis and treatment of MTC. Key words: Medullary thyroid cancer; Calcitonin; RET gene; Multiple endocrine neoplasia

Evaluación de la eficacia y del impacto clínico de la PET-18F-FDG en el diagnóstico de recurrencia del carcinoma medular de tiroides con calcitonina elevada y pruebas de imagen negativas

AimTo evaluate the efficacy and clinical impact of the FDG-PET in the diagnosis of suspicion of recurrence of medullary thyroid cancer (MTC) in patients with elevated serum calcitonin and negative imaging test. Material and methodsWe performed a retrospective study of 31 consecutive cases from february 2001 to october 2007 of 17 women and 14 men, mean age 56.2 years (range: 26-88), with anatomical-pathology diagnosis of medullary thyroid cancer and suspicion of recurrence due to abnormal elevation of calcitonin and negative imaging tests. All of the patients underwent whole body FDG-PET scan with a dedicated PET or PET-CT 60minutes after intravenous injection of 333-434 MBq of 18F-FDG. Results were confirmed by pathology study in 45.2% of the patients and by clinical follow-up with a mean of 4 years (range: 16 m-8 years) ResultsSensitivity was 88%, specificity 84.6%, positive predictive value 88%, negative predictive value 84.6% and diagnostic accuracy 87%. The results of the FDG PET modified the therapeutic strategy in 14 cases (45.2%). A comparison was made of the mean values of calcitonin using the Student's «t» test between positive PET studies for the disease and negative ones. No significant differences were found (P=.3). ConclusionsIn patients with MTC and suspected recurrence with elevated calcitonin and negative imaging test, the FDG is the best test for the diagnosis of occult recurrence in MTC with elevated calcitonin and negative imaging techniques with elevated clinical impact. It facilitates the therapeutic management of the patients with MTC recurrence, and should be included in the diagnosis algorithm in these patients.

Clinical relevance of RET variants G691S, L769L, S836S and S904S to sporadic medullary thyroid cancer

Based on reports of higher frequencies among patients with sporadic medullary thyroid cancer (MTC) relative to external controls, the RET (REarranged during Transfection) variants G691S, L767L, S836S and S904S have been considered disease modifiers, suggesting greater lifetime risks of MTC. Other studies, employing different external controls, failed to confirm this association. Using a complementary approach, this study aimed at exploring differences in clinico-pathological characteristics among patients with sporadic MTC carrying no (wildtype), one (heterozygotes) or both (homozygotes) homologue RET variants in the germline, with wildtype cases acting as internal controls. Included in this investigation were 150 patients with complete genetic information on G691S, L769L, S836S and S904S RET alleles operated on for sporadic MTC at a tertiary referral centre. Not one statistically significant dose-response relationship was identified between any RET variant (wildtype vs RET heterozygotes vs homologue RET homozygotes) and patient age at MTC diagnosis, gender, primary tumour size, extrathyroidal extension, numbers of involved and removed lymph nodes, or distant metastasis. L769L and S836S homozygotes, unlike G691S and S904S homozygotes, were either rare or absent, limiting the analyses to comparisons of heterozygosity versus wildtype. On time-to-event analysis, G691S, L769L, S836S or S904S carriers and noncarriers developed MTC at similar rates. In carriers and noncarriers of the RET variants G691S, L767L, S836S and S904S, sporadic MTC appeared clinically and pathologically indistinguishable. This observation, along with the inconclusive evidence of previous association studies, calls for larger longitudinal association studies with age- and sex-matched external controls and additional functional studies of RET biology.

Calcitonin screening in patients with thyroid nodules

SummaryAim: The positive predictive value (PPV) of a slightly elevated basal calcitonin (CT) for the diagnosis of medullary thyroid cancer (MTC) is still under debate. Patients, methods: A total of 11 270 patients with thyroid nodules underwent calcitonin screening. Patients with known elevation of CT, renal insufficiency, bacterial infection, alcohol abuse, protonpump inhibitor therapy or autoimmune thyroid disease were excluded from further analysis. Serum CT was determined by the solid-phase, enzyme-labeled, two-site chemiluminescent immunoassay Immulite 2000. If possible, a pentagastrin test was done to differentiate cases of hypercalcitoninaemia. Results: Hypercalcitoninsemia was found in 32 patients. 20 patients underwent surgery. In 10 patients a MTC was found. The PPV of hyper calcitoninaemia for MTC was 31%. The PPV increased to 50% for those patients who underwent surgery (10/20). A subgroup of 26 patients presented with basal CT between 13 and 50 pg/ml, 14 of them underwent surgery, in 4 cases evidence of MTC was revealed. This resulted in a PPV of 15% (4/26), although the value increased to 28% when only surgically treated patients were considered (4/14). Conclusion: Taking all clinical data into account, calcitonin screening has an acceptable PPV for medullary thyroid cancer in patients with thyroid nodules. Therefore, we recommend calcitonin screening in centers for thyroid disorders.

Medullary thyroid cancer in the past, present and future: from bench to bedside

The diagnosis and treatment of medullary thyroid cancer (MTC) has changed considerably over the past 40 years, although survival has not improved over the past three decades. From the first clinical descriptions of MTC and the multiple endocrine neoplasia syndromes to the identification of the RET proto-oncogene, the concept of prophylactic thyroidectomy has become a reality for some families. The surgery is usually performed by high-volume surgeons in specialized centers with results that rarely leave patients with complications but with maximum survival benefit. For patients with unresectable or metastatic disease, many new targeted agents have been developed, some of which have shown great promise and are close to being approved for a disease which hitherto has had no systemic treatment options. This article highlights the important advances in the diagnosis and management of MTC.

Diagnosis of medullary thyroid cancer

Medullary thyroid cancer (MTC) accounts for 5-10% of all thyroid cancers. The majority of medullary thyroid cancers are sporadic, but 25% of cases are inherited as a result of germline mutations in the RET proto-oncogene. In sporadic cases MTC presents as a thyroid nodule discovered at palpation or at thyroid ultrasonography, and is indistinguishable from thyroid nodules of different histology. Since effective treatment of MTC is only possible when the tumour is limited to the thyroid gland, early discovery has a decisive impact on how radical initial surgical treatment needs to be. Recent data suggest that in sporadic cases, early discovery of thyroid nodular disease is possible when screening serum calcitonin measurement, while screening for germline RET proto-oncogene mutations is fundamental in first degree relatives of patients with hereditary MTC.

Medullary thyroid cancer: early detection and novel treatments

Medullary thyroid cancer (MTC) is derived from the parafollicular cells of the thyroid. Understanding the molecular biology behind specific mutations of the RET gene and their prognostic implications have led to the establishment of tailored treatment modalities for certain patients. We review the most recent studies on the molecular biology, calcitonin screening, diagnosis, imaging, and treatment of MTC. Newly identified rearranged during transfection point mutations have helped with MTC prognosis and have resulted in the establishment of new treatment guidelines. Screening for MTC in the United States with basal serum calcitonin for patients with thyroid nodules would cost $11,793 per life-year saved (LYS), compared with colonoscopy and mammography screening. For metastatic or recurrent disease, neck ultrasound, chest computed tomography scan, liver MRI, bone scintigraphy, and axial skeleton MRI have been proven superior to 18F-FDG PET/computed tomography. For patients with nonoperable metastatic disease, novel chemotherapeutic agents, such as vandetanib, targeting rearranged during transfection, vascular endothelial growth factor receptor and epidermal growth factor receptor, are showing promise. Such agents are currently in phase II trials. There have been several recent advances in the diagnosis, molecular biology, imaging, and treatment options of MTC. By potentially downstaging of disease, and treating metastatic disease more effectively, overall survival and outcomes of patients may improve.

Medullary Thyroid Cancer Responsiveness to Pentagastrin Stimulation: An Early Surrogate Parameter of Tumor Dissemination?

Because of its outstanding sensitivity, stimulation of calcitonin secretion with iv injection of pentagastrin is widely used for biochemical diagnosis of medullary thyroid cancer. The objective of this study was to explore the relationship between the results of the pentagastrin stimulation test and extent of disease in patients with previously untreated medullary thyroid cancer. This was a retrospective study. The investigation took place at a tertiary referral center. Included were 89 patients with increased basal calcitonin levels who had a pentagastrin test at this institution before initial neck surgery for medullary thyroid cancer. Measurements included basal and stimulated calcitonin levels, carcinoembryonic antigen levels, primary tumor diameter, extrathyroidal extension, lymph node metastases, and distant metastases. There was a strong dose-dependent relationship between a less than 10-fold increase in preoperative calcitonin levels after iv stimulation with pentagastrin and both the frequency (41-54 vs. 4-27%; P = 0.001) and number (means of 3.0-10.8 vs. 0-1.1 positive nodes, P < 0.001) of lymph node metastases. Weaker associations were identified with the respective frequency of extrathyroidal extension (14-27 vs. 0-7%; P = 0.027), distant metastasis (9-23 vs. 0%; P = 0.017), and postoperative normalization of calcitonin (40-55 vs. 53-82%; P = 0.029). On multivariate analysis, only lymph node metastases were associated with a less than 10-fold increase in preoperative calcitonin levels. Based on these clinical data and preclinical literature, reduced responsiveness to stimulation with pentagastrin may reflect early dedifferentiation. Evidence of this condition may enable early risk stratification in patients with medullary thyroid cancer.

Abnormal Carcinoembryonic Antigen Levels and Medullary Thyroid Cancer Progression

Medullary thyroid cancer cells are capable of secreting carcinoembyronic antigen (CEA). An abnormal preoperative CEA level may have important implications for the management of this condition. Retrospective analysis. Tertiary referral center at a university hospital. One hundred fifty patients with a histopathologic diagnosis of medullary thyroid cancer and preoperative CEA measurements using the same assay. Main Outcome Measure We used univariate and multivariate analyses to quantify the relationship between preoperative CEA level and tumor progression. On multivariate analysis, abnormal preoperative CEA levels were significantly associated with the initial operation rather than reoperation, larger primary tumors, positive lymph nodes, and distant metastasis. When analyses were limited to the 54 patients with increased CEA levels before the initial operation, there was a respective significant association between successive CEA levels (4.7-10.0, 10.1-30.0, 30.1-100.0, and >100.0 ng/mL) and lymph node metastases (>10 positive nodes: 0%, 9%, 53%, and 69% [P<.001]), involvement of cervical lymph node compartments (central: 33%, 36%, 73%, and 93% [P=.002]; lateral [ipsilateral]: 20%, 27%, 67%, and 88% [P=.001]; and lateral [contralateral]: 22%, 10%, 36%, and 73% [P=.008]), and distant metastasis (0%, 27%, 13%, and 75% [P<.001]). When CEA levels exceeded 30.0 ng/mL, surgical cure was exceptional. In medullary thyroid cancer, an abnormal CEA level heralds advanced disease. Carcinoembryonic antigen levels greater than 30.0 ng/mL indicate central and lateral (ipsilateral) lymph node metastases, whereas CEA levels greater than 100.0 ng/mL signify lateral (contralateral) lymph node metastases and distant metastasis.

Detection of Occult Medullary Thyroid Cancer Recurrence with 2-Deoxy-2-[F-18]fluoro-d-glucose-PET and PET/CT

2-deoxy-2-[F-18]fluoro-D-glucose (FDG)-positron emission tomography (PET) has an established role in restaging of various cancers, including papillary and undifferentiated thyroid carcinoma. However, controversies exist regarding its ability to reliably assess recurrent medullary thyroid cancer (MTC). We were therefore prompted to review our experience with FDG-PET for detection of occult MTC. This is a retrospective study (Apr 1, 1997-Mar 31, 2004) of 13 patients with histologic diagnosis of MTC, who had PET examinations. The group included six men and seven women, 15-62 years old (average: 48+/-13). The PET scan request was triggered by rising levels of calcitonin and negative anatomical imaging studies. Recurrent/metastatic disease was identified by PET in seven (54%) of the 13 patients. The lesions were located in superior mediastinum (4), cervical lymph nodes (3), thyroid bed (2), lung (1) and liver (1). The calcitonin levels ranged from 52 to 5,090 pg/ml (average: 1,996 pg/ml) in patients with negative PET scans and from 132 to 9,500 pg/ml (average: 3,757 pg/ml) in patients with positive studies. The sensitivity and specificity of FDG-PET for disease detection in this cohort were 85.7% (95% CI: 48.7-97.4) and 83.3% (95% CI: 43.6-96.9), respectively. Our findings suggest a significant role for FDG-PET in patients with suspected MTC recurrence, with sensitivity of 85.7% and specificity of 83.3% for disease detection. FDG-PET provides additional information in a significant fraction of cases (54%) and could be used for restaging of patients with MTC and elevated levels of biomarkers (calcitonin). Additional studies are necessary to further evaluate the role of FDG-PET in MTC.

Natural history, diagnosis, treatment and outcome of medullary thyroid cancer: 37 years experience on 157 patients

Aim The analysis of a 37-year retrospective study on diagnosis, prognostic variables, treatment and outcome of a large group of medullary thyroid cancer (MTC) patients was conducted, in order to plan a possible evidence-based management process. Methods Between Jan 1967 to Dec 2004, 157 consecutive MTC patients underwent surgery in our centre: 60 males and 97 females, mean age 47.3 years (range 6–79). Total thyroidectomy was performed in 143 patients (91.1%); central compartment (CC) node dissection (level VI) in 41 patients; central plus lateral compartment (LC) node dissection (levels II, III, and IV) in 82 patients. Subtotal thyroidectomy was initially performed in 14 cases: 10 of them were re-operated because of persistence of elevated serum calcitonin levels. Results After a median post-surgical follow-up of 68 months (range 2–440 months), 42.9% of patients were living disease-free, 39.8% were living with disease, 3.1% were deceased due to causes different from MTC, and 3.2% were deceased due to MTC. The overall 10-year survival rate was 72%. At uni-variate statistical analysis (a) patient's age at initial treatment (>45 years; ≥45 years), (b) sporadic vs. hereditary MTC, (c) disease stage, and (d) the extent of surgical approach resulted as significant variables. Instead, at multivariate statistical analysis, only (a) patient's age at initial diagnosis, (b) disease stage, and (c) the extent of surgery resulted as significant and independent prognostic variables influencing survival. Conclusion The presence of lymph node and distant metastases at first diagnosis significantly worsened prognosis and survival rate in our series. Early diagnosis of MTC is very important, allowing complete surgical cure in Stages I and II patients. Due to the relatively bad prognosis of MTC, especially for disease Stages III and IV, it appears reasonable to recommend radical surgery including total thyroidectomy plus CC lymphoadenectomy as the treatment of choice, plus LC lymphoadenectomy in patients with palpable and/or ultrasound enlarged neck lymph nodes.

Prognosis of medullary thyroid carcinoma

Medullary thyroid cancer (MTC) is a rare cancer. There is a relative paucity of data over the last decade with regard to the prognosis of these patients. Therefore, the authors used the population-based Surveillance, Epidemiology, and End Results (SEER) registry to update what to their knowledge is one of the largest series of patients with MTC reported to date. All patients with a diagnosis of MTC with active follow-up in the SEER database from 1973 to 2002 were included. Univariate and multivariate regression analyses were used to assess the associations between demographic, clinical, and pathologic characteristics of patients and survival. A total of 1252 patients with MTC were identified over 29 years of follow-up. In all, 87% of patients were white and 60% were female, with a mean age of 50 years. Although many variables were significant on univariate analysis, SEER stage and age at diagnosis were found to be the strongest predictors of survival in the multivariate analysis. Prognosis was poor in patients with advanced disease (hazards ratio [HR], 4.47), or those age >65 years (HR, 6.55). Patients who underwent surgery fared better than those who did not. Overall, 51% of patients had less than the currently recommended treatment guidelines for MTC. Adjuvant radiation therapy was found to be independently associated with a decreased survival (HR, 1.65). Stage of disease and age at diagnosis were found to be the strongest predictors of survival for patients with MTC. To the authors' knowledge there has been no change in stage at diagnosis or a significant improvement in survival noted over the last 30 years. Many patients underwent surgery that was deemed less than optimal for stage of disease.

Extent of Disease and Practice Patterns for Medullary Thyroid Cancer

There have been significant improvements in the management of medullary thyroid cancer (MTC), and consensus treatment guidelines have been established by numerous international and national societies. It is unclear if the advances in diagnosis and treatment of MTC have led to earlier diagnosis and more complete initial treatment of patients with MTC. Patients with MTC (n=1,070) were identified in the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) database from 12 population-based cancer registries between 1973 and 2000. Four equal-time quartiles (group I=1973 to 1979, group II=1980 to 1986, group III=1987 to 1993, and group IV=1994 to 2000) were compared for changes in demographics, extent of disease, and treatment. Mean tumor size was significantly larger in 1988 than in 1989 through 2000 (p=0.044), but there was no significant trend toward smaller tumor size. The number of patients having total or near total thyroidectomy increased significantly in the latter two quartiles (p < 0.001) but not the number of patients having cervical lymph node dissection. Unfortunately, 15% of patients in group IV still had less than total or near total thyroidectomy, and 41% had no cervical lymph node dissection. There were no significant differences in age, gender, rate of lymph node or distant metastasis, SEER stage, TNM stage, and cause-specific mortality among the four time groups and annually. There was no significant trend toward earlier stage of disease at diagnosis and treatment and no significant increase in the survival of patients with MTC during a 28-year period. A high proportion of patients continue to receive less than optimal initial surgical treatment.

Identification of calcitonin and calcitonin gene-related peptide messenger ribonucleic acid in medullary thyroid carcinomas by hybridization histochemistry.

Synthesis and secretion of calcitonin and calcitonin gene-related peptide (CGRP) were studied in medullary thyroid carcinomas (MTC) by hybridization histochemistry on tissue sections and by Northern gel analysis of mRNA. Five patients with MTC and elevated serum levels of calcitonin and CGRP were studied. Surgically obtained tumor samples (four primary and three lymph node metastases) were extracted after freezing, and the RNA was fractionated on Northern gels. Hybridization was carried out with 32P-labeled synthetic oligodeoxyribonucleotides coding specifically for calcitonin and CGRP. Calcitonin- and CGRP-specific mRNAs approximately 1000 nucleotides in length were demonstrated in all 7 tumor samples. However, neither calcitonin nor CGRP mRNA was detected in a pheochromocytoma from 1 of the patients who had multiple endocrine neoplasia type II. A series of unselected lung carcinomas yielded the same result. Hybridization histochemistry was carried out on sections from the same tumors using the same probes. The mRNAs for calcitonin and CGRP were located in all cells of neoplastic MTC appearance, with CGRP mRNA at significantly lower levels. This demonstrated that both calcitonin and CGRP mRNA were present within the same tumor cells. The lung tumors and pheochromocytoma were negative with both probes. Hybridization histochemistry is likely to be of use in diagnosis of medullary thyroid cancer and in studying the calcitonin-CGRP mRNA processing mechanism in whole cells.

Urine Calcitonin as a Test for Medullary Thyroid Cancer

Although the radioimmunoassay of serum calcitonin (CT) has facilitated the diagnosis of medullary thyroid cancer (MTC) one may encounter patients whose basal serum levels of CT are normal or nearly normal. In such cases clinicians have utilized intravenous stimulation tests such as calcium or pentagastrin to obtain a diagnostic increase in serum CT. We have reported finding immunoreactive CT in the urine of man and have found it to be a useful technique for the diagnosis and study of patients at risk for MTC or other hypercalcitonemic diseases. Using basal urine CT alone we were able to separate 73% of patients at risk for MTC into clearly normal or abnormal groups. For the remaining 27% a stimulation test with subsequent determination of urine CT was required. The radioimmunoassay of urine CT is a simple, reliable, accurate test for the screening diagnosis of MTC. A protocol for the screening workup of a patient at risk for MTC is given.