Hereditary Medullary Thyroid Cancer: Age-Appropriate Thyroidectomy Improves Disease-Free Survival

Background

Twenty-five percent of medullary thyroid cancer (MTC) cases are hereditary. The ideal age for prophylactic thyroidectomy is based on the specific RET mutation involved. The purpose of this study was to determine whether such age-appropriate prophylactic thyroidectomy results in improved disease-free survival.

Methods

Twenty-eight patients underwent thyroidectomy for hereditary MTC at our institution. Age-appropriate thyroidectomy was defined according to the North American Neuroendocrine Tumor Society (NANETS) guidelines. Patients who had age-appropriate surgery (group 1, n = 9) were compared to those who had thyroidectomy past the recommended age (group 2, n = 19).

Results

The mean age was 13 ± 2 years, and 61 % were female. Patients in group 1 were younger than in group 2 (4 ± 1 vs. 17 ± 2 years, p < 0.01). There were no significant differences in gender or RET mutation types between these two groups. Group 1 patients were cured with no disease recurrence compared with group 2 patients who had a 42 % recurrence rate (p = 0.05). Subanalysis of group 2 identified that patients who underwent surgery without evidence of disease did so at a shorter period following the guidelines compared with those who underwent therapeutic surgery (2 ± 2 vs. 16 ± 2 years, p = 0.01) and had longer disease-free survival (100 vs. 27 %, p = 0.005).

Conclusions

Patients with hereditary MTC should undergo age-appropriate thyroidectomy based on RET mutational status to avoid recurrence. Patients who are past the recommended age should have surgery as early as possible to improve disease-free survival.     

Genotype-Phenotype Based Surgical Concept of Hereditary Medullary Thyroid Carcinoma

Background Since DNA tests have enabled reliable identification of asymptomatic RET (rearranged during transfection) gene carriers, myriads of publications have appeared on genotype-phenotype relationships. A comprehensive appraisal of this body of evidence using evidence-based methodology is pending. Methods This study was based on systematic evaluation of the literature using evidence-based criteria. Results (1) There is a distinct age-related progression of hereditary medullary thyroid carcinoma (MTC) in carriers of RET mutations (grade C). (2) Among the high-risk RET mutations, those in codon 634 cause higher penetrance rates of the multiple endocrine neoplasia 2A phenotype (MTC, pheochromocytoma, and parathyroid hyperplasia/adenoma) than mutations in codons 609, 611, 618, and 620, irrespective of the amino acid substituting for cysteine (grade C). (3) DNA-based screening is superior to calcitonin-based screening in asymptomatic RET carriers (grade C). (4) Using a worst-case scenario, i.e., considering the earliest finding of MTC in asymptomatic RET carriers, pre-emptive thyroidectomy should be performed before that time (grade C) to be truly prophylactic. Specifically, for carriers of highest-risk mutations (codon 918): within the first year of life; for carriers of high-risk mutations (codon 609, 611, 618, 620, 630, and 634): before the age of 5 years; and for carriers of least-high risk mutations (codon 768, 790, 791, 804, and 891): before the age of 5-10 years. Strict adherence to these grade C recommendations can result in undertreatment of the former (codon 634) and overtreatment of the latter. Conclusions These genotype-phenotype correlations provide a solid foundation on which to base surgical concepts, leaving little room for randomized controlled clinical trials.     

甲状腺髓样癌35例治疗体会

目的总结甲状腺髓样癌(medullary thyroid carcinoma,MTC)临床特征及治疗方法。方法回顾分析1997年1月~2005年12月经治的35例MTC的临床及病理资料。结果35例均予手术切除原发灶并加行颈淋巴结清扫术,术后放疗5例,化疗7例。所有病例均经病理证实为MTC,淋巴结转移率为51.4%。32例术后随访2~10年,5年生存率为87.5%。结论MTC治疗应以根治性切除为原则,切除范围应比其他类型的甲状腺癌积极,术后可以辅以多种非手术治疗。     

Single Center Experience in Primary Surgery for Medullary Thyroid Carcinoma

Medullary thyroid carcinoma (MTC) is a rare disease, and most studies are either based on small numbers or multicenter studies with their inherent difficulties. Since 1995, a total of 440 patients with MTC underwent surgery in our clinic. A primary operation was performed in 188 patients (43% of 440). In 60 patients, the primary operation was performed because of a germline RET mutation (prophylactic surgery). Most (84%, 158/188) of the patients had pathologic calcitonin levels. Notably, MTC was found in almost 10% (3/30) of patients with normal calcitonin levels. However, all patients with lymph node metastases (LNMs) had elevated calcitonin levels. Total thyroidectomy (TTx) was performed in all patients. Lymph node dissection (LND) was performed at various extensions: one-compartment LND in 35% (66/188), three-compartment LND in 31% (58/188), and four-compartment LND in 29% (22/188). In general, lymph node dissection increased the likelihood of complications. LNM and distant metastases (DM) correlated with the extent of the primary tumor (pT category). The presence of LNM ranged from 17% (pT1 tumor) to 100% (pT4 tumor), whereas the presence of DM ranged from 0% (pT1 tumor) to 81% (pT4 tumor). Biochemical cure (normal calcitonin levels) was obtained in 72% (137/188) of patients. All 60 patients undergoing prophylactic surgery (tumor stage pT0/pT1) were biochemically cured. In contrast, only 60% (77/128) of the remaining patients were cured. The data suggest that primary surgery should be scheduled as soon as possible to treat patients at a node-negative stage. In the case of normal basal and elevated stimulated calcitonin levels, TTx and cervicocentral LND is recommended. If the basal calcitonin level is elevated, LND should include the cervicolateral compartment.This article was presented at the International Association of Endocrine Surgeons meeting, Uppsala, Sweden, June 14–17, 2004.     

Long-Term Outcome After Surgery for Medullary Thyroid Carcinoma: A Single-Center Experience

Background

Medullary thyroid carcinoma (MTC) is a rare C cells-derived tumor, with a hardly predictable long-term prognosis. This study was aimed to evaluate the predictive factors of cure and survival after surgery for MTC in a monocentric series.

Methods

A retrospective analysis of the long-term outcomes was assessed in 255 MTC patients operated between 1980 and 2015 at Padua University hospital.

Results

Sporadic MTC occurred in 65.1% and hereditary MTC in 34.9% of patients. At a median follow-up of 93 months (range 7–430), the cure rate was 56.8%. The overall 10-year survival was 84.4%, and MTC-related death rate was 15.3%. Patients who died because of MTC had a median age of 61 years (range 21–84) and were at stages III–IV in all cases; deaths occurred in 18% of sporadic MTC, 6% of MEN2a and 66.7% of MEN2b patients. None of the patients at stages I–II died because of the disease, but 17.7% had persistent/recurrent disease. Based on univariate analysis, age, gender, genetic variant, extent and year of surgery, tumor size, lymph-nodal metastases and tumor stage significantly affected cure and survival rates. At multivariate analysis, only patient- and tumor-related features (age, lymph-nodal status and stage) remained significant independent prognostic factors.

Conclusions

Radical surgery is the only chance of definitive cure in MTC, but it is possible only at early stage; in advanced stages, even extensive surgery could not grant cure and prolonged survival. Stage, nodal metastases and age remain the main predictive factors for cure and survival.

     

对甲状腺癌应慎行甲状腺全切术

据国内、外文献[1-3]报道,甲状腺癌已不是少见病,其发病率在逐年升高: 美国2002年甲状腺癌发病率达8.7/10万,较30年前高2.49倍,2005年有25 690例新病例;我国上海市2004年甲状腺癌男性的发病率为3.71/10万,女性为10.49/10万,较1987年分别上升3.71倍和3.75倍. 我院2007年共收治初治甲状腺癌206例,较10年前增加5倍,其中尤其是乳头状癌已占甲状腺癌80%以上[2].故对甲状腺癌的处理越来越受到人们的重视.     

Surgical Experience in Children With Differentiated Thyroid Carcinoma

Background: The optimal surgical treatment in children with well-differentiated thyroid carcinoma remains an important point of discussion. In this study, we evaluated our surgical experience and reviewed the literature accordingly to identify the most adequate treatment.Methods: We retrospectively analyzed 21 children, all under the age of 18 years at the time of diagnosis, with differentiated thyroid carcinoma (17 papillary, 3 follicular, and 1 Hürthle cell carcinoma). Total thyroidectomy was performed, followed by radioiodine therapy, as a part of the initial treatment in all patients. The results were compared with data from the literature.Results: Eleven children (52%) who presented with cervical lymph node metastases were treated by a modified radical neck dissection. Pulmonary metastases were seen at diagnosis in three patients. Six patients developed temporary complications. During follow-up, with a median of 11 years (range, 2–26 years), two patients (10%) developed recurrences, and no patient died during this observation period. A literature search confirmed our experience of excellent results without an increase of complications in the more aggressively treated patients.Conclusions: In children with differentiated thyroid cancer, treatment should consist of total thyroidectomy, followed by a modified radical neck dissection (when indicated) and iodine-131 ablation treatment. This aggressive approach seems to be justified because of the high incidence of nodal involvement and the low complication and recurrence rate after surgery.     

Latent Subclinical Medullary Thyroid Carcinoma: Diagnosis and Treatment

n = 11), palpable metastatic lymph node ( n = 6), distant metastases ( n = 4). In nine cases the diagnosis was made by both fine-needle aspiration cytology and serum CT measurement. In the four other cases the initial cytology was incorrect, but the diagnosis was revised on the basis of elevated basal CT values. In 11 patients (group 2) presenting with nodular thyroid disease, SMTC was not clinically detectable. SMTC was preoperatively suspected by elevated CT levels: basal CT > 10 pg/ml and pentagastrin-stimulated CT peak > 100 pg/ml. One patient in group 1 with distant metastases was not operated on. All of the other 12 patients underwent total thyroidectomy and extensive lymph node dissection. The mean size of the tumors was 27 mm. Lymph node involvement was found in nine patients. After surgery, CT levels returned to normal in five patients but remained elevated in five others; the two remaining patients died of distant metastases. All 11 patients in group 2 underwent total thyroidectomy and central neck dissection. None of the 11 patients had nodal extension. All 11 patients are biochemically cured. It was concluded that routine measurement of basal serum CT in those with nodular thyroid disease allows early, preoperative diagnosis of subclinical SMTC and improves the results of surgery.     

Alternative Surgical Strategies and Favorable Outcomes in Patients with Medullary Thyroid Carcinoma in Japan: Experience of a Single Institution

Background  Medullary thyroid carcinoma (MTC) accounts only for 1.4% of all thyroid malignancies in Japan. Since 1996, we have performed hemithyroidectomy, instead of total thyroidectomy, for sporadic nonhereditary MTC when the primary lesion is located in only one lobe. Regarding lymph node dissection, modified radical neck dissection (MND) at least ipsilateral to the tumor has been routinely performed, even if there is no clinically apparent metastasis. We investigated the clinical outcomes of MTC patients in our department. Methods  A series of 118 patients with MTC who underwent initial surgery between 1975 and 2005 were enrolled in this study. The RET gene mutations were analyzed for all patients and 46 had germline RET gene mutations. Of those 46 patients, 26 were diagnosed as MEN 2A and 2 were diagnosed as MEN 2B. Postoperative follow-up periods averaged 141 months. Results  Of 115 patients who did not have distant metastasis at surgery and who underwent locally curative surgery, 78 (67.8%) were biochemically cured. All patients without pathological lymph node metastasis were biochemically cured, and 44.8% of patients with node metastasis were also biochemically cured. The 10-year and 20-year disease-free survival rates were 89.0% and 82.5%, respectively. None of the patients who did not show lymph node metastasis and only 2 (2.6%) of 78 patients who were biochemically cured showed clinically apparent carcinoma recurrence. The 10-year and 20-year cause-specific survival rates were 96.6% and 91.7%, respectively. Lymph node metastasis, tumor size >4 cm, extrathyroid and extranodal tumor extensions significantly affected cause-specific survival of patients. Conclusions  Clinical outcomes of MTC patients in our series were better than those in Western countries, a result that might have resulted in part because of our routine MND regardless of whether clinically apparent node metastasis was detected.     

Medullary Thyroid Carcinoma: Ethical Issues for the Surgeon

Medullary thyroid cancer is a disease with an established genetic inheritance pattern for which evidence-based guidelines recommend genetic testing and subsequent management of affected patients and their family members. The perceived stigma of genetic testing, coupled with issues involving confidentiality and disclosure, create potential conflict and confusion. In some cases, there is a need for genetic testing and prophylactic surgery in children, augmenting the need for a judicious approach that balances respect for individual autonomy and parental rights with the best interest of the child. We provide an overview of the ethical issues facing surgeons caring for patients with familial medullary thyroid carcinoma, and recommend interventions and resources to assist in decision making in these difficult situations.     

Occult Micro Medullary Thyroid Carcinoma: Therapeutic Strategy and Follow-up

Twenty micro medullary thyroid carcinomas (MTCs) were found in histologic specimens of 19 patients in our department from 1990 to 1998. There were 14 women and 5 men, with a median age of 63 years. The indication for surgery was goiter in 12 patients and a solitary nodule in 7 patients (three differentiated cancers). Altogether, 18 patients had unifocal micro-MTCs with a median diameter of 3.6 mm. One patient had a bilateral MTC (3 and 5 mm, respectively). Surgical procedures consisted of 9 total thyroidectomies and 10 lobectomies or subtotal thyroidectomies. Of these 10 patients, 4 underwent reoperation (totalization). One was operated on 48 months after a positive pentagastrin test: There was no thyroid residual tumor but three lymph node micrometastases. Among the six patients in whom thyroid tissue was left, a 91-year-old woman died of unrelated cause and the five others remain disease-free without biologic abnormalities at follow-ups of 18 to 70 months. Considering the aggressiveness of MTCs, total thyroidectomy with central compartment dissection is theoretically indicated. However, among the nine total thyroidectomies and four secondary totalizations associated with at least central compartment dissection, no other thyroid lesion was observed and only one case of lymph node microinvasion was found. Because of the morbidity associated with reoperation and neck dissection, we propose that it is indicated only for microcarcinomas > 5 mm in diameter, in cases of an abnormal response to pentagastrin, or when it is difficult to ensure prolonged follow-up of the patient.     

Medullary Thyroid Carcinoma: Long-Term Outcomes of Surgical Treatment

Background

Medullary thyroid carcinoma (MTC) accounts for 5 to 10% of all thyroid cancers but is responsible for a disproportionate number of deaths.

Methods

We performed a retrospective review to describe clinical outcomes in patients with medullary thyroid carcinoma, screening a subset of patients for somatic mutations in the RET and p18 genes and performing genotype-phenotype correlation in a tertiary-care referral hospital from 1967 to 2009.

Results

We studied a total of 94 patients identified from a prospectively maintained thyroid cancer database. Data gathered included patient demographics, serum calcitonin, clinical outcomes, histopathology, genetic analysis, and status at final follow-up. A subset cohort (n = 50) was screened for somatic mutations in the RET gene and the three exons of the p18 gene. The subset cohort was composed of hereditary medullary thyroid carcinoma (HMTC) (n = 19, index patients = 10, screen detected = 9) and sporadic medullary thyroid carcinoma (SMTC) (n = 31). There were no mutations in the p18 gene in the subset cohort.

Conclusions

A total of 67 SMTC and 27 (28.7%) HMTC cases identified. SMTC were older at initial presentation (52 vs. 34, P = 0.003), had higher preoperative serum calcitonin levels (7968 vs. 1346 ng/L, P = 0.008), and had lymph node recurrence (P = 0.001) compared to HMTC. The tumors were smaller in HMTC (P = 0.038). Overall 10-year survival in SMTC versus HMTC was 69 versus 93% (P = 0.12). On multivariate analysis, vascular invasion (hazard ratio 6.4, P = 0.019) was an adverse predictor for disease-free survival. HMTC in the era of RET analysis presents with a smaller primary tumor, lower preoperative serum calcitonin levels, and lower rates of lymph node metastasis. Mutations in the p18 gene were not a major factor in medullary thyroid carcinoma tumorigenesis.     

Laparoscopic Adjustable Gastric Banding in Adolescents: The Austrian Experience

Background: Morbid obesity is a rising problem in adolescents in the industrial nations. Up to 25% of children have a body mass index (BMI) higher than the 85th age- and sex-adjusted percentile. Obesity in youth is associated with increased risk for morbidity and mortality in adulthood. In addition, these patients suffer from psychological problems and decreased quality of life. Bariatric procedures have shown effective long-term results in adults, but they are still discussed controversially in adolescent patients. Methods: Between 1998 and 2004, 50 adolescent patients with a mean age of 17.1±2.2 years (range 9-19 years) underwent laparoscopic adjustable gastric banding (LAGB) in Austria. The psychological changes were analyzed by using Moorehead-Ardelt/BAROS questionnaire. Results: The mean BMI decreased from 45.2±7.6 kg/m² at time of surgery to 32.6±6.8 kg/m² after a mean follow-up of 34.7±17.5 months. The mean excess weight loss was 61.4±35.5%. Most of the adolescents showed remarkable improvements in their quality of life. The outcome was regarded as "excellent or very good" in 32 patients, "good" in 12 patients and "fair" in 5 patients. Only one patient noticed no alterations after surgery. Two-thirds of the preoperative co-morbidities resolved, and one-third improved during follow-up. Except for one port dislocation, no peri- or postoperative complications arose. Conclusion: LAGB is an effective and attractive treatment option in very carefully selected obese adolescents, because of its adjustability and the preservation of the gastrointestinal passage. The majority of patients showed a remarkable improvement in their quality of life.     

甲状腺髓样癌26例临床分析

目的探讨甲状腺髓样癌临床特点、诊断、手术原则和术后处理。方法回顾性分析26例甲状腺髓样癌的临床资料,其中散发性24例,家族性2例。均行手术治疗,7例术后行60Co放疗。结果26例中随访22例(84.6%),平均随访(62.7±26.1)月;失访4例。死亡5例,死于肺转移3例,死因不明2例。术后随访5年者17例,5年生存率为70.6%(12/17),术后复发4例。结论甲状腺髓样癌术前诊断困难,大部分病人仅以甲状腺肿块就诊,手术应以患侧甲状腺叶加峡部切除为主,对术前B超示双侧甲状腺肿块病人可行甲状腺全切术或近全切除术,有淋巴结转移者加行同侧颈淋巴结清扫术。     

Thyroid Venous Catheterization in the Early Diagnosis of Familial Medullary Thyroid Carcinoma

In kindreds with familial medullary thyroid carcinoma (MTC), individuals are often detected whose peripheral plasma calcitonin (CT) levels are undetectable in the basal state but increase minimally following provocative testing. The proper management of such patients has been uncertain, but most investigators have advocated repeat testing and evaluation after an interval of several months. The present study was conducted to evaluate the diagnostic implications of these modest increases in plasma calcitonin. In 25 kindred members at direct risk for familial medullary thyroid carcinoma (MTC), basal peripheral plasma calcitonin (CT) levels were less than 240 pg/ml. Following provocative testing with intravenous calcium or pentagastrin or both, calcitonin values remained below 240 pg/ml in eight subjects (Group A), however, they were mildly elevated (260-580 pg/ml) in 12 subjects (Group B) and moderately elevated (700-940 pg/ml) in five subjects (Group C). Following the transfemoral placement of a catheter into the inferior thyroid vein (ITV), provocative testing was repeated, and ITV and peripheral blood samples were collected simultaneously. Basal ITV plasma CT levels were below 240 pg/ml in all patients in Group A, however, they were mildly elevated (500 pg/ml) in one of the 12 patients in Group B and moderately elevated (800 pg/ml, 1400 pg/ml) in two of the five patients in Group C. Following provocation, ITV plasma CT levels became markedly elevated in one patient in Group A and in all of the patients in Groups B(2520±635 pg/ml) and C (6322±2598 pg/ml). Thyroidectomy was performed in patients whose ITV plasma CT level was elevated following provocative testing. Medullary thyroid carcinoma of C-cell hyperplasia were evident either on microscopic (1/1 patient in Group A;9/12 patients in Group B; and 2/5 patients in Group C), or gross (3/12 patients in Group B;3/5 patients in Group C) examination of thyroidectomy specimens. In only one of 14 patients was metastatic MTC noted on histologic examination of resected cervical lymph nodes. Postoperative peripheral plasma CT levels were unchanged from basal and less than 240 pg/ml following provocative testing in all but one patient. The present study then provides definitive evidence that patients at direct risk for familial MTC who have even minimally abnormal responses in peripheral plasma CT following provocative testing generally harbor some stage of a C-cell proliferative disorder. Identification of such individuals with early disease is important because thyroidectomy offers an extremely high cure rate.     

Oncologic Outcomes After Completion Thyroidectomy for Patients with Well-Differentiated Thyroid Carcinoma

Background

At our institution, thyroid lobectomy is employed as a definitive operation for unifocal intrathyroidal low risk cancers and thus completion thyroidectomy is rarely performed. The purpose of this study was to identify the indications for selective completion thyroidectomy and to report oncologic outcomes.

Methods

A retrospective review was performed to identify patients who underwent planned completion thyroidectomy for well-differentiated thyroid carcinoma (WDTC) from 2001 to 2010 based on initial lobectomy pathology. Assessment for risk of recurrence was based on the American Thyroid Association Initial Risk Stratification.

Results

During the 10-year study period, 79 patients underwent completion thyroidectomy for WDTC. Forty-four (56 %) patients were low risk and 35 (44 %) were intermediate risk. Completion thyroidectomy was recommended for 64 patients, whereas 15 patients were given an option of surveillance but ultimately decided to have surgery. Patients in the “recommended group” had more T3 tumors and fewer T1a tumors (p = 0.005 and 0.006, respectively). These patients also were more likely to be intermediate risk (p = 0.008) and to present with aggressive histology (p = 0.002). The rate of contralateral tumors (n = 27) was similar between both groups (35 and 33 %, respectively). Contralateral cancers were micropapillary in 24 of 27 (89 %) patients, 10 (40 %) of whom had multifocal disease. There were two pulmonary recurrences and no local-regional recurrences (median follow-up of 42.3 months).

Conclusions

Completion thyroidectomy is infrequent and performed for a select group of intermediate and low risk WDTCs at our institution with low recurrence rates. Incidental multifocal and unifocal contralateral cancers are common after completion thyroidectomy.