Thyroid Pathology Flashcards
Where does the thyroid gland originate from?
Develops from evagination of the pharyngeal epithelium = descends from foramen caecum to normal location along thyroglossal duct
What are some embryological abnormalities of the thyroid gland?
Failure to descend = lingual thyroid
Excessive descent = retrosternal location in mediastinum
Thyroglossal duct cyst
What is the thyroid composed of?
Follicles = each follicle is surrounded by flat to cuboidal follicular epithelial cells
What is at the centre of each follicle in the thyroid?
Dense amorphic pink material containing thyroglobulin
What is the other name for C cells?
Parafollicular cells = slightly larger cells with clearer cytoplasm, secrete calcitonin (results in lower serum Ca)
Where does TSH bind to on the thyroid?
To TSH receptor on the surface of thyroid epithelial cells
What does activation of G-proteins cause?
Conversion of GTP to GDP and production of cAMP
What does cAMP increase the production of?
T3 and T4 = both circulate in free and bound forms
What does the binding of T3 and T4 to the receptors on target cells cause?
Complex translocates to nucleus and binds to thyroid response elements on target genes = stimulates transcription of these genes (increases BMR)
What are some features of autoimmune thyroiditis?
Increased incidence in family members, concordance rate high in monozygotic twins, susceptibility associated with HLA haplotype, linked to other autoimmune things
What are some polymorphisms of immune regulation associated genes that cause autoimmune thyroiditis?
CTLA-4 = negative regulator of T cell responses PTPN-22 = inhibits T cell function
What kind of polymorphisms in CTLA-4 are linked with autoimmune diseases?
Polymorphisms that cause reduced protein level or function
What do they symptoms and signs of thyrotoxicosis occur as a result of?
Excess T3 and T4
What is the main cause of thyrotoxicosis?
Hyperthyroidism = 85% due to Grave’s disease, hyperfunctioning nodules, adenomas, carcinomas, TSH secreting pituitary adenoma (rare)
What are other causes of thyrotoxicosis?
Thyroiditis, ectopic production (struma ovarii), factitious (exogenous intake)
Who gets Grave’s disease?
10 times more common in women, affects those most often aged 20-40
What is Grave’s disease?
Autoimmune disorder = antibodies to TSH receptor, thyroid peroxisomes and thyroglobulin
What are some anti-TSH receptor antibodies linked with Grave’s disease?
Thyroid stimulating immunoglobulin = relatively specific
Thyroid growth stimulating immunoglobulin
TSH binding inhibitor immunoglobulin = may explain episodes of hypofunction
What is the triad of features that Grave’s disease presents with?
Hyperthyroidism with diffuse enlargement of the thyroid, eye changes (exophthalmos), pretibial myxoedema
What causes the eye changes in Grave’s disease?
Fibroblasts (etc) expressing TSH receptors
What causes the symptoms and sings of hypothyroidism?
Low levels of T3 and T4
What are some causes of hypothyroidism?
Most causes due to Hashimoto’s thyroiditis
Iodine deficiency, drugs, post therapy, congenital abnormalities, inborn errors of metabolism
What are some rare causes of hypothyroidism?
Secondary (pituitary) and tertiary (hypothalamus) pathology
What is Hashimoto’s thyroiditis?
Gradual failure of thyroid function = autoimmune destruction of thyroid tissue
Who gets Hashimoto’s thyroiditis?
10-20 times more common in women, aged 45-60, associated with HLA-DR3 and DR5, polymorphisms in CTLA-4 and PTPN-22 may be present
What are some anti-thyroid antibodies involved in Hashimoto’s thyroiditis?
Anti-thyroglobulin and anti-peroxidase = cause antibody cell mediated cytotoxicity when bound
What are some immune cells involved in Hashimoto’s thyroiditis?
CD8 positive cells may mediate destruction of thyroid epithelium
How does cytokine mediated cell death occur in Hashimoto’s thyroiditis?
Gamma interferon from T cell activation recruits macrophages that may damage thyroid follicles
What may precede Hashimoto’s thyroiditis?
Transient hyperfunction (Hashitoxicosis)
What does Hashimoto’s thyroiditis put patients at risk of?
Other autoimmune diseases and development of B cell NHL in the affected gland
What is a goitre?
Any enlargement of the thyroid gland
What may cause a goitre to develop?
Lack of dietary iodine or lack of bio-availability of iodine
How does reduced T3/T4 production cause goitres?
Causes rise in TSH, stimulating gland enlargement = may maintain euthyroid state, if compensation fails then patients have goitrous hypothyroidism
What are the types of diffuse goitres?
Endemic = >10% of population affected
Sporadic
What are some features of sporadic diffuse goitres?
More common in women, occur in puberty and young adults, most causes have unknown cause, may be due to ingestion of substances limiting T3/T4 production or inborn errors of metabolism (dyshormonogenesis)
What are some features of diffuse goitres?
Usually euthyroid = present with mass effects
T3 and T4 normal but TSH high
In children dyshormonogenesis may cause cretinism
How do multinodular goitres arise from long standing simple goitres?
Recurrent hyperplasia and involution = enlargement can be impressive, differential diagnosis is thyroid neoplasm
How do multinodular goitres arise?
Variations of response in follicular cells to external stimuli = mutations in TSH signalling pathway
What can multinodular goitres cause?
Follicle rupture, haemorrhage, scarring, calcification
What are the mass effects of multinodular goitres?
Cosmetic, airway obstruction, dysphagia, vessel compression
What may develop form multinodular goitres?
Autonomous nodules = may cause hyperthyroid, occur in 10% after ten years, low risk of malignancy
What are adenomas?
Discrete solitary swelling encapsulated by surrounding collagen cuff = composed of neoplastic thyroid follicles
What can adenomas be confused with?
Dominant nodule in multinodular goitre or follicular carcinoma
What are some features of adenomas?
Usually non-functional
Can secrete thyroid hormones = cause thyrotoxicosis (TSH independent)
What mutations cause adenomas?
<20% have mutant ras or PIK3CA
Mutations of TSHR signalling pathway in functional adenomas (10-75%)
What are some features of carcinomas?
1.5% of all cancers, can affect any age group, more common in females (except childhood and elderly)
Where are most carcinomas derived from?
Most are well differentiated and are derived from follicular epithelium (medullary from C cells)
What are the types of thyroid carcinomas, from most to least common?
Papillary, follicular, medullary, anaplastic
What are some environmental associations of carcinomas?
Ionising radiation = papillary
Iodine deficiency = follicular
What are some genetic features of papillary carcinomas?
Activate MAP kinase pathway = rearrangements of RET or NTKR1, mutations of ras, activating point mutation in BRAF
What mutations cause follicular carcinomas?
Mutations in PI3K or AKT pathways, mutations in ras family (usually N-ras), translocation involving Pax8 and PPAR gamma
What are some additional mutations that cause anaplastic carcinomas?
p53 and beta catenin mutations
Abnormalities in what cause medullary carcinomas?
MEN2 = germline RET mutations
What are papillary carcinomas?
Usually solitary nodule = can be multifocal, often cystic, may be calcified (psammoma bodies)
How do papillary carcinomas sometimes present?
Lymph node metastases = if thyroid tissue or psammomas body in lymph node then search for occult papillary carcinoma
What are local effects of papillary carcinomas that suggest locally aggressive disease?
Hoarseness, dysphagia, cough, dyspnoea
Can papillary carcinomas spread haematogenously?
Yes - rarely spread this way, but when they do it is most often to the lungs
What is the prognosis of papillary cancer?
Overall good survival = 95% at 10 years
Worse prognosis with age >40, extra-thyroid extension and distant metastases
How do follicular carcinomas present?
More common in females, patient in 40s-50s, usually single nodule = slowly enlarging, painless, non-functional
How do follicular carcinomas spread?
Rarely lymphatic spread
Most commonly spread haematogenously to the bone, lungs and liver
What kind of growth pattern do follicular carcinomas have?
Invasive
What are some features of a widely invasive follicular carcinoma?
More solid and less follicular architecture, more mitotic activity
What are some features of a minimally invasive follicular carcinoma?
Follicular architecture (well-differentiated), may have part of surrounding capsule, difficult to distinguish from follicular adenoma (need capsular/vascular invasion)
What does the prognosis of follicular carcinoma depend on?
Extent on invasion and stage at presentation:
High stage at presentation = 50% mortality at 10 years
Minimally invasive lesions = >90% survival at 10 years
What are medullary thyroid carcinomas (MTC)?
Relatively rare tumour = derived from C cells, can secret calcitonin
What are the types of medullary thyroid carcinomas?
Sporadic = 70%, solitary nodule
Associated with Multiple Endocrine Neoplasia = MEN IIA or IIB)
Familial medullary carcinoma = bilateral/multicentric
Who gets medullary thyroid carcinomas?
MEN cases are in very young patients
Sporadic and familial cases are seen in adults aged 40s-50s
What are some features of medullary thyroid carcinomas?
Composed of spindle or polygonal cells arranged in nests, trabeculae or follicles, have associated amyloid deposition
How do medullary thyroid carcinomas present?
Neck mass with local effects = dysphagia, hoarseness, airway compromise
Paraneoplastic syndrome = diarrhoea (VIP production), Cushing’s (ACTH production)
What is the prognosis of medullary thyroid carcinomas?
Treated with total thyroidectomy = local recurrence in 35%, 5 year survival is 70-80%
What are some good prognostic indicators for medullary thyroid carcinomas?
Young, female, familial type, tumour size, confined to gland
What are some indicators of aggressive behaviour in medullary thyroid carcinomas?
Necrosis, many mitoses and small cell morphology
What are some features of anaplastic carcinomas?
Undifferentiated and aggressive tumours, usually older patients, rapid growth and involvement of neck structures and death
Having a history of what can predispose patients to anaplastic carcinomas?
Differentiated thyroid cancer
Who are samples taken for thyroid cytology?
Aspirates are taken and interpreted without architecture = provides a minimally invasive assessment of the likelihood of malignancy
What is the grading of thyroid tissue?
Thy 1 = insufficient/uninterpretable Thy 2 = benign Thy 3 = atypia probably benign/equivocal Thy 4 = atypia suspicious of malignancy Thy 5 = malignant
What type of carcinoma can be well assessed using the grading of thyroid tissue?
Papillary carcinomas
Why are all follicular lesions given a Thy 3 grading?
Features can be difficult to interpret as relationship to capsule isn’t assessed
What are some features of the parathyroid gland?
Usually four glands, but 10% only have two or three
Variable position
What cell makes up the parathyroid glands?
Chief cells = secret PTH, act on calcium homeostasis, round cells with moderate cytoplasm and round central nuclei
What cells support the chief cells in the parathyroid glands?
Oxyphil cells = slightly larger cells with acidophilic cytoplasm
What is the most common cause of hyperparathyroidism?
Small adenomas
Hyperplasia is responsible for 5-10% and carcinomas for about 1%
What can hyperplasia of the parathyroid glands be associated with?
Both MEN I and MEN IIa
What are some features of hyperparathyroidism caused be adenomas?
Single gland involved (weighing 0.5-5g), other glands atrophic, microscopically resembles normal parathyroid, may see fibrous connective tissue capsule with adjacent rim of compressed parathyroid tissue
What occurs in hyperparathyroidism caused by hyperplasia?
Typically involves all glands = collectively weigh rarely >1.0g
What occurs in hyperparathyroidism caused by secondary causes?
Secondary = chronic hypocalcaemia causes compensatory over-activity (renal failure, low Ca intake, vitamin D deficiency)
What occurs in tertiary hyperparathyroidism?
Parathyroid activity becomes autonomous = associated with hypercalcaemia
What are some bone and GI complications of hyperparathyroidism?
Bone disease = pain, fracture, osteoporosis, osteitis fibrosa cystica
GI = nausea, constipation, peptic ulcer, pancreatitis, gallstones
What are some CNS and CVS complications of hyperparathyroidism?
CNS = depression, lethargy, seizures CVS = calcification of aortic and mitral valves
What are some other complications of hyperparathyroidism?
Nephrolithiasis = renal stones and complications Neuromuscular = weakness, fatigue
What are some causes of hypoparathyroidism?
Very rare = usually post-op, rarely congenital absence (DiGeorge syndrome), familial variant exisits
What are some associations of familial hypoparathyroidism?
Primary adrenal insufficiency and mucocutaneous candidiasis
How can hypoparathyroidism alter the mental state of a patient?
Emotional lability, anxiety, depression, confusion, psychosis
What is tetany?
Caused by hypoparathyroidism = neuromuscular irritability (spasms), confirmed by Chvostek’s and Trousseau’s signs
How can hypoparathyroidism affect the heart and the eyes?
Prolongation of the OT interval on ECG
Calcification of lens and cataract formation in eyes
When can dental abnormalities occur due to hypoparathyroidism?
If there was hypocalcaemia during development
What are some complications of hypoparathyroidism?
Basal ganglia calcification, Parkinson’s raised ICP, papilloedema
