Citation for published version (APA): Verbeek, H. (2015). Medullary Thyroid Carcinoma: from diagnosis to treatment [S.l.]: [S.n.]

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1 University of Groningen Medullary Thyroid Carcinoma Verbeek, Hans IMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite from it. Please check the document version below. Document Version Publisher's PDF, also known as Version of record Publication date: 2015 Link to publication in University of Groningen/UMCG research database Citation for published version (APA): Verbeek, H. (2015). Medullary Thyroid Carcinoma: from diagnosis to treatment [S.l.]: [S.n.] Copyright Other than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons). Take-down policy If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim. Downloaded from the University of Groningen/UMCG research database (Pure): For technical reasons the number of authors shown on this cover page is limited to 10 maximum. Download date:

2 General introduction and aims of the thesis

3 General introduction The thyroid One of the largest endocrine organs of the human body is the thyroid. This butterfly-shaped organ is located in the neck, in front of the trachea, directly below the larynx (Figure 1A). The thyroid is composed of follicles, surrounded by follicular and parafollicular cells (C-cells) (Figure 1B). Endocrine organs, such as the thyroid, produce hormones; biochemical active messengers which are released in the blood and regulate body functions. The thyroid produces thyroxine (T4), tri-iodotyronine (T3) (thyroid hormones) and calcitonin. The thyroid hormones are involved in the metabolic rate throughout the body, while calcitonin exerts an effect on calcium levels. C- cells Follicular cells Follicle A. B. Figure 1 Schematic representation of the thyroid gland (A) and (B) a histological section of thyroid tissue showing the different thyroid cells. Thyroid hormone production is a complex process and involves selective uptake of iodine which is bound to thyroglobulin, a large protein synthesized in the follicular thyroid cells to form eventually thyroxine and tri-iodotyronine. To release these hormones in the bloodstream, they are cleaved from the thyroglobulin which takes place intracellular. In the circulation, thyroid hormones are bound for 99% to the thyroxine binding globulin, and only 1% is free available for uptake by tissue cells. 8

4 General introduction and aims of the thesis Thyroid hormones act throughout the whole body and increase metabolism by activating transcription of many genes. Although thyroxine is much more present in the circulation, triiodotyronine is the active form of thyroid hormone and therefore almost all thyroxine is diodinated in order to have an effect on gene transcription. Calcitonin is the other hormone of the thyroid produced in the parafollicular C-cells, which account for about 0.1% of all thyroid cells. These cells have another embryological origin than the follicular thyroid cells. Calcitonin is a 32-amino acid peptide. The main effect of calcitonin is decreasing serum calcium levels, mainly by inhibiting bone resorption. 1,2 However, in comparison to the parathyroid hormone (PTH) secreted by the parathyroids, the effect of calcitonin on calcium metabolism is limited. Thyroid nodules Thyroid nodules are common in the general population; they are detected in up to 7% of patients with neck palpation and on ultrasound even up to 70%. 3-6 Functional imaging methods such as PET imaging also frequently reveal thyroid nodules. 7 Thyroid nodules are more present in women than in men and the incidence of thyroid nodules also increases with age. 3,8,9 Benign nodules can be caused by clonal expansion of follicular cells (hyperplasia), increase of the colloid follicles (colloid nodules), formation of cysts (cystic nodules) or inflammation (thyroiditis). 10,11 Most nodules are benign; only 5% to 10% of patients with palpable thyroid nodules have thyroid cancer. Thyroid cancer Five major histological types of thyroid cancer are recognized; papillary, follicular, medullary, poorly differentiated and undifferentiated (anaplastic) cancer. Papillary and follicular cancer (also known as differentiated thyroid cancer) arise from the follicular epithelium and account for 80-90% of all thyroid cancers. Medullary thyroid cancer arises from the parafollicular C-cells and accounts for approximately 5%-10% (Figure 2). Poorly differentiated thyroid carcinoma also arises from the follicular epithelium but exhibits a more aggressive growth pattern compared to differentiated thyroid carcinoma, although less aggressive than undifferentiated thyroid carcinoma. In undifferentiated thyroid carcinoma undifferentiated cells exhibit features indicative of epithelial differentiation and immunohistochemical staining is generally negative for thyroglobulin and calcitonin. Undifferentiated thyroid carcinoma covers the last 5%-10% of the cases. 11 9

5 Medullary thyroid cancer MTC was first described in a patient 1906 as a malignant goiter with amyloid by Jaquet. 12 In 1959, Hazard defined a case of thyroid carcinoma with a solid non follicular structure with amyloid in the stroma as a MTC. 13 MTC can occur sporadically (75%) or as part of a familial syndrome called Multiple Endocrine Neoplasia type 2 (MEN 2). This syndrome is caused by a mutation in the REarranged during Transfection (RET) gene and a MEN2A and MEN2B variant are discerned. Other manifestations of the MEN2 syndromes are a pheochromocytoma and hyperparathyroidism (MEN2A) or neurofibromatosis (MEN2B) (Table 1). Figure 2 Histological section of medullary thyroid carcinoma Table 1 Clinical expression of familial MTC-associated syndromes 14 FMTC MEN 2A MEN2B MTC 100% 100% 100% Pheochromocytoma 0% 10-60% 50% Hyperparathyroidism 0% 10-25% 0% Marfanoid habitus 0% 0% 100% Intestinal ganlioneuromatosis 0% 0% 60-90% Mucosal neuromas 0% 0% % Clinical presentation and diagnosis Most MTC patients present with an asymptomatic palpable solitary thyroid nodule or lymph node. Some patients have symptoms such as dyspnea, dysphagia, coughing or hoarseness. Due to excessive calcitonin production diarrhea or flushing may occur. 15,16 In very rare cases ectopic ACTH production of the neuroendocrine cells can cause Cushing syndrome. 17 At 10

6 General introduction and aims of the thesis presentation, about 50% of the MTC patients have lymph node metastases and distant metastasis are diagnosed in around 15% of patients. 18,19 Fine needle aspiration cytology is generally the first diagnostic procedure for thyroid nodules. However, the sensitivity of this procedure, without the use of additional immunohistochemical analysis, for detecting MTC is limited. 20 Since MTC originates from the calcitonin producing C-cells, this hormone can be used as a sensitive tumour marker. Another tumour marker used in MTC is carcinoembryonic antigen (CEA), however this marker is less sensitive. Serum calcitonin levels are not only determined in patients suspected of MTC, but are also used as screening tool for detection of MTC in patients with thyroid nodules. Although calcitonin testing in patients with thyroid nodules can detect MTC in an early stage, it also increases the risk of unnecessary surgery as a proportionate number of patients with thyroid nodules have an elevated basal calcitonin based on other causes than MTC (e.g. thyroiditis, idiopathic, sepsis and chronic renal failure) Treatment According to the current American Thyroid Association (ATA) guidelines, treatment for sporadic MTC consists of complete surgical removal of the thyroid (total thyroidectomy) and the adjacent lymph nodes in the central compartment (central compartment dissection). If the disease has spread to lateral lymph nodes of the neck, a lateral lymph node dissection is also indicated. 25 However a proportionate number of MTC patients cannot be cured due to the extensiveness of the disease at presentation. 26,27 In contrast to papillary and follicular thyroid cancer, MTC patients do not benefit from adjuvant radioactive iodine treatment as the C-cells do not have uptake of iodine. 28 Therefore adequate surgery is of crucial importance in MTC, including meticulous nodal dissection in the central and/or lateral neck. Although current ATA guidelines provide clear recommendations for the surgical approach, the effect of adherence to these recommendations on the outcome of MTC patients remains unclear. Follow-up Despite extensive surgery, a large proportion of MTC patients cannot be cured. 29 Although many patients with residual disease have a good life expectancy, some will develop progressive disease. 30 Therefore follow-up is important including regular determinations of calcitonin and CEA. If these tumour markers are elevated or increasing, further diagnostic work-up is needed using morphological (US/MRI/CT) and functional imaging (positron 11

7 emission tomography (PET)). Although calcitonin and CEA doubling times are currently the most reliable markers for progression, time consuming serial measurements are required for accurate determination. Early detection of progressive disease is important because appropriate therapeutic interventions, such as local surgical treatment, may delay symptomatic deterioration. Therapeutic strategies are based on the outcome of the imaging procedure and the doubling time of the tumour markers, and covers a wait and see policy with close monitoring, a surgical intervention or systemic (targeted) therapy, if possible in a clinical trial. Systemic treatment Traditional chemotherapeutic regimens have not been proven to be effective in the palliative treatment of MTC. Recently developed tyrosine kinase inhibitors have shown improvement of progression free survival in MTC patients. 31,32 However, most studies have used one particular TK inhibitor without analysis of the mutations present in the tumour. This makes it difficult to compare these compounds for different patient groups. Most tyrosine kinase inhibitors target multiple intracellular pathways, which can cause next to the intended effect also side-effects, including cardiac toxicity and hand-foot syndrome. 33,34 Therefore careful consideration must be given when applying these new therapies. Aims and outlines of the thesis This thesis covers problems encountered in the diagnosis and treatment of primary and recurrent MTC. The aims of the studies in this thesis were to: 1. Address the value of calcitonin testing for detection of MTC in patients with thyroid nodules. 2. Evaluate the recommendations regarding surgical treatment by the current ATA guidelines for MTC patients. 3. Detect MTC patients with progressive recurrent disease in an early stage. 4. Optimize treatment with targeted therapy (tyrosine kinase inhibitors) for MTC patients with RET mutations/translocations with recurrent disease. Chapter 2 encompasses an introduction to MTC and the difficulties in diagnosis. To illustrate the different clinical presentation and behaviour of MTC, three patients with different stages 12

8 General introduction and aims of the thesis of disease are presented. A brief overview of currently used methods for diagnosis, treatment options and follow-up is provided. MTC patients detected in an early stage of the disease have a better prognosis. As almost all MTCs secrete calcitonin, systematic determination of calcitonin might detect these tumours in patients presenting with a thyroid nodule. However, the role of routine calcitonin testing remains unclear, and no consensus exists between different guidelines. Chapter 3 focuses on the value of routine calcitonin testing for detection of MTC in patients with thyroid nodules. A formal systematic meta-analysis was performed to determine the diagnostic accuracy of the calcitonin test. Sixteen studies were eventually included in which patients with nodular thyroid disease underwent basal calcitonin testing and 187 MTC patients were identified. Summary estimates of sensitivity and specificity for different cut-off values and subgroups were determined. Surgery is the most important therapeutic option for curative treatment of MTC. For MTC patients presenting with a palpable thyroid nodule without suspected lymph node involvement, treatment consists of a total thyroidectomy and central compartment dissection. In many institutes this approach is followed by an unilateral elective nodal dissection of the lateral neck. When suspected nodal involvement is present, a therapeutic lateral lymph node dissection, according to the American Thyroid Association (ATA) 2009 guidelines is performed. As the effect of adherence to these recommendations on the outcome of MTC patients is unclear, we retrospectively evaluated these guidelines with respect to locoregional control and clinical outcome. In Chapter 4 we reviewed the surgical and pathology reports of 86 patients treated between 1980 and 2010 in two major tertiary referral centres. We compared the clinical outcome (reoperations, biochemical cure, survival and complications) of the patients treated adequately according to ATA guidelines versus patients treated inadequately. Furthermore, we examined to which extent clinical outcome of patients was influenced by one-step versus a two-step intended curative surgical procedure, institute of initial curative surgery (experienced centre versus non-centre hospital). Finally, influence of patient and tumour characteristics on clinical outcome were evaluated. After surgery, follow-up is important in patients with MTC, as a large proportion of patients with biochemical residual disease will develop clinical recurrent disease. Although prognosis is good in most patients with recurrent disease, some patients develop progressive disease. 13

9 Regular determinations of calcitonin and CEA are useful in the early identification of these patients, because therapeutic interventions, such as surgery for local tumour control, can be of value in these patients. If tumour markers increase, further diagnostic work-up with anatomical and/or functional imaging is required. In Chapter 5 we aimed to provide an overview of the available PET imaging methods used for MTC and other types of thyroid cancer. In Chapter 6 we investigated the potential of 18 F-deoxyglucose (FDG-PET) and 18 F- diphenylalanine (DOPA-PET) to identify progression in MTC patients. PET positivity was compared with biochemical parameters (calcitonin and CEA serum levels and doubling times) in 47 patients. In a subgroup of 21 patients whole body metabolic burden (WBMTB) was assessed with standardized uptake value and the number of lesions, and compared with biochemical parameters. Furthermore, survival was compared with 18 F-DOPA PET or 18 F- FDG PET positivity. In MTC, but also PTC patients with progressive disease, systemic targeted therapy with tyrosine kinase inhibitors is currently considered. As activating mutations or rearrangements in the RET gene can cause MTC and PTC, tyrosine kinase inhibitors that target the RET receptor might be promising. In Chapter 7 we aimed to determine which inhibitor is the most effective and if there is rationale for mutation based therapy. We cultured and treated three cell lines expressing a MEN2A (MTC-TT), a MEN2B (MZ-CRC-1) mutation, and a RET/PTC (TPC-1) rearrangement. We compared four tyrosine kinase inhibitors (axitinib, sunitinib, vandetanib and cabozantinib) in vitro. We evaluated the effects on cell proliferation, RET expression, RET autophosphorylation and on RET downstream pathways (Extracellular Signal-regulated Kinase (ERK)). In Chapter 8 a general discussion is provided and future perspectives are addressed. In Chapter 9 a summary of this thesis in Dutch is given. 14

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