Thyroid Physiology

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Thyroid Physiology

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1. Histologically the thyroid is composed of follicles lined by a single layer of epithelial cells ( cuboidal to collumnar). They contain colloid the major constituant of which is Tg 90% of body’s iodine is in the thyroid Histologically the thyroid is composed of follicles lined by a single layer of epithelial cells ( cuboidal to collumnar). They contain colloid the major constituant of which is Tg 90% of body’s iodine is in the thyroid

2. Thyroid Physiology Circulating iodide is actively taken up and concentrated by the thyroid by an energy dependent Na/I transporter (NIS) ( based on Na/K antiport potential) The thyroid is also the site of production of thyroglobulin. Iodide is transported at the apical membrane by Pendrin (a chloride iodide symporter). Here it is oxidised by the action of TPO to iodine and linked to tyrosine residues present in thyroglobulin in the colloid thus forming MIT and DIT. This iodinated Tg is stored within the colloid as a prohormone. And is transported back through the thyroid cell by endocytosis and free T3 and T4 are released into the blood stream where they are bound to plasma proteins albumin pre albumin and TBG. The availability of iodide exerts a regulatory effect independent of TSH T4 is the principle circulating hormone, but T3 is the acticve hormone. Conversion is by peripheral deiodinaion Circulating iodide is actively taken up and concentrated by the thyroid by an energy dependent Na/I transporter (NIS) ( based on Na/K antiport potential) The thyroid is also the site of production of thyroglobulin. Iodide is transported at the apical membrane by Pendrin (a chloride iodide symporter). Here it is oxidised by the action of TPO to iodine and linked to tyrosine residues present in thyroglobulin in the colloid thus forming MIT and DIT. This iodinated Tg is stored within the colloid as a prohormone. And is transported back through the thyroid cell by endocytosis and free T3 and T4 are released into the blood stream where they are bound to plasma proteins albumin pre albumin and TBG. The availability of iodide exerts a regulatory effect independent of TSH T4 is the principle circulating hormone, but T3 is the acticve hormone. Conversion is by peripheral deiodinaion

3. Environmental Goitrogens Uneven distribution of goitre even in areas of equal iodine deficiency. Concomitant exposure to naturally occurring anti thyroid agents magnifies severity of goitre in iodine deficient areas and is likely have a role in goitre in non iodine deficient areas. Firstly to review thyroid hormone production Iodide is taken up by the thyroid by an energy dependent Na/I transporter (NIS) It is freely diffusable in the cell. It is oxidised at the apical membrane by the action of TPO and linked to tyrosine residues present in thyroglobulin in the colloid thus forming MIT and DIT. These are then coupled to one another to form T3 and T4. Through a process of endocytosis of colloid back into the thyroid cell thyroid hormone are released into the blood stream where they are bound to plasma proteins albumin and TBG. Iodine has an effect to prevent proteolysis and release of thyroid hormones. Amiodarone which is rich in iodine has a similar effect Uneven distribution of goitre even in areas of equal iodine deficiency. Concomitant exposure to naturally occurring anti thyroid agents magnifies severity of goitre in iodine deficient areas and is likely have a role in goitre in non iodine deficient areas. Firstly to review thyroid hormone production Iodide is taken up by the thyroid by an energy dependent Na/I transporter (NIS) It is freely diffusable in the cell. It is oxidised at the apical membrane by the action of TPO and linked to tyrosine residues present in thyroglobulin in the colloid thus forming MIT and DIT. These are then coupled to one another to form T3 and T4. Through a process of endocytosis of colloid back into the thyroid cell thyroid hormone are released into the blood stream where they are bound to plasma proteins albumin and TBG. Iodine has an effect to prevent proteolysis and release of thyroid hormones. Amiodarone which is rich in iodine has a similar effect

4. Regulation of Secretion by TSH The release of thyroid hormones is under the direct control of TSH. Low serum levels of T3 and T4 promote TSH secretion from the anterior pituitary whereas high serum levels of thyroid hormones inhibit its release.TSH secretion is stimulated by Thyrotropin releasing hormone from the hypothalamus. Circulating levels of thyroid hormones also control release of this.The release of thyroid hormones is under the direct control of TSH. Low serum levels of T3 and T4 promote TSH secretion from the anterior pituitary whereas high serum levels of thyroid hormones inhibit its release.TSH secretion is stimulated by Thyrotropin releasing hormone from the hypothalamus. Circulating levels of thyroid hormones also control release of this.

5. This talk is on neoplastic thyroid disease. This covers goitre in iodine deficient and replete areas and thyroid cancer. This talk is on neoplastic thyroid disease. This covers goitre in iodine deficient and replete areas and thyroid cancer.

6. Goitre / Struma Goitre is a term for thyroid enlargement ‘Gutter’ meaning throat Chinese described goitre 5000 yrs ago Recognised long before thyroid gland Goitre comes from the Latin word for throat ‘gutter’. Goitre is a non specific enlargement of the thyroid and in the euthyroid individual can be divided in to those seen in iodine deficient/ iodine replete area s and cancer The WHO have an interesting definition of a goitre A THYROID WHOSE LATERAL LOBES HAVE A VOLUME GREATER THAN THE TERMINAL PHALANGES OF THE THUMB OF THE PERSON BEING EXAMINED References made to goitre from as long ago as 2000 BC in Hindu Incantations In Roman times an association was made between a large neck and coming from the mountainous regions such as the Alps. Julius Caesar remarked at the frequent occurrence of a big neck as one of the characteristics of the Gauls Painters depicted women with goitre as a sign of beauty and it was certainly depicted in art long before it was mentioned in the Medical literature in 14th century. This is a Medieval Biblical illustration for psalm 52. Goitre comes from the Latin word for throat ‘gutter’. Goitre is a non specific enlargement of the thyroid and in the euthyroid individual can be divided in to those seen in iodine deficient/ iodine replete area s and cancer The WHO have an interesting definition of a goitre A THYROID WHOSE LATERAL LOBES HAVE A VOLUME GREATER THAN THE TERMINAL PHALANGES OF THE THUMB OF THE PERSON BEING EXAMINED References made to goitre from as long ago as 2000 BC in Hindu Incantations In Roman times an association was made between a large neck and coming from the mountainous regions such as the Alps. Julius Caesar remarked at the frequent occurrence of a big neck as one of the characteristics of the Gauls Painters depicted women with goitre as a sign of beauty and it was certainly depicted in art long before it was mentioned in the Medical literature in 14th century. This is a Medieval Biblical illustration for psalm 52.

7. The normal thyroid was recognised in the Renaissance, but it wasn’t until 1619 that it was recognised that goitre arose from the thyroid. Michelangelo is certain to have known about it from his studies on dissection and very famously depicted the Creator with a goitre in the Separation of Light from Darkness depicted on the ceiling of the Sistine chapel The normal thyroid was recognised in the Renaissance, but it wasn’t until 1619 that it was recognised that goitre arose from the thyroid. Michelangelo is certain to have known about it from his studies on dissection and very famously depicted the Creator with a goitre in the Separation of Light from Darkness depicted on the ceiling of the Sistine chapel

8. Endemic Goitre Iodine deficiency (<50µg/day) 7% world population 1000 million at risk of deficiency In areas of iodine deficiency goitre is endemic. Iodide intake of less than 50ug/day. These areas include high mountainous regions such as Peru Argentina Chile and the Himalayas The WHO has identified 7% of the worlds population as suffering from clinically apparent goitre Children are at risk from cretinism where intake falls below 25ug/day. More prevalent in females. Clinically they are EUTHYROID but TSH at the upper end of normal and thyroid hormones at the lower end Iodide deficiency still exists despite the proven value of iodination programmes. Treatment of children with iodide can cause goitre regression but has little effect on goitre size in adults. In fact it can cause thyrotoxicosis. However Goitre not equally prevalent in areas with equal iodine deficiency and other factors come in to play similar to those that induce goitre in iodine replete areas In areas of iodine deficiency goitre is endemic. Iodide intake of less than 50ug/day. These areas include high mountainous regions such as Peru Argentina Chile and the Himalayas The WHO has identified 7% of the worlds population as suffering from clinically apparent goitre Children are at risk from cretinism where intake falls below 25ug/day. More prevalent in females. Clinically they are EUTHYROID but TSH at the upper end of normal and thyroid hormones at the lower end Iodide deficiency still exists despite the proven value of iodination programmes. Treatment of children with iodide can cause goitre regression but has little effect on goitre size in adults. In fact it can cause thyrotoxicosis. However Goitre not equally prevalent in areas with equal iodine deficiency and other factors come in to play similar to those that induce goitre in iodine replete areas

9. UK iodine deficiency Common in many areas up to 1960’s Daily iodine increased from 80 to 255?g/day Main source of iodine is from milk and dairy products Some evidence for iodine deficiency in vegans In the UK, endemic goitre was present in many areas until the 1960’s, with the most iodine deficient areas shown on the map. As you can see it extends well beyond Derbyshire ! Since the second world war average iodine consumption has increased from 80 to nearly 300ug /day, and this is due to changing farming practices. Since the 1930’s iodine has been added to animal feed and salt licks, initially to improve animal growth, but has passed into dairy products, especially milk, and so to humans. Despite calls by the MRC for salt and food iodination for humans from as long ago as the forties, in the UK there is no compulsory iodine additives to food. Consequently there is some evidence in vegans of mild iodine deficiency.In the UK, endemic goitre was present in many areas until the 1960’s, with the most iodine deficient areas shown on the map. As you can see it extends well beyond Derbyshire ! Since the second world war average iodine consumption has increased from 80 to nearly 300ug /day, and this is due to changing farming practices. Since the 1930’s iodine has been added to animal feed and salt licks, initially to improve animal growth, but has passed into dairy products, especially milk, and so to humans. Despite calls by the MRC for salt and food iodination for humans from as long ago as the forties, in the UK there is no compulsory iodine additives to food. Consequently there is some evidence in vegans of mild iodine deficiency.

10. Iodination of Salt Netherlands since 1924 Not in the UK Europe 28% salt iodinated, worst in world The answer to iodine deficiency is simple iodination of salt. In the Netherlands salt is iodinated and has been since 1924.The rest of Europe sadly lags behind. In the UK salt is not iodinated and in Europe as a whole only 28% is iodinated. The answer to iodine deficiency is simple iodination of salt. In the Netherlands salt is iodinated and has been since 1924.The rest of Europe sadly lags behind. In the UK salt is not iodinated and in Europe as a whole only 28% is iodinated.

11. Iodine Replete Goitre Thyroid nodules seen in up to 50% of autopsies Confirmed with high resolution USS 8% palpable Framingham study (US) 4.2% population Lifetime risk for thyroid nodule 5-10% Females: Males = 4:1 Thyroid enlargement is as I have said common Autopsy studies have shown that >50% of patients have one or more thyroid nodule USS studies using high resolution scans have confirmed this finding Of these only 8% are palpable In the Framingham study in Massachusetts 4.2% had a thyroid nodule and lifetime risk for developing a nodule was estimated at 5-10%Thyroid enlargement is as I have said common Autopsy studies have shown that >50% of patients have one or more thyroid nodule USS studies using high resolution scans have confirmed this finding Of these only 8% are palpable In the Framingham study in Massachusetts 4.2% had a thyroid nodule and lifetime risk for developing a nodule was estimated at 5-10%

12. Whickham Survey (1977) Survey of 2779 individuals in NE England 15.5% had palpable, and 6.9% had visible goitre. The best known UK population study of thyroid disease is the Whickham Survey, in North East England, where over 2700 individuals were selected at random from the electoral register and examined. Their thyroids were assessed and broadly divided into normal, palpable goitre and visible goitre. Overall there was a 15.5% incidence of palpable goitre, and as you can see from the graph, the majority of the goitres were in the pre-menopausal females, and that after the menopause the incidence of goitres fell. This cross-sectional study became longitudinal when they followed up the same people 20 years later, and found that the incidence of goitres in the surviving females had fallen from 26% to 10%, confirming the assumption that goitres can regress as people age.The best known UK population study of thyroid disease is the Whickham Survey, in North East England, where over 2700 individuals were selected at random from the electoral register and examined. Their thyroids were assessed and broadly divided into normal, palpable goitre and visible goitre. Overall there was a 15.5% incidence of palpable goitre, and as you can see from the graph, the majority of the goitres were in the pre-menopausal females, and that after the menopause the incidence of goitres fell. This cross-sectional study became longitudinal when they followed up the same people 20 years later, and found that the incidence of goitres in the surviving females had fallen from 26% to 10%, confirming the assumption that goitres can regress as people age.

13. Predisposing Factors Genetics Goitrogens Drugs Auto immune thyroid disease Thought to be due to TSH stimulation of growth but majority show no biochemical or clinical evidence of thyroid dysfunction

14. Family and twin pair studies indicate predisposition for euthyroid goitre - susceptibility locus at Ch 14q (MNG-1) in several families Rare inherited defects in: Hormone Synthesis and Transport TSH Receptor defects Genetic This is a very exciting time for the determination of the genetic basis of disease It has been known for a long time that there is a higher incidence of goitre in some families, and that MZ twins have higher concordance for goitre than DZ twins. Recently a susceptibility locus for non-toxic goitre has been identified in several families There are rare inherited defects in thyroxine synthesis which can cause goitre. The TSH receptor and the Na I symporter have been cloned, and have activating and inhibiting polymorphisms which can lead to goitre. However no genetic cause is identified for the majority of goitres. This is a very exciting time for the determination of the genetic basis of disease It has been known for a long time that there is a higher incidence of goitre in some families, and that MZ twins have higher concordance for goitre than DZ twins. Recently a susceptibility locus for non-toxic goitre has been identified in several families There are rare inherited defects in thyroxine synthesis which can cause goitre. The TSH receptor and the Na I symporter have been cloned, and have activating and inhibiting polymorphisms which can lead to goitre. However no genetic cause is identified for the majority of goitres.

15. Pendred’s Syndrome Na independent Cl-/ I- transporter 7.5% of all congenital deafness SNHL and euthyroid goitre Cochlea - enlarged vestibular aqueduct endolymphatic duct and sac Pendreds syndrome was described in 1896 100 years later the gene was discovered on Ch 7q. Encodes a protein Pendrin a sodium independent Iodide Chloride transporter expressed in the thyroid, cochlea and kidney. AR condition Incidence of 1:50-100,000 said to account for 7.5 % of all congenital deafness. However with the identification of the gene a diagnosis can be made with a higher degree of accuracy than previously possible. Classically it is an association of SNHL and euthyroid goitre. Goitre is variably present. Studies suggest that there has been an over diagnosis of Pendred’s in the past. The most common abnormality o f the cochlea is an enlarged vestibular aqueduct found in 80% of Pendreds and an enlarged endolymphatic duct and sac found in 100% of Pendreds (JCEM 2000). Pendreds syndrome was described in 1896 100 years later the gene was discovered on Ch 7q. Encodes a protein Pendrin a sodium independent Iodide Chloride transporter expressed in the thyroid, cochlea and kidney. AR condition Incidence of 1:50-100,000 said to account for 7.5 % of all congenital deafness. However with the identification of the gene a diagnosis can be made with a higher degree of accuracy than previously possible. Classically it is an association of SNHL and euthyroid goitre. Goitre is variably present. Studies suggest that there has been an over diagnosis of Pendred’s in the past. The most common abnormality o f the cochlea is an enlarged vestibular aqueduct found in 80% of Pendreds and an enlarged endolymphatic duct and sac found in 100% of Pendreds (JCEM 2000).

16. Growth Factors Insulin-like growth factors Fibroblast growth factors TGF-? Angiogenic growth factors VEGF Angiopoietin Placental-derived growth factor Numerous growth factors have been identified in the thyroid, and shown to alter in goitre development. Imbalances in their interactions alters replication and differentiation and promotes growth.TSH interactions with autocrine and paracrine actions of these growth factors seems essential and may be the mechanism for formation of a goitre. We have discussed goitrogens earlier onNumerous growth factors have been identified in the thyroid, and shown to alter in goitre development. Imbalances in their interactions alters replication and differentiation and promotes growth.TSH interactions with autocrine and paracrine actions of these growth factors seems essential and may be the mechanism for formation of a goitre. We have discussed goitrogens earlier on

17. Differentiated Thyroid Cancer High prevalence (5-36%) of occult micro- papillary cancer at post-mortem Incidence is low (1.2- 3.8/100 000/yr) 1200 new cases/yr 1% of all new malignancies 0.5% of cancer deaths 7th most common cancer in women A high prevalence of papillary microcarcinomas is seen at post mortem. (5-36%) However the incidence of DTC is low illustrating that clinically apparent disease is the tip of the iceberg Thyroid cancer accounts for 1% of malignancies, and is the most common endocrine cancer. Prognosis is relatively good, however 10-15% of patients overall will die of their cancer, and there is considerable cost and morbidity of the long term follow-up and treatment. Annual incidence is 2.3 per 100 000 women and 0.9 per 100 000 men Approx 1000 new cases per year and 250 deaths per yearA high prevalence of papillary microcarcinomas is seen at post mortem. (5-36%) However the incidence of DTC is low illustrating that clinically apparent disease is the tip of the iceberg Thyroid cancer accounts for 1% of malignancies, and is the most common endocrine cancer. Prognosis is relatively good, however 10-15% of patients overall will die of their cancer, and there is considerable cost and morbidity of the long term follow-up and treatment. Annual incidence is 2.3 per 100 000 women and 0.9 per 100 000 men Approx 1000 new cases per year and 250 deaths per year

18. Incidence increases with age, median age 45-50 Thyroid cancer is rare below the age of 16. In children and adolescents however thyroid nodules have a higher rate of malignancy Females > Males 2-3:1 Mortality greater in elderly Differentiated Thyroid Cancer The incidence of DTC increases with age, peaking in the 5th decade, and is rare in children. However a young person with a nodule has a higher chance of malignancy, and may have more aggressive disease. The mortality is greater in the elderly.The incidence of DTC increases with age, peaking in the 5th decade, and is rare in children. However a young person with a nodule has a higher chance of malignancy, and may have more aggressive disease. The mortality is greater in the elderly.

19. The ‘Solitary’ Thyroid Nodule Majority are dominant nodules within MNG If a nodule is truly solitary there is a 20% risk of malignancy compared with 5-10% in a euthyroid multinodular goitre 15-25% of all nodules are cystic As you know, the majority of clinically solitary nodules are not solitary on further investigation, and are part of a multinodular thyroid. The risk of cancer in a palpable nodule is 5%, although it is 20% if the nodule is truly solitary 15-25% of all nodules are cystic. Other benign nodules include hyperplastic nodules,adenomas and teratomas.As you know, the majority of clinically solitary nodules are not solitary on further investigation, and are part of a multinodular thyroid. The risk of cancer in a palpable nodule is 5%, although it is 20% if the nodule is truly solitary 15-25% of all nodules are cystic. Other benign nodules include hyperplastic nodules,adenomas and teratomas.

20. Risk Factors Ionizing radiation Family History Solitary Nodule Male Gender Iodine intake Underlying Thyroid disease So a nodule is more likely to be cancer if There is a positive family history Increase in size of nodule Patient is <14 and >65 years old Male There is a history of ionizing radiation exposure Increase in TSH Thyroid antibodies are presentSo a nodule is more likely to be cancer if There is a positive family history Increase in size of nodule Patient is <14 and >65 years old Male There is a history of ionizing radiation exposure Increase in TSH Thyroid antibodies are present

21. Ionising Radiation Treatment of children with ionising radiation confers a risk of 1-7% of developing thyroid cancer within 30 years Exposure at very young age confers greatest risk Prognosis similar to ‘spontaneous’ Thyroid cancer is one of the most common radiation induced malignancies. Exposure to as little as 6Gy increases the risk 6 fold. The thyroid is most sensitive to radiation exposure in children and adolescents. Historically ionising radiation was used in children to treat acne and to cause involution of enlarged lymphoid tissue such as seen in tonsillitis. It was found that this radiation as a child confers a risk of1-7%of developing thyroid cancer within 30 years. Exposure at a young age confers greatest risk. Children <5 have a twofold higher risk than those treated between 5 and 9 and a five fold risk than those between 10 and 14 Cancer can develop upto 40 years after exposure, the peak incidence is seen between 15 and 25 years prognosis similar to that of ‘spontaneous’ cancer but frequency of multicentricity is higher Thyroid cancer is one of the most common radiation induced malignancies. Exposure to as little as 6Gy increases the risk 6 fold. The thyroid is most sensitive to radiation exposure in children and adolescents. Historically ionising radiation was used in children to treat acne and to cause involution of enlarged lymphoid tissue such as seen in tonsillitis. It was found that this radiation as a child confers a risk of1-7%of developing thyroid cancer within 30 years. Exposure at a young age confers greatest risk. Children <5 have a twofold higher risk than those treated between 5 and 9 and a five fold risk than those between 10 and 14 Cancer can develop upto 40 years after exposure, the peak incidence is seen between 15 and 25 years prognosis similar to that of ‘spontaneous’ cancer but frequency of multicentricity is higher

22. Radioactive Iodine Chernobyl 1986 Vast amounts of Iodine -131,-132 and -133 released Substantial contamination No immediate prophylactic stable iodine administered Level of endemic iodine deficiency The best documented effects on the thyroid have been following the Chernobyl nuclear disaster in 1986. Effects were due to the release of vast quantities of iodine 131,132 and 133. There was substantial contamination due to the massive amounts released and the lack of warning to not eat contaminated food. The thyroid uptake was also high due to the lack of prophylactic stable in the immediate period after the exposure and perhaps also to a pre-existing iodine deficiency. Most radiation induced thyroid cancer are well differentaited papillary and have a similar natural history to non radiation induced carcinoma The best documented effects on the thyroid have been following the Chernobyl nuclear disaster in 1986. Effects were due to the release of vast quantities of iodine 131,132 and 133. There was substantial contamination due to the massive amounts released and the lack of warning to not eat contaminated food. The thyroid uptake was also high due to the lack of prophylactic stable in the immediate period after the exposure and perhaps also to a pre-existing iodine deficiency. Most radiation induced thyroid cancer are well differentaited papillary and have a similar natural history to non radiation induced carcinoma

23. Chernobyl (1986) This graph shows the incidence of thyroid cancer in several areas of the former Soviet Union in children aged under 15 at the time of the accident As you can see the number of children with thyroid cancer increases from almost none, to a peak after 10 years. It has been estimated from these figures that iodine tablets prior to exposure will reduce the radiation to the thyroid by 98% and should be an essential part of any future nuclear accident. This graph shows the incidence of thyroid cancer in several areas of the former Soviet Union in children aged under 15 at the time of the accident As you can see the number of children with thyroid cancer increases from almost none, to a peak after 10 years. It has been estimated from these figures that iodine tablets prior to exposure will reduce the radiation to the thyroid by 98% and should be an essential part of any future nuclear accident.

24. Effect of Age The increase in risk to children has been put down to the relatively high dose to a small thyroid and the fact that they were the largest consumers of milk which was the main source of contaminationThe increase in risk to children has been put down to the relatively high dose to a small thyroid and the fact that they were the largest consumers of milk which was the main source of contamination

25. Risk Factor –Familial Syndromes Familial Polyposis coli Large GI polyps & papillary thyroid cancer (APC 5q21) Gardner’s syndrome SI/LI polyps, osteoma, fibromas, lipomas & papillary thyroid cancer (APC 5q21) Cowden’s disease Hamartomas, MNG, cancer breast colon lung & follicular thyroid cancer There are several inherited syndromes that increase the risk of thyroid cancer, FPC (large intestinal polyps and PTC), Gardners (SI and LI polyps, fibromas, osteomas and lipomas and PTC) increase the rate of thyroid cancer 100 fold. There are several inherited syndromes that increase the risk of thyroid cancer, FPC (large intestinal polyps and PTC), Gardners (SI and LI polyps, fibromas, osteomas and lipomas and PTC) increase the rate of thyroid cancer 100 fold.

26. Oncogenes 5% PTC due to AD inheritance RET activation (10q11.2) is seen in 3-33% of PTC and 60-80% where there has been radiation exposure TRK and MET are increased in papillary cancers P53 mutations rare except in anaplastic carcinoma Several oncogenes have been implicated in thyroid cancer Expression of c-myc is stimulated in normal thyroid cells by TSH, and the proto-oncogene is expressed in adenomas and carcinomas. Over expression of h-ras, are found in adenomas and carcinomas, but h-ras mutations are also found in nodular goiter tissue suggesting that h-ras mutations could be an early event in oncogenesis Activation of ret protooncogene is seen in 10-30% of papillary thyroid cancers and are even more common where there has been radiation exposure Several oncogenes have been implicated in thyroid cancer Expression of c-myc is stimulated in normal thyroid cells by TSH, and the proto-oncogene is expressed in adenomas and carcinomas. Over expression of h-ras, are found in adenomas and carcinomas, but h-ras mutations are also found in nodular goiter tissue suggesting that h-ras mutations could be an early event in oncogenesis Activation of ret protooncogene is seen in 10-30% of papillary thyroid cancers and are even more common where there has been radiation exposure

27. Papillary Thyroid Cancer 65% Thyroid cancer in UK 30-87% multicentric Association with previous irradiation Seen in children Lymph node spread common (60%) Distant spread uncommon

28. Follicular Thyroid Cancer 30% thyroid cancer in UK Usually focal Realated to Iodine deficeincy Older patient (6th decade) Lymph node spread lesscommon (10%) Distant haematogenous metastases to lung and bone (20-30%)

29. Time course Pain Pressure Stridor Voice change Drug history Risk Factors Inspection Palpation Neck Larynx

30. Investigations Bloods TFT’s, Thyroid AA’s FNA 86% sensitivity and 89% specificity Imaging USS (irregular, no halo, solid, hypoechoic, microcalcifications) CT (beware contrast) MRI

31. Cytology Reporting Thy 1 inadequate Thy 2 non neoplastic Thy 3 follicular lesion Thy 4 suspicious of malignancy Thy 5 diagnostic of malignancy

32. Size, Age (45), Metastases, Completeness of resection, Invasion. PTC <1 cm - lobectomy and T4 suppression FTC <1cm - lobectomy and T4 suppression FTC 1-2cm ?lobectomy alone +T4 supp Risk TNM, AMES, MACIS

33. Neck Level VI - high risk, palpable disease Lateral neck - level IIa-V preserving non lymphatic structures (MRND type 3)

35. Prognosis

36. Prognosis Papillary 72% men and 80% women Independent poor prognosic indicators: Age <10 or >40 Male gender Grade Stage Completness of Resection

37. Medullary Thyroid Carcinoma 5% of cases of thyroid cancer 80 % are sporadic Familial non-MEN MTC MEN 2a • MEN 2b (+) phaeochromocytoma - Marfanoid habitus hyperparathyroidism - ganglioneuromatosis MTC accounts for approx. 5% of thyroid cancers. Incidence of 1 in a million (60-80 cases /year in the UK). MTC arises from the parafollicular C cells The majority are sporadic. It is important to differentiate between truly sporadic and an index case for familial disease. FH of tumours associated with MEN should be sought. There is also non-MEN familial MTC. C cell hyperplasia and Ret transformation are highly indicative of familial disease Diagnosis is usually made on serum Calcitonin levels or genetic screening MTC accounts for approx. 5% of thyroid cancers. Incidence of 1 in a million (60-80 cases /year in the UK). MTC arises from the parafollicular C cells The majority are sporadic. It is important to differentiate between truly sporadic and an index case for familial disease. FH of tumours associated with MEN should be sought. There is also non-MEN familial MTC. C cell hyperplasia and Ret transformation are highly indicative of familial disease Diagnosis is usually made on serum Calcitonin levels or genetic screening

38. Germ line RET mutations in MEN 2 and familial MTC Several codons implicated Risk for age related progression codon dependent Codon 918 associated with poor prognosis MTC and RET proto-oncogene Germline mutations have been detected in this oncogene in all patients with MEN II a and b, and familial MTC EUROMEN study identified 207 patients form 145 families with germ line Ret mutations and showed an age-related progression from C cell hyperplasia to MTC to nodal disease. In up to 97% of patients with Men IIA, mutations are found in codons 609, 611, 618, 620, and 630 and similar changes are seen in Familial MTC. In patients with the MEN II B syndrome, almost all, if not all, mutations involve an amino acid substitution of threonine for methionine at codon (918). Somatic mutations in ret are present in up to half of patients with sporadic MTC and are almost always in codon 918. Mutations in this codon are thought to imply a poor prognosis Predictive testing of family members allows for surgery to be performed before maliganant progression Thyroidectomy and central node dissection in first year of life for highest risk group to Thyroidectomy between 5-10 in lowest risk group Germline mutations have been detected in this oncogene in all patients with MEN II a and b, and familial MTC EUROMEN study identified 207 patients form 145 families with germ line Ret mutations and showed an age-related progression from C cell hyperplasia to MTC to nodal disease. In up to 97% of patients with Men IIA, mutations are found in codons 609, 611, 618, 620, and 630 and similar changes are seen in Familial MTC. In patients with the MEN II B syndrome, almost all, if not all, mutations involve an amino acid substitution of threonine for methionine at codon (918). Somatic mutations in ret are present in up to half of patients with sporadic MTC and are almost always in codon 918. Mutations in this codon are thought to imply a poor prognosis Predictive testing of family members allows for surgery to be performed before maliganant progression Thyroidectomy and central node dissection in first year of life for highest risk group to Thyroidectomy between 5-10 in lowest risk group

39. Rarer Tumour Types Anaplastic Lymphoma Squamous CA and Sarcomas are very rare and are usually invading from surrounding tissues.

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