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.     

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.     

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

Background

Medullary 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.

Methods

In 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.

Results

In 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.

Conclusion

MTC patients had excellent prognosis in our institutions, indicating that our surgical strategies were appropriate.

     

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。     

Clinicopathologic Characteristics and Prognosis of Diffuse Sclerosing Variant of Papillary Thyroid Carcinoma in Japan: An 18-Year Experience at a Single Institution

Background  Diffuse sclerosing variant (DSV) is a variant of papillary thyroid carcinoma that has diffuse involvement in one or both thyroid lobes without forming a dominant mass. We investigated the biological characteristics of DSV in Japan. Methods  We investigated biological behaviors and prognoses of DSV in 35 patients who underwent surgical treatment between 1989 and 2007. Results  After excluding papillary microcarcinoma, DSV accounts for 0.7% of papillary carcinoma. DSV occurs more frequently in younger patients and is clinically apparent as lymph node metastasis and lung metastasis more frequently than other papillary carcinomas, but the incidence of extrathyroid extension did not differ between the metastases. Routine radioiodine ablation therapy after initial surgery was not performed unless distant metastasis was clinically apparent at surgery. The disease-free survival rate of DSV was significantly worse than that of a pair-matched control group. However, only two patients, one with lung metastasis at surgery and another who underwent only palliative surgery, have died of carcinoma to date. Conclusions  Although cause-specific survival of DSV was good, its disease-free survival was worse than that of the control group because of the unavailability of routine radioiodine ablation therapy. Therefore, DSV requires careful surgical resection to minimize the carcinoma recurrence.     

Clinicopathologic Characteristics and Clinical Outcomes of Esophageal Basaloid Squamous Carcinoma: Experience at a Single Institution

This retrospective study investigated the clinicopathologic characteristics and clinical outcomes of esophageal basaloid squamous carcinoma (BSC). Among 190 patients with esophageal carcinoma treated surgically between 1998 and 2011, we identified 9 (4.7%) with BSC. All of the patients were male, with a median age of 65 years. The frequencies of venous invasion, lymphatic invasion, and lymph node metastasis were 56%, 89%, and 67%, respectively. A total of 2 patients were pathologic stage 1, 5 were stage 2, and 2 were stage 3. Tumor recurrence was observed in 56% of the patients. The 5-year survival rate for patients with esophageal BSC was 40%, which was compatible with the figure of 53.8% for control patients (n = 18) with typical squamous cell carcinoma matched for sex, age, tumor location, and pathologic stage (P = 0.45). Although esophageal BSC shows aggressive lymph-vascular invasion and has a high likelihood of recurrence, its prognosis seems identical to that of typical squamous cell carcinoma.     

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.     

Favorable Surgical Results in 433 Elderly Patients with Papillary Thyroid Cancer

Papillary thyroid cancer (PTC) has a good prognosis among patients younger than 45 years old, but the prognosis in elder is worse and treatment strategy is not well established. We retrospectively analyzed the clinical features and outcomes of 433 patients with PTC aged 70 years or older. The patients consisted of three groups: group A (n = 327); patients receiving surgical treatment, group B (n = 51); patients with microcancer (maximal diameter, ≤ 1.0 cm) who did not undergo surgical treatment, group C (n = 55); patients in whom surgery was contraindicated due to age, high surgical risk or complication by other illnesses. In group A, the mean tumor size was 2.6 ± 1.5 cm, and 218 patients (66.7%) had pathologically confirmed lymph node metastasis; 110 patients (33.6%) had extrathyroidal invasion. The 5- and 10-year overall survival rates (OSR) in group A were 97.2% and 85%, respectively, which was significantly higher than the 5-year OSR in group C (62.6%). The 5- and 10-year disease-specific survival rates (DSSR) in group A were 98.5% and 91.3%, respectively, which was also significantly higher than the 5-year DSSR in group C (81.8%). Although the patients in group B did not receive any treatment, none of them demonstrated cause-specific death or progression of disease. Papillary thyroid cancer in elderly patients, except for microcancers, may be biologically aggressive. Thus surgery is recommended for these patients, if their general status is judged able to tolerate the stress of anesthesia and surgery.     

Effect of Anti-TNF Agents on Postoperative Outcomes in Inflammatory Bowel Disease Patients: a Single Institution Experience

Background

Anti-tumor necrosis factor (TNF) agents have been an integral part in the treatment of inflammatory bowel disease. However, a subset of inflammatory bowel disease patients ultimately requires surgery and up to 30 % of them have undergone treatment with anti-TNF agents. Studies assessing the effect of anti-TNF agents on postoperative outcomes have been inconsistent. The aim of this study is to assess postoperative morbidity in inflammatory bowel disease patients who underwent surgery with anti-TNF therapy prior to surgery.

Methods

This is a retrospective review of 282 patients with inflammatory bowel disease undergoing intestinal surgery between 2013 and 2015 at the Mount Sinai Hospital. Patients were divided into two groups based on treatment with anti-TNF agents (infliximab, adalimumab, certolizumab) within 8 weeks of surgery. Thirty-day postoperative outcomes were recorded. Univariate and multivariate statistical analyses were carried out.

Results

Seventy-three patients were treated with anti-TNF therapy within 8 weeks of surgery while 209 patients did not have exposure. Thirty-day anastomotic leak, intra-abdominal abscess, wound infection, extra-abdominal infection, readmission, and mortality rates were not significantly different between the two groups.

Conclusions

The use of anti-TNF medications in inflammatory bowel disease patients within 2 months of intestinal surgery is not associated with an increased risk of 30-day postoperative complications.

     

Merkel Cell Carcinoma: 30-Year Experience from a Single Institution

Background

Merkel cell carcinoma (MCC) is a rare cutaneous malignancy. Few single-institution series have been reported.

Methods

Review of MCC patients treated at our institution between 1980 and 2010. Patient, tumor, and treatment variables were analyzed to determine MCC-specific outcomes.

Results

We identified 161 patients with MCC. There was a 2.5-fold increase in cases over the last decade. Median length of follow-up was 36 months. Stage at diagnosis was I in 35 %, II in 21 %, IIIa in 12 %, IIIb in 23 %, and IV in 9 %. The 5-year MCC-specific survival rates were 87, 63, 42, and 0 % for stages I, II, III, and IV, respectively. Death from the disease occurred in 10 % of patients with T1 and in 50 % with larger lesions. One-third of patients presented with nodal disease. Sentinel lymph node biopsy (SLNB) identified micrometastases in 9 out of 27 (33 %) early-stage patients. Recurrence developed in 56 % of SLNB-positive and 39 % of SLNB-negative patients. Half of patients recurred after a median time of 9 months. Proportions of first recurrence location were distant (52 %), nodal (27 %), and local (21 %). Adjuvant treatments did not improve recurrence or survival rates. One-third of patients died of the disease.

Conclusions

SLNB identifies micrometastasis in one-third of early-stage patients. Negative SLNB may predict for improved but not necessarily favorable outcome. Initial tumor size and clinical nodal disease predict for poor outcome. High recurrence rates warrant the development of more effective adjuvant therapies, and better markers of recurrence and treatment response for MCC are needed.     

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.

     

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.     

Prophylactic Thyroidectomy in 75 Children and Adolescents with Hereditary Medullary Thyroid Carcinoma: German and Austrian Experience

RET proto-oncogene were found in 1993 to account for hereditary medullary thyroid carcinoma (MTC), surgeons obtained the opportunity to operate on patients prophylactically (i.e., at a clinically asymptomatic stage). Whether this approach is justified, and, if so, when and to which extent surgery should be performed remained to be clarified. A questionnaire was sent to all surgical departments in Germany and Austria. All of the patients who fulfilled the following criteria were enrolled: (1) preoperatively proved RET mutation; (2) age ≤ 20 years, (3) clinically asymptomatic thyroid C cell disease; and (4) TNM classification pT0–1/pNX/pN0–1/M0. Seventy-five patients were identified, and fifteen mutations were detected in six codons. Two adolescents had unilateral pheochromocytomas as part of the multiple endocrine neoplasia II (MEN-II) syndrome. No hyperparathyroidism was noted. All patients underwent total thyroidectomy, and 57 patients went on to have lymph node dissection. Parathyroid glands were removed in 34 patients and autografted in 11. Histopathology revealed MTC in 46 patients (61%, youngest 4 years); C cell hyperplasia (CCH) only was detected in the other 29 patients. Three patients had lymph node metastases (LNMs) the youngest being age 14 years. Calcitonin levels were not useful for differentiating between CCH and MTC, but in all patients with LNMs at least the stimulated calcitonin levels were assayed. After surgery, five patients (6.7%) sustained permanent hypoparathyroidism, and one patient (1.3%) had a permanent unilateral recurrent nerve palsy. All but three patients (96%) were biochemically cured. In conclusion, prophylactic total thyroidectomy can be performed safely in experienced centers. We recommend prophylactic total thyroidectomy at age 6. Cervicocentral lymph node dissection should be included when calcitonin levels are elevated or if patients are older than 10 years. Bilateral lymph node dissection should be performed if LNMs are suspected or when patients with elevated calcitonin are older than 15 years.     

Palliative Surgical Management of Patients with Unresectable Pancreatic Adenocarcinoma: Trends and Lessons Learned from a Large, Single Institution Experience

Introduction

Routine palliative bypass has been advocated for palliation of patients with pancreatic adenocarcinoma who have inoperable disease discovered at the time of surgery. We examined trends in the relative use of palliative bypass over time with an emphasis on identifying changes in surgical indications, type of bypass performed, as well as perioperative outcomes associated with surgical palliation.

Methods

Between 1996 and 2010, 1,913 patients with pancreatic adenocarcinoma in the head of the pancreas were surgically explored. Data regarding preoperative symptoms, intraoperative findings, type of surgical procedure performed, as well as perioperative and long-term outcomes were collected and analyzed.

Results

Of the 1,913 patients, 583 (30.5%) underwent a palliative procedure. Most patients presented with jaundice (72.2%). The majority of patients were evaluated by CT scan (97.4%), which revealed a median tumor size of 3.2 cm. Most patients who underwent surgical palliation (64.5%) had a double bypass, while a minority had either gastrojejunostomy (28.2%) or hepaticojejunostomy (7.2%) alone. While the number of pancreaticoduodenectomies remained relatively stable over time, there was a temporal decrease in the utilization of palliative bypass (P?P?=?0.005). Palliative failure rates were 2.3% after hepaticojejunostomy and 3.1% after grastrojejunostomy. Patients with unsuspected metastatic disease had a worse survival compared with patients who had locally unresectable disease (median survival: 5 vs. 8 months, respectively; HR?=?1.43, P?=?0.001).

Conclusion

Palliative bypass procedures were less frequently performed over time, probably due to a significant decrease in the rate of unanticipated advanced locoregional disease at the time of exploration. While palliative bypass was effective, survival in the setting of metastatic disease was extremely short.     

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.     

Regulatory T Cells in Peripheral Blood, Lymph Node, and Thyroid Tissue in Patients with Medullary Thyroid Carcinoma

Background  

Immunological response of the human body is controlled by the suppressive characteristics of regulatory T cells (Tregs). In various diseases a change in the number of Tregs is evident. For example, whereas Tregs are reduced in auto-immunological processes, an increase of Tregs is found with various malignant tumors. Regarding medullary thyroid carcinoma (MTC) no such studies have been performed to date.