ظظظ/ -Dana Alrafaiah. -Amani Nofal. - MousaAlabbadi. 1 P a g e

ظظظ/ -2 -Dana Alrafaiah -Amani Nofal - MousaAlabbadi 1 P a g e

You don t need to go back to slide from 34-77 to any info. Only check the clinical picture. From the last lecture, adenomas can be functional or non- functional The old literature: nonfunctioning adenomas are more common but recent studies are finding more gonadotroph adenomas and old nonfunctional ones are now mostly FSH/LH containing adenomas. For exam purposes, the answer depends on old literature. Revision: Thyroid gland Thyroid gland is composed of a right lobe, a left lobe and an isthmus inbetween with 4 parathyroid glands located on its posterior aspect. Feedback inhibition loop: Increased serum levels of T3 and T4 will have negative feedback effect on both the pituitary gland and the hypothalamus; it will inhibit the release of TSH from the anterior pituitary and TRH from the hypothalamus. Thyroid disorders Thyroid diseases are very common, and like other endocrine glands there s hyper and hypofunction- hyperthyroidism and hypothyroidism. 2 P a g e

Inflammation Thyroiditis also occurs leading to the destruction of the gland and has types that are autoimmune(majority) and others. Enlargements are mostly Euthyroid; not associated with hyper or hypothyroidism (T3 and T4 levels are normal). An example is Diffuse and Multinodular Goiter MNG which is the most common disease of the thyroid gland and will be further discussed as we proceed. Neoplasms of the thyroid are relatively common. Recall that there are functional adenomas and non-functional adenomas, when discussing the thyroid gland the nonfunctional adenomas are the most common type. This is at least according to older literature from 10-15 years ago, recently more sensitive tests that depend on transcriptional factors and other molecules say gonadotrophic adenomas are more common now. HYPERTHYRODISIM/THYROTOXICOSIS Endocrine pathology is associated with biochemical changes that can be observed in the serum. Hyperthyroidism is hyper function of the thyroid gland leading to increased T3 and T4 levels and decreased TSH( negative feedback inhibition). TSH serum levels is the most sensitive test that indicates hyperthyroidism. Hyperthyroidism with increased levels of TSH is an indication of a TSH producing pituitary adenoma.(in this case only ) Signs and symptoms: Palpitations, tachycardia,nervousness, impaired fertility, weight loss despite eating a lot, heat intolerance (the opposite happens in hypothyroidism) and other signs and symptoms all over the body; GI tract, mood swings and the menstrual cycle etc. 3 P a g e

NOTE: at this level hyperthyroidism and thyrotoxicosis will be used interchangeably (some claim that hyperthyroidism is a subtype of thyrotoxicosis which is a clinical syndrome, however for simplification purposes they represent the same thing for us) Within the gland itself Most common causes of hyperthyroidism. Normal thyroid gland (problem is not within the gland itself) (High TSH) After a complete thyroidectomy, Hormone Replacement Therapy (HRT) should be administered to maintain normal thyroid function in its absence. A dose of 30 or 50 mg of thyroxin is given and monitored to make sure no abnormalities occur. However, if the levels increase abnormally leading to hyperthyroidism we call this condition factitious thyrotoxicosis. A dermoid/teratoma found in the ovaries of 18-19 yrs old females. A cross section of the tumour shows different types of normal tissue such as bone, hair, teeth etc. if thyroid tissue is also present then we call this teratomastrumaovarii, it produces T3 and T4 and increase their levels in the blood. 95% of such teratomas are benign. (rare but can occur) 4 P a g e

EXAMPLE: a man comes to the clinic, he is often agitated, has tachycardia, eats a lot but doesn t gain any weight. You suspect hyperthyroidism. What is the first test that you should conduct? TSH levels. (Remember it s the most sensitive test) If the TSH levels are elevated, this indicates a pituitary adenoma. You refer your patient to imaging for an MRI to examine sellaturcica and the tumor, and find out with it s a micro or a macro adenoma etc. If the TSH levels are low, you have to know the reason behind that. This can be determined by obtaining a radioactive iodine uptake scan; here we inject the blood with radioactive iodine and let some time pass, then we measure iodine levels in the blood to see if it has been up taken by the thyroid gland - high uptake or if the levels are the same- low uptake. Low uptake indicates a primary thyroid problem (problem within the gland itself; the gland cannot take iodine from the blood to synthesize its hormones due to a problem with its cells), such problems include: thyroiditis, ectopic thyroid hormone, exogenous thyroid hormone. High uptake poses another question, how is the distribution of the radioactive iodine? It could be Homogenous or nodular; Homogenous indicates Graves disease,while nodular distribution can be one of two: single or multiple areas.multiple areas indicate Toxic multinodular goiter (rare but can happen). A single area indicates Toxic adenoma. This diagram illustrates the needed work up to diagnose a patient with suspected hyperthyroidism. 5 P a g e

*note: the most common disease of thyroid is multinodular goiter (most cases are euthyroid ) rarely goiter can be associated with hyperthyroidism (toxic goiter ) NOTE: check your patients eyes when hyperthyroidism is suspected; as you will find many signs associated with it there, such as exophthalmos, wide gaze vision etc. (will be further discussed). NOTE: Another diagnostic scan is PETscan- stands for Positron Emission Tomography- which is used in staging cancer. This scan uses a radioactive sugar molecule-fludeoxyglucose (FDG). It measures its uptake by the body in addition to creating a 3D image that allows us to examine the region properly; it detects 1 cm nodules which can lead to diagnosis of papillary thyroid carcinoma. This type of scanning increases the detection of thyroid cancer and is the cause for the increased detected incidences in recent years. HYPOTHYROIDSM The biochemical formula is increased TSH levels (primary) and decreased T3 and T4 levels. Clinical presentation: In children- Cretinism. Remember that T3 and T4 are needed for mental growth in addition to physical growth, so in their absence the child would have impaired CNS and bone growth, mental retardation, short stature, coarse facial features, protruding tongue and umbilical hernia. Early detection and treatment of cretinism is extremely vital to prevent mental retardation (most importantly) in addition to all other complications. Cretinism is now supposedly gone since in most countries children are screened early on for thyroid abnormalities and parents have better awareness about signs and symptoms that indicate hypothyroidism, all leading to early detection and treatment. 6 P a g e

In adults-myxedema. Here growth is over( no mental or physical retardation), and complications include: slow physical and mental activity, cold intolerance(opposite of hyperthyroidism), overweight, low cardiac output, GI symptoms like constipation, decreased sweating, cool pale thick skin especially on the chin(opposite of pretibial myxedema). Causes of hypothyroidism: Ablation is damaged to thyroid gland For localized tumours in one lobe For treatment of squamous cell carcinoma of the tongue or larynx, that leads to damage to neck causing hypothyroidism MOST COMMON Result of end organ resistance, one of the mechanisms of endocrine dysfunction Lithium based drugs are used in treatment of psychic illnesses like mania. Currently the most common cause of hypothyroidism in noniodine deficient areas. (In the Himalayas and South America where iodine is deficient, iodinated salt is sold everywhere in order to prevent iodine deficiency, so even in those areas we find Hashimoto thyroiditis to be the most common cause of hypothyroidism). 7 P a g e

Notice how the signs and symptoms of hyper and hypothyroidsm are mostly the opposite of each other and involve all bodily functions. Clinically speaking it s not difficult to differentiate the two from each other. AUTOIMMUNE TYROID DISEASES a very common and large group that includes: Hashimoto thyroditis, Granulomatous thyroditis(de Quervain) and subacute lymphocytic thyroditis. NOTE: some do not consider Granulomatous thyroditis atrue immune disease because it s not associated with anti-thyroid antibodies. However, it is still included as some argue that it has an underlying autoimmune cause. HASHIMOTO THYRODITIS (CHRONIC LYMPHOCYTIC THYRODITIS) Most common cause of hypothyroidism in areas with no iodine deficiency (very important).initial presentation (phase) includes a transient increase in T3 and T4 levels (thyrotoxicosis) before it develops into hypothyroidism. This may lead to misdiagnosis if the patient presents to the hospital at this stage (gradual hypothyroidism, rarely initial transient Hashitoxicosis). It is also common in middle aged females (45-60 years). 8 P a g e

Basic pathogenesis: Autoimmune destruction of thyroid epithelial follicular cells -which release T3 and T4- by high anti-thyroid antibodies. People who have it are at an increased risk of developing papillary thyroid carcinoma and primary B-cell NH lymphoma (4-6 times more at risk). 3 1 2 The body s tolerance towards its own thyroid epithelial cells is maintained by memory cells that recognize those cells as normal and do not produce antibodies against them. If this tolerance is disrupted then antibodies will be produced (can be detected in the serum) and will attack thyroid cells by antibody-dependent cell-mediated cytotoxicity (1). CD4+ T cells will react with thyroid antigens and produce cytokines such as interferon ɣ (IFN-ɣ), which in turn activates macrophages resulting in thyrocyte injury(2). CD8+ cytotoxic T cells will be activated as well leading to T-cell-mediated cytotoxicity. 9 P a g e

Histologically: we can observe: 1-lymphoid inflammation: the thyroid gland is destroyed due to inflammation resulting in abnormal lymphoid follicles. 2- Atrophy of follicles. And no colloid 3- Hurthle cell change: enlarged thyroid follicular cells with large cytoplasm that appear pinkish and eosinophilic due to increased number of mitochondria. Under the microscope: Lymphocytic follicular inflammation and atrophy+ Hurthle cell change. SUBACUTE GRANULOMATOUS (DE Quervian) THYROIDITIS Granulomatous inflammation (thyroiditis), the onset of which is acute and characterized by neck pain and results in a firm thyroid. Remember: granulomatous inflammation is associated with chronic inflammation that includes epithelioidhistocytes, reactive T cells and plasma cells. It could be necrotizing(tb) or non-necrotizing (sarcidosis). Some trace de quervian thyroiditis to viral causes; they claim the presence of coxsackievirus or EPV antibodies in the serum but nothing is proved yet. De Quervian is also more common in females aged 30-50 years and has an initial transient thyrotoxicosis phase before developing into hypothyroidism (same as in Hashimoto thyroiditis). This inflammation is a self-limiting disease that resolves on its own within 6-8 weeks, it is usually diagnosed clinically and patients are not referred to pathologists. 10 P a g e

OTHER LESS COMMON THYROIDITIS: 1. Subacute lymphocytic thyroiditis: a chronic lymphoid inflammation with no granulomas or Hurthle cell change. Common in middle aged women who are post-partum. Like the previous two inflammation, has an initial transient thyrotoxicosis then gradual hypothyroidism. It s an autoimmune disease where circulating anti-bodies are found. The gland s size is normal. 2. Riedel thyroditis: specific type of inflammation characterized by IgG4 mediated destruction of the gland with severe fibrosis to the point where the thyroid becomes stony-hard. IgG4 can cause the same destruction in many organs. Fibrosis is mediated by Transforming Growth Factor-β (TGF-β). GRAVES DISEASE (TOXIC DIFFUSE GOITER) Remember: toxic indicates thyrotoxicosis (hyperthyroidism) due to high homogeneous uptake. This disease was described by Robert Graves in 1835. It is the most common cause of endogenous hyperthyroidism and includes the triad of: thyrotoxicosis(with its associated signs and symptoms), opthalmopathy (eye signs, like exopthalmos) and dermopathy(skin, like pretibial myxedema). *The doctor said this picture is not important* 11 P a g e

AUTOANTIBODIES OF GRAVES DISEASE: Normally T3 and T4 are released upon stimulation of the thyroid gland by TSH, which is released from the anterior pituitary. Thyroid hormones release is regulated; when their levels increase in the blood there s feedback inhibition on the release of TSH to prevent further secretion of T3 and T4. In Graves this mechanism is lost; there are antibodies that bind to TSH receptor on the thyroid continuously stimulating it and resulting in overproduction of T3 and T4 withno response to the feedback inhibition on the pituitary gland that would normally occur due to these increased levels. **autoimmune,hla-dr3 and CTLA-4 / women 20-40 years ** sometimes TSH- binding inhibitor Ig, may cause hypothyroidism. Histologically: Exopthalmos Observe that the follicles are surrounded by a white columnar cells that resorb the colloid, the colloid is pale with scalloped margin 12 P a g e

Pretibial Myxedema: subcutaneous deposition of fat tissue on the shin. DIFFUSE AND MULTINODULAR GOITER This is a very common disease and it is the most common disease of the thyroid gland. It is usually euthyroid; the goiter is not associated with hyper or hypothyroidism, however there are rare cases in which we have goitrous hypothyroidism. The underlying pathogenesis in not yet understood; some claim there s hormonal imbalance with continuous stimulation and inhibition of the gland causing it to enlarge and shrink throught the years, leading to hyperplasia, hypertrophy and elevated TSH levels. This disease is more common in females, and can be endemic-more prevalent in certain geographical regions or sporadic. It starts initially diffused then becomes multinodular, however it usually is detected in the nodular phase. The goiter will enlarge and cause pressure on the surrounding tissue leading to difficulty in swallowing, breathing, pain and spontaneous hemorrhage(mass and cosmetic effect). In certain rare cases, one or two of the nodules will release T3 and T4 increasing their levels and leading to toxic MNG also known as Plummer syndrome. Clinical features: Middle aged female with multiple masses. 13 P a g e

Note the fibrosis along with the nodules. Under the microscope: variable size follicles. Thyroid gland after resection: note the right and left lobe, the isthmus and the nodules. THYROID NEOPLASMS Benign neoplasms are much more common the malignant ones. Most of those benign neoplasms are non-functional adenomas as was mentioned before. However, risk of malignancy increases with: - Solitary nodules more than multiple nodules. - Male nodules more than female nodules. - Ages younger than 20 and older than 70 years old. - Family history and previous history of radiation. - Cold nodules much more than hot nodules. What is cold/hot nodule? 14 P a g e

In iodine uptake scan, a cold nodule has no iodine uptake(inactive), while a hot nodule uptakes iodine and has zero(less than 1%) chance of becoming malignant. NOTE: MNG is more common than benign neoplasms. FINE NEEDLE ASPIRATION Routine initial tool for evaluating thyroid neoplasms. Simple, cost effective, very accurate and is now well-standardized. If the mass is palpable then the procedure can be carried out normally, however if it is not the case is referred to a radiologist who conduct it under the guidance of ultrasounds. After the sample is obtained it is put on a slide, stained and examined under the microscope for features of follicular carcinoma for example. Recent recommendations suggest that ALL FNA procedures should be done under ultrasound s guidance. FOLLICULAR ADENOMAS NOTE: the word follicle could be associated with adenoma or carcinomas. However, the word adenoma-in the context of thyroid neoplasms- indicates only follicular adenomas as there s no such thing as papillary adenomas only papillary carcinomas. Most common adenomas are follicular adenomas. The underlying pathogenesis is driver mutations in TSH stimulation and less commonly RAS mutations, leading to autonomous adenoma. Follicular adenomas come solitary, they are well-circumscribed within an intact thick capsules that has no infiltrations in it or vascular invasion. Bland cells or Hurthle cells may be present and in that case it is called Hurthle cell adenoma. Occasional atypia can be seen as well. The aforementioned intact capsule is the main feature through which we distinguish between follicular adenomas and follicular carcinomas(carcinomas have both capsular and vascular invasion). 15 P a g e

Normal compressed resected lobe. Capsule (note that there s no infiltration). Tumor tissue Hurthle cell adenoma Remember Hurthle cells are large cells with pinkish cytoplasm due to increased number of mitochondria Note: some people claim that hurthle cell carcinoma is more dangerous than follicular carcinoma. THYROID MALIGNANCIES Common but not aggressive, they generally have good prognosis even in the presence of lymph node metastasis. They re more common in females and risk factors include: ionizing radiation (Chernobyl 1986) and iodine deficiency. Primary malignancies of the thyroid gland: 1- Papillary carcinoma: represent 75-85% of thyroid malignancies. Metastasizes to cervical lymph nodes. Treatment of this carcinoma includes total thyroidectomy and lymph node dissection on right and left side of the neck.(note: remember there s no papillary adenoma). 2- Follicular carcinoma: 5-15% of all malignancies. Metastasizes through the hematogenous route to the bones and the lungs. 3- Anaplastic carcinoma: one of the most aggressive human cancers, patients live up to only one year after diagnosis. <5% 16 P a g e

4- Medullary carcinoma: not very common(5%), tumor arises in parafollicular cells that produce calcitonin. May be a part of Multiple EndocrineNeoplasia syndrome type2 (MEN2). 5- Lymphomas: remember patients with Hashimoto thyroiditis have an increased risk of developing Papillary Thyroid Carcinoma(PTC) and B-cell non Hodgkin lymphoma. In recent years studies began on what is the underlying genetic abnormalities resulting in malignancies, it was found that RET/PTC and BRAF are linked to papillary carcinoma while RAS is linked to follicular and anaplastic carcinomas. This can help in determining the best candidates for thyroidectomies and aids in avoiding unnecessary surgeries which will reduce costs and possible complications. PAPILLARY THYROID CARINOMA The most common thyroid carcinoma, relatively inactive (indolent). Has good prognosis with 95% 10 years survival case, even in the presence of lymph node metastasis(50% of PTC have lymphoid metastasis at the time of presentation, which is why when thyroidectomy is preformed, lymph node dissection is automatically done in the same surgery). 17 P a g e

Can be uni and multifocal- the two lobes and the isthmus all have nodules. Preoperative diagnosis by FNA is accurate because since there s no papillary adenoma, once papillary features are detected that automatically indicates papillary carcinoma. There are 15 papillary features such as: papillae, psammomabodies(calcification), pseudonuclear inclusions and nuclear features (which are of great importance in diagnosis): nuclear grooves and Orphan Annie eye nuclei. Resected thyroid: firm and calcified This section shows well-formed papillae lined by empty appearing nuclei or Orphan Annie eye Orphan Annie eye nuclei Orphan Annie eye 18 P a g e

Calcifications Nuclear groove Inclusions FOLLICULAR CARCINOMA(macro follicles that lack papillary nuclear features). Solitary cold nodule that upon evaluation exposes capsular and vascular invasion; these two characteristics differentiates it from follicular adenoma. Common in women aged 40-60 years old and in iodine deficient regions. Metastasizes through the hematogenous route to the bones, lungs and liver. It doesn t metastasize to the lymph nodes which is why when follicular carcinoma is removed no lymph node dissection is carried out. 50% of patients die within 10 years. Vascular invasion 19 P a g e Capsular invasion Notice the mushrooming of the tumor tissue into the capsule and how it pierces it.

ANAPLASTIC CARCINOMA This type is rare, representing less than 5% of all thyroid malignancies. It is extremely aggressive and infiltrates the surrounding it can enlarge to the point where it suffocates the patient. It has a mortality rate of 100%. The cells are undifferentiated and can be easily distinguished using FNA. Occurs in 25% of people with previous history of a well-differentiated carcinoma-papillary or follicular carcinoma. >than 65 years. MEDULLARY CARINOMA Arises from C-cells or parafollicular cells which are neuroendocrine cells of the thyroid gland that release calcitonin, which in turn leads to decreased calcium serum levels and hypocalcemia. It can be a part of Multiple Endocrine Neoplasia syndrome type 2(MEN2)a &b, and can be sporadic(70%) and in this case patients are of older-ages 50-60 yrs or familial(30%) and patients here are of younger ages. RET receptor tyrosine kinase mutations on chromosome 10 result in medullary carcinoma. If a person is diagnosed with this type of carcinoma his/her entire family should be tested for this mutation, and those who appear to be positive have to undergo a prophylactic thyroidectomy even if no medullary carcinoma is present, because future risk remains high. Medullary carcinoma ismulticentric and contains amyloid. It is also a great mimicker; underthe microscope it can look like any tumor (plasmatic, spindle etc), so usually when you examine a tumor that doesn t look strictly papillary or follicular you always think of medullary carcinoma. This pinkish material is amyloid which is protein deposition produced by cancer cells. 20 P a g e

Sometimes you can t tell whether the cells are C-cells or follicular cells, so we stain using Immunohisto chemistry (IHC), the brown colour indicates calcitonin which conforms that this is medullary carcinoma. Diagnosis of medullary carcinoma: amyloid deposition and calcitonin. Parathyroid gland Chief cells produce PTH, the gland is controlled by free calcium levels in the blood more than by tropic hormones. Like other endocrine glands there s hypo/hyper functions and tumors, but tumors here rarely have a mass effects because the parathyroid glands themselves are very small, so even a 1 cm mass is considered massive, meaning the gland doesn t enlarge to the point where it can have a mass effect. Functions of the parathyroid glands: - Reabsorption of Ca from renaltubules. - Excretion of PO4 into urine. - Vitamin D conversion to active form. - Stimulates osteoclast activity on bone resorption. The end result is increased calcium levels in the blood. HYPERPARATHYROIDISM It can be primary, secondary and tertiary. Complications include: Osteitisfibrosacystica, Brown tumor of bone, nephrolithiasis, nephrocalcinosis and metastatic calcifications. Primary HPT is due to adenomas in 85-95% of the cases, hyperplasia in 5-10% and carcinoma in 1% of the cases. Mutations in Cyclin D1 gene on 21 P a g e

chromosome 1 or MEN1 mutations can be the underlying genetic abnormalities leading to HPT. ( go to slide 73) When calcium and PTH levels are elevated we carry out an uptake scan to see which of the 4 parathyroid glands is actively causing this, we suspect parathyroid gland abnormalities because it is known that parathyroid adenoma is one of the most common causes of hypercalcemia and hyperparathyroidism. Once the abnormal gland is identified, it is resected, and samples of the serum before and after the resection are obtained and compared to make sure the correct gland has been removed (PTH will be more sensitive that calcium). CAUSES OF Hypercalcemia. Rare Due to chronic renal failure and continuous stimulation of the gland Rare Cancer metastasizes to the bone, causing bone destruction and the release of calcium into the blood 22 P a g e

*Focus on primary and secondary HPT as tertiary HPT is more difficult to dignose* HYPOPARATHYROIDSIM 23 P a g e