Clinico-pathological Characteristics and Survival Analysis of 300 Thyroid Cancer Cases in One Referral Hospital in Kelantan, Malaysia: A 10-year study

Among all cancer types, one of the fastest growing types in the world is thyroid cancer [1]. Malaysia has 14 states of which seven of these states namely Sabah [2-3], Sarawak [4-5], Kelantan [6], Terengganu, Pahang, Perlis, and Kedah are noted to have the high incidence of goiter [7]. Thyroid specimens surgically removed for multi-nodular goiter at Hospital Universiti Sains Malaysia (HUSM) showed 34-60% of them had malignant transformation; a high figure compared to the international incidence of 4 to 17% [8]. In Kelantan Abstract

Introduction apjcc.waocp.com Nor Hayati Othman, et al: Clinico-pathological Characteristics and Survival Analysis of 300 Thyroid Cancer Cases ASR of 5.1, higher than the national average [9]. In the non-endemic state of Pulau Pinang, thyroid cancer is not listed as one of the top 10 cancers while in the endemic states of Sabah and Kelantan, thyroid cancer is the top 5 cancers [9]. The most common thyroid cancer seen in Malaysia and elsewhere is papillary carcinoma (PTC) [10][11]. Often patients come in advanced stage making surgery problematic [12]. The Malays [10] and the Ibans [11] have a higher predilection to have thyroid cancer compared to other races. Females have the cumulative risk of three to four times more than males and the peak age is 35-45 years. In other countries, PTC incidence is also high in countries which are endemic with iodine deficiency [13][14][15].
This study is to evaluate the trend of incidence of thyroid cancer in Kelantan over a ten year period between 2006 to 2015 and map them against the geographic location of these patients. The previous study on iodine deficiency in Kelantan [6] showed that those living inlands/highlands had the higher prevalence of iodine deficiency. We wanted to investigate whether iodine deficiency is a risk factor for thyroid malignancy. Kelantan is made up 4 coastal districts namely Bachok, Kota Bharu, Pasir Puteh, and Tumpat and 5 inland/highland districts; Pasir Mas, Jeli, Gua Musang, Kuala Kerai, and Macang. Being a referral centre, all cases of thyroid cancers seen in other hospitals in Kelantan and adjacent states are referred to HUSM for further management. We also analysed the survival of the patients according to tumour types.

Materials and Methods
The registry of patients diagnosed histologically as thyroid cancer from the year 2006 to 2015 was retrieved from the medical record office of Hospital Universiti Sains Malaysia (HUSM). From these data, the variables extracted for each year were age, gender, residential addresses (classified under the nine districts of Kelantan and under 'Others' if the patients were from outside Kelantan), the tumour types and the current status (alive or dead) of the patients. The data were scrutinized to ensure no repeat entry in the same case. These data were analyzed using IBM SPSS statistics software version 24 for Windows. The level of significance was set at p<0.05. The survival analyses were carried out using Kaplan Meier approach. Survival was estimated by sex, age, and duration of illness for each of the tumour type.

General Results
A total of 300 thyroid cancers were recorded from 2006 to 2015, the trend of thyroid cancer over this ten-year period showed that the incidence remains low in the first few years but increased rapidly from 2010 onwards ( Figure 1). The average rise of cancer per year is 27.2% Throughout this period, 241/300(80.3%), were women and 59/300 (19.7%) were men. Female to male ratio was 4.1:1 (p=000). The mean age for women was 49.78 years (SD15.17) while for men was older at 53.27 years (SD14.45).

Tumor Type
Papillary carcinoma was the commonest tumor type for all years ( Figure 2). The breakup by gender and the tumour type is in Table 1. All patients who had anaplastic carcinoma were women. Majority of the patients with papillary carcinoma; 182/230 (79.1%) and follicular carcinoma; 48/58 (82.8%) were women. The peak age was at the 5th decade ( Figure 3). The youngest patient was 11 years old and the oldest, 86 years of age and both had papillary carcinoma. Those patients with anaplastic carcinoma were older than 50 years. There were two cases of medullary carcinoma one each per gender.

Discussion
This study highlights few findings; thyroid cancer showed a rising trend in Kelantan from 2006 to 2015 at an annual rate of about 2.7%. Women were four times more at risk than men; the peak age was in the fifth decade, older than those seen in countries affected by radiation exposure. Majority of patients were from the Kota Bharu District and the one and five years survival rates per each tumour type were comparable with data worldwide.
Thyroid cancer incidence is rising globally for the last few decades while the mortality is declining [16]. For example, in Shanghai, there were increasing cases of thyroid cancer from 34 to 137 in men and from 102 to 536 in women between 1983 and 2007 [17]. From our study we notice the trend of thyroid cancer in Kelantan is also increasing rapidly from 11 cases in 2006 to 67 cases in the year 2015 for all tumor types, resembling those seen in Shanghai and France [18]. This increase concerned exclusively for papillary carcinoma. In the literature during 60's to 80's, thyroid cancer was more

Geographical location of patients based on tumour type
When the patients were mapped against their residential addresses, the majority of patients were from the Kota Bharu District (p=000). Figure 4 demonstrates the location of these patients according to the tumour types. The 2 medullary cancers were from outside Kelantan state.

Survival Analysis
Over the ten year period, seven of the anaplastic carcinoma patients have died. The break-up of the number of deaths per each tumour type is shown in Table 2. The survival at one year and 5th year is as shown in Table 3. Survival is best for papillary carcinoma and worst for anaplastic carcinoma. In general, those below 40 years old had better survival compared to older patients. For all three types of cancer, the survival at 1-year was 90% and 88% at 5-years. Women had higher survival than men for all cancers. The survival decreased with age for all tumor types. The details of the number of alive and dead patients over this ten years are shown in Table 2 and the 1-year and 5-year survival rates in Table 3. The Kaplan Meier curves for each tumour type (except Medullary carcinoma) are shown in Figures 5-7. To the time of writing the two cases of medullary carcinoma patients are still alive beyond 5 years.   apjcc.waocp.com Nor Hayati Othman, et al: Clinico-pathological Characteristics and Survival Analysis of 300 Thyroid Cancer Cases common in the younger age group. However, in our study, it was found to be more common in the fourth and fifth decades, similar to what is observed in the United States [19]. Improvement in clinical practice and more refined diagnostic techniques in HUSM are also contributing to the increase in the number of cases seen over the years [20]. This is also true elsewhere [18], [21]. Other explanations, including environmental influences, is one of the possible factors contributing to the increase in incidence [22]. Known factors of thyroid carcinomas are radiation exposure [23], genetics [24][25], obesity [26] and iodine deficiency [27][28][29]. Kelantan population has been observed to have chronic iodine deficiency [30]. Animal experiments have shown an increasing incidence of thyroid carcinomas after prolonged iodine deficiency [31]. Chronic Multi-Nodular Goitre (MNG) has a been associated with thyroid cancer especially papillary carcinoma [32][33]. In cancers associated with iodine deficiency, papillary thyroid carcinomas are more than other cancers supporting the results of our study where papillary cancer is the most common. Interestingly, we observed the districts near coastlines (Bachok, Kota Bharu, Pasir Puteh, and Tumpat) had the higher frequency of thyroid cancers than those districts located far inland. We would have expected that the people living near coastlines to be less iodine-deficient than the folks who live inland. A previous study was done on goitrous patients in Kelantan, 22.7% MNG or nodular hyperplasia expressed RET protein, the protein known to be involved in thyroid cancer [34]. The cause of MNG is chronic iodine deficiency. Ret gene mutation is associated with thyroid cancer [35].
Malaysian women are given iodized salt supplementation only during pregnancy when they attend antenatal checkup in hospitals. Provision of iodine may need to be extended lifelong. Countries which have introduced effective iodine supplementation in their diet have shown a reduction in papillary cancer [18]. Iodine deficiency alone is not the only risk factor [36]. The main risk factor remains exposure to nuclear radiation. However, there is no known radioactive fallout in Kelantan state nor elsewhere in Malaysia unlike those living in nuclear fall-outs such as Hiroshima, Nagasaki, Fukushima, and Chernobyl or other regions. What then could we attribute the reasons why thyroid cancer is high in Kelantan? Could we postulate people living in Kelantan coastline are more at risk as they are nearest to Japan?      Could this also be the reason why Kelantan, Terengganu, Sarawak, and Sabah are the states in Malaysia that have the high incidence of thyroid cancers? Further studies are needed to answer this. The mean age of patients in our study is 49.78 years for women 53.27 for men, much older than those reported in other countries [37] probably confirms earlier findings that long-standing goiter may complicate cancer development. The thyroid glands of these patients may have started to enlarge during childhood. The age of patients with papillary carcinomas seen in patients who are exposed to radiation is younger while those due to chronic iodine deficiency is older as seen in this study.
Our study shows that the overall survival of thyroid cancer is comparable with other studies [38][39]. In our study, survival from papillary and follicular carcinomas was higher in women similar to what was found in France [18]. Others have not found that gender influence survival differences [15]. Our study observed that those below 40 years old had better survival than older patients, finding similarly noted by other researchers [40].
Studies have shown iodized salt supplementation has reduced goiter prevalence [41] thus reduces the risk of cancer development [18][19]. Supplementation leads to an increase in the ratio of differentiated to undifferentiated carcinoma [42]. The prognosis and survival of differentiated thyroid cancer have also improved after iodized salt supplementation [42].
In conclusion, the trend of thyroid cancer in Kelantan is increasing over the ten-year period from 2006 to 2015. It has a female preponderance. The mean age is 49.78 years for women 53.27 for men, several years older than those thyroid cancers associated with radiation exposure. Since Kelantan is not known to have radioactive exposure, the cause of thyroid cancer in this population is probably secondary to prolonged iodine deficiency. The five-year survival for differentiated thyroid cancer is above 90%, comparable with most published studies.