Annual increase in the frequency of papillary thyroid carcinoma as diagnosed by fine-needle aspiration at a cytology unit in Sicily

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1 HORMONES 2013, 12(1):46-57 Review Annual incease in the fequency of papillay thyoid cacinoma as diagnosed by fine-needle aspiation at a cytology unit in Sicily Massimo Rizzo, 1 Alessando Sindoni, 2,3 Raffaele Talamo Rossi, 1 Osola Bonaffini, 1 Stefania anetta, 1 Claudio Scisca, 1 Giuseppe Altavilla, 1 Lucia Denao, 4 Antonio Rosanò, 2 Giovanna Saaceno, 5 Fancesco Timachi, 5 Salvatoe Benvenga 2,5,6 1 Depatment of Human athology, Section of Clinical Oncology, 2 Maste ogam on Childhood, Adolescent and Women s Endocine Health, 3 Depatment of Biomedical Sciences and of Mophological and Functional Images, Unit of Nuclea Medicine, 4 Depatment of Envionmental, Health, Social and Industial otectionism, 5 Depatment of Clinical and Expeimental Medicine, Univesity of Messina, 6 Intedepatmental ogam of Clinical and Molecula Endocinology & Women s Endocine Health, A.O.U. oliclinico G. Matino, Messina, Italy The fist and second authos contibuted equally to this wok. ABSTRACT Objective: An inceased fequency of papillay thyoid cacinoma (TC) has been epoted in the liteatue, including studies based on fine-needle aspiation cytology (FNAC). Design: To substantiate ou own ascetainment of such an incease, we etieved all the diagnoses of ultasound-guided FNAC which was pefomed on 11,389 patients efeed fo cytological evaluation of a single o dominant thyoid nodule fom 1988 to FNAC yielded 11,258 adequate specimens. Results: The numbe of patients with TC was 200 (age ys) and inceased significantly fom 1988 to 2010 (= 0.916, <0.001). Expessing data as pecent of FNAC in any given yea, TC and colloid goite inceased, while adenomatous goite, follicula lesions and anaplastic o medullay thyoid cance deceased. TC accounted fo 0% of all FNAC diagnoses in 1988 but fo 2% in 2010, with a peak of 2.6% in Of inteest, chonic lymphocytic thyoiditis (CLT) also inceased, peceding the incease of TC by 5-6 yeas. Conclusion: We conclude that in the egions on eithe side of the Stait of Messina (Italy), TC has become pogessively moe fequent duing the 23-yea peiod between 1988 and 2010 and that this incease lagged behind the incease of CLT. Key wods: Fine-needle aspiation cytology, apillay thyoid cacinoma, Thyoid cance Addess fo coespondence: Alessando Sindoni, MD, Dipatimento di Scienze Biomediche e delle Immagini Mofologiche e Funzionali, U.O.C. di Medicina Nucleae, A.O.U. oliclinico G. Matino, Via Consolae Valeia Messina, Italy, Tel.: ; Fax: ; alessandosindoni@alice.it Received , Accepted

2 Cytological epidemiology of thyoid cance 47 INTRODUCTION Fine-needle aspiation cytology (FNAC) is the diagnostic modality of choice in the evaluation of thyoid nodules, which in the vast majoity of cases ae nonneoplastic (benign). 1 FNAC is ecommended as the initial diagnostic test fo such lesions because of its simplicity and eliability. Even though FNAC cannot diffeentiate between benign and malignant thyoid nodules in 100% of cases, it helps substantially in selecting patients fo sugey. Indeed, FNAC has deceased sugical intevention by 25% and has inceased the yield of cance in sugical specimens fom 15% to moe than 30%. 2 With epoted sensitivity ates exceeding 90%, 1-3 cytological featues ae paticulaly accuate in the peopeative detection of papillay thyoid cance (TC), which accounts fo 70% of all thyoid malignancies. 4 As descibed in detail unde Discussion, thee ae seveal FNAC-based studies epoting the fequency of TC, 5-20 howeve, with some limitations. None of these studies 5-20 addessed the yea-to-yea change of TC ove a peiod of time longe than 15 yeas, paticulaly in compaison with othe thyoid lesions. We theefoe sought to assess the yealy change in the FNAC pevalence of TC and, fo compaison, of othe lesions ove a wide peiod of time in patients with thyoid nodules. Accodingly, we quantified the annual fequency of TC and associated demogaphic indices (gendes and age at pesentation). MATERIALS AND METHODS All patients who come to ou Unit ae efeed fo cytological evaluation of thei single o dominant thyoid nodule, all of them confimed as cold nodules when thyoid scintigaphy had been pefomed. The Cytology Unit of ou Univesity Hospital is pat of the Depatment of Oncology and ultasound-guided FNAC (US-FNAC) of thyoid nodules is pefomed daily. The thyoid is only one of the ogans examined in this Unit, with beast, live and othe abdominal ogans also being investigated, both in inpatients and outpatients. The ovewhelming majoity of thyoid FNAC is pefomed in outpatients, most of who ae efeed by endocinologists. All these patients come fom Noth-Easten Sicily, with a minoity coming fom Calabia, which is the egion acoss the Stait of Messina. US-FNAC was and continues to be equested fo the diagnostic wok-up of thyoid nodules, independently fom thyoid volume. Stating fom 1988, the team membes (sonogaphist and cytologists) have been the same and cytological diagnoses have been compute-stoed. Of 11,389 FNACs pefomed unde US guidance on 11,389 subjects (9,341 women and 2,048 men, F:M atio= 4.6:1) with a single o dominant thyoid nodule in the 23-yea peiod between Januay 01, 1998 and Decembe 31, 2010, FNACs wee pefomed in 11,258 pesons. FNACs wee consideed adequate 21 when a smea contained at least 6 goups each with 10 o moe benign, wellpeseved cells. Ove the yeas the cytology team was composed of the same opeatos and used the same methodology. Cells wee aspiated fom the single o dominant thyoid nodule by the ultasonogaphist (C.S.). The sonogaphist punctued, with a minimum of 5 passes unde continuous eal-time US guidance, povided by 7.5 o 10 MHz high fequency tansduces. FNAC was pefomed by standad technique, using a 23-gauge needle attached to a 20-ml disposable syinge mounted on Cameco s metal syinge holde. No local anesthesia was employed. Alcohol-fixed and ai-died smeas wee pepaed; one o two slides wee utilized fo apid staining (a apid apanicolaou method) to make an immediate intepetation of the specimen and a cytological pe-diagnosis. The othes specimens wee stained by the apanicolaou and the May-Gumwald-Giemsa methods because expeience demonstated a geate efficiency when the two methods ae coupled. Fo the puposes of the pesent study we etieved all FNAC diagnoses obtained in each of the said 23 yeas, disegading the inadequate ones (n=131 o 1.15%). Next, we categoized the diagnoses of adequate FNACs into the following goups: colloid goite (CG), adenomatous goite (AG), follicula lesions (FL), Hüthle cell tumos (HCT), TC, anaplastic thyoid cance (ATC), medullay thyoid cance (MTC), othes. This last goup (n= 767) consisted of benign and malignant lesions. Benign lesions (n=740) epesented thee types of thyoiditis: chonic lymphocytic thyoiditis (CLT), also known as Hashimoto s thyoiditis (HT, n=700), De Quevain s thyoiditis (n=38) and Riedel s thyoiditis (n=2). The identification of DQT and RT, made

3 48 M. Rizzo ET AL afte FNAC evaluation, was based on the following cytopathologic featues: DQT was diagnosed based on the pesence of numeous multinucleate histiocytes, few mixed inflammatoy cells, abundant epitheliod histiocytes and lymphocytes. Giant cells suounding and engulfing colloid wee paticulaly chaacteistic. The giant cells in ganulomatous thyoiditis wee often vey lage and could be of eithe Langhans o foeign-body types. Theefoe, in contast to CLT, follicula cente (immatue) lymphocytes and Hüthle cells wee unusual. We have also seen degeneative changes in follicula cells, esidual o scanty colloid, vey few macophages and cellula debis (dity backgound). Geneally, in RT the findings on FNA ae non-specific. The aspiate is pooly cellula, scanty o acellula. It may include a few fiboblasts (fibosis) and a vaiable ate of inflammatoy cells, such as leukocytes, lymphocytes and histiocytes. Howeve, when the lined (wooden) fibosis pemitted the penetation of the needle, the chaacteistic finding was the pesence of fiboblasts, also in tissue fagments. These two cases of RT wee thyoidectomized and diagnoses confimed at histology. Othe malignant lesions (OML, n=27) included lymphomas (n=2), squamous cacinoma (n=2), soft tissue tumos (n=5), melanoma (n= 1) and metastatic lesions (n=17), paticulaly fom the laynx, lungs, kidneys and beasts. Accoding to the Bitish Thyoid Association, 22 the AACE/AME Task Foce on Thyoid Nodules, 23 the Italian Consensus Woking Goup 24 and the Bethesda system fo Thyoid Cytopathology, 21 CG, AG, CLT, DQT and RT ae benign lesions, and they ae categoized as THY2/TIR 2; FL and HCT ae neoplastic/polifeative lesions, and they ae categoized as THY3/TIR3; TC, ATC and MTC ae malignant lesions, and they ae categoized as THY5/TIR5. Inadequate (o disegaded) FNACs ae classified as THY1/TIR1, while FNACs suspicious fo malignancy ae classified as THY4/TIR4. Based on ou expeience with appoximately 2,800 cytology and histology paied diagnoses afte total/ nea total thyoidectomy, the following FNAC diagnoses ae coect with these ates: 86% (CG), 61% (AG), 98% (TC), 100% (ATC), 92% (MTC), 92% (CLT); the ate of FL and HTC being malignant (that is, follicula cacinoma o Hüthle cell cacinoma) is 66% and 15%, espectively. In the emaining cases (appoximately 8,400), almost all cytological diagnoses wee CG, AG and CLT. Statistical analysis Continuous vaiables ae expessed as mean ± SD and categoical vaiables as pecentages. Diffeences between means wee assessed by the ANOVA test, while the pecentages of categoical vaiables (cytological diagnoses) based on classes of yeas wee evaluated by the χ 2 test. To test fo linea tend of change of a given index ove time, eason s coelation coefficient was calculated between the index and the 23 calenda yeas. Regadless of the test, a value of <0.05 was consideed statistically significant, while a value between 0.05 and 0.10 was consideed bodeline significant. Statistical analysis was pefomed using Kyplot v2.0 beta 13 vesion. RESULTS All data ae summaized in Tables 1-3 and illustated in Figues 1-3. As shown in Figue 1, the numbe of adequate FNACs inceased linealy (= 0.956, <0.001). The highest incease between two subsequent yeas occued between 1998 and 1999 (+75%), the smallest between 2005 and 2006 as well as between 2006 and 2007 (+3% both). Dividing patients into yea goups of equal duation, also in ode to maximize numbes fo scantily epesented diagnoses, the chi squae test showed, with espect to numbe of total FNACs, that: the distibution of CG and CLT was significantly inceased (<0.001), the distibution of TC was bodeline inceased (= 0.075), the distibution of HCT and MTC emained unchanged (= 0.59 and 0.22, espectively), the distibution of AG, FL, ATC, suspicious fo malignancy and OML was significantly deceased (<0.001) (Table 1). On a pecent basis, CG and CLT wee the only categoies that inceased significantly ove time, at a linea ate (<0.001) (Table 2). In contast, TC inceased bodeline significantly (= 0.062) (Table 2), while AG, FL, ATC and OML deceased significantly (Table 2), and MTC deceased nealy significantly (= 0.080) (Table 2). In Figue 3, all lesions whose numbe augmented

4 Cytological epidemiology of thyoid cance 49 half a yea olde. Moeove, males wee pogessively moe epesented ove the 23-y peiod. Thee wee no cases of TC in 1988, but thee wee 26 in 2006 and 17 in 2010 (Figue 2). As mentioned above, distibution of TC as a function of calenda yeas was tendwise significant in the yeas (= 0.075) (Table 1), but it became significant consideing distibution in the fou 5-yea peiods between 1988 and 2007 (χ 2 = 8.2, = 0.040). Indeed, the numbe of TC doubled in compaed to , and tipled in compaed to and in compaed to (Table 1). Duing , the numbe of both total FNAC and total adequate FNAC inceased by only 1.4-fold (537 to 781, and 530 to 775) and at a significantly linea pace. Figue 1. Yealy numbe of total FNACs (continuous line) and adequate FNACs (discontinuous line) pefomed at ou cytological unit ove the study peiod ( ). The numbe of total FNACs inceased fom 75 (yea 1988; adequate, n=73) to 1,075 (2008; adequate, n=1,069, a 15-fold change) and deceased in 2009 and The two cuves ovelap because thee wee only 131 inadequate specimens out of a total of 11,389 FNACs (1.2%) pefomed in 11,389 pesons. ove time ae epesented on the same scale in tems of fold-incease. Fom this Figue, one can appeciate compaatively the time it took fo any such lesion to incease by a given facto, fo instance to double. Diffeences among lesions ae evident in the new millennium, while they stat becoming appeciable fom the late 90 s. It took 13 yeas fo both TC and CG to incease by 10-fold (yea 2001); theeafte, it took only thee yeas fo TC to double again (22-fold ove the initial numbe), wheeas CG did not double yet in the following six yeas. CLT was the only othe lesion that gew faste than TC (see below unde the heading Non TC lesions ). TC Demogaphics of the 200 cases of TC (158 women, 42 men; age 10 to 83 yeas) ae summaized in Table 3. Consistently, men wee at least 2 yeas younge than women, a not statistically significant diffeence, except in the last 3 yeas when men wee Non TC lesions Not unexpectedly, CG was the leading lesion, which was at least 39 times moe epesented than TC (Table 1), with the lowest numbe (51) in 1988 and the highest numbe (901, an 18-fold incease) in Concening the 27 malignant lesions categoized as Othes, thee wee none in the yeas 1988, 1993, 1995, 1998, 1999, 2001 and 2004; in each of the emaining yeas, we obseved 1 to 3 such lesions [data not shown]. As shown in Figue 3, CLT was the only lesion that gew faste than TC, stating aleady in the mid-90 s. It took 6 to 8 yeas fo CLT to incease by 10-fold, and by the yea 1999 CLT had doubled again (19-fold incease ove the initial value in 1988). One yea late, CLT continued to double (35-fold incease ove the initial value), and doubled again afte anothe 4 yeas (66-fold ove the initial value). The 2007 value (90-fold incease ove the initial value) is double with espect to the value in 2002 (44-fold incease ove the initial value). Compaing the CLT cuve with the TC cuve, it is evident that TC lags behind CLT by 5-6 yeas (Figue 3). In addition, it is stiking that both CLT and TC had two peaks in aound the same yeas. The implication of this paallelism between CLT and TC is the still contovesial issue that CLT might be a pecanceous lesion, in that CLT would favo the appeaance of TC.

5 50 M. Rizzo ET AL Table 1. Fine-needle aspiation cytology (FNAC) diagnoses in 11,389 single o dominant thyoid nodules fom 11,389 pesons duing the yeas and 5-yea-classes theeof (except the last thee yeas) a Total FNAC (total adequate FNAC) 11,389 (11,258) Colloid goite (CG) Othes (chonic lymphocytic thyoiditis, CLT) Statistics n=9, % (81.2%) n= % (6.2%) apillay thyoid cance (TC) n= % (1.8%) Hüthle cell tumos (HCT) n= % (0.28%) Medullay thyoid cance (MTC) n= % (0.11%) Adenomatous goite (AG) n= % (6.6%) Follicula lesions (FL) n= % (2.7%) Anaplastic thyoid cance (ATC) n= % (0.17 %) Suspicious fo malignancy n= % (0.38%) Othes (malignant lesions) n= % (0.24%) 510 (498) n= % (60.8%) n=6 1.2% (1.2%) n=7 1.4% (1.4%) n=2 0.4% (0.4%) n=2 0.4% (0.4%) n= % (21.9%) n=44 8.6% (8.8%) n=5 1.0% (1.0%) n=7 1.4% (1.4%) n=9 1.8% (1.8%) 1,076 (1,040) 2,494 (2,459) Significantly inceased n= % (78.5%) n=25 2.3% (2.4%) n=2, % (82.7%) n= % (6.0%) Bodeline inceased n=13 1.2% (1.2%) n=1 0.09% (0.10%) n=2 0.2% (0.2%) n=32 1.3% (1.3%) Unchanged n=6 0.2% (0.2%) n=1 0.04% (0.04%) Significantly deceased n= % (10.8%) n=43 4.0% (4.1%) n=3 0.3% (0.3%) n=4 0.4% (0.4%) n=7 0.6% (0.7%) n= % (6.1%) n=68 2.7% (2.8%) n=6 0.2% (0.2%) n=2 0.08% (0.08%) n=3 0.1% (0.1%) 4,440 (4,400) n=3, % (81.8%) n=311 7% (7.1%) n=92 2.1% (2.1%) n=12 0.3% (0.3%) n=4 0.09% (0.09%) n= % (6.2%) n=79 1.8% (1.8%) n=3 0.07% (0.07%) n= % (0.25%) n=5 0.1% (0.1%) 2,869 (2,861) n=2, % (83.4%) n= % (7.3%) n=56 2% (2%) n=11 0.4% (0.4%) n=3 0.1% (0.1%) n= % (3.6%) n=67 2.3% (2.3%) n=2 0.07% (0.07%) n=19 0.7% (0.7%) n=3 0.1% (0.1%) <0.001 <0.001 =0.075 =0.590 =0.220 <0.001 <0.001 <0.001 <0.001 <0.001 a ecentages in paentheses have adequate FNAC as denominato. In the statistics column, values coespond to the chi-squae test that was pefomed with espect to the numbe of all FNAC, including inadequate. Statistics did not change using total adequate FNAC. Statistically significant values ae typed bold and, if bodeline significant ( 0.10 to 0.05), they ae also typed in italics. Statistical values do not change substantially if numbes pedicted fo the 5-yea peiod ae consideed. Fo instance, in the case of TC with a pedicted numbe of 93 cases (1.95% of 4768 pedicted adequate FNACs), χ 2 =8.39, = DISCUSSION Hee we have shown that in the metopolitan, semiual and ual aeas seved by ou cytological unit (Noth-Easten Sicily and Southen Calabia), TC has become pogessively moe fequent duing the 23-yea peiod between 1988 and 2010 with a 9.5-fold aveage incease in the 18 yeas between 1990 and Such an inceased fequency of TC

6 Cytological epidemiology of thyoid cance 51 Table 2. eason s coelation coefficient of the ate of the indicated cytological diagnoses in 11,389 thyoid nodules fom 11,389 pesons with the yea of diagnosis duing the peiod % of total FNAC Colloid goite (CG), n=9,136 Adenomatous goite (AG), n=743 Follicula lesions (FL), n=301 Hüthle cell tumos (HCT), n=32 apillay thyoid cance (TC), n=200 Anaplastic thyoid cance (ATC), n=19 Medullay thyoid cance (MTC), n=12 Suspicious fo malignancy, n=43 Othes (chonic lymphocytic thyoiditis, CLT), n=700 Othes (malignant lesions), n= to < to < to < to to a to < to to to < to a Due to the two peaks of TC in 1991 and 1994 (3.0% and 3.1% of total FNAC), coelation did not each statistical significance. This was eached (= 0.579, = 0.024) consideing yeas 1996 though Statistically significant values ae typed bold and, if bodeline significant ( 0.10 to 0.05), they ae also typed in italics. cannot be accounted fo by the inceased numbe of FNACs pefomed ove the same 23-yea peiod, the latte incease likely eflecting changes in health cae level of access as well as public awaeness of the impotance of endocine/thyoid check-up and thyoid diseases. The discepancy is evident in the new millennium ( ), when TC inceased by an aveage of 3.4-fold ove yea 2000 but FNAC inceased by an aveage of 1.6-fold. In the yea 1989, the single TC obseved accounted fo 1.1% of the 87 FNAC, while the 22 and 26 cases of yeas 2004 and 2006 accounted fo 2.8% of 781 and 2.6% of 982 FNAC, espectively. In paticula, in the yeas the aveage incease ove yea 2000 was 2.1-fold, in contast to the simultaneous aveage of 0.6-fold and 0.5-fold decease fo AG and FL, espectively. These opposite diections of changes of TC vs AG and FL undescoe that TC follows diffeent pathways of oncogenic tansfomation of the thyoid follicula cell leading to thyoid neoplasia. As summaized in Table 4, a total of 16 studies (17 with ous) have evaluated the local epidemiology of thyoid cance/tc based on FNAC Of these, only ous and anothe thee 5,6,13 have cohots geate than 10,000, wheeas nine have cohots smalle than 1,000. 7,8,10,11,15,17-20 Moeove, only 7/16 studies including ous 6-8,10,12,13 spanned a peiod longe than 10 yeas, but only 2/16 6,13 and ous epoted yea-to-yea changes. Finally, among the lagest studies, 5,6,13 only ous coves the yeas afte One limitation of FNAC studies with long case seies spanning a lengthy peiod is the changes in the diagnosis of thyoid nodules and thei clinical management ove time, which ae highly dependent upon seveal vaiables such as: diagnostic citeia, teminology, management guidelines, adequacy of the sample and also the physical chaacteistics of the biopsied thyoid lesion and opeato expeience (i.e. the individual pefoming the biopsy and intepeting the cytomophology). In ou study, the same cytopathology team assessed all FNAB samples and employed the same technique fo the collection and pepaation of samples, thus neutalizing o educing not only inte-obseve vaiability but also the abovementioned limiting vaiables. 25 When these lagest studies ae consideed, 5,6,13 ou ate of malignancy of 2.3% (Table 4, footnote) matches the 2.4% ate of the othe Italian cohot, 5 is simila to the 3.4% of the Taiwanese cohot 13 but is somewhat lowe than the 5.6% of the Dutch cohot 6. Two-digit ates ae almost invaiably epoted in cohots smalle than 1,000 cases (Table 4), with the emakable exception of the 2.3% ate obseved in Geece, 8 a Southen Euopean county like Italy. CLT was the only lesion that showed the highest

7 52 M. Rizzo ET AL Table 3. Demogaphics of the 200 cases of papillay thyoid cance (TC) diagnosed by fine-needle aspiation cytology in 11,389 pesons duing the yeas and 5-yea-classes theeof (except the last thee yeas) Total FNAC (females, males) 11,389 (9,341, 2,048) Numbe of TC (TC pe time peiod- as % of Total No. of TC) 200 (100%) 510 (426, 84) 7 (3.5%) 1,076 (915, 161) 13 (6.5%) 2,494 (2,097, 397) 32 (16%) 4,440 (3,627, 813) 92 (46%) 2,869 (2,276, 593) c 56 (93) c (28%) F: M atio in TC 3.8:1 7:0 5.5:1 4.3:1 4.7:1 2.1:1 (2.0:1) c No. of TC, m ± SD pe yea (all) 8.7 ± ± ± ± ± ± 1.5 (18) c % TC in females as % total FNAC 1.69% 1.64% 1.20% 1.24% 2.09% 1.67% in females a % TC in males as % of total FNAC 2.05% % 1.51% 1.97% 3.04% in males b TC as % of all TC 100 % [n=200] 3.5% 6.5% 16% 46% 28% (31.2%) c TC, age (yeas) of all patients 42.4 ± ± ± ± ± ± 15.6 TC, age (yeas) of female patients 42.9 ± ± ± ± ± ± 15.1 TC, age (yeas) of male patients 40.8 ± 16.2 N/A 45.0 ± ± ± ± 17.1 a eason s coelation coefficient of the fou pecentages ove time was not statistically significant (= 0.427, = 0.473). b eason s coelation coefficient of the fou pecentages ove time was tendwise significant (= 0.962, <0.001). c In paenthesis, pojection ove the 5-yea peiod , if tend pesists. fold incease of pecentage change fom 1988 to 2010 based on total FNAC. These data agee with a numbe of studies epoted in the liteatue, paticulaly with the studies methodologically close to ous Because the annual incease of CLT peceded the annual incease of TC with an oveall paallelism Figue 2. evalence of TC as pecentage of all adequate FNACs pefomed in each yea. evalence does not change if expessed as % of nodules because the numbe of patients and numbe of nodules coincide. The steepest incease was between the yeas 2000 and 2004 (fom n= 5 to n= 22, +4.4-fold, = 0.933, 0.28 to 0.99, = 0.020; fom 0.93% to 2.82%, +3.0-fold, = 0.903, 0.10 to 0.99, = 0.035). between the two cuves (Figue 3), and because both CLT and TC displayed a simila decease of F:M atio ove the yeas (this study and Ref. 27), thee ae gounds to believe that envionmental changes may have favoed both thyoid autoimmune disease and TC-oiented thyoid oncogenesis. Howeve, thyoid autoimmunity esponded to such envionmental changes moe quickly than thyoid oncogenesis, thus explaining why the inceased fequency of CLT peceded the inceased fequency of TC. An association has been contovesially suggested between CLT and TC. Fioe et al 29 showed that the fequency of TC in nodula-clt patients was significantly highe compaed with patients with non- CLT nodula goite and was stongly coelated with TSH levels. These authos 29 hypothesized that highe TSH levels incease the pobability that mutated oncogenes 30 may cause clinically detectable cance. Moeove, eaangements of RET oncogene (RET/ TC), which ae fequently detected in TC, may also be found in the thyoids of patients affected by CLT, with no histopathological evidence of TC. 31 Thee ae numeous envionmental factos that

8 Cytological epidemiology of thyoid cance 53 Figue 3. Fold incease in numbe of patients with the specified cytological diagnosis ove the indicated study peiod ( ). Note the log 10 scale on the vetical axes. may favo the development of thyoid nodules (including TC) and thei tends ove time. Such factos include: low iodine as well as goitogenic o nongoitogenic natual substances contained in vaious foods (e.g. chloate, thiocyanate, nitates, isoflavones); 32,33 heavy metals and polluting chemicals that ae inceasingly known to affect thyoidal gowth and homeostasis (e.g. polychloinated biphenyls, phthalates, bisphenol A and othe plasticizes). Compaed to othe aeas mentioned in Table 4, in which some o all these factos could play an impotant ole in TC incidence, we think that anothe envionmental facto is the pesence of the Etna volcano in Easten Sicily, pecisely in the povince of Catania which is just south of ou povince. This volcano hosts a majo aquife that povides dinking wate and iigation to lage agicultual aeas neaby. Vaious chemicals (including HCO 3, SO 4, calcium, fluoide, chloide, magnesium, boon, manganese, ion, vanadium and also 222 Radon) wee found inceased in wate samples fom vaious souces of this volcanic aquife. 34 Finally, active volcanoes like Etna poduce suspended paticulate matte and gases that may contaminate the envionment. Howeve, investigation into the natue of these tiggeing envionmental factos was not the goal of ou pesent wok.

9 54 M. Rizzo ET AL Table 4. Summay of the intenational liteatue on the detection of papillay thyoid cance (TC) in patients who undewent fine-needle aspiation cytology (FNAC) fo single o multiple thyoid nodules ove a peiod compaable to that of the pesent study a Continent, County Yea(s) of study Refeence FNAC Fequency of TC (% of total FNAC) Euope, Italy (23 yeas) Euope, Italy (8 yeas) Euope, The Nethelands Euope, Czech Republic (15 yeas) (17 yeas) Euope, Geece (11 yeas) N. Ameica, USA (Massachusetts) N. Ameica, USA (New Yok) N. Ameica, USA (Miami and Nashville) (9 yeas) (11 yeas) (7 yeas) Rizzo, 2012 (this study) 11,389 FNAC on 11,389 patients with single o dominant nodule who undewent US-FNAC. Adequate FNAC = 11,258 (98.8%, on 11,258 patients). The numbe of adequate FNAC inceased linealy fom a minimum of 73 in 1988 to a maximum of 1,069 in 2008, a 15-fold change ( = 0.956, < 0.001). Rago, FNA cytology in 47,775 nodules fom 34,266 patients. Netea Maie, Between 1989 and 2003 a total of 44,141 FNAB wee pefomed. The numbe of FNABs pefomed each yea pogessively inceased fom 1,093 in 1989 to 4,123 in Matinek, In the peiod , 781 FNACs on pesons with focal lesions in the thyoid gland. Adequate aspiates in 213 pesons. Zagoianakou, A total of 900 patients, between 1993 and 2003, who had palpable o visible thyoid nodule by ultasonogaphy, undewent FNA. In 179 (19.9%) FNA was inadequate. Fates, ,208 patients had at least one thyoid nodule lage than 10 mm in maximal diamete and undewent US-guided FNAC. Adequate cytology = 1,985. Chales, Review of 422 patients who undewent thyoid sugey. All patients had FNAB pio to sugey. Adequate cytology = 400. Lew, A etospective eview of pospectively collected data of 797 consecutive patients with dominant nodules >1 cm who undewent FNA and thyoidectomy. TC= 200/11389 (1.8%) b In pecentage the incease was fom 0% in 1988 to 1.97% in 2010 (= by coelation), with a peak of 2.6% in Moeove, colloid goite and chonic lymphocytic thyoiditis wee the only categoies that inceased at a linea ate in pecentage ( <0.001) 2.4% wee indicative o suspicious fo cacinoma A diagnosis of thyoid cance (TC) was made in 2,493 cases (5.6%) based on FNAB. The numbe of TCs at cytopathological examination also inceased yealy by 9.5% (Ρ <0.0001). Theefoe, the popotion of TC diagnosed o suspected at cytological examination among all of the pefomed FNAB did not change duing the study peiod (Ρ = 0.07). Howeve, thee was a slight incease in incidence of TC of 2.1% pe yea (Ρ <0.001) paticulaly in stage I tumos, possibly, in pat, because of a maked incease in use of FNAB. TC in 28/245 cases (11.4%). ecentage of TC on adequate FNAC= 13.1% (28/213). TC in 21/900 cases (2.3%). ecentage of TC on adequate FNAC= 2.9% (21/721). TC in 261/2,208 cases (11.8%). ecentage of TC on adequate FNAC= 13.1% (261/1,985). TC in 81/422 patients (19.2%) on FNAC. ecentage of TC on adequate FNAC= 20.2% (81/400). 147/797 (18.4%) positive fo malignancy, 85/797 (10.7%) suspicious fo TC.

10 Cytological epidemiology of thyoid cance 55 Table 4. (Continued) Summay of the intenational liteatue on the detection of papillay thyoid cance (TC) in patients who undewent fine-needle aspiation cytology (FNAC) fo single o multiple thyoid nodules ove a peiod compaable to that of the pesent study a Continent, County Yea(s) of study Refeence FNAC Fequency of TC (% of total FNAC) Oceania, Austalia (egion of Tasmania) (11 yeas) Asia, Taiwan (14 yeas) Asia, Koea (3 yeas) Asia, Koea (2 yeas) Asia, Koea (4 yeas) Asia, Koea 03/ /2008 (2 yeas) Asia, China 12/ /2003 (4 yeas) Asia, Yemen (5 yeas) Afica, Kenya 10/ /2002 (7.58 yeas) Bugess, A total of 3,452 individuals undewent a thyoid pocedue, compising 1,968 sugical and 1,756 FNAB cytologic pocedues in 1,532 patients. Thyoidectomy and thyoid FNAB inceased by 7% and 49.7% pe annum, espectively. Lin, ,748 patients examined in one medical cente (FNAC consideed the fist-line examination pocedue). Ko, Among 1,613 consecutive FNAs of the thyoid, 207 patients (12.8%) who undewent both FNAs and sugey wee selected fo eview. Adequate cytology= 1,532 (95%). Nam-Goong, 317 nodules (all impalpable) fom 267 patients who undewent US-FNAC. Cytological diagnosis included 101 inadequate specimens (32%) Choi, ,614 patients undewent US-guided FNAC, of whom 392 (15.0%) wee inadequate. 343/2,614 undewent thyoidectomy. Choi, FNAC in 658 patients. Inadequate specimens wee 96 (13.7%). Cheung, Total FNAC= Inadequate FNAC= 32 (17.9%). 184 patients wee diagnosed with TC (confimed by histology), of whom 121/1,532 (7.9%) had TC. The likelihood of diagnosing a TC in any given thyoidectomy specimen inceased fom 3.3% in 1988 to 7.7% in Diagnoses of TC in patients peviously assessed by FNAB inceased by 99.7% pe yea (Ρ <0.005). Malignancy on cytology = 740 / 21,748 (3.4%). aticulaly, 424 / 21,748 patients (1.94%) wee confimed by histology. Malignancy in 118/1,613 (7.4%) FNAs. Of 207 thyoid lesions who undewent both FNAs and sugey, 98 wee TC (98/1,613= 6.1%). 42/317 (nodules) wee TC (13.2%). ecentage of TC on adequate FNAC= 19.4% (42/216) /2,614 (11.8%) malignant o suspicious fo malignancy; - 73/2,614 wee indeteminate; - 1,838/2,614 benign /343 wee TC on histology (12%) positive malignancy of whom 46 undewent thyoidectomy (43/79 wee TC at histology); - 22 indeteminate cytology. 27/179 (15.1%) TC o suspicious fo TC. Al-Hueibi, 243 FNAs due to thyoid swellings. 4 (1.6%) suspicious fo TC, 7 (2.9%) TC El Hag, patients with thyoid swellings undewent FNA Neoplasia (13.9%). a These studies wee etieved though a ubmed seach by enteing the stings: apillay thyoid cacinoma AND FNA o Thyoid cacinoma AND FNA o Thyoid cance AND FNA o Thyoid nodule AND FNA. b To pemit compaison with othe cohots of this table, ate of malignancy is 2.32% (1.8% TC % ATC % MTC % OML), while ate of malignancy and suspicious fo malignancy combined is 2.56% (2.32% %). Inteestingly, esults in ou study epoted in Table 1 on MTC show a lowe fequency of MTC with espect to the Czech Republic and Koea, a highe fequency with espect to Taiwan, China and the USA, and simila esults with espect to The Nethelands.

11 56 M. Rizzo ET AL The authos have no conflict of inteest to declae. REFERENCES 1. Causo D, Mazzafei EL, 1991 Fine needle aspiation biopsy in the management of thyoid nodules. Endocinologist 1: Ghaib H, Goellne JR, Johnson DA, 1993 Fine-needle aspiation cytology of the thyoid: a 12-yea expeience with 11,000 biopsies. Clin Lab Med 13: Ghaib H, Goellne JR, 1993 Fine-needle aspiation biopsy of the thyoid: an appaisal. Ann Inten Med 118: Mittendof EA, McHeny CR 2004 Thyoid cance. In: Cameon JL, ed. Cuent Sugical Theapy. 8th ed. hiladelphia, a: Elsevie Mosby; pp, Rago T, Fioe E, Scutai M, et al, 2010 Male sex, single nodulaity, and young age ae associated with the isk of finding a papillay thyoid cance on fine-needle aspiation cytology in a lage seies of patients with nodula thyoid disease. Eu J Endocinol 162: Netea-Maie RT, Aben KK, Caspaie MK, et al, 2008 Tends in incidence and motality of thyoid cacinoma in The Nethelands between 1989 and 2003: coelation with thyoid fine-needle aspiation cytology and thyoid sugey. Int J Cance 123: Matínek A, Dvoácková J, Honka M, Hoácek J, Klvana, 2004 Impotance of guided fine needle aspiation cytology (FNAC) fo the diagnostics of thyoid nodules - own expeience. Biomed ap Med Fac Univ alacky Olomouc Czech Repub 148: Zagoianakou, Malamou-Mitsi V, Zagoianakou N, et al, 2005 The ole of fine-needle aspiation biopsy in the management of patients with thyoid nodules. In Vivo 19: Fates MC, Benson CB, Doubilet M, et al, 2006 evalence and distibution of cacinoma in patients with solitay and multiple thyoid nodules on sonogaphy. J Clin Endocinol Metab 91: Chales MA, Helle KS, 1997 Cytologic deteminants of well-diffeentiated thyoid cance. Am J Sug 174: Lew JI, Snyde RA, Sanchez YM, Solozano CC, 2011 Fine needle aspiation of the thyoid: coelation with final histopathology in a sugical seies of 797 patients. J Am Coll Sug 213: Bugess JR, Tucke, 2006 Incidence tends fo papillay thyoid cacinoma and thei coelation with thyoid sugey and thyoid fine-needle aspiate cytology. Thyoid 16: Lin JD, Chao TC, Huang BY, et al, 2005 Thyoid cance in the thyoid nodules evaluated by ultasonogaphy and fine-needle aspiation cytology. Thyoid 15: Ko HM, Jhu IK, Yang SH, et al, 2003 Clinicopathologic analysis of fine needle aspiation cytology of the thyoid. A eview of 1,613 cases and coelation with histopathologic diagnoses. Acta Cytol 47: Nam-Goong IS, Kim HY, Gong G, et al, 2004 Ultasonogaphy-guided fine-needle aspiation of thyoid incidentaloma: coelation with pathological findings. Clin Endocinol (Oxf) 60: Choi YJ, Kim SM, Choi SI, 2008 Diagnostic accuacy of ultasound featues in thyoid micocacinomas. Endoc J 55: Choi YJ, ak YL, Koh JH, 2008 evalence of thyoid cance at a medical sceening cente: pathological featues of sceen-detected thyoid cacinomas. Yonsei Med J 49: Cheung YS, oon CM, Mak SM, Suen MW, Leong HT, 2007 Fine-needle aspiation cytology of thyoid nodules--how well ae we doing? Hong Kong Med J 13: Al-Hueibi KA, Al-Hueibi AA, Abdulmughni YA, et al, 2003 The diagnostic value of fine needle aspiation cytology in thyoid swellings in a univesity hospital, Yemen. Saudi Med J 24: El Hag IA, Kollu SM, Chiedozi LC, 2003 The ole of FNA in the initial management of thyoid lesions: 7-yea expeience in a distict geneal hospital. Cytopathology 14: Ali SZ, Cibas ES 2010 The Bethesda System fo Repoting Thyoid Cytopathology: Definitions, Citeia, and Explanatoy Notes. Ali SZ, Cibas ES (eds), Spinge, New Yok. 22. Bitish Thyoid Association. Guidelines fo the management of thyoid cance in adults. London: Royal College of hysicians of London and the Bitish Thyoid Association, Available fom URL: bitish-thyoid-association.og/ 23. Ghaib H, apini E, Valcavi R, et al; AACE/AME Task Foce on Thyoid Nodules, 2006 Ameican Association of Clinical Endocinologists and Associazione Medici Endocinologi medical guidelines fo clinical pactice fo the diagnosis and management of thyoid nodules. Endoc act 12: Fadda G, Basolo F, Bondi A, et al; SIAEC-IA Italian Consensus Woking Goup, 2010 Cytological classification of thyoid nodules. oposal of the SIAEC-IA Italian Consensus Woking Goup. athologica 102: Baloch ZW, Bedossian C, 2012 Following the steps of Abu al-qasim to Bethesda and beyond: the continuing delibeations in thyoid fine-needle aspiation. Diagn Cytopathol 40 Suppl 1: E Slowinska-Klencka D, Spony S, Klencki M, opowicz B, Lewisnski A, 2006 Chonic thyoiditis- cuent issue in the cytological diagnostics of the thyoid gland. Endokynol ol 57: Rizzo M, Rossi RT, Bonaffini O, et al, 2010 Inceased annual fequency of Hashimoto s thyoiditis between yeas 1988 and 2007 at a cytological unit of Sicily. Ann

12 Cytological epidemiology of thyoid cance 57 Endocinol (ais) 71: Koch CA, Salis NJ, 2001 The spectum of thyoid diseases in childhood and adulthood: natual histoy, diagnosis, diffeential diagnosis, and management. J Endocinol Invest 24: Fioe E, Rago T, Latofa F, et al, 2011 Hashimoto s thyoiditis is associated with papillay thyoid cacinoma: ole of TSH and of teatment with L-thyoxine. Endoc Relat Cance 18: Salis NJ, Benvenga S 2004 Molecula signaling in thyoid cance. In: Molecula basis of thyoid cance. Faid NR (ed). Kluwe Academic ublishes, Boston; pp, Asa SL 2004 The pathology of thyoid cance. In: Molecula basis of thyoid cance. Faid NR (ed). Kluwe Academic ublishes, Boston; pp, Diamanti-Kandaakis E, Bouguignon J, Giudice LC, et al, 2009 Endocine-disupting chemicals: an Endocine Society scientific statement. Endoc Rev 30: Zoelle RT, Bown TR, Doan LL, et al, 2012 Endocinedisupting chemicals and public health potection: a statement of pinciples fom The Endocine Society. Endocinology 153: ellegiti G, De Vathaie F, Scollo C, et al, 2009 apillay thyoid cance incidence in the volcanic aea of Sicily. J Natl Cance Inst; 101: