Discussion on the different diseases of the Thyroid

1. Lecturer: Mark Lester Dalanon, MD
Pathology of the Endocrine
System

2. Course Outline
• Pituitary Gland
• Pituitary Adenoma
• Acromegaly
• Hypopituitarism
• Thyroid Gland
• Hashimoto’s Thyroiditis
• Cretinism
• Subacute Thyroiditis (de Quervain’s)
• Riedel’s Thyroiditis
• Multinodular Goiter
• Grave’s Disease
• Thyroid Storm / Thyrotoxicosis
• Papillary Thyroid Carcinoma
• Follicular Carcinoma
• Medullary Carcinoma
• Undi
ff
erentiated or Anaplastic Carcinoma
• Parathyroid Gland
• Hyperparathyroidism (Primary, Secondary, Tertiary)
• Hypoparathyroidism
• Pseudohypoparathyroidism
• Endocrine Pancreas
• Diabetes Mellitus (Type 1 and Type 2)
• Pancreatic Neuroendocrine Tumors
• Adrenal Glands
• Hyperaldosteronism
• Addison’s Disease
• Waterhouse-Friderichsen Syndrome
• Pheochromocytoma
• Neuroblastoma
• Multiple Endocrine Neoplasia Syndrome
• Review Questions

3. Disorders of the Endocrine System
Hyperfunction Hypofunction
Hyperplasia of the Gland Congenital Defects
Hormone Producing Tumors Infections
In
fl
ammation
Autoimmune Disorders
Neoplasms
Loss of Blood Flow

4. Disorders of the Pituitary Gland

5. Pituitary Adenoma
• Prolactinoma is the most common
• Macroadenoma if the size of the tumor is >1cm
• Clinical Findings:
• Amenorrhea
• Galactorrhea
• Low Libido
• Infertility
• Bitemporal Hemianopia due to impingement of the Optic
Chiasm
• Treatment
• Dopamine Agonist which shrinks the Prolactinoma
• Bromocriptine and Cabergoline
Pituitary Adenoma on MRI Imaging

6. Acromegaly
• Excess Growth Hormone in Adults
• Gigantism is increased Growth Hormone in Children (Linear Bone Growth)
• Typically caused by Pituitary Adenoma (Somatotroph Adenoma)
• Clinical Findings:
• Large Tongue
• Deep voice
• Large Hands and Feet
• Impaired Glucose Tolerance (GH is a counter regulatory hormone of Insulin)
• Diagnosis
• Increase Serum IGF-1
• Failure to Suppress Serum GH follow Oral Glucose Test
• Pituitary Mass on MRI or CT Scan
• Treatment
• Resection
• Followed by Somatostatin Analogue (Octreotide) if not cured Signs and Symptoms

7. Cushing’s Syndrome
• Increased in CORTISOL level
• EXOGENOUS Cause:
• Used of Steroids - Primary Cause of Decrease
Adrenocorticotropic Hormone (ACTH)
• ENDOGENOUS Causes:
• Cushing's Disease (70%) - Pituitary Adenoma (Corticotroph
Adenoma)
• Ectopic ACTH (15%) - Nonpituitary tissue secreting ACTH
(e.g. Small Lung Cell Cancer and Bronchial Carcinoids)
• Adrenal (15%) - Adrenal Adenoma, Carcinoma, Nodular
Adrenal Hyperplasia
Adrenal Adenoma

8. Cushing’s Syndrome: Clinical Features

9. Negative Feedback Loop

10. Dexamethasone Suppression Test

11. Classifications of Pituitary Adenomas

12. Hypopituitarism
• Decreased secretion of ALL Pituitary Hormones
• 70% to 90% of ANTERIOR PITUITARY is destroyed before it
becomes clinically evident
• Causes:
• Nonsecreting Pituitary Adenoma
• Craniopharyngioma
• Sheehan’s Syndrome
• Empty Sella Syndrome
• Brain Injury and Hermorrhage
• Radiation
• Treatment:
• Substitution Therapy using Corticosteroids, Thyroxine,
Sex Steroids, Human Growth Hormone
•
Clinical Features in patients with Hypothyroidism

13. Hypopituitarism
• Sheehan’s Syndrome
• Ischemic infarct of the Pituitary following
Postpartum Bleeding
• Usually presents with failure to Lactate
•

14. Disorders of the Thyroid Gland

15. Hypothyroidism vs Hyperthyroidism: Signs and Symptoms
Hypothyroidism Hyperthyroidism
Cold Intolerance (Decrease Heat Production) Heat Intolerance (Increase Heat Production)
Weight Gain, Decrease in Appetite Weight Loss, Increase in Appetite
Hypoactivity, Lethargy, Fatigue, Weakness Hyperactivity
Constipation Diarrhea
Decrease Re
fl
exes Increase Re
fl
exes
Myxedema (Facial/Periorbital) Pretibial Myxedema (Grave’s Disease)
Dry, Cool Skin; Coarse, Brittle Hair Warm, Moist skin; Fine Hair
Bradycardia, Dyspnea on excretion
Chest pain, Palpitations, Arrythmias, Increased
B-Adrenergic Receptors
SPEEDING things UP
SLOWING things DOWN

16. Hypothyroidism vs Hyperthyroidism: Laboratory Findings
Hypothyroidism Hyperthyroidism
Increased TSH
(For Primary Hypothyroidism)
Decreased TSH
(For Primary Hyperthyroidism)
Decreased TSH
(For Secondary Hypothyroidism)
Increased TSH
(For Secondary Hyperthyroidism)
Decreased Free T4 Increased Free or Total T4
Increased Free or Total T3

17. Hashimoto’s Thyroiditis
• Most common cause of Hypothyroidism
• Autoimmune Disorder
• Anti-TSH (Speci
fi
c for Hashimoto’s Thyroiditis and
Graves Disease)
• Anti-Thyroid Peroxidase Antibodies
• Anti-Thyroglobulin Antibodies
• Associated with HLA-DR5 (Goitrous Form), HLA-DR3
(Atrophic Form)
• Increased risk of Non-Hodgkin’s Lymphoma
• Can cause Hyperthyroidism early in course due to rupture
of thyroid follicle releasing thyroid hormone into the
circulation
•

18. Hashimoto’s Thyroiditis
• Histology:
• Hürtle cells
• Lymphocytic in
fi
ltrates with Germinal Centers
• Clinical Findings:
• Moderately Enlarged and Non-Tender thyroid gland
•
Lymphocytic Infiltrates with Germinal Center
•
Hürthle cells
•
Gross Appearance

19. Cretinism
• Severe Fetal Hypothyroidism
• Endemic Cretinism occurs when there is prevalent
Endemic Goiter (lack of dietary Iodine)
• Sporadic Cretinism is caused by defect in T4
formation or developmental failure in thyroid
formation.
• Clinical Findings: (5 Ps)
• Pot belly
• Pu
ff
y face
• Protruding Umbilicus
• Protuberant Tongue
•
Protruding Umbilicus
Protruding Tongue
Pot belly
Puffy Face

20. Subacute Thyroiditis (de Quervain’s)
• Self limited Hypothyroidism
• Usually following a Flu-like illness or Viral
Infection
• Clinical Findings:
• Elevated ESR
• Jaw pain
• Very tender Thyroid Gland
• May have episodes of Hyperthyroidism early
in course
• Histology:
• Granulomatous In
fl
ammation
•
Multinucleated Giant Cell
Fibrosis
Normal Thyroid Follicles

21. Riedel’s Thyroiditis
• Normal Thyroid gland is replaced by
fi
brous
tissue causing Hypothyroidism
• Clinical Findings
• Fixed, Hard (Rock-like), and Painless thyroid
gland
• Histology
• Prominent In
fl
ammatory In
fi
ltrates composed
of Plasma Cells (mostly IgG-4 producing),
Lymphocytes and Macrophages aswell as
numerous Eosinophils
• Treatment
• Steroids
• Surgery if with compression symptoms
•
Microscopic Appearance
Inflammatory Infiltrates
•
Fibrosis
Gross Appearance: Cut edge is Avascular, with a characteristic white color

22. Multinodular Goiter
• Most common disease of the Thyroid
• Iodine de
fi
ciency is most common cause worldwide (U.S
most goiters are due to autoimmune thyroiditis)
• Clinical Findings
• Di
ff
use or nodular enlargement with distorted outer
surface
• Histology
• Variable sized dilated follicles with
fl
attened to
hyperplastic epithelium
• Treatment
• Thyroidectomy (very large goiters; > 80 - 100 mL)
• Radioiodine therapy
• Jod-Basedow Phenomenon
• Thyrotoxicosis due to rapid correction to Iodine
de
fi
ciency
•Physical Examination
Large Neck Goiter
•
Microscopic Appearance: Variably sized dilated follicles with flattened
hyperplastic epithelium
Dilated Thyroid Follicles
•
Gross Appearance

23. Grave’s Disease
• Autoimmune disease characterized by hyperthyroidism
• Due to circulating autoantibodies against thyrotropin
(TSH receptor)
• Disease often present in stressful situations such as
Child Birth
• Clinical Findings:
• Exophthalmus (Proptosis and Lid Retraction)
• Pretibial Myxedema (Only seen in Graves Disease)

24. Grave’s Disease
Pretibial Myxedema
Exophthalmus (Proptosis and Lid Retraction)

25. Thyroid Storm / Thyrotoxicosis
• Stress-Induced Catecholamine surge
• Seen in serious complication of Graves Disease and
other Hyperthyroid disorders
• Can lead to death due to Arrhythmia
• May have increase Alkaline Phosphatase (ALP) due to
increase Bone Turnover

26. Papillary Thyroid Carcinoma (PTC)
• Most common type of Thyroid Cancer
• BRAFV600E is the most frequent mutation
• RET or NTRK1 proto-oncogene is seen in 30%
of all PTCs
• Diagnosis is based on nuclear features
• Carries Excellent prognosis
• Histology:
• Orphan Annie Eye - Nuclear Clearing
• Psammoma Bodies - Not speci
fi
c since it
can be seen in other tumors
• Nuclear Grooves
•
Papillary Thyroid Carcinoma on Cytology

27. Papillary Thyroid Carcinoma (PTC)
Nuclear Grooves or Coffee Bean Nuclei
Orphan Annie Eye Nuclei Psammoma Bodies

28. Follicular Carcinoma
• Thyroid carcinoma with follicular di
ff
erentiation
but no papillary nuclear features
• Second most common thyroid carcinoma (6 -
10%)
• Insu
ffi
cient dietary iodine is a risk factor
• Diagnosis is based on capsular or vascular
invasion but without papillary nuclear features
• Histology:
• Trabecular or solid pattern of follicles
• Capsular invasion and/or Vascular invasion
• Follicular Adenoma - If there’s no evidence of
capsular or vascular invasion
•
Gross Appearance
Minimally Invasive
•
Microscopic Appearance
Capsular Invasion

29. Medullary Thyroid Carcinoma
• Derived from the Parafollicular “C” Cells which produces
Calcitonin
• Associated with MEN Types 2A and 2B
• Laboratory Findings:
• High serum Calcitonin and CEA levels
• Histology:
• Sheets of cells
• Amyloid Stroma
Gross Appearance
•
Microscopic Appearance
Amyloid
Tumor Cells

30. Undifferentiated or Anaplastic Carcinoma
• Rare
• Poor prognosis
• Common in Older patients
• Signs and Symptom:
• Rapidly Enlarging, Bulky Neck Mass
• Hoarseness
• Dysphagia
• Dyspnea
• Histology:
• Extensive tumor necrosis
• Marked nuclear pleomorphism
• High mitotic activity
CT Scan Image
•
Microscopic Appearance

31. Disorders of the Parathyroid

32. Hyperparathyroidism: Primary
• Usually caused by Parathyroid Adenoma
• Signs and Symptoms:
• Mnemonic: Stones, Bones, Groans and
Psychiatric Overtones
• Laboratory Findings:
• Hypercalcemia (Increase Ca in Blood)
• Hypercalciuria (Excess Ca in Urine)
• Hypophosphatemia (Decrease Phosphorus)
• Elevated Alkaline Phosphates (ALP)
Gross Appearance of Parathyroid Adenoma

33. Osteitis Fibrosa Cystica
• Complication of Primary Hyperparathyroidism
• Also called von Recklinghausen disease of bone
• Most frequently encountered in the ribs, clavicles, long bones,
pelvic girdle, craniofacial bone
• Gross Appearance:
• Cortex is thinned
• The marrow contains increased amounts of
fi
brous tissue
• Foci of Hemorrhage and Cyst Formation
Physical Finding
• CT Scan Imaging
• Gross Appearance

34. Hyperparathyroidism: Secondary
• Complication of Chronic Kidney Disease
• Less Vitamin D causes decrease GI Absorption of
Calcium leading to Hypocalcemia
• Hypocalcemia stimulate PTH release
• Laboratory Findings:
• Elevate ALP
• Hypocalcemia

35. Hyperparathyroidism: Secondary

36. Hyperparathyroidism: Tertiary
• Sequela of Secondary Hyperthyroidism
• Refractory (Autonomous) Hyperparathyroidism due to Chronic Renal Disease
• Long-standing gastrointestinal malabsorption causing prolonged hypocalcemia which leads to
parathyroid hyperplasia
• Laboratory Findings:
• Increase PTH
• Normal to Elevated Serum Calcium

37. Hypoparathyroidism
• Due to incidental surgical excision during Thyroid Surgery
• Other Causes:
• Autoimmune Disease
• DiGeorge Syndrome (Parathyroid Gland Aplasia/
Hypoplasia)
• Clinical and Laboratory Findings:
• Hypocalcemia
• Tetany - Hallmark of Hypocalcemia
• Chvostek’s Sign
• Tapping of Facial Nerve causes Facial Muscle
Contraction
• Trousseau’s Sign
• Spasm of the Carpal Muscles
Chvostek’s Sign
Trousseau’s Sign

38. Pseudohypoparathyroidism
• Also known as Albright Hereditary
Osteodystrophy
• Autosomal dominant
• Kidney is not responsive to PTH due to
defect in the G-protein–coupled receptors
• Clinical and Laboratory Findings:
• Hypocalcemia
• Short Stature
• Shortened 4th and or 5th digits
Short 4th and 5th Digits
Short Stature

39. Disorders of the Endocrine Pancreas

40. Diabetes Mellitus
• Types:
• Type 1 - Insulin De
fi
ciency due to autoimmune
destruction of the beta cells in the pancreas
• Type 2 - Resistance of the peripheral tissue to
the action of insulin.
• Acute Manifestation
• Polydipsia
• Polyuria
• Polyphagia
• Weight Loss
• Increased Growth Hormone and Epinephrine

41. Diabetes Mellitus
• Acute Manifestation
• Diabetic Ketoacidosis
• Common in Type 1 Diabetes Mellitus
• Buildup of acids in the bloodstream called
ketones due to fat breakdown
• Hyperosmolar Coma
• Common in Type 2 Diabetes Mellitus
• Hyperosmolar Hyperglycemic Syndrome
(HHS) or Nonketotic Hyperglycemic
Syndrome
• Severe Hyperglycemia, Hyperosmolality, and
Dehydration
• Absence of signi
fi
cant ketoacidosis
Type 1 DM
Type 2 DM

42. Diabetes Mellitus
• Chronic Manifestation
• Nonenzymatic Glycosylation
• Small Vessel Disease
• Retinopathy
• Glaucoma
• Nephropathy
• Large Vessel Atherosclerosis
• Coronary Artery Disease
• Peripheral Occlusive Disease
• Gangrene

43. Diabetes Mellitus
• Chronic Manifestation (cont):
• Osmotic Damage
• Neuropathy (Motor, Sensory and Autonomic
Degeneration
• Cataracts (Sorbitol Accumulation)
• Laboratory Findings:
• Fasting Serum Glucose
• Oral Glucose Tolerance Test
• HbA1c (Re
fl
ects average blood Glucose over
prior 3 months)
Source: CDC

44. Comparative Features of Type 1 and Type DM

45. Pancreatic Neuroendocrine Tumors: Zollinger-Ellison Syndrome
• GASTRIN producing secreting tumor
• Seen in the Pancreas and Duodenum
• Associate with MEN Type 1 Syndrome
• Signs and Symptoms
• Recurring Ulcers
• Thickening of the stomach and small
intestine rugae
Zollinger-Ellison Syndrome Triad

46. Disorders of the Adrenal Gland

47. Hyperaldosteronism
• Increased in ALDOSTERONE level
• Primary Cause:
• Due to Adrenal Hyperplasia or an Aldosterone Secreting Adenoma
(Conn’s Syndrome)
• Symptoms: Hypertension, Hypokalemia, Metabolic Alkalosis, Low
Plasma Renin
• Treatment: Surgery or Spironolactone (Aldosterone Antagonist)
• Secondary Causes:
• Due to Renal Artery Stenosis, Chronic Renal Failure, CHF, Cirrhosis or
Nephrotic Syndrome causing High Plasma Renin
• Renal perception of Low Intravascular Volume due to Overactive
Renin-Angiotensin System
• Treatment: Spironolactone (Aldosterone Antagonist) Adrenal Cortex Layers

48. Addison’s Disease
• Primary Chronic Adrenal Insu
ffi
ciency due Adrenal Atrophy or Destruction
• Causes: Autoimmune Disease, Tuberculosis, Metastasis
• All three Cortical divisions are involved (Spares the Medulla)
• Decreased Aldosterone
• Hypotension, Hyperkalemia and Metabolic Acidosis
• Decreased Cortisol
• Weakness, Anorexia, GI Disturbance, Skin Pigmentation and Weight Loss
• Decreased Sex Steroid Hormone
• Decrease muscle mass and strength and decrease bony density
• Hot
fl
ashes and other menopausal symptoms (in Women)
• Erectile dysfunction (in Men)
Adrenal Cortex Layers

49. Waterhouse-Friderichsen Syndrome
• Acute Adrenal Crisis due Adrenal Hemorrhage
• Causes:
• Neisseria Meningitidis Septicemia
• Disseminated Intravascular Coagulation
• Endotoxic Shock
• Symptoms: Shock, Coagulopathy, and Petechial Rash
Diffuse Purpuric Rash
Hemorrhagic necrosis of the Adrenal Glands
Diffuse Purpuric Rash
Diffuse Purpuric Rash

50. Pheochromocytoma
• Most common tumor of the Adrenal Medulla
• Tumor is derived from Chromatin Cells
• Tumor secrete Epinephrine, Norepinephrine and Dopamine
• Signs and Symptoms
• Episodic Hyperadrenergic Symptoms 5 Ps
• Pressure (Elevated Blood Pressure / Hypertension)
• Pain (Headache)
• Perspiration
• Palpitations (Tachycardia)
• Pallor
Gross Appearance
Microscopic Appearance: Tumor nests (Zellballen)
of epithelioid chief cells in a vascular stroma

51. Pheochromocytoma
• Laboratory Findings:
• Urinary Vanillylmandelic acid (VMA) (Breakdown product
of Norepinephrine and Epinephrine)
• Elevated Plasma Catecholamines
• Treatment
• Surgical Removal is the de
fi
nitive management (after
alpha and beta blockade)
• Phenoxybenzamine (irreversible alpha-antagonist) given
fi
rst to avoid Hypertensive Crisis
• Beta-blockers given to slow heart rate

52. Neuroblastoma
• 4th most common malignant tumor in childhood
• Tumor occurs in the Renal Medulla but can occur
anywhere along the Sympathetic Chain
• Physical Findings:
• Abdominal Enlargement
• Periorbital Ecchymosis (due to tumor metastasis to
the orbit)
• Horner’s Syndrome (Miosis, Ptosis, Enophthalmos,
Anhidrosis)
• Paralysis (due to Paraspinal metastasis)
• Watery diarrhea syndrome
Physical Findings

53. Horner’s Syndrome

54. Neuroblastoma
• Laboratory Findings:
• Elevated Homovanillic Acid (HVA) in the Urine
which is a breakdown product of Dopamine
• Overexpression of N-myc oncogene (associated
with rapid tumor progression)
• Histologic Findings:
• Nodules of small round blue cells
• Formation of Homer-Wright Pseudorosettes
Homer-Wright Pseudorosettes

55. Multiple Neuroendocrine Neoplasia (MEN)

56. 3P and 0M
2P and 1M 1P and 2M
Wermer’s Syndrome
Sipple’s Syndrome
All MEN Syndromes are Autosomal Dominant
Ret Gene Mutation
Ret Gene Mutation

57. Review Question

58. A 29-year-old, previously healthy woman collapsed after
complaining of a mild sore throat the previous day. On
examination she is hypotensive and febrile with purpuric skin
lesions. Her peripheral blood smear shows schistocytes.
Imaging studies show her adrenal glands are enlarged, and
there are extensive bilateral cortical hemorrhages. Infection
with which of the following organisms best accounts for these
findings?
A. Cytomegalovirus
B. Histoplasma capsulatum
C. Mycobacterium tuberculosis
D. Neisseria meningitidis
E. Streptococcus pneumoniae

59. A 43-year-old man from Stockholm, Sweden, has had low-volume watery
diarrhea for the past 3 months. He now has midepigastric pain. Over-the-
counter antacid medications do not relieve the pain. On physical
examination, he is afebrile; on palpation, there is no abdominal
tenderness and no masses. An upper gastrointestinal endoscopy shows
multiple 0.5- to 1.1-cm, shallow, sharply demarcated ulcerations in the
first and second portions of the duodenum. He is given omeprazole. Three
months later, repeat endoscopy shows that the ulcerations are still
present. Which of the following analytes is most likely to be increased in
his in serum or plasma?
A. Gastrin
B. Glucagon
C. Insulin
D. Somatostatin
E. Vasoactive intestinal polypeptide (VIP)

60. A 45-year-old man has felt a lump on the left side of his neck for 4
months. Physical examination shows a nontender nodule on the left
lobe of the thyroid gland. An adjacent cervical lymph node is
enlarged and nontender. Laboratory studies show no thyroid
autoantibodies in his serum, and the T 4 and TSH levels are normal.
A thyroidectomy is performed; the figure shows the microscopic
appearance of the nodule. Which of the following etiologic factors is
most likely to be involved in the pathogenesis of the thyroid nodule
in this patient?
A. Autoimmunity
B. Chronic dietary iodine deficiency
C. Consumption of goitrogens
D. RET gene mutation
E. Viral infection
•

61. Thank You