anaplastic thyroid cancer ( atc ) is one of the most aggressive tumours known in medicine .
even though a multimodal approach is used in treating these patients , average survival rate is expressed in months , and one - year survival is 15% [ 1 , 2 ] .
fortunately , atc is a very rare malignancy with an incidence of roughly 2 per 1,000,000 residents .
although atc represents only 2% of all thyroid cancers , it is the cause of death in half of patients whose definitive cause of death is thyroid malignancy . given that atc is a very rare malignancy , it has not been extensively researched .
risk factors for atc have not been sufficiently studied , and its aetiology essentially remains unknown .
there have been numerous case - control studies for all histopathological types of thyroid cancer , even medullary thyroid cancer [ 4 , 5 ] .
apart from our previous study , we did not encounter in the literature other case - control studies of atc ; even though being such an aggressive tumour , it attracts great attention in oncology and endocrinology . probably , one of the possible reasons for this is that a long period of observation is required to gather a significant number of cases , given that atc is quite rare .
we published the first part of our research , with a smaller number of cases and one control group , ten years ago . following that study ,
this research was continued and we published our results with a greater number of cases and two control groups .
the first control group consisted of patients with papillary thyroid cancer , while the second control group was formed from patients with goitre [ 7 , 8 ] . in this paper
we will briefly recapitulate the results of our previous studies and present our new results where the control group was formed from examinees from the general population .
this paper gives the final results of our long - time research that aimed to identify potential risk factors for the development of atc .
the diagnosis of atc was based on the definite histopathological findings for operated patients ( 55 ) and on the basis of the results of fine needle aspiration biopsy for patients that were not operated on ( 71 ) .
all patients were diagnosed at the clinic where the study was carried out , from 1993 to 2005 .
the control group was formed from the general population with the same place of residence as the patients from the studied group .
there were twice as many examinees in the control group , which amounts to 252 .
examinees that were included in the control group were chosen from neighbours of patients from the studied group in the exact same manner .
they were individually matched by place of abode , gender , and age ( 2 years ) .
all examinees ( cases and controls ) were interviewed by the same doctor . before the interview ,
all examinees were made familiar with the aim of the study and voluntarily decided whether they would take part in the research .
it consisted of questions regarding sociodemographic characteristics , habits , life in endemic goitre areas , exposure to radiation , and professional exposure to chemicals .
the next batch of questions consisted of questions about personal history in regard to previous thyroid diseases and thyroid function , other endocrine disorders , other malignancies , various health disorders , diagnostic and therapeutic procedures , previous operations , and use of medicaments .
another group of questions examined family history in regard to thyroid diseases , other diseases of endocrine glands , malignant tumours , and hereditary diseases .
also , detailed data was gathered for menstrual , hormonal , and reproductive characteristics of female examinees .
if a significant health disorder was reported , it was double checked in available medical documentation ; or , if not available , it was double checked with the closest siblings . in statistical analysis
all variables that were statistically related to atc , at a level of significance of p  0.10 , were included in a multivariate conditional logistic regression analysis model ( mlr ) , to identify independent risk factors for atc .
in table 1 basic sociodemographic characteristics , blood type groups , and habits of examinees are shown .
most of the cases were female with a ratio of 1.5  :  1 .
in the cases group , age ranged from 37 to 88 years , with an average age of 67 years .
only 10% of cases were younger than 50 years , and only one case was younger than 40 years .
more patients resided in an urban area ( 69.8% ) than in a rural area ( 30.2% ) .
most cases and even controls had completed only primary school ( 52.4% and 44.0% , resp . ) or had not completed primary school ( 30.2% and 24.6% ) . in general , cases had a lower education level ( only partial or full primary school ) compared to the controls , and this was statistically significant according to ulr .
a statistical significant difference was observed in the number of examinees with blood group type b. this blood group was present in 10.3% of cases and 4.4% of controls .
of the 13 cases with type b blood group , twelve had b+ , while one had b blood group .
we did not find any statistically significant associations within the habits of the examinees ( cigarette smoking , alcohol , and coffee consumption ) .
life in an endemic goitre area did not prove to be statistically significant . among the cases ,
30.2% had a previously diagnosed goitre or thyroid nodules , on average for 18 years ( ranging from 1 to 50 years ) .
six cases had a previous thyroid operation ( three for well - differentiated thyroid cancer and three for benign thyroid diseases ) . on average ,
the time between the operation and atc presentation was a bit longer than five years .
there was not a single examinee with goitre in the control group , except for one with hyperthyroidism and one with hashimoto thyroiditis .
one of the cases , who had been previously operated for well - differentiated thyroid cancer , received i131 therapy , before the anaplastic transformation occurred .
five patients in the cases group were on substitution or suppressive therapy with l - thyroxine .
we found that examinees from the cases group had twice as many nonthyroid malignancies ( 8.7% versus 4.4% ) than the examinees from the control group .
the most common malignancy was cervical cancer ( three cases ) and skin cancer ( basocellular cancer ) in three cases .
this was followed by breast cancer ( two cases ) , lung cancer ( one case ) , colorectal cancer ( one case ) , and prostatic cancer ( one case ) .
professional exposure to chemicals was not statistically significant . in comparison to the control group ,
there were twice as many examinees in the cases group with diabetes , and according to ulr this difference was statistically significant . even though cases were exposed to radiotherapy more often than controls ( 1.6% versus 0.4% as it is in table 2 ) , according to ulr this difference was not statistically significant . a family history of thyroid diseases or other malignancies did not show statistical significance .
menarche was more common in both of the groups ( cases and controls ) , before the age of 15 years .
the number of female examinees who had menarche at the age of 15 years or later was much greater in the cases group ( 20.8% versus 9.1% ) .
a statistical difference was not observed , according to ulr , in relation to normal menstruations , pregnancy , number of children , number of miscarriages , and deliberate terminations of pregnancy .
the same applied to the use of oral contraceptives and menopause estrogens . in the cases group ,
19.2% of examinees were pregnant before the age of 19 , while in the control group there were 9.2% , and this proved to be a statistically significant difference .
variables that were , according to ulr , statistically significantly related to atc were included in a mlr model .
these are education level , type b blood group , goitre , personal history of nonthyroid malignancies , diabetes , late menarche , and an early first pregnancy .
are independently related to atc and represent independent risk factors for atc : low education level , type b blood group , and goitre .
according to the results of this study , when the control group was formed from the general population , independent risk factors for atc were low education level ( or = 1.42 , 95% ci = 1.091.86 ) , type b blood group ( or = 2.41 , 95% ci = 1.035.66 ) , and goitre or thyroid nodules ( or = 25.33 , 95% ci = 5.66126.65 ) .
people with a lower level of education have generally lower health awareness , and they rarely and/or much later seek medical attention . also , adequate health care is less frequently available .
gaitan et al . point out that a lower education and a lower socioeconomic status are associated with a higher incidence of atc and that other thyroid cancers are usually discovered in a more advanced stage [ 9 , 10 ] .
the importance of education is also observed in the paper of memon et al . , where they find that twelve or more years of education significantly decreases the risk of thyroid cancer ( or = 0.6 , 95% ci = 0.30.9 ) .
searching the available literature , we did not encounter any papers that associate type of blood group with atc or any other histopathological type of thyroid cancer . on the other hand ,
find that type b blood group increases the risk of oesophageal cancer , especially in men .
type a blood group is associated with a risk for cancer for various localisations , such as gastric cancer ( especially in patients with a positive family history ) , cancer of the larynx and hypopharynx , pancreatic cancer , breast cancer , and rectal cancer [ 1318 ] . according to the study of marinaccio
et al . , type a blood group , apart from increasing the risk for cervical and ovarian cancer , is a bad prognostic factor for these types of cancer .
we will now compare the results of this study with the results of our previous studies that also researched risk factors for atc , but with different control groups .
our first case - control study of risk factors for atc had a slightly smaller number of cases ( 110 ) and one hospital control group . according to that study , independent risk factors for atc were goitre ( or = 37.55 , 95% ci = 4.86290.11 ) , life in an endemic goitre area ( or = 2.56 , 95% ci = 1.056.22 ) , a personal history of other nonthyroid malignancies ( or = 5.51 , 95% ci = 1.0429.25 ) , diabetes ( or = 4.06 , 95% ci = 1.2912.81 ) , and a lower level of education ( or = 2.44 , 95% ci = 1.175.06 ) .
our present study identified three independent risk factors for atc , compared to our previous study where we identified five .
two of these risk factors are the same in both studies , and those are a lower level of education and goitre .
our present study could not identify life in an endemic area as a risk factor , since the control group was matched by place of abode . practically , the main differences between these two studies are that one found diabetes and a personal history of other nonthyroid malignancies as independent risk factors , while the other identified type b blood group as an independent risk factor for atc .
similar results were obtained when we conducted a case - control study with the same 126 cases of atc that were included in the present study , but the control group was formed from 252 patients with goitre . in fact , the development of atc is preceded by long - term goitre in nearly half of patients .
this is one of the main reasons that we decided to form the control group from patients operated for goitre whose definite pathohistological findings confirmed a benign disease .
this allowed us to establish potential risk factors for the development of atc in patients with goitre .
these risk factors could further help us , as additional criteria , when deciding which patients with benign goitre should undergo operative treatment .
when patients operated for goitre were used as the control group , there were five variables independently related to the development of atc . among these were a lower level of education ( or = 1.85 , 95% ci = 1.212.82 ) and type b blood group ( or = 3.69 , 95% ci = 1.1012.49 ) , which were identified in our present study as well , using a different control group . apart from these two factors ,
the other three factors were a personal history of other nonthyroid malignancies ( or = 4.37 , 95% ci = 1.1117.31 ) , late menarche , at the age of 15 or later ( or = 2.63 .
95% ci = 1.155.88 ) , and an early pregnancy , before the age of 19 ( or = 2.96 , 95% ci = 1.266.96 ) .
these two reproductive factors , as found in our present study , were also statistically significantly associated with atc , according to ulr , but were not found to be independent risk factors .
a late menarche and an early pregnancy have been identified as a risk factor for thyroid cancer in women , where its incidence is several times higher than in men [ 2123 ] .
significantly different results were found when the control group consisted of the same number of cases with atc ( 126 ) but where the controls were formed from examinees with papillary thyroid cancer .
atc can develop from preexistent well - differentiated thyroid cancer , which is found in 1871% of cases with atc [ 2426 ] .
since , in a significant number of cases with atc , well - differentiated thyroid cancer has been proven to coexist , on definitive histopathological findings , we decided to form the control group from patients with papillary thyroid cancer , to try and identify which factors could be responsible for the dedifferentiation , that is , anaplastic transformation of well - differentiated thyroid cancer .
based on the results of mlr , when the control group consisted of patients with papillary thyroid cancer , age proved to be the only independent risk factor for the development of atc ( or = 1.11 , 95% ci = 1.051.15 ) . therefore , in comparison to other observed variables , there were no statistically significant differences between patients with atc and patients with papillary thyroid cancer .
at the end , we would like to point out that in our case - control research of risk factors for atc we tried to surpass one of the greatest problems in the design of case - control studies and that is the choice of the control group .
we overcame this problem by forming several control groups with different criteria and with a bigger number of controls than cases .
however , one of the greatest problems of these studies is the fact that they consist of a relatively small number of cases with atc ; but , on the other hand , there are just a few centres in the world that published papers with more than 100 cases of atc , and unfortunately they have not conducted any case - control studies for risk factors for atc .
therefore , the results of our study should be tested in a study with a higher number of cases , which could only be achieved by a multicentric study with several high volume centres in the world .
 
 background . anaplastic thyroid cancer ( atc ) is a form of thyroid cancer with very poor prognosis , but is fortunately quite rare . 
 its aetiology is unknown and not well researched . 
 aim . 
 the aim of this study was to identify potential risk factors for atc . 
 material and method . 
 case - control study of 126 atc patients ( 77 females and 49 males ) and 252 controls individually matched by gender , age , and place of abode . in statistical analysis 
 we used a cox regression model . 
 results . 
 univariate logistic regression showed that the risk factors for atc are low education level , type b blood group , goitre , other nonthyroid malignancies , diabetes , late menarche , and an early first pregnancy . 
 multivariate logistic regression analysis showed that independent risk factors for atc are low education level ( or  =  1.42 , 95% ci  =  1.091.86 ) , type b blood group ( or  =  2.41 , 95% ci  =  1.035.66 ) , and goitre ( or  =  2533 , 95% ci  =  5.66126.65 ) . 
 conclusion . 
 independent risk factors for atc are : low education level , type b blood group , and goitre . 
1. Introduction
2. Material and Method
3. Results
4. Discussion