CHAPTER 18B. THYROID CANCER - thyroidmanager.org

1 1 CHAPTER18B. THYROID CANCERF urio Pacini, MDThyroid Unit, Univ of Siena, Siena ItalyLeslie J DeGroot,MD,Univ of Rhode Island, Providence, RIRevised 27 March2013 INCIDENCE AND DISTRIBUTIONThe annual incidence of THYROID CANCER variesconsiderably in different registries, ranging from 100,000 individuals in men and from per 100,000 in women (106,107).It is particularlyelevated in Iceland and Hawaii, being nearly two times higher than in North European countries, Canadaand the Hawaii, the incidence rate of THYROID CANCER in each ethnic group is higher than thatregistered in their country of origin (108), and it is particularly common among Chinese males andFilipino females. Most of the differences are probably due to ethnic or environmental factors (such asspontaneous backgroundradiation) or dietary habits (109), but different standards of medical expertiseand health care may also play a role in the efficiency of CANCER American CANCER Societyindicated incidence in the USA of nearly 10/100,000 population in 2003.

2 The reported incidence hasbeen increasing at more than 5%/yr for a sharp contrast with these data concerning the incidence of clinical thyroidcancer, is the prevalencefound in autopsy series or screening studies indicate a surprising frequency rangingfrom over (110,111).A survey of consecutive autopsies at Grace-New Haven Hospital of thyroids to harbour unsuspected THYROID CANCER (111).Another had discrete benignadenomas, and nearly half showed nodularity. The high prevalencemay beattributed to carefulexamination of the gland, but probably also reflects a highly selected group of older patients dying in ahospital. Up to 6% of THYROID glands in autopsied adults in the United States, and over 20% in Japan,also harbour microscopically detectable foci of THYROID carcinoma, which are believed to be of no biologicsignificance. Altogether autopsy studies suggest that THYROID CANCER is in many instances not diagnosedduring life or is not the immediate cause of death.

3 Both suggestions are inagreementwith the ratherleisurely growth of the majority of THYROID tumors, especially the frequent small papillary annual mortality from THYROID CANCER in 2003 was 5 per million formenand 6per million for women(112).The discrepancy between incidence and mortality reflects the good prognosis for most thyroidcancers. Recent statistics suggest about 6 deaths /million in the classificationof THYROID tumorsis given inTable of the THYROID (Adapted, and Revised, from WHO Classification) Adenomas ( , below) cell (probably malignant)C. TeratomaII. Malignant papillary variant of papillary THYROID variants:tall cell,columnar cell, oxyphyl, adenocarcinomas(variants:Hurthle cell carcinoma or oxyphyl carcinoma, clear-cellcarcinoma, insular carcinoma) , cell epidermoid tumorThyroid tumors are rare in children and increase in frequency in each aretwo-threetimes as frequent in women as in the past, it was generally believed that THYROID tumors weremore frequent in areas of endemic goiter, and reports from Colombia and Austria support this association(113) (see CHAPTER 11).

4 More recent studies suggest that in iodine deficient countries the number ofnodules is increased and, as a consequence, also the number of THYROID cancers is increased (114).Surveys conducted in the United States found no relation between usual geographicresidence andincidence of THYROID , if not all, THYROID adenomas are monoclonal, as, presumably, are most carcinomas (115).Colloidnodules may be either mono-or tumors represent the persistent growth of the progenyof one cell which has somehow escaped the mechanisms which maintain normal cell division at aboutonce each years (116).The process of oncogenesis is conceived to be a series of events induced by genetic and environmentalfactors which altergrowth control. At the phenomenologic level these factors may be considered as"initiators" and "promoters". Initiators include such agents as chemicals and irradiation which inducetumors, and promoters are agents such as phenobarbital, which in rats augments TSH secretion andradically increases tumor development.

5 In man x-ray treatment is the sole known initiator,and other thanelevated TSH, no promoters are such as phenobarbital, dilantin and PCBs, whichare known THYROID tumor promoters in animals through liver microsomal hormone degrading enzymeinduction leading to increased THYROID hormone metabolism, do not appear to have a detectable adverseeffect in man in doses usually employed (117).3 Oncogenes(Fig. 18-11)We now begin to understand oncogenesisin more details. More than 30 "oncogenes" have beenrecognized in the human most likely genetic events in THYROID CANCER are reported in genes, normally silent, can become activated bychromosomal translocations, deletions, ormutations, and then can "transform" normal cells into a condition of uncontrolled growth. Most onco-genes appear to be closely related to normal growth factors, genes that control cell division, or tohormone receptors.

6 In general, these genes, when turned on, promote cellgrowthand cell activationof one such gene may not be enough to produce malignancy,but if accompanied by expression of another oncogene, or if gene mutation or reduplication occurs, thecell mayprogress towarda malignant potential. Informationonexpressionof oncogenes in humanthyroid tissue is rapidly accumulating. Expression of c-myc is stimulated in normal THYROID cells by TSH,and the proto-oncogene is expressed in adenomas and mutations of h-ras atcodons 12, 13, and 61, and over expression of h-ras, are found in adenomas and carcinomas, but h-rasmutations are also found in nodular goiter tissue (118), suggesting that h-ras mutations could be an earlyevent in oncogenesis (119). Other studies, it should be noted,find ras mutations uncommon (120).Figure 18-11. Possible role of oncogene activation, receptor or G-protein mutation, or tumor repressor genealterationin the induction of THYROID and co-workers (121) cloned an oncogene which is frequently and specifically expressed inpapillary THYROID cancers.

7 This oncogene is found on chromosome 10and involves an intrachromosomalrearrangement of the tyrosine kinase domain of the ret oncogene so that it is attached to one of threeThyroidFollicularCellPTCRET-PTCB-RA FTRK, META denomaaLOH 11q13 LOH 3pPPAR- /PAX-8 TSH-RGS- Hyper-functioningAdenomaAnaplasticCarcin omaPapillaryTCFollicularTCRASPI3Kc-mycCD -44p-53PI3Kp-53PI3 KRET-PTCB-RAF, RAS, PI3 KTRK, MET4differentpromoters, producing retPTC-1, retPTC-2, and retPTC-3. As a mean, one of these translocationproducts is found in about 20% of PTC, although in different series a large variation is observed (20-70%). This rearrangement leads to constitutive expression ofthe has been shown that intra-thyroidal expression of the ret/PTC1 oncogene can induce THYROID CANCER (122). BRAF mutations, in theform of point mutations, are the most frequent alterations in papillary carcinoma, and undifferentiatedcancers that have arisen from papillary tumors(123), approaching 40% of all PTCs (124).

8 Recently a mutational change has been associated with follicular 5of 8 follicular cancers,Kroll et al (125) found translocation of the DNA binding domain of PAX8 to domains A-F of theperoxisome proliferator-activater receptor (PPAR) gamma1 gene. The fusion oncogene is able totransform thyrocytes, so appears to be able to produce malignancies(126). Although initially thought tobe exclusively present in follicular cancers, it is now known to be present infollicular adenomas as well(127).Mutation or deletion of the p53 tumor suppressor gene is found in some differentiated THYROID cancers,and many undifferentiated cancers, suggesting that this genetic deletion may be one of thefinal stepsleading to anaplastic CANCER proliferation of studies in thisfield has provided many clues tothyroid virus 40-like sequences are found in many THYROID cancers, as well asother cancers, andtheTag gene sequence found is known to beoncogenic in animal models (128).

9 Mutated and non-functional THYROID hormone receptors are recognized in up to 90% of PTC by oneauthor, suggesting a role in oncogenesis, but other workersfind these mutations to be rare(129,130).Thetumor suppressor gene TSG101 isover-expressed in most PTCs (131).Overexpression of manyother genes-galectin-3,Thymosin beta-10,hTERT, CD97, CD26, VEGF-has been detected, but ofcourse a question always is whether these changes represent the cause or the result of in the proteins involved in the normal TSH-receptor-G protein-adenylcyclase-kinase signaltransduction pathway also play a role in tumor TSHreceptor mutations have beenfoundbyParma and co-workers (132) to be the cause of most hyperfunctional nodules, and are nowknown to be common in "hot" nodules in patients with multi-nodular mutations involve theextracellular loops of the transmembrane domain and thetransmembrane segments, and are proven toinduce hyperfunction by transfection studies.

10 However these mutations are not associated with of the stimulatory GTP binding protein subunit are also present in some patientswith hyperfunctioning THYROID adenomas (133). TSH-R mutations are, however, unusualin THYROID CANCER (134), (excepting hyperfunctional adenomas). TSH-R expression tends to be lost as cancers de-differentiate, and persistence of expression is associated with a better prognosis (135).In addition to positive genetic factors, oncogenesis frequently involves loss of tumor suppressor Thesegenesare normallypresentonbothsets(maternaland paternal)ofchromosomes. In retinoblastoma the inherited lack of one suppressor (RB)gene does not cause disease, but if a genetic event (deletion,recombination, mutation, etc.) causesfailureof expressionof the second allele, CANCER ensues. The presence oftumor-specific suppressorgenesis often detected because of lack of heterozygosity of chromosomal markers associated withdeletions of segments of genetic material.