Preoperative Calcitonin Research Articles

Medullary thyroid carcinoma with double negative calcitonin and CEA: a case report and update of literature review

BackgroundMedullary thyroid carcinoma is a malignant uncommon and aggressive tumour of the parafollicular C cells. In about 75% of cases it is sporadic while, in case of RET mutation, it is associated to multiple endocrine neoplasia type 2 (25% of cases). The biochemical features of medullary thyroid carcinoma include the production of calcitonin and carcinoembryogenic antigen. The above-mentioned features are useful in the diagnostic process as well as in the follow up and in the prognostication of the disease. Even if calcitonin elevation is strongly associated to MTC, it can also be found increased in many pathological different conditions as pregnancy, lactation, C-cells hyperplasia, autoimmune thyroiditis, end stage renal disease, lung and prostate cancer and several neuroendocrine tumours. Major medullary thyroid tumours are usually connected to high doses of circulating calcitonin, in fact non-secretory variants have hardly been described.Case presentationWe herein report the case of a 59 years old male, who had undergone total thyroidectomy for multinodular goiter with negative preoperative calcitonin, showing medullary thyroid carcinoma at definitive pathology. To the best of our knowledge, this is the first case documenting a non-secretory medullary thyroid carcinoma, with double negative markers at the time of diagnosis and at the relapse.ConclusionA Literature review underlining pathological hypothesis, differential diagnosis and alternative and innovative biomarkers to identify non-secretory medullary thyroid carcinoma was carried out.

Long-Term Oncologic Outcomes After Curative Resection of Familial Medullary Thyroid Carcinoma.

Long-term outcomes after curative resection in patients with germline RET mutations and medullary thyroid cancer (MTC) are highly variable and mutation-specific oncologic outcomes are not well-described. Sixty-six patients identified from 1986 to 2017 from a single-institution cancer database were assessed for recurrence and survival using Kaplan-Meier estimates, and correlated with clinicopathologic features using log-rank or Cox proportional hazards. Median follow-up was 9.3years (range 0.3-31.5), median tumor diameter was 1.5cm (range 0.1-7.5), and preoperative calcitonin was known in 41 patients [median 636 (range 0-9600)]. Overall survival (OS) of the cohort was 94% at 10years, the cumulative incidence of locoregional recurrence was 38% at 10years, and 19/24 (79%) patients underwent repeat neck operation. The cumulative incidence of distant recurrence was 27% at 10years. Predictors of distant recurrence were tumor size, positive lymph nodes, and pre- and postoperative carcinoembryonic antigen, but not calcitonin. M918T mutation-bearing patients had 10-year distant recurrence-free survival of 0%, compared with 83% in all other patients (p < 0.001), and equivalent 10-year OS (100% vs. 92%; p = 0.49). Structural and metastatic recurrence is common in patients with germline RET mutations, and MTC and can occur 20years after initial treatment, however survival remains high. Management should focus on optimal surveillance strategies and long-term control of structural disease.

Prediction of lateral neck lymph node metastasis according to preoperative calcitonin level and tumor size for medullary thyroid carcinoma.

Medullary thyroid carcinoma (MTC) accounts up to 10% of all thyroid cancers, but is responsible for a disproportionate number of deaths. While surgery is the only curative treatment for MTC, indications for lateral neck lymph node (LLN) dissection are controversial. We performed a retrospective review to describe clinical outcomes in 93 MTC patients from July 1995 to March 2015. We analyzed their clinicopathologic factors, and cut-off values of tumor size and calcitonin levels were calculated using a receiver operating characteristic curve. Using the instances of lymph node metastases, the tumor size cut-off value was 0.95 cm (area under curve, AUC = 0.697) in patients with ipsilateral central lymph node (CLN) metastases, 2.25 cm (AUC = 0.793) in contralateral CLN metastases, and 1.75 cm (AUC = 0.753) in ipsilateral LLN metastases. The cut-off values of preoperative calcitonin levels were 226.6 pg/mL (AUC = 0.746) in ipsilateral CLN, 755.0 pg/mL (AUC = 0.840) in contralateral CLN metastases, and 237.0 pg/mL (AUC = 0.775) in ipsilateral LLN metastases. This study supports the notion that ipsilateral LLN metastases occur before contralateral CLN metastases. Therefore, ipsilateral LLN dissection should be considered in patients with contralateral CLN metastases. The extent of surgery should be based on the status of LN metastases, preoperative basal calcitonin level, and tumor size to help individualize the extent of surgery.

MON-562 Retrospective Analysis of Medullary Thyroid Carcinoma: Comparison between Individuals with and without RET Germline Mutation

Introduction: Medullary thyroid carcinoma (MTC) is a rare neuroendocrine tumor accounting for 3-5% of all thyroid cancers. MTC may be sporadic or familial, making RET analysis an indispensable diagnostic tool. This study compares demographic and pathological characteristics of MTC in patients followed at our institution, according to the presence of germline RET mutation. Methods: Data files of 93 patients to whom genetic screening was requested were analysed. Among these, 78 patients were diagnosed with MTC between 1984-2018; 2 were lost for follow-up. Results: Germline mutation in RET gene was reported in 27,63% of patients, while 72,37% presented a sporadic form. Among familial cases, 20 correspond to MEN type 2A and 1 MEN type 2B. In this series, 69.7% of our patients were women and the median age of diagnosis was 49 years old (IQR 33.50-60.00). The median value of preoperative calcitonin (CT) was 1121 ng/mL (IQR 445-4387) and demonstrated correlation with the primary tumor size (r=0.655; p < 0.001). Seventy-five patients were submitted to thyroid surgery, 66,67% at our institution while the remaining were referred to us after surgery. The sensitivity of fine needle aspiration citology was 61,29% with results corresponding to MTC or suspected MTC. Results of preoperative CT revealed a sensitivity of 97,9%. Although not statistically significant, the prevalence in women was higher in sporadic group (72,7%) vs familial (61,9%). Patients with MEN2 were younger than those with sporadic MTC (median 32 vs. 56 years, respectively; p < 0.001). Pre and postoperative CT levels were not statistically different between both groups. Comparing tumors’ histological features, only multifocality and bilaterality had statistically significant differences. Multifocality was more common in the presence of RET mutation (94,4% vs 30.4%; OR=38.857; p<0.001) and these patients also had more chance to have bilateral disease (73,7% vs 5.8%; OR= 45.733; p<0.001). There were no significant differences regarding tumor size, encapsulation, linfovascular, perineural or capsula invasion, extrathyroidal extension or margins invasion among both groups. Using TNM classification system (AJCC 8th ed), 35.9% of patients were in stage 1, 15,6% in 2, 1,6% in 3 and 46,9% in stage 4. There were no statistically differences between familial and sporadic group. Most cases of MEN2 were in stage 1 (40%) and 4 (46,7%), probably due to the presentation form (familiar screening vs. index case). There were no significant differences between groups on the disease progression and current state. Conclusion: In our series, patients with MEN2 were younger and their tumors were more often multifocal and bilateral. However, presence of RET mutation does not influence current disease status, probably due to early detection. This study highlights the importance of genetic screening allowing earlier diagnosis and appropriate treatment.

MON-561 Medullary Thyroid Cancer in a Single Institution: Factors Associated With Biochemical Failure

Background: Medullary thyroid carcinoma (MTC) is a rare thyroid cancer with a disproportionate high mortality and can be sporadic or familial. Surgery is the only potentially curative treatment. Our aim was to access demographic, clinical and pathological characteristics of MTC patients associated with biochemical failure after surgery. Methods: Retrospective observational study of patients with MTC diagnosed between 1984 and 2018 and followed-up in our institution. Results: We evaluated 76 individuals with MTC, 27.6% with hereditary MTC, 69.7% female, median of age 49 years-old (IQR 33.50-60.00). The median of preoperative calcitonin levels was 1121 pg/mL (IQR 445-4383), being ≥500 pg/mL in 72.3%. Preoperative calcitonin levels, when performed, had a sensitivity of 97.9%. According to TNM staging (AJCC 8th ed.), 35.9% were in stage I, 15.6% in stage II, 1.6% in stage III and 46.9% in stage IV. One patient had poor functional status, contraindicating surgery. A total of 75 patients were submitted to thyroidectomy (or completion thyroidectomy when indicated) with lymph node dissection at our institution (n=50) or an outside one (n=25). Biochemical cure (BC) was achieved in 48 (64%) patients after surgery; of these, 7 (14.58%) relapsed. BC was 95.7% in stage II, 100% in stages II/III and 24.1% in stage IV (p<0.001). Biochemical failure occurred in 36% of patients, all of them with preoperative calcitonin levels ≥500 pg/mL (p<0.001). There were no significant differences in sex, age, presence of germline RET mutation and results of fine-needle aspiration cytology between groups. Regarding histological features, patients with biochemical failure had higher tumor size (2.5 cm vs. 1.9 cm, p=0.025), multifocality (66.7% vs. 37.5%, p=0.024), vascular invasion (76.5% vs. 43.8%, p=0.028), perineural invasion (23.4 % vs. 0%, p=0.024), capsular invasion (82.4% vs. 12.1%, p<0.001), extrathyroidal extension (57.9% vs. 7.9%, p<0.001), surgical margin positivity (57.9% vs. 7.9%, p<0.001) and lymph node positivity (100% vs. 33.3%, p<0.001). Preoperative calcitonin levels (OR per increments of 500 pg/mL=1.183; p=0.012), tumor size in cm (OR=2.093; p=0.003), multifocality (OR=2.769; p=0.049), vascular invasion (OR=4.250; p=0.024), capsular invasion (OR=27.000; p<0.001), extrathyroidal extension (OR=85.000; p<0.001), surgical margins positivity (OR=17.455; p=0.001) and lymph nodes positivity (OR=62.500; p<0.001) were predictors of biochemical failure. The 5-year survival rate was higher in the BC group (91.7% vs. 74.1%; p=0.049). Conclusions: Several tumor histological characteristics were the best predictors for biochemical failure and preoperative calcitonin level was the only significant predictor performed before surgery. Demographic data, RET mutation and cytology were not associated with BC. These findings highlight that early detection is important to achieve BC in MTC.

Cure and survival of sporadic medullary thyroid carcinoma following systematic preoperative calcitonin screening.

The improvement in outcome of sporadic medullary thyroid carcinoma (MTC) during the last decades remains controversial, even if a trend toward a better prognosis has been recently proposed. This study was aimed to determine the time trend cure and survival rates in sporadic MTC according to the use of systematic preoperative calcitonin screening. Retrospective analysis of 178 sporadic MTC patients operated between 1980 and 2017 was performed. The impact of prognostic factors on cure and survival following the introduction of routine preoperative calcitonin screening in 2001 was evaluated according to the year of surgery. Since 2001, a significant decline of node-positive tumors (from 56.1 to 34.7%) and advanced stage at diagnosis (stage III/IV from 56.1 to 34.7%) occurred, with a concomitant significant increase in cure rate (64.5% vs 38.6%; p = 0.0012) and survival (p < 0.05). At univariate analysis, the cure was achieved more frequently in more recently operated patients (64.5% vs 38.6%; p = 0.0012), in disease staging I/II (86.5% vs 13.5%; p < 0.0001), in patients undergoing preoperative calcitonin screening (63.8% vs 23.5%; p < 0.0001) and in the absence of lymph node metastases (86.5% vs 13.5%; p < 0.0001). At multivariate analysis, only preoperative calcitonin screening and stage at diagnosis turned out to be significant independent prognostic factors for cure and survival. The outcome of sporadic MTC improved in the new millennium; diagnosis was achieved earlier, at a less advanced stage. Routine preoperative calcitonin screening may have contributed to improve cure and survival rates.

Time to calcitonin normalization after surgery for node-negative and node-positive medullary thyroid cancer

It remains unclear when postoperative serum calcitonin levels should be measured in patients with medullary thyroid cancer (MTC) and, specifically, whether this decision should be based on the preoperative calcitonin level or nodal status. A cohort of patients with previously untreated MTC was studied. Kaplan-Meier analyses, stratified by preoperative calcitonin level, nodal status and number of nodal metastases, were performed to determine time to calcitonin normalization after initial surgery, with statistical analysis by means of the log rank test. Some 213 patients with node-negative and 182 with node-positive MTC were included in the study. Postoperative calcitonin levels normalized in a mean of 3·5 versus 3·7 days respectively among patients with preoperative calcitonin levels of 10-100 pg/ml (P = 0·815); 4·8 versus 5·3 days in those with preoperative calcitonin levels of 100·1-500 pg/ml (P = 0·026); 5·3 versus 9·9 days in patients with preoperative calcitonin levels of 500·1-1000 pg/ml (P = 0·004); and 6·6 versus 57·7 days among those with preoperative calcitonin levels exceeding 1000 pg/ml (P < 0·001). Calcitonin levels normalized in a mean of 4·7 days when nodal metastasis was not present, 5·2 days in those with one to five nodal metastases, 7·0 days in patients with six to ten nodal metastases, and 57·1 days among patients with more than ten nodal metastases. Postoperative calcitonin normalization curves paralleled each other in patients with node-negative MTC, but diverged in those with node-positive disease and with more nodal metastases. Calcitonin levels typically normalize within 1 week; and within a fortnight in those with node-positive MTC and preoperative calcitonin levels of 500·1-1000 pg/ml. With node-positive MTC and preoperative calcitonin levels exceeding 1000 pg/ml, and with more than ten nodal metastases, calcitonin normalization takes longer.

Static Prognostic Factors and Appropriate Surgical Designs for Patients with Medullary Thyroid Carcinoma: The Second Report from a Single-Institution Study in Japan

BackgroundMedullary thyroid carcinoma (MTC) originates from calcitonin-producing cells of the thyroid. In 2009, we published our first report on the biological characteristics and prognosis of 118 MTC patients. Herein, we enrolled a larger number of patients with longer follow-up periods to further study the biological characteristics and appropriate therapies for MTC.MethodsIn general, hemithyroidectomy and total thyroidectomy were performed for sporadic MTC confined to the thyroid lobe and for hereditary MTC with central node dissection, respectively. Moreover, prophylactic modified radical neck dissection was performed on the side of macroscopic tumors.ResultsIn total, 233 patients (99 hereditary and 134 sporadic) were enrolled. The median follow-up time was 128 months (range 7–445 months). Biochemical cure was obtained in 36 (62%) of the 58 patients who underwent prophylactic MND and were pathologically positive for lateral node metastasis. None of the patients had recurrence in the preserved thyroid. Distant recurrence was detected in 19 patients, and 12 died of MTC. Preoperative calcitonin and carcinoembryonic antigen levels, tumor size (T) > 4 cm, the male sex, clinical and pathological node metastases (N1), distant metastasis (M1), extrathyroid extension (Ex), and a lack of biochemical cure had prognostic impacts on distant recurrence and/or carcinoma-related mortality on univariate analysis. On multivariate analysis, Ex was independently correlated with distant recurrence, and Ex, T > 4 cm, and M1 independently affected carcinoma-related mortality.ConclusionMTC patients had excellent prognosis in our institutions, indicating that our surgical strategies were appropriate.

CALCITONIN SECRETORY INDEX AND UNSUSPECTED NODAL DISEASE IN MEDULLARY THYROID CARCINOMA

Medullary thyroid carcinoma (MTC) is a rare thyroid malignancy originating from parafollicular C-cells with the potential for aggressive behavior. The extent of lymph node (LN) dissection at the time of surgery is controversial, with different schools of thought prevailing. Some systematically perform LN dissections, whereas others base their decision on radiologic evidence of disease and some with the assistance of pre-operative calcitonin (CT) levels. We retrospectively assessed the correlation between pre-operative CT levels and clinico-pathologic factors among 42 patients with MTC between 1994 and 2015. Furthermore, we refined the use of pre-operative serum CT levels and explored for the first time a test called the Calcitonin Secretory Index (CSI, ng/mL/mm). Pre-operative CT levels correlated independently with tumor size ( P<.0001), number of metastatic LNs ( P<.01), and increased rates of distant metastasis. The CSI better predicted early LN disease ( P<.045). Patients with early LN metastasis had a CSI >30 ng/mL/mm, a representative threshold above which the surgical cure declines considerably. In our experience, pre-operative CT levels and now the CSI appear as sensitive and specific risk stratification markers for MTC. Despite negative findings on dedicated pre-operative neck imaging in addition to total thyroidectomy, a CSI >30 ng/mL/mm would prompt bilateral central node dissection. Due to the small sample size, our study provides preliminary evidence of the value of CSI in clinical practice. ANOVA = analysis of variance; ATA = American Thyroid Association; CSI = Calcitonin Secretory Index; CT = calcitonin; LN = lymph node; MTC = medullary thyroid carcinoma; ROC = receiver operating characteristic.

Prophylactic thyroidectomy in children with multiple endocrine neoplasia type 2.

In patients with multiple endocrine neoplasia type 2 (MEN2) syndrome, genetic testing offers early diagnosis, stratifies the risk of developing medullary thyroid cancer (MTC) and informs the timing of thyroidectomy. The efficacy of treatment, which depends on timely and safe surgery, is not well established. This was a retrospective review of diagnostic and clinicopathological outcomes of prophylactic thyroidectomy in children with MEN2 between 1995 and 2013 in the UK. American Thyroid Association (ATA) 2009 guidelines were used as a benchmark for adequate treatment. Seventy-nine children from 16 centres underwent total thyroidectomy. Thirty-eight patients (48 per cent) underwent genetic testing and 36 (46 per cent) had an operation performed above the age recommended by the ATA 2009 guidelines; pathology showed MTC in 30 patients (38 per cent). Late surgery, above-normal preoperative calcitonin level and MTC on pathology correlated with late genetic testing. Twenty-five children had lymphadenectomy; these patients had more parathyroid glands excised (mean difference 0·61, 95 per cent c.i. 0·24 to 0·98; P = 0·001), and were more likely to have hypocalcaemia requiring medication (relative risk (RR) 3·12, 95 per cent c.i. 1·54 to 6·32; P = 0·002) and permanent hypoparathyroidism (RR 3·24, 1·29 to 8·11; P = 0·010) compared with those who underwent total thyroidectomy alone. Age did not influence the development of complications. Late genetic testing may preclude age-appropriate surgery, increasing the risk of operating when MTC has already developed. Early genetic testing and age-appropriate surgery may help avoid unnecessary lymphadenectomy and improve outcomes.

Preoperative Clinical and Sonographic Predictors for Lateral Cervical Lymph Node Metastases in Sporadic Medullary Thyroid Carcinoma.

Total thyroidectomy and cervical lymph node (LN) dissection is generally recommended in patients with medullary thyroid carcinoma (MTC). However, there is no clear evidence for whom to perform prophylactic lateral neck dissection in MTC patients without evident lateral cervical lymph node (LCLN) metastasis in preoperative images. This study evaluated the preoperative features for predicting the LCLN metastasis of MTC. The study included 26 MTC patients with LCLN metastasis at initial surgery (N1b group) and 47 MTC patients without any LN metastasis or recurrence of disease (N0-NED group). The association between LCLN metastasis and preoperative clinical and sonographic characteristics (size, location, solid component, shape, margin, echogenicity, calcification, and subcapsular location of the tumor) were evaluated. There were no significant differences in age and sex between the N1b and N0-NED groups. Preoperative serum levels of calcitonin >65 pg/mL were associated with LCLN metastasis (p < 0.001). In preoperative neck ultrasonography (US), patients in the N1b group were more commonly found with a larger tumor (>1.5 cm) of irregular shape with a spiculated margin and a subcapsular location than those in the N0-NED group (p = 0.029, p < 0.001, p < 0.001, and p < 0.001, respectively). Increases in the number of these LCLN metastasis-related features were significantly associated with higher risk for LCLN metastasis (p < 0.001). The presence of two or more predictors was an appropriate cutoff point for predicting LCLN metastasis of MTC with 73.1% sensitivity and 91.5% specificity. MTC tumors with high preoperative calcitonin levels (>65 pg/mL), larger size (>1.5 cm), irregular shape, spiculated margins, and subcapsular locations in the neck US are at higher risk for LCLN metastasis. MTC patents with fewer than two predictors might be suitable for treatment without prophylactic LCLN dissection.

Carcinoembryonic antigen levels correlated with advanced disease in medullary thyroid cancer

BackgroundMedullary thyroid cancer (MTC) cells are capable of secreting various tumor markers including calcitonin and carcinoembyronic antigen (CEA). The purpose of this study is to determine whether abnormal CEA levels may be used as a tumor marker to predict the severity of disease in MTC.MethodsA retrospective analysis was completed for 33 patients with MTC who had preoperative serum CEA levels. Univariate and multivariate analyses were used to quantify the relationship between serum CEA levels and tumor stage and prognosis.ResultsOn multivariate analysis, elevated preoperative CEA levels were significantly associated with the size and stage of tumor, distant metastasis, decreased biochemical cure, and mortality. There was a significant association between tumor size greater than 37 mm and elevated CEA levels (> 271 ng/ml). There was also a positive correlation with increased cancer stage (> 377 ng/ml), distant metastasis (> 405 ng/ml), and contralateral compartment location of lymph node metastasis (> 162 ng/ml). When pre-operative CEA levels are > 500 ng/ml, patient mortality was 67%.ConclusionIn this study, both pre-operative calcitonin and CEA levels were significantly correlated with the extent of disease in MTC. While calcitonin has a linear relationship with disease progression, abnormal CEA levels were a better indicator of advanced disease. CEA levels > 271 ng/ml are significant for advanced tumor size and staging, metastasis to the central compartment, and decreased chance of biochemical cure. CEA levels greater than 500 ng/ml are associated with significant patient mortality.

Prognostic Variables Affecting Primary Treatment Outcome for Medullary Thyroid Cancer

Identifying prognostic risk factors and determining the efficacy of common surgical treatments is critical to determine optimal treatment strategies for patients with medullary thyroid carcinoma (MTC). The objective of this study was to review a contemporary institutional experience with MTC primary treatment with 2 goals: to identify prognostic factors that impact survival and to study the effect of neck dissection on those outcomes. This study was a retrospective case series of patients with MTC who underwent at least a total thyroidectomy with curative intent. Clinical parameters including tumor and nodal staging with corresponding pathology findings were identified. Survival endpoints included overall survival, disease-free survival, and biochemical cure. Sixty-seven patients were included. The majority presented with early T-stage disease. Fifty (76%) patients were N0 at presentation. Seventeen (24%) had some evidence of neck disease on clinical examination or imaging. Forty (71%) achieved biochemical cure, and the 5-year biochemical recurrence-free survival for those cases was 86.5%. Among patients who had successful resection of all gross disease, 92% had no evidence of structural disease at 5 years. Overall survival was 91% at 5 years. Increased pre-operative calcitonin (Ct) level, primary tumor size, extrathyroidal extension, and neck metastases decrease the rate of biochemical cure. Larger tumor size increases the risk of structural disease recurrence and biochemical relapse after initial cure. The presence and number of neck metastases correlate with biochemical relapse. The presence of lateral neck nodes (pN1b) does not have different survival implications than centrally confined disease (pN1a). This study shows increasing tumor size, increased Ct level, and cervical metastases are poor prognostic factors. Patients with large tumors, high Ct level, or unfavorable pathologic findings may warrant more aggressive initial treatment, although limitations of the study prevent any conclusion regarding the effect of neck dissection. ATA = American Thyroid Association BRFS = biochemical recurrence-free survival CND = central neck dissection Ct = calcitonin DFS = disease-free survival MTC = medullary thyroid carcinoma OR = odds ratio OS = overall survival pCND = prophylactic CND.

Prognostic value of preoperative serum calcitonin concentration on primary surgery outcomes in medullary thyroid cancer

Prognostic value of preoperative serum calcitonin concentration on primary surgery outcomes in medullary thyroid cancer

Craniofacial Fibrous Dysplasia: Retrospective Study on the Relationship Between the Tumor Volume Changes and the Circulating Serum Calcitonin and Serum Alkaline Phosphatase.

The purpose of this study was to determine the usefulness of serum alkaline phosphatase (ALP) and calcitonin in the follow-up of tumor volume changes in patients with craniofacial fibrous dysplasia. Twenty patients with isolated craniofacial fibrous dysplasia were included, who met our criteria for long-term follow-up. Three-dimensional computed tomography scans were obtained, and tumor segmentation was performed. The tumor volume was measured preoperatively, immediate postoperative and during long-term follow-up. Serum ALP and calcitonin levels were obtained at the same times to assess their correlation with tumor volumes. Preoperative calcitonin levels were correlated with the presence of tumor (P = 0.0442), whereas ALP levels were not (P = 0.1125). There were no significant associations between tumor volume and ALP or calcitonin levels in the preoperative or postoperative periods. During long-term follow-up, serum ALP was significantly associated with tumor recurrence (P = 0.0096), but serum calcitonin was not (P = 0.4760). However, serum levels of ALP did not reflect the tumor volume changes. Serum ALP may be useful as a laboratory test for follow-up of patients with isolated craniofacial fibrous dysplasia. However, it cannot represent the tumor's volume changes and 3-dimensional computed tomography scans with tumor volume measurement are mandatory for detecting significant volume changes during follow-up. Investigation of the serum calcitonin in the preoperative period is also recommended on a large scale because it was related to the presence of the tumor.

Molecular diagnosis and comprehensive treatment of multiple endocrine neoplasia type 2 in Southeastern Chinese.

BackgroundMultiple endocrine neoplasia type 2 (MEN2) is an autosomal dominant inherited endocrine malignancy syndrome. Early and normative surgery is the only curative method for MEN 2-related medullary thyroid carcinoma (MTC). In patients with adrenal pheochromocytoma, cortical-sparing adrenalectomy (CSA) can be utilized to preserve adrenocortical function.MethodsWe present twenty-six of 33 MEN2 patients underwent prophylactic thyroidectomy with varying neck dissection and eight of 24 MEN2A patients with PHEO underwent adrenal-sparing surgery. Direct sequencing of entire RET exons was performed in all participants.ResultsThe RET mutations (p.C634Y [n = 10], p.C634R [n = 9], p.C634F [n = 2], p.C618Y [n = 8], p.C618R [n = 3], and p.M918T [n = 1]) were confirmed in 20 symptomatic patients and identified in 13 at-risk relatives (RET carriers). Twenty-six of 33 MEN2 patients underwent thyroidectomies with neck dissections; the mean age at the time of the first thyroid surgery and the tumor diameter of the 6 RET carriers was decreased compared with 20 symptomatic patients (P < 0.001 and P = 0.007, respectively), while the disease-free survival was increased (80% vs.10%, P = 0.0001). Seven RET carriers who were declined surgery. One of 20 symptomatic patients with MTC bone metastases after surgery received vandetanib therapy for 20 months and responded well. Additionally, 8 of 24 MEN2A patients who initially had unilateral pheochromocytomas underwent CSA, 1 developed contralateral pheochromo cytomas 10 years later, then also accepted and also agreed to a CSA. None of the patients required steroid replacement therapy.ConclusionsBased on our results, integrated RET screening and the pre-operative calcitonin level is an excellent strategy to ensure earlier diagnosis and standard thyroidectomy. CSA can be utilized to preserve adrenocortical function in patients with pheochromocytomas.Electronic supplementary materialThe online version of this article (doi:10.1186/s13053-015-0026-1) contains supplementary material, which is available to authorized users.

Serum calcitonin negative medullary thyroid carcinoma: a systematic review of the literature.

Generally, calcitonin (CT) values below the upper reference limit rule-out medullary thyroid carcinoma (MTC) with very high accuracy. However, sparse cases of serum-calcitonin-negative MTC (CT-NEG-MTC) have been reported. Here we reviewed CT-NEG-MTC reported in literature, discussed the potential causes and proposed a practical laboratory and clinical approach. A comprehensive literature search was conducted by using the terms "medullary thyroid carcinoma" AND "non-secreting calcitonin" OR "undetectable calcitonin". The search was updated until December 2014. Original articles that described CT-NEG-MTC were eligible for inclusion. Only MTC cases with preoperative CT below the upper reference limit were included in the present review. Eleven papers with 18 CT-NEG-MTC cases (age 50 years, size 26 mm) were retrieved. Four patients with poorly differentiated MTC died within 3 years. Different CT assays were employed and different reference values were adopted. Preoperative serum CT values were below the institution cut-off levels in all cases, and undetectable in four patients. In some papers negative CT results were confirmed by additional tests. Further laboratory investigations were performed in some of the included studies. In patients with well founded suspicious of MTC and within the reference limits/undetectable CT other laboratory investigations [carcinoembryonic antigen (CEA), procalcitonin, CT stimulation, CT in washout of nodule's aspiration] have to be performed. Surgical approach to CT-NEG-MTC does not differ from those secreting CT. Postoperative follow-up of these rare cases should include periodical imaging and measurement of all potential markers. Patients with poorly differentiated MTC are at higher risk of disease-related death, and require more aggressive follow-up strategy.

Epidemiology and Clinical Presentation of Medullary Thyroid Carcinoma.

Medullary thyroid carcinoma (MTC) is a rare neuroendocrine tumor originating from the thyroid C cells producing mainly calcitonin (CTN) used as tumor marker. MTC occurs either sporadic (75%) or in a hereditary form (multiple endocrine neoplasia type 2, MEN2), due to germline mutations in the RET proto-oncogene. The discovery of an MTC in a patient has several diagnostic implications involving a specific strategy: preoperative evaluation of the tumor marker CTN and the extent of the disease, classification of MTC as sporadic or hereditary by DNA testing, and screening for associated endocrinopathies in hereditary MTC. Elevated CTN is a highly sensitive and specific tumor marker for diagnosis and follow-up of MTC. CTN is directly related to the tumor mass. In patients with nodular thyroid disease, diagnosis of MTC could be made by CTN determination as an indicator of tumor burden in conjunction with fine-needle aspiration. Patients with confirmed sporadic or hereditary MTC should have a total thyroidectomy and depending on the preoperative CTN value and the extent of disease additional dissection of the lymph nodes in the central and lateral neck compartment. In MEN 2 patients diagnosed by screening, the time of prophylactic thyroidectomy depends on RET mutation and CTN level.

Prevalence by Age and Predictors of Medullary Thyroid Cancer in Patients with Lower Risk GermlineRETProto-Oncogene Mutations

Age-related risk of medullary thyroid carcinoma (MTC) development in presymptomatic carriers of lower risk germline RET mutations is uncertain; such data may aid counseling patients regarding timing of thyroidectomy. From an institutional database and an exhaustive literature review, we identified 679 patients with American Thyroid Association (ATA) level A or B mutations who were identified because of family screening (index cases of MTC were excluded to minimize selection bias). We evaluated age at thyroidectomy or last evaluation if no thyroidectomy, preoperative calcitonin level (elevated or not), the mutated codon, and outcome (MTC vs. no MTC after thyroidectomy or no clinical evidence of MTC if thyroid intact). Data were used to estimate the cumulative prevalence of MTC and/or assess likelihood of MTC stratified by codon. After exclusion of cases with missing data or small representation, 503 patients with mutations in codons 533, 609, 611, 618, 620, 791, and 804 were analyzed. 236 patients had MTC. Cumulative prevalence and median time to MTC varied by codon and within ATA risk levels (p<0.0001). Patients with a codon 620 mutation were 2.8-6.9 times more likely to have MTC than other level B mutation carriers, and 5.1-21.7 times more likely than level A mutation carriers included in our focus population. The youngest median time to MTC was 19 years for codon 620 and the oldest was 56 years for codon 611. Cumulative prevalence of MTC by age 20 was 10% or lower for codons 533, 609, 611, 791, and 804. By age 50, it ranged from 18% for codon 791 to 95% for codon 620. An elevated preoperative calcitonin level strongly predicted MTC on final pathology, though false-negative rates varied by codon (p<0.0001). Positive predictive values ranged from 76% to 100% by codon with an overall positive predictive value of 87% across codons. This study offers a better understanding of the age-related development of MTC in lower risk RET mutation carriers, provides evidence of further distinctions between lower risk mutations within ATA subgroups, and clarifies the clinical significance of codon 791 mutations. The data support individualized "codon-based" management approaches coupled with clinical data such as calcitonin levels.

Dynamic Risk Stratification for Recurrence in Medullary Thyroid Cancer

Objectives: Develop a dynamic postoperative risk stratification tool for medullary thyroid cancer (MTC) recurrence, based on patient, tumor and treatment characteristics. Methods: 124 MTC patients who were treated entirely at Memorial Sloan-Kettering Cancer Center between 1986-2010 were identified. Immediate postoperative risk groups were defined as low, intermediate, and high based upon extent of extrathyroid extension, presence of regional or distant metastases and preoperative calcitonin level. Response to therapy categories were then defined as excellent, acceptable, and poor based upon 6-month calcitonin level and presence of radiological structural disease. Overall risk groups based upon the immediate postoperative risk and the response to therapy category were then defined. Results: The median age was 55 years (range: 6-88). Median follow-up was 66 months (range: 1-229). In the immediate postoperative risk groups, the 5-year risk of structural recurrence for low, intermediate, and high risk groups was 5.9%, 24.9%, and 67.8% respectively ( P &lt; 0.001). For the overall risk groups, the 5-year risk of structural recurrence for low, intermediate, and high risk groups was 3.2%, 24.0%, and 45.9% ( P &lt; 0.001). Low risk patients with poor responses increased their recurrence risk from 5.9% to 24.9%, while high risk patients with excellent responses reduced their recurrence risk from 67.8% to 24.9%. Conclusions: A clinically useful dynamic risk stratification tool to predict risk of recurrence in MTC patients over time is introduced. Its prognostic value may augment patient counseling on prognosis and help determine the frequency and extent of follow up investigations.