Pathology Of Thyroid Diseases

Pathology of Thyroid Diseases Anatomy

Thyroid Gland Anterior surface Right, Left Lobe Connected by narrow Isthmus

Autoimmune Thyroid Diseases Hashimoto Thyroiditis Hypothyroidism

Graves Disease Hyperthyroidism

Thyroid Follicle Cuboidal epithelium Filled with Colloid Parafollicular “C” cells

Hypothalamus-Pituitary-Thyroid Axis

Clinical Features of Thyroid Pathology Hyperthyroidism Hypothyroidism Mass lesions of Thyroid Hyperthyroidism Clinical syndrome which results from exposure of body tissues to excess circulating levels of free thyroid hormones Hypermetabolic state Due to over activity of Sympathetic Nervous System Causes  Graves’ Disease (95%)  Multinodular Goiter with Toxic Nodule (Toxic nodular goiter)  Functioning Follicular Adenoma/ Carcinoma  TSH secreting Pituitary Adenoma (2°)  Germ Cell Tumour (Strauma ovarii, Choriocarcinoma)  Thyroiditis (Hashimoto Thyroiditis)  Hypothalamic Disorder (↑ TRH)

Hypothyroidism 1°  Developmental (Thyroid Dysgenesis)  Thyroid Hormone Resistance Syndrome  Post-ablative (Surgery, Radioiodine, External Radiation)  Autoimmune (Hashimoto Thyroiditis)  Iodine Deficiency  Drugs (Lithium, Iodides, p-adminosalicylic acid)  Congenital Biosynthetic Defect (Dyshormonogenetic Goiter) 2°  Hypothalamic Disorder  Pituitary Failure Infant/ Early Childhood (Cretinism) Impaired development of skeletal system, CNS, intellectual growth  Mental Retardation  Short Stature  Coarse Facial Features  Protruding Tongue  Umbilical Hernia Older Child/ Adult (Myoedema) Slowing of Physical, Mental Activity Serum TSH ↑ Sensitive Screening Test

Thyroiditis Inflammation of Thyroid Gland Infectious, Non-Infectious Hashimoto Thyroiditis (Chronic Lymphocytic Thyroiditis) Subacute Granulomatous Thyroiditis (DeQuervain Thyroiditis) Subacute Lymphocytic Thyroiditis

Congenital Anomalies of Thyroid Gland Normal Development Evagination of developing pharyngeal epithelium that descends as part of Thyroglossal duct from Foramen Cecum (at base of tongue) → Anterior Neck Ectopic Thyroid Tissue Lingual Thyroid (base of tongue) Sites Abnormally High in Neck Substernal Thyroid Gland due to Excessive Descend Thyroglossal duct or cyst Congenital anomalies Persistent sinus remain as a vestigial remnant of tubular development of thyroid gland Part of tube may be obliterated leaving small segments to form cysts (filled with mucinous secretion) Site  Midline of Neck  Anterior to Trachea  Base of Tongue → Normal Position of Thyroid Gland

Sites of Thyroglossal Duct/ Cyst

Thyroglossal Cyst

Hashimoto Thyroiditis (Chronic Lymphocytic Thyroiditis) Most common cause of Hypothyroidism 45 – 60 y/o Female ↑ Autoimmune Destruction of Thyroid Gland CD8 Cytotoxic T-cell mediated Cell Death Cytokine mediated Cell Death Binding of Antithyroid Antibodies followed by ADCC HLA-DR5 HLA-DR3 Pathogenesis

Gross Diffusely Enlarged Thyroid Gland Pale, Gray-Tan, Firm, Nodular (somewhat) Atrophic Gland after Fibrosis Histology Extensive Infiltration of Parenchyma by Mononuclear Inflammatory Infiltrate, Fibrosis  Lymphocytes  Plasma Cells  Well Developed Germinal Centers Thyroid Follicles  Atrophic  Lined by Hurthle cells (Eosinophilic granular cytoplasm) Interstitial Connective Tissue ↑, Abundant

Subacute Granulomatous Thyroiditis (DeQuervain Thyroiditis) Caused by Viral Infection Post-Viral Inflammatory Process Viral Initiated Antigenic Stimulation to CD8 T cells Result Follicular Destruction Enlargement  Unilateral  Bilateral Gross Yellow-White Rubbery Histology Aggregation of  Lymphocyte  Histiocyte  Plasma Cells Resulting Granuloma

Graves Disease (Toxic Goiter) Common cause of Endogenous Hyperthyroidism Diffuse Hypertrophy, Hyperplasia of Thyroid Follicular Epithelial Cells Female ↑ 20 – 40 y/o Genetic Factors  HLA-B8  HLA-DR3 Autoimmune Thyroid Disease IgG Antibodies against TSH-Receptor on Thyroid Follicular Cells  Thyroid Stimulating Ig  Thyroid Growth-Stimulating Ig  TSH-Binding Inhibitor Ig Clinical Manifestation Diffuse Enlargement of Thyroid Gland Hyperthyroidism Infiltrative Ophthalmopathy with resultant Exopthalmos Localized, Infiltrative Dermopathy Pathogenesis

Subacute Granulomatous Thyroiditis Foreign body Giant Cells (GC) Destruction of Thyroid Follicles

Subacute Granulomatous Thyroiditis

Hashimoto’s Thyroiditis Symmetrically Atrophic Thyroid Gland

Graves Disease Diffuse Hyperplasia Uniform, Diffuse Enlargement Red Meaty appearance

Hashimoto’s Thyroiditis Lymphoid Follicle (LF) Atrophic Thyroid Follicle (TF)

Hashimoto’s Thyroiditis Thyroid Parenchyma is replaced by dense lymphocytic infiltrate Lymphoid Follicles with Germinal Centers

Gross Diffusely Enlarge Gland with Soft, Meaty Appearance resembling normal muscle Histology Crowding of Follicular Epithelium Small Papillae projecting into Lumen, Encroach on Colloid Papillae Colloid Lack of Pale Fibrovascular cores Scalloped Margin

Hashimoto’s Thyroiditis Lymphoid Follicle (LF) Thyroid Follicles (TF)

Graves Disease Follicles are lined by Crowded, Tall, Columnar Epithelium Cells activity resorb the Colloid (C) in centers of follicles Resulting Scalloped appearance of the edges of Colloid

Graves Disease Tall columnar thyroid epithelium lines the hyperplastic infoldings into colloid Vacuoles are cleared in the colloid next to epithelium Scalloping out of Colloid

Diffuse, Multinodular Goiters Due to Impaired Synthesis of Thyroid Hormone mainly caused by Dietary Iodine Deficiency Compensatory ↑ of TSH Hypertrophy, Hyperplasia of Follicular cells to overcome Hormonal Deficiency Euthyroid Metabolic State Diffuse Nontoxic (Simple) Goiter (Diffuse Hyperplasia) Diffusely Enlarged gland without nodularity Goiters Colloid Endemic Sporadic Enlarged Follicles filled Geographical areas ↓ Frequent with Colloid where Soil, H2O, Food Female ↑ supply with ↓ Iodine Puberty, Young Female Goitrogens play role Cassava Cabbage Cauliflower Brussels Sprouts 2 Phases Hyperplastic Colloid Involution Diffuse, Symmetrically Enlarge Brown, Glassy, Translucent Follicles lined by crowded columnar Follicular Epithelium is cells which may Flattened, Cuboidal Pile Up, form Projections Colloid is Abundant

Multinodular Goitre (MNG) (Nodular Hyperplasia) Recurrent episodes of Hyperplasia, Involution combined to produce Irregular Enlargement of Thyroid Rupture of Follicle, Hemorrhages – Fibrosis Most Extreme Thyroid Enlargement Long standing simple goiters can lead to MNG Mistaken for Neoplasm Mass Effect  Cosmetic effects  Airway obstruction  Dysphagia  Compression of Large Vessels in Neck, Upper Thorax Gross Multilobulated, Asymmetrically Enlarged glands Brown, Gelatinous colloid containing  Irregular Nodules  Haemorrhage  Fibrosis  Calcification  Cystic changes Histology Colloid-rich Follicles lined by Flattened, Inactive Epithelium Areas of Follicular Hypertrophy, Hyperplasia with Degenerative Changes  Haemorrhages  Fibrosis  Calcification  Cystic changes

Diffuse Goiter Mass Effect of Enlarged Thyroid Gland

Multinodular Goitre Nodular Enlargement of Thyroid gland Irregular Nodularity on surface

Multinodular Goitre Asymmetrical Enlargement Irregular, Nodular Surface Areas of Haemorrhages Cystic Degeneration Fibrosis

Nodular Hyperplasia with Benign Papillary formations protruding into cystically dilated follicle

Multinodular Goitre Multiple Nodules Areas of Cystic Degeneration, Haemorrhage, Fibrosis, Calcification

Multinodular Goitre (Colloid Goitre) Varying sizes of Colloid filled distended follicles Separated by Fibrous Septae (FS) Epithelial Linings are flat

Nodular Hyperplasia Sanderson’s Polster

Neoplasms of Thyroid Gland Follicular Adenoma Gross Solitary, Spherical, Encapsulated, Well-demarcated from surrounding parenchyma Average size – 3cm in diameter Bulging, Compress Adjacent Thyroid, Gray-White → Brown

Histology Constituent cells form uniform-appearing Follicles containing Colloid Epithelial cells vary in Cell, Nuclear Morphology (Hurthle cell adenoma, Clear cell carcinoma, Signet ring cell adenoma) Hallmark Intact, Well formed capsule encircling tumor (distinguish from follicular carcinoma)

Follicular Adenoma Focal Haemorrhagic area Adenoma of Thyroid Well circumscribed tumour Sharp line of demarcation between tumour, adjacent thyroid tissue (arrow)

Follicular Adenoma Solitary, Well-Circumscribed Nodule Surrounded by a Thin White Capsule Follicular Adenoma (FA) Well-differentiated neoplasm (closely resemble normal tissue)

Follicular Adenoma Intact Fibrous Capsule

Carcinoma of Thyroid Gland Papillary Carcinoma (75 – 85%) Follicular Carcinoma (10 – 20%) Medullary Carcinoma (5%) Genetic Factors Genetic Factors Genetic Factors Most Inherited Mutations in RAS oncogenes Mutation RET, NTRK1, BRAF oncogene Associated with (most common – NRAS) RAS Mutation MEN-2, RET protooncogene mutation Environmental Factors st Exposure to Ionizing Radiation (particularly during 1 2 decades of life) (especially Head, Neck region) Long-standing Multinodular Goiter, Pre-existing Hashimoto Thyroiditis Most common Thyroid Cancer Single Nodule Neuroendocrine Tumour 20 – 40 y/o Well circumscribed or Infiltrative Derived from Parafollicular C Cells Associated with (Majority of Ca) Difficult to distinguish from Secrete Calcitonin Previous Ionizing Radiation Follicular Adenoma by gross examination (role in Diagnosis, Post-operative Follow up) Gross Larger lesions – penetrate Capsule May elaborate other polypeptide hormone Solitary or Multifocal  Somatostatin Uniform cells forming small follicles containing Granular, discernible Papillary Foci Colloid, sometimes lined by Hurthle cells  Serotonin Foci of Calcification Capsular and/or Vascular Invasion  VIP Lymphatic Invasion (uncommon) 80% - Sporadic 20% - Association with MEN 2A, 2B Gross Solitary or Multiple Lesions Involving Both Lobes Firm, Pale, Gray→Tan, Infiltrative Larger Lesion Asymmetrically enlarged  Foci of Haemorrhage Cystic Tumour  Necrosis Contain Papillary Structures  Extend through Capsule Histology Polygonal → Spindle shapped cells Invasive Invasive Arranged in Nests, Trabeculae, Follicles Follicular Carcinoma Follicular Carcinoma Acellular Amyloid Deposits Vascular Invasion Capsular Invasion (derived from altered calcitonin molecules) Tan-White Calcitonin, Amyloid (demonstrated by IHC) Solid, Infiltrative Tumour EM – Membrane bound electron dense Ill-Defined margins in Right Lobe granules within cytoplasm of cells Histology (Hallmarks) Branching papillae (Fibrovascular stalk covered by single → multiple layers of cuboidal epithelial cells) Diagnostic Nuclear Features  Clear or Empty (Ground Glass, Orphan Annie Eye Nuclei)  Intranuclear Inclusion Follicular Carcinoma Intranuclear Grooves Capsular Invasion Psammoma Bodies (Concentrically lamellated calcified structures Medullary Carcinoma within cores of papillae) Tumour with Amyloid Foci Lymphatic Invasion

Follicular Carcinoma Metastatic Invasion into Bone Papillary Carcinoma of Thyroid Medullary Carcinoma Solid Pattern of Growth Deposition of Amyloid

Papillary Carcinoma of Thyroid Fibrovascular cores (FVC) lined by epithelium having clear nuclei Small psammoma body (arrow)

Medullary Carcinoma (Congo Red Stain) Amyloid Stroma

Medullary Carcinoma (Polarised microsp.) Amyloid

Papillary Carcinoma of Thyroid Nuclear Grooving (arrows)

Papillary Carcinoma of Thyroid Nuclear Inclusion (arrow)

Papillary Carcinoma of Thyroid Psammoma Bodies (Fine Needle Aspiration Smear)

Medullary Carcinoma +ve Immunohistochemical Stain Calcitonin

Anaplastic Carcinoma (< 5%) Genetic Factors Inactivating Point Mutation in p53 Tumour Suppression Gene

Undifferentiated Tumour of Thyroid Follicular epithelium Aggressive Tumour, Rapidly Growing Most Cases Spread beyond Thyroid Capsule into adjacent neck structure or metastasize distantly Older Patients (65 y/o) ↑ Morphology Highly Anaplastic cells  Large, Polymorphic Giant Cells  Spindle cells with Sarcomatous appearance  Mixed Spindle cells, Giant cells  Small cells

Anaplastic Carcinoma Giant Cell Type

Anaplastic Carcinoma Spindle Cell Type