PATHOLOGY OF ENDOCRINE SYSTEM THYROID GLAND PARATHYROID GLANDS

PATHOLOGY OF ENDOCRINE SYSTEM THYROID GLAND PARATHYROID GLANDS DR. BUSHRA ALTARAWNEH, MD ANATOMICAL PATHOLOGY MUTAH UNIVERSITY SCHOOL OF MEDICINE- DEPARTMENT OF LABORATORY MEDICINE & PATHOLOGY ENDOCRINE SYSTEM LECTURES 2021

NODULES IN THE THYROID : • Nodules in thyroid may be multiple or solitary • Any solitary nodule in the thyroid has to be investigated as some are neoplastic. Investigations include FNA , Radioactive image technique, Ultrasound, & (T 4, T 3 & TSH ) levels ü HOT nodule takes up radioactive substance ( functional) ü COLD nodule does not it take up ( nonfunctional )

GENERAL RULES OF NODULES IN THE THYROID : 1 - Solitary nodule is MORE likely to be NEOPLASTIC than multiple 2 - Hot nodules are more likely to be BENIGN 3 - Not every cold nodule is malignant. Many are nonfuctioning adenomas, or colloid cysts , nodules of nodular goitre…. etc Up to 10% of cold nodules prove to be malignant. 4 - Nodules in younger patients are more likely to be NEOPLASTIC 5 - Nodules in males are more likely to be NEOPLASTIC. 6 - History of previous radiation to the neck is associate with increased risk of malignancy

NEOPLASMS OF THE THYROID : ADENOMAS: Usually single. Well defined capsule Commonest is follicular± Hurthle cell change May be toxic Size 1 - 10 cm. Variable colour

PATHOGENESIS : • The TSH receptor signaling pathway plays an important role in the pathogenesis of toxic adenomas. • Activating somatic mutation in TSH receptor is identified leading to overproduction of c. AMP • 20% have point mutation in RAS oncogene, PIK 3 CA, or PAX 8/PPARG fusion gene.

MACROSCOPIC PICTURE 1 - Uniform follicles , lined by cuboidal epithelial cells. 2 - Focal nuclear pleomorphism, nucleoli …. ( Endocrine atypia ) 3 - Presence of a capsule with tumor compressing surrounding normal thyroid outside. * Integrity of capsule is important in the differentiation of adenoma from well differentiated follicular carcinoma. Capsular &/ or vascular invasion → Carcinoma * Papillary changes : is more likely to prove malignant (no papillary adenoma ).

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Adenoma with intact thick capsule © 2005 Elsevier

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Capsular invasion

CARCINOMAS OF THYROID : ü Incidence about 1 -2% of all malignancies. ü Wide age range , depending on type. ü Generally commoner in females, but in tumors occurring in children or elderly , equal incidence in both sexes. ü Most are derived from follicular cells ü Few are derived from ‘C’ cells

TYPES OF THYROID CARCINOMA : 1 - Papillary Carcinoma ( 75 - 85% ), any age, but usual type in children. 2 - Follicular Carcinoma ( 10 - 20% ), More in middle age. 3 - Medullary Carcinoma ( 5% ) age 50 -60 but younger in familial cases with MEN syndrome. 4 - Anaplastic Carcinoma ( 5% ) , old age. Presenting symptom is usually a mass , maybe incidental in a multinodular goitre especially papillary, & follicular.

GENETIC ALTERATIONS IN FOLLICULAR CELL-DERIVED MALIGNANCIES OF THE THYROID GLAND

PATHOGENESIS OF THYROID CANCER : 1 - Genetic lesions : Most tumors are sporadic. Familial is mostly Medullary CA ØPapillary Carcinoma: • Chromosomal rearrangement : Tyrosine kinase receptor gene (RET) on chr. 10 q 11 ret/PTC Activates RET & MAP signaling tyrosine kinase activity ( 1/5 of cases especially in children) § Point mutation in BRAF oncogene also activates MAP signaling pathway (1/3 -1/2)

ØFollicular Carcinoma : • RAS mutation in ½ of cases OR • Translocation PAX 8 - PPAR γ 1 fusion gene in 1/3 of cases. • Loss of PTEN. Ø Medullary Carcinoma : • RET mutation Receptor activation Ø Anaplastic Carcinoma : - Probably arising from dedifferentiation of follicular or papillary CA. ( RAS, or PIK 3 CA mutations) - This results in inactivation of P 53.

2 - Environmental Factors : § Ionizing radiation specially in first two decades. Therapeutic OR after nuclear disasters. § Most common is Papillary CA. with RET gene rearrangement §Incidence of follicular CA is more in endemic areas of iodine deficiency. 3 - Preexisting thyroid disease : § Long standing multinodular goiter → → Follicular CA § Hashimoto thyroiditis → Papillary CA and B cell lymphoma

TYPES OF THYROID CARCINOMAS

1 - PAPILLARY CARCINOMA : ü Most common malignant tumor of thyroid gland ( 70 -80 %). ü Affect female more than male. ü Cold on Scan by radioactive Iodine. ü Gross : small nodules without sharp margins ( irregular margins) , some of them appear encapsulated. ü Solitary or multifocal, solid or cystic, calcification. ü M/E: Composed of papillary architecture with fibrovascular core with cuboidal cells , less commonly may show follicles. The diagnosis is based on NUCLEAR FEATURES : Clear ( Glassy ), with grooves & inclusions. Psammoma bodies are common. ü Metastases mainly by lymphatic (ipsilateral L. N. ), sometimes from occult tumor. Hematogenous spread late ü Prognosis is GOOD ( 10 years survival more than 90 % ).

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FNA of Papillary CA (nuclear changes) © 2005 Elsevier

Psammoma body in Papillary CA

2 - FOLLICULAR CARCINOMA : ü Account for 15 % of thyroid malignancy. ü Usually cold but rarely functional ( hot ) ü Well circumscribed with prominent capsule or infiltrative, composed of follicles , sometimes of Hurthle Cells. ü In well differentiated encapsulated tumors , the diagnosis is based on CAPSULAR & VASCULAR invasion (*adenoma). ü Not all showing histological vascular invasion show metastasis. ü Metastasize usually by blood Lungs, Bone, Liver. . etc. ü Treatment by surgery Radioactive Iodine Thyroxin. ü Prognosis is not as good as papillary except in very well ü differentiated forms. ü M/E: Tumors composed of cuboidal cells forming follicles filled with colloid or solid nest , strands of less differentiated cells. ü Clinically : present as slowelly enlarged painless nodule (cold nodule)

Follicular Carcinoma © 2005 Elsevier

Capsular invasion) © 2005 Elsevier

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3 - MEDULLARY CARCINOMA: ü Account for 5 % of thyroid carcinoma. ü Arise from C cells(parafollicular cells) CALCITONIN ü 80% Sporadic , or 20 % familial MEN Syndrome. ü M/E : Composed of polygonal or spindle cells , usually with demonstrable AMYLOID in the stroma (altered calcitonin deposite). ü Calcitonin demonstrated in tumor cells. ü Level of calcitonin in serum may be useful for follow up ü Calcitonin may be raised in family members, together with demonstrable RET mutation ( Marker for early diagnosis). ü Metastases by blood stream. ü Prognosis intermediate , worse in sporadic & MEN syndromes.

Medullary CA with amyloid

Congo red for amyloid

4 - ANAPLASTIC CARCINOMA : ü Markedly infiltrative tumor , invading the neck, rapidly progressive PRESSURE SYMPTOMS. ü Large cell anaplastic or small cell variant ( undifferentiated cells ). ü Radiosensitive tumor , no surgery. ü Prognosis is extremely bad ( die within 2 years of diagnosis ), metastasis to distal site. ü Morphology : Composed of pleomorphic giant cells, spindle cells or small cell anaplastic varients, which may be confused with lymphoma. ü P 53 mutation identified , consistent with tumor progression.

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PARATHYROID GLAND

ü Derived from the third and fourth pharyngeal pouches. ü 90% of people have four glands. ü Location: mostly close to the upper or lower poles of the thyroid. ü Can be found anywhere along the line of descent of the pharyngeal pouches. ü There are two types of cells with intervening fat : - Chief & Oxyphil cells

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HYPERPARATHYROIDISM, MORPHOLOGY OF THE GLAND 41 1 -Parathyroid adenoma in 80% of cases: Gross : Well circumscribed, nodular enlargement of one gland : soft , encapsulated nodule. Usually, the rest of the gland as well as other glands are atrophic. M/E : The cells are polygonal, uniform chief cells. Nests of clear and oxyphil cells may be seen. 2 -Nodular hyperplasia in 5% of cases : (multiglandular ) There is enlargement of all glands. Microscopically there is chief cell hyperplasia usually, in a nodular or diffuse pattern. 3 -Multiple adenomas in 4%. 4 -Parathyroid carcinoma in 1%. Diagnosed only by metastases.

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HYPERPARATHYROIDISM: PATHOLOGICAL CHANGES IN OTHER ORGANS: Skeletal system: - Bone erosion ( resorption by osteoclasts) & bone restructing ( osteoblast new bone formation ) with result friagile bone , liable for fractures, bleeding , fibrosis, cysts formation and hemorrhage (brown tumor : osteitis fibrosa cystica). - Chondrocalcinosis and pseudogout may occur. Renal system: -Ca. Stones. & Nephrocalcinosis. Metastatic calicification in other organs: -Blood vessels. -Stomach -Others. 45 -Lung

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HYPERPARATHYROIDISM, CLINICAL PICTURE 50% of patients are asymptomatic. Lab diagnostic finding : Patients show Ca & PARATHORMONE levels in serum. Symptoms and signs of hypercalcemia: - GIT: Nausea, constipation, peptic ulcer. - Urinary: Polyuria, polydipsia, renal colic -CNS: Depression, drowsiness. -Musckeloskeletal: Muscle weakness, bone pain. Commonest cause of hypercalcemia is wide spread (painfull bone, renal stone, abdominal groan, mental moan) 47 metastases to bone.

SECONDARY HYPERPARATHYROIDISM : Occur in any condition associated with chronic hypocalcemia, mostly chronic renal failure. RF phosphate excretion s. phosphate: depress Ca PTH lab finding : include PTH , Ca , s. phosphate. Morphology: -The glands are hyperplastic, similar to those of primary cases. -Renal osteodystrophy. Tertiary Hyperparathyroidis indicates extreme activity of the parathyroid autonomous (needs surgery ). 48 -Bone changes and metastatic calcifications may be seen.

HYPOPARATHYROIDISM : ONE CAUSE OF HYPOCALCEMIA. 49 CAUSES: 1. Congenital absence ( aplasia : Di. George syndrome). 2. Damage to the gland or its vessels during thyroid surgery ( surgical ablation ). 3. Idiopathic, autoimmune disease. 4. Pseudohypoparathyroidism, tissue resistance to PTH. Clinical features: (Chvostek or trosseau signs ). Tetany, convulsion, neuromuscular irritability ( Ca). Mucocutaneous candidiasis ( defect in T cell function ? ) Diagnostic lab finding : Ca, PTH, s. phosphate. Treatment : of all type of hypothyroidism by supplement of diet with calcium & vitamin D.

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