Medullary thyroid carcinoma: surgical treatment advances Gianlorenzo Dionigi a, Maria Laura Tanda b and Eliana Piantanida b

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1 Medullary thyroid carcinoma: surgical treatment advances Gianlorenzo Dionigi a, Maria Laura Tanda b and Eliana Piantanida b a Department of Surgical Sciences and b Clinical Medicine, University of Insubria, Varese, Italy Correspondence to Gianlorenzo Dionigi, MD, Endocrine Surgery Research Center, Department of Surgical Sciences, University of Insubria, Ospedale di Circolo Polo Universitario, Viale Guicciardini Varese, Italy Tel: ; fax: ; gianlorenzo.dionigi@uninsubria.it Current Opinion in Otolaryngology & Head and Neck Surgery 2008, 16: Purpose of review In recent years new technologies have been proposed and applied in thyroid surgery, among these molecular diagnosis and endoscopic procedures. The authors review relevant medical literature published on the influence of these new techniques in the treatment of medullary thyroid cancer. Searches were last updated in October Recent findings Mutations of the RET proto-oncogene have been demonstrated to be causative of the familial form of medullary thyroid cancer. The number and type of recognized RET genetic mutations have grown over the last years, especially after the introduction of genetic screening in the work-up of all patients with medullary thyroid cancer. Prophylactic surgery for patients carrying a positive RET proto-oncogene is highly effective. Cervical endoscopic procedures have been recently described and applied for positive RET carriers: a video-assisted thyroidectomy with central compartment dissection (level 6) has proved feasible, safe and effective for these patients. Summary There have been some important papers in the recent literature that apply to many aspects of new technologies for medullary thyroid cancer treatment. This article discusses some of these articles, emphasizing where this literature makes new contributions and supports established recommendations. Keywords endoscopic thyroidectomy, genetic testing, medullary thyroid carcinoma, RET proto-oncogene, video-assisted central compartment lymphadenectomy Curr Opin Otolaryngol Head Neck Surg 16: ß 2008 Wolters Kluwer Health Lippincott Williams & Wilkins X Introduction Medullary thyroid cancer (MTC) arouses considerable interest because of its distinctive biochemical, genetic and clinical features [1,2]. In about 25% of cases, MTC is inherited as an autosomal dominant trait and occurs either as part of multiple endocrine neoplasia (MEN) type 2A or 2B or as familial MTC (FMTC) [1,2]. MTC is usually located in the area of highest C cell concentration: the lateral upper two thirds of the gland (Fig. 1). In familial disease, this is the site of its first identifiable manifestation: C cell hyperplasia (CCH), the precursor lesion of MTC [3]. CCH is usually diagnosed when more than six C cells are seen per follicle or more than 50 intrafollicular calcitonin-positive cells are seen in at last one low-power (100) field [3]. The transition from benign CCH to invasive MTC is marked by disruption of the follicular basement membrane by C cells [3,4 ]. The progression of CCH to MTC occurs at different rates depending on the genetic mutations in the RET protooncogene identified on chromosome 10 [4 ]. The evolution of genetic testing The number and type of recognized RET genetic mutations have grown over recent years, especially after the introduction of RET genetic screening in the work-up of all patients with MTC, both hereditary and sporadic types [5,6,7]. Currently, identification of point mutations of the RET proto-oncogene allows identification of gene carriers in about 100% of cases [8,9]. Genotype phenotype correlation has been established, showing clustering of mutations in exons 10 and 11 in classical MEN2A syndrome, in exon 16 codon 918 in MEN2B syndrome [10]. In FMTC a codon 532 mutation may be found in exon 8; codons 609, 611, 618, 620, in exon 10; codon 630 in exon 11; codons 768, 790 in exon 13; codon 804 in exon 14 and codon 891 in exon 15 [11]. Identification of a mutation in a family enables certain determination of members who carry the mutations and those who do not. Noncarriers are discharged from further regular biochemical screening tests [10,11]. Genetic X ß 2008 Wolters Kluwer Health Lippincott Williams & Wilkins

2 Medullary thyroid carcinoma Dionigi et al. 159 Figure 1 Medullary thyroid cancer Positive immunostaining reaction for calcitonin gene related peptide and calcitonin (diaminobenzidine haematoxylin 400). screening allows early identification of children at risk before any chemical abnormality becomes evident and allows early prophylactic total thyroidectomy [12 ]. Studies have demonstrated a direct correlation between early diagnosis of MTC and outcome [12 ]. RET testing is indicated in patients with presumed sporadic MTC; members of known MTC kindreds; all patients with pheochromocytoma; and children with Hirschprung s disease [12 ]. The decision to perform thyroidectomy in MEN2 carriers should be based predominantly on the result of a RET mutation than calcitonin testing. This recommendation stems from several unique features of MEN2 [13]. Children operated upon in their teenage years in the era of provocative calcitonin testing usually experienced long-term cure, but many were identified only after MTC had developed. Calcitonin testing cannot reliably distinguish between CCH and micro MCT. Provocative calcitonin testing of select patients for thyroidectomy is associated with an incidence of false-positive tests as high as 10%, which may result in unnecessary thyroidectomy. RET testing has a higher true-positive rate and a lower negative rate than any other test, thus faciliting earlier thyroidectomy in carriers. Nearly every case has an identifiable RET mutation. When a RET mutation is found in an index case all first degree relatives must be screened to determine which individuals carry the gene. This is performed twice and on separate blood samples to exclude errors. Theoretically, half of first-degree relatives do not carry the mutated gene and their risk of developing the disease is similar to that of the general public. (1) As for the timing and extent of prophylactic surgery, Machens [14] recommended an individualized approach according to genotype: high risk (codons 634 and 618) with the youngest ages being 3 and 7 years at MTC diagnosis; intermediate risk (codons 790, 620 and 611) with ages of 12, 34, and 42 year at diagnosis; low risk (codons 768 and 804) with ages of 47 and 60 years, at diagnosis, respectively. (2) During the Seventh International Workshop on MEN the consensus was to stratify management of hereditary MTC into three levels on the basis of genetic information [13]. Level 1 or lower-risk patients are children with RET codon 609, 768, 790, 804 and 891 mutations and have the least high risk among the three RET codon mutation stratifications. This group should undergo prophylactic thyroidectomy. There was little consensus on the management of these mutations: some opt for a strategy similar to the high-risk group, others suggested thyroidectomy at age 10 and still others opted for periodic pentagastrinstimulated calcitonin testing. These patients should undergo thyroidectomy when the pentagastrin test becomes positive (calcitonin > 10 pg/ml) or during the third or fourth decade of life. Level 2 or intermediate-risk patients are children with any RET codon 611, 618, 620 or 634 mutation and are classified as having high risk for MTC and should undergo thyroidectomy, including removal of the posterior capsule, before the age of 5 years. Level 3 or highestrisk children have MEN2B or RET codon 918 or 883 mutation and should have a total thyroidectomy within the first 6 months of life, preferably within the first month of life. Thyroid surgery should include a central neck dissection. If metastases are identified, more extensive neck dissection is appropriate. A report by the Euromen Study Group [8 ] gives another opinion on the selection of patients for surgery and management of familial MTC. This group collected data from 200 carriers of a RET mutation who were under age 20 years and who had undergone total thyroidectomy for MTC under 10 mm confined to the thyroid. The most common RET codon was 634 (62.8%) followed by codon 618 (9.2%), codons 620 and 790 (6.8% each), codon 791 (2.4%), codons 609, 611, 804 and 918 (1.9% each), and codon 630 (0.5%). There was a significant age-related progression from CCH to MTC, and to nodal metastases in patients whose RET mutations were grouped according to the extracellular and intracellular domain codons affected. The mean age at the time of diagnosis was 8.3 years among patients who had CCH and extracellular domain mutations, and was 11.2 years among those with

3 160 Head and neck oncology intracellular domain mutations (P ¼ 0.01). Among patients with node-negative MTC, the mean age at diagnosis was 10.2 years in those with extracellular domain mutations and 16.6 years in those with intracellular domain mutations (P ¼ 0.002). The mean age at diagnosis among patients with node-positive MTC was 17.1 years in those with extracellular domain mutations and none of the patients with intracellular domain mutations had nodal metastases during the first two decades of life. They found that grouping the rare RET mutations at extracellular and intracellular domain mutation was not a useful way of identifying the optimal age at which asymptomatic carriers should undergo prophylactic thyroidectomy. The authors opine that as more clinical information emerges, some of the rare RET mutations may need to be reclassified if they turn out to behave differently from the others in that group. The Euromen report [8 ] demonstrates the following points: With any codon 634 mutation, regardless of the amino acid substitution, MTC commonly appears before the age of 10 years but perhaps of the greatest importance, it may occur in children as young as 17 months; MTC is rarely metastatic before the age of 14 years, regardless of the amino acid substitution; nodal metastases were found an average of 6.6 years after MTC had appeared. These observations support the recommendation for prophylactic thyroidectomy at least by 5 years if not earlier for carriers of the 634 RET mutation. Among asymptomatic carriers of mutations in codon 611, 618 or 620 none had evidence of MTC before the age of 5 years, suggesting early thyroidectomy is not necessary. Among asymptomatic carriers of mutations in codon 609, 630, 768, 790, 791 or 891 the data do not support the need for prophylactic thyroidectomy before the age of 10 years or for central lymph-node dissection before the age of 20 years. Contributions of endoscopic/mini-invasive surgery The first endoscopic procedure in the cervical area was performed by Gagner [15]. For thyroidectomy, different minimal invasive techniques have been increasingly reported [16,17]. In 1998, Miccoli [18] developed a technique of minimally invasive video-assisted thyroidectomy (MIVAT), a completely gasless procedure. Selection criteria for patients are reported in Table 1. Traditionally, open thyroidectomy requires a 6 8 cm, or bigger, transverse wound on the lower neck while Miccoli s approach is very small in wound length [18]. Conversion to the traditional open approach sometimes may be required but it is rare when selection criteria are respected [18]. Table 1 Selection criteria for minimally invasive video-assisted thyroidectomy Indications Controindications Dominat nodule size 35 mm TUEVS 25 ml Low-risk papillary thyroid cancer RET gene carriers TUEVS, thyroid ultrasound estimated volume. Large goiter (VTS > 20 ml) Local advanced cancer and lymph node metastases Hyperthyroidism Thyroiditis Previous neck irradiation Previous neck surgery Obesity Stocky neck Pain following the MIVAT is much less than with the conventional thyroidectomy, because there is less dissection, traction and destruction of tissues [18]. The only kind of thyroid cancer that may be attacked with MIVAT is a small papillary carcinoma without lymph node involvement. Up to now Miccoli s technique is the mini-invasive thyroid procedure more widely used in operating rooms [19]. The small operative space, the possible trouble linked with long insufflations, the endoscopic instrumentation inadequate, as for size and design, to operate on the neck, appeared to constitute important obstacles to the diffusion of these other minimally invasive thyroidectomies [20]. Drawbacks of MIVAT, however, are the fact that a minority of patients qualifies for this approach (the volume of the thyroid masses to be removed often exceeds the possibilities of endoscopic neck surgery), and that the learning curve is quite long for the surgeon and that surgeons experienced both in endocrine and in endoscopic surgery are scarce [20]. Since RET gene mutation carriers have often normal ultrasound thyroid volume, small nodules and, if involved, small lymph nodes, they indeed represent the best candidates for a mini-invasive approach especially when considering that they are usually young and concerned about the cosmetic results and the period of hospitalization [21,22 ]. In fact, the excellent results obtained by MIVAT in the last few years induced Miccoli to propose this procedure together with a central compartment lymphadenectomy to RET gene mutation carriers found by genetic screening: these patients were definitively cured without any surgical complication [21,22 ]. Miccoli [22 ] proved that prophylactic surgery for patients carrying a positive RET proto-oncogene is highly effective in curing those likely to experience the development of a medullary carcinoma: in particular the video-assisted procedures have proved feasible for central compartment dissection. In this study, patients with a positive RET proto-oncogene underwent total thyroidectomy and central compartment lymphadenectomy (level 6) via a video-assisted approach. Technically, once the thyroidectomy is accomplished through the central unique access, the central compartment is approached. The endoscope is placed at the head

4 Medullary thyroid carcinoma Dionigi et al. 161 of the patient, thus allowing a full vision of the superior mediastinum. The recurrent laryngeal nerve is followed as the main anatomic landmark. All the lymphatic tissue between the carotid sheath and the trachea is dissected until the innominate trunk is reached. A transient hypoparathyroidism occurred in one patient, and a permanent hypoparathyroidism occurred in another one. No laryngeal nerve palsy was present. All the patients were discharged on postoperative day 1. Histology showed a medullary carcinoma in 10 patients and diffuse CCH in five patients. The mean number of lymph nodes removed was five. Calcitonin levels were undetectable in all six patients who had a follow-up period longer than 1 year [21,22 ]. Conclusion To discuss even a fraction of these articles is not possible in a short review. There have been some important papers in the recent literature, however, that apply to many aspects of new technologies to cure MTC. Prophylactic thyroidectomy for RET proto-oncogene carriers, before a clinically evident MTC develops, is currently performed in several centers, with a very high cure rate [23 25]. In the future, genotype phenotype correlation studies in patients with identified RET mutations could define the RET signal transduction pathway and its role in the development of neural crest derivates and MTC tumour development [26,27,28 ]. Currently, endoscopic thyroidectomy has become an important technique for managing surgical disease of the thyroid: when initially introduced, it was in fact used principally for thyroid nodules. Careful central compartment node clearance, which is mandatory for all patients who present with a positive pentagastrin test result is one of the most important surgical steps for RET protooncogene carriers [29,30]. For this reason, surgeons have been reluctant to adopt endoscopic procedures to remove thyroid plus lymph nodes for these patients [20]. On the other hand, the small size of the tumours and of the gland makes these patients ideal candidates for minimally invasive video-assisted procedures. The procedure demonstrated an adequate level 6 lymphadenectomy, a complication rate comparable with that for conventional procedure, a better cosmetic outcome and less postoperative pain [21]. More cases with longer follow-up are necessary to estimate the impact of the video-assisted approach on central neck lymphadenectomy. Acknowledgements The authors are grateful to professor Luigi Bartalena for general support, excellent technical assistance and helpful discussion. References and recommended reading Papers of particular interest, published within the annual period of review, have been highlighted as: of special interest of outstanding interest Additional references related to this topic can also be found in the Current World Literature section in this issue (p. 178). 1 Thomas N, Jacob JJ. Medullary thyroid carcinoma. ANZ J Surg 2007; 77: Vezzosi D, Bennet A, Caron P. Recent advances in treatment of medullary thyroid carcinoma. Ann Endocrinol (Paris) 2007; 68: Ball DW. Medullary thyroid cancer: therapeutic targets and molecular markers. Curr Opin Oncol 2007; 19: Machens A, Dralle H. Genotype phenotype based surgical concept of hereditary medullary thyroid carcinoma. World J Surg 2007; 31: This study was a systematic evaluation of the literature using evidence-based criteria. These are the conclusions: There is a distinct age-related progression of hereditary MTC in carriers of RET mutations. Among the high-risk RET mutations, those in codon 634 cause higher penetrance rates of the MEN2A phenotype than mutations in codons 609, 611, 618 and 620. DNA-based screening is superior to calcitonin-based screening in asymptomatic RET carriers. Timing for prophylactic thyroidectomy: 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. 5 Elisei R, Romei C, Cosci B, et al. Ret genetic screening in patients with medullary thyroid cancer and their relatives: experience with 807 individuals at one center. J Clin Endocrinol Metab 2007; 92: In this large series, the authors unexpectedly discovered a germline RET mutation in 35 of 481(7.3%) apparently sporadic MTC patients. Moreover, the prevalence of RET mutations in noncysteine codons was higher in MTC that presented as apparently sporadic (P < ). 6 de Groot JW, Kema IP, Breukelman H, et al. Biochemical markers in the follow-up of medullary thyroid cancer. Thyroid 2006; 16: Szinnai G, Sarnacki S, Polak M. Hereditary medullary thyroid carcinoma: how molecular genetics made multiple endocrine neoplasia type 2 a paediatric disease. Endocr Dev 2007; 10: Al-Rawi M, Wheeler MH. Medullary thyroid carcinoma: update and present management controversies. Ann R Coll Surg Engl 2006; 88: Adequate resection of the primary tumour and cervical lymph nodes is important to optimize outcome and minimize the risk of recurrent disease in MTC. 9 Machens A, Niccoli-Sire P, Hoegel J, et al. Early malignant progression of hereditary medullary thyroid cancer. N Engl J Med 2003; 349: Keatts EL, Itano J. Medullary thyroid cancer and the impact of genetic testing. Clin J Oncol Nurs 2006; 10: Shaha AR, Cohen T, Ghossein R, Tuttle RM. Late-onset medullary carcinoma of the thyroid: need for genetic testing and prophylactic thyroidectomy in adult family members. Laryngoscope 2006; 116: Pelizzo MR, Boschin IM, Bernante P, et al. Natural history, diagnosis, treatment and outcome of medullary thyroid cancer: 37 years experience on 157 patients. Eur J Surg Oncol 2007; 33: Early diagnosis of MTC is very important. The authors recommend radical surgery including total thyroidectomy plus central compartment lymphoadenectomy as the treatment of choice, plus lateral compartment lymphoadenectomy in patients with palpable or ultrasound enlarged neck lymph nodes. The presence of lymph node and distant metastases significantly worsened prognosis and survival rate. 13 Brandi ML, Gagel RF, Angeli A, et al. Guidelines for diagnosis and therapy of MEN type 1 and type 2. J Clin Endocrinol Metab 2001; 86: Machens A, Gimm O, Hinze R, et al. Genotype phenotype correlations in hereditary medullary thyroid carcinoma: oncological features and biochemical properties. J Clin Endocrinol Metab 2001; 86: Terris DJ, Chin E. Clinical implementation of endoscopic thyroidectomy in selected patients. Laryngoscope 2006; 116: Timon C, Miller IS. Minimally invasive video-assisted thyroidectomy: indications and technique. Laryngoscope 2006; 116: Lombardi CP, Raffaelli M, Princi P, et al. Video-assisted thyroidectomy: report on the experience of a single center in more than four hundred cases. World J Surg 2006; 30: Miccoli P, Berti P, Frustaci GL, et al. Video-assisted thyroidectomy: indications and results. Langenbecks Arch Surg 2006; 391: Miccoli P, Bellantone R, Mourad M, et al. Minimally invasive video-assisted thyroidectomy: multiinstitutional experience. World J Surg 2002; 26:

5 162 Head and neck oncology 20 Duh QY. Minimally invasive endocrine surgery: standard of treatment or hype? Surgery 2003; 134: Miccoli P, Elisei R, Berti P, et al. Video assisted prophylactic thyroidectomy and central compartment nodes clearance in two RET gene mutation adult carriers. J Endocrinol Invest 2004; 27: Miccoli P, Elisei R, Donatini G, et al. Video-assisted central compartment lymphadenectomy in a patient with a positive RET oncogene: initial experience. Surg Endosc 2007; 21: Video-assisted central compartment lymphadenectomy in RET carriers is proved to be effective and safe. 23 Ball DW. Medullary thyroid cancer: monitoring and therapy. Endocrinol Metab Clin North Am 2007; 36: Boikos SA, Stratakis CA. Molecular mechanisms of medullary thyroid carcinoma: current approaches in diagnosis and treatment. Histol Histopathol 2008; 23: You YN, Lakhani V, Wells SA Jr, Moley JF. Medullary thyroid cancer. Surg Oncol Clin North Am 2006; 15: Hoff AO, Hoff PM. Medullary thyroid carcinoma. Hematol Oncol Clin North Am 2007; 21: de Groot JW, Links TP, Plukker JT, et al. RET as a diagnostic and therapeutic target in sporadic and hereditary endocrine tumors. Endocr Rev 2006; 27: Messina M, Robinson BG. Technology insight: gene therapy and its potential role in the treatment of medullary thyroid carcinoma. Nat Clin Pract Endocrinol Metab 2007; 3: Gene therapy might have therapeutic potential for patients with progressive metastatic MTC that is incurable by conventional treatments. The authors review a number of gene-therapy strategies that have been explored, primarily those that use replication-deficient adenovirus vectors to transfer therapeutic genes to tumor cells. 29 Peixoto Callejo I, Americo Brito J, Zagalo CM, Rosa Santos J. Medullary thyroid carcinoma: multivariate analysis of prognostic factors influencing survival. Clin Transl Oncol 2006; 8: Ogilvie JB, Kebebew E. Indication and timing of thyroid surgery for patients with hereditary medullary thyroid cancer syndromes. J Natl Compr Canc Netw 2006; 4: