Endocrine System
Question 1. Write a note on pituitary adenoma.
Answer:
Pituitary adenoma
- The most common cause of hyperpituitarism
- Can range in size from less than 1 cm (microadenomas) to more than 1 cm (macroadenoma)
Genetic abnormalities
- G-protein mutations are the most common alterations
- Cyclin D1 overexpression and RB gene mutation are also seen
- HRAS mutations can be seen
Read and Learn More Preparatory Manual of Pathology Question and Answers
Morphology
Gross
- Soft and well-circumscribed
- Small adenomas confined to the sella turcica
- Large lesions extend superiorly into the suprasellar region, compressing the optic chiasm and cranial nerves
Microscopy
Uniform, polygonal cells arranged in sheets or cords, without supporting connective tissue or reticulin
Note: In non-neoplastic anterior pituitary parenchyma, cellular monomorphism and absence of a significant reticulin network are not seen as seen in pituitary adenomas
Question 2. Write a note on craniopharyngiomas
Answer:
Craniopharyngiomas
- Arise from the vestigial remnants of Rathke’s pouch
- Bimodal age distribution: First peak at 5 to 15 years of age and second peak at 65 years or older
- Associated with Wnt signaling pathway abnormalities
Morphology
- 3 to 4 cm in diameter, cystic and multiloculated
- Adamantinomatous craniopharyngioma (seen in children) and papillary craniopharyngioma (seen in adults)
Two types
1. Adamantinomatous craniopharyngioma
- Nests or cords of stratified squamous epithelium, with palisading of the squamous epithelium at the periphery
- Compact, lamellar keratin formation (“wet keratin”) is a diagnostic feature
- Dystrophic calcification is a frequent finding
- Cyst formation is common and contains cholesterol-rich, thick brownish-yellow fluid compared to “machine oil”
2. Papillary craniopharyngioma
- Solid sheets and papillae lined by well-differentiated squamous epithelium
- Lacks keratin, calcification, and cysts
- Peripheral palisading of squamous epithelium is absent
Question 3. Define cretinism. Enumerate the causes of hypothyroidism.
Answer:
Cretinism: Hypothyroidism develops in infancy or early childhood
Causes of hypothyroidism
1. Primary
- Genetic defects in thyroid development (PAX8, TSH receptor mutations)
- Post-ablative, surgery, radioiodine therapy, or external irradiation
- Hashimoto thyroiditis, iodine deficiency
- Drugs (lithium, iodides, p-amino salicylic acid)
- Dyshormonogenetic goiter (inborn errors of thyroid metabolism)
2. Secondary (central)
- Pituitary failure
- Hypothalamic failure
Question 4. What is a thyroid storm?
Answer:
Thyroid storm
- It is a medical emergency
- Characterized by abrupt onset of severe hyperthyroidism in patients with underlying Graves’ disease
- Results from an acute elevation of catecholamines, due to infection, surgery, cessation of antithyroid medication, or stress
- Patients are febrile and there is tachycardia out of proportion to the fever
Question 5. Discuss the pathogenesis and morphology of Hashimoto thyroiditis.
Answer:
- The most common cause of hypothyroidism in areas where iodine levels are sufficient
- Age group: 45 to 65 years
- F: M:: 10: 1 to 20: 1
Pathogenesis
- Destruction of thyroid follicular epithelial cells by CD8+ T cells or CD4+ T-helper cells
- Presence of circulating auto-antibodies against thyroglobulin and thyroid peroxidase
- Polymorphisms in cytotoxic T lymphocyte-associated antigen-4 (CTLA4) and protein tyrosine phosphatase-22 (PTPN22)
Morphology
Gross
- Diffuse enlargement of the thyroid gland
- Cut surface nodular, pale, yellow-tan, firm
Microscopy
- Extensive infiltration of thyroid parenchyma by mononuclear inflammatory infiltrate containing small lymphocytes, plasma cells, and well-developed germinal centers
- Thyroid follicular epithelial cells show abundant eosinophilic, granular cytoplasm, termed Hürthle cells
Question 6. Write a short note on Graves’ disease.
Answer:
Graves’ disease
- The most common cause of endogenous hyperthyroidism
- Age group: 20-40 years, F:M:: 10:1
Triad of:
- Hyperthyroidism is associated with diffuse enlargement of the gland
- Infiltrative ophthalmopathy with resultant exophthalmos
- Localized, infiltrative dermopathy, called pretibial myxedema
Pathogenesis
- An autoimmune disorder characterized by auto-antibodies against TSH receptor
- The most common antibody detected is thyroid-stimulating immunoglobulin (TSI)
- TSI binds to the TSH receptor and increases the release of thyroid hormones
- Polymorphisms in CTLA4, PTPN22 genes and HLA-DR3 allele are noted
Morphology
Gross
- Diffuse symmetric enlargement of the thyroid gland
- Cut surface: Soft, meaty appearance resembling muscle
Microscopy
- Follicles are lined by tall, columnar epithelium
- Epithelial cells project into the lumens of the follicles and actively reabsorb the colloid, resulting in the scalloped appearance of the edges of the colloid
- Interstitium consists of lymphocytes and plasma cells
Question 7. Write a note on colloid goiter.
Answer:
Colloid goiter
- Also called diffuse non-toxic (simple) goiter
- Two forms: Endemic and sporadic
1. Endemic goiter
- Prevalent in more than 10% of the population in a given region
- Occurs due to dietary iodine deficiency or due to goitrogens (Cruciferae family, cabbage, cauliflower, Brussels sprouts, turnips, and cassava)
2. Sporadic goiter
- Female preponderance
- Peak incidence at puberty or young adulthood
Morphology
Gross
- Enlarged lobes of thyroid glands, whose cut surface is brown, glassy, and translucent
Microscopy
1. Hyperplastic phase
- The thyroid gland is diffusely and symmetrically enlarged
- Follicles are lined by crowded columnar cells
2. Colloid involution
- If dietary iodine is increased, follicular epithelial cells involute (epithelial lining is cuboidal or flattened) to form an enlarged, colloid-rich gland (colloid goiter)
Question 8. Classify neoplasms of the thyroid. Write in detail about papillary carcinoma of the thyroid.
Answer:
Major neoplasms of the thyroid gland
- Papillary carcinoma
- Follicular carcinoma
- Anaplastic (undifferentiated) carcinoma
- Medullary carcinoma
Papillary carcinoma of the thyroid
- The most common form of thyroid cancer
- Age group: 25–50 years, associated with previous exposure to ionizing radiation Pathogenesis
- RET gene on chromosome 10 shows fusion with the PTC gene on chromosome 17, resulting in RET/PTC fusion gene proteins with increased tyrosine kinase activity
- A gain-of-function mutation in the BRAF gene
- BRAF mutations correlate with metastatic disease and extrathyroidal extension
Morphology
Gross
- Solitary or multifocal, well-circumscribed, and encapsulated
- Cut surface: Shows papillary structures
Microscopy
- Branching papillae with fibrovascular stalk covered by single to multiple layers of cuboidal epithelial cells, which can show features of anaplasia
- Nuclei of papillary carcinoma cells appear optically clear and are termed ground glass or Orphan Annie eye nuclei
- Intranuclear inclusions (“pseudo-inclusions”) due to invaginations of the cytoplasm
- Intranuclear grooves due to deep infolding of nuclear membranes
- Psammoma bodies: Concentrically calcified structures, within the cores of papillae, can be seen
Variants of papillary carcinoma of the thyroid: Follicular variant, tall cell columnar variant, diffuse sclerosing variant, papillary microcarcinomas
Question 9. Write a note on the thyroglossal duct cyst.
Answer:
Thyroglossal duct cyst
- Characterized by cystic dilation of thyroglossal duct
- Location: Midline of the neck, in the region of the hyoid bone
Microscopy
- The Cyst wall is lined by pseudo-stratified ciliated or squamous epithelium
- Mucus glands and thyroid follicles are commonly seen in the subjacent stroma
Question 10. Write briefly on types of hyperparathyroidism.
Answer:
Three types
1. Symptomatic primary hyperparathyroidism
- Bone disease and pain (painful bones)
- Nephrolithiasis (renal stones)
- Constipation, nausea, peptic ulcers, pancreatitis, gallstones (abdominal groans)
- Depression, lethargy, and seizures (psychic moans)
- Neuromuscular symptoms: Weakness and fatigue
2. Secondary hyperparathyroidism
- Increase in serum PTH levels, seen in patients with chronic hypocalcemia
- Hypocalcemia leads to compensatory overactivity of the parathyroid glands
- Cause: Chronic renal failure
3. Tertiary hyperparathyroidism
- Parathyroid activity may become autonomous and excessive, with resultant hypercalcemia
- Cause: Secondary hyperparathyroidism leads to adenoma formation, resulting in autonomous PTH secretion
Question 11. Mention skeletal changes in hyperparathyroidism.
Answer:
1. Osteoporosis
- Bones involved: Phalanges, vertebrae, and proximal femur
- Affects cortical bone more severely than medullary bone
- Dissecting osteitis: Osteoclasts dissect centrally along the length of the trabeculae, creating the appearance of railroad tracks
2. Brown tumors
- Bone loss predisposes to micro fractures and secondary hemorrhages, resulting in an influx of macrophages followed by reparative fibrous tissue
3. Osteitis fibrous cystic (von Recklinghausen disease of bone):
- A hallmark of severe hyperparathyroidism
- Combination of increased osteoclastic activity, per trabecular fibrosis, and cystic brown tumors
Question 12. Write WHO criteria for diagnosing diabetes mellitus.
Answer:
WHO diagnostic criteria for diabetes include
- Fasting plasma glucose ≥126 mg/dl
- Random plasma glucose ≥200 mg/dl
- 2-hour plasma glucose ≥200 mg/dl during an oral glucose tolerance test (OGTT) with a loading dose of 75 gm
- Glycated hemoglobin (HbA1C) level ≥ 6.5%
Question 13. Write a note on the actions of insulin.
Answer:
Metabolic actions of insulin
1. Striated muscle
- Increased glucose uptake
- Increased glycogen synthesis
- Increased protein synthesis
2. Liver
- Decreased gluconeogenesis
- Increased glycogen synthesis
- Increased lipogenesis
3. Adipose tissue
- Increased glucose uptake
- Increased lipogenesis
- Decreased lipolysis
Question 14. Describe the etiopathogenesis of diabetes. What are its complications?
Answer:
Pathogenesis of type 1 diabetes mellitus
- Autoimmune disease resulting in islet cell destruction
1. Genetic susceptibility
- HLA-DR3 or HLA-DR4 haplotype, concurrently with HLA-DQ 8 haplotype, increases the risk
- Variable number of tandem repeats (VNTRs) in the insulin gene
- Polymorphisms in CTLA4 and PTPN22 genes
2. Environmental factors
- Viral infection can trigger an immune response, which results in antibody production and thus destruction of islet tissues
Note:
- Autoantibodies against islet antigens are found in the majority of patients with type 1 diabetes
Pathogenesis of type 2 diabetes mellitus
1. Genetic factors
Polymorphisms in genes associated with insulin secretion
2. Environmental factors
- Obesity and a sedentary lifestyle lead to insulin resistance
Complications of diabetes
- Diabetic macrovascular disease: Resulting in an increased risk of myocardial infarction, stroke, and lower extremity ischemia
- Diabetic microvascular disease: Resulting in diabetic retinopathy, nephropathy, and neuropathy
Question 15. Discuss in detail the pathogenesis of chronic complications of diabetes.
Answer:
Pathogenesis of chronic complications
- HbA1C provides a measure of glycemic control over the lifespan of a red cell (120 days)
- HbA1C levels should be maintained below 7% in diabetic patients
- Mechanisms by which end-organ damage is brought
1. Formation of advanced glycation end (AGE) products
AGE binds to its receptor (RAGE), which is expressed on endothelium, vascular smooth muscle, and inflammatory cells. Effects of AGE-RAGE complex in vessel walls:
- Release of TGF β, leading to deposition of excess basement membrane material
- . Release of VEGF, resulting in neovascularisation and is implicated in retinopathy
- Generation of reactive oxygen species (ROS) in endothelial cells
- Increased proliferation of vascular smooth muscle cells
Activation of protein kinase C
- Hyperglycemia results in increased production of diacylglycerol (DAG)
- Increased DAG results in the activation of intracellular protein kinase C (PKC), which in turn stimulates the production of VEGF, and TGF-β by the vascular endothelium
3. Oxidative stress and disturbances in polyol pathways
- Glucose is metabolized to sorbitol by aldol reductase and sorbitol is reduced to fructose (a reaction that uses NADPH as a cofactor)
- NADPH is also required by the enzyme glutathione reductase in a reaction that regenerates reduced glutathione (GSH)
- Reduction in GSH, results in increased cellular susceptibility to ROS (“oxidative stress”)
- In hyperglycemia, intracellular NADPH is utilized by aldol reductase
- Hence, there is reduced GSH regeneration, resulting in oxidative stress
- Also, sorbitol can show accumulation in the lens, resulting in cataract formation
Question 16. Write a note on macrovascular complications seen in diabetes.
Answer:
Macrovascular complications in diabetes
- Endothelial dysfunction results in accelerated atherosclerosis involving the aorta and large- and medium-sized arteries
- Results in myocardial infarction (the most common cause of death in diabetics), gangrene of the lower extremities
- Hyaline arteriolosclerosis: Amorphous, hyaline thickening of the wall of arterioles, resulting in narrowing of the lumen of the vessel wall
Question 17. Write a note on diabetic microangiopathy.
Answer:
Diabetic microangiopathy
- Diffuse thickening of the basement membrane is seen in the capillaries of the skin, skeletal muscle, retina, renal glomeruli, medulla and tubules, Bowman capsule, peripheral nerves
- Resulting in diabetic nephropathy, retinopathy, and neuropathy
Diabetic nephropathy (already discussed in the kidney chapter) - Glomerular lesions; arteriolosclerosis; pyelonephritis Diabetic ocular complications
- Hyperglycemia resulting in the formation of cataracts, glaucoma, diabetic retinopathy Diabetic neuropathy
- Peripheral neuropathy depends on the duration of the diabetes
Question 18. Write a note on Zollinger-Ellison syndrome.
Answer:
Zollinger-Ellison syndrome (gastrinomas)
Sites
- Gastrinoma triangle: Sites from which they can arise include the pancreas, duodenum, and peripancreatic soft tissues
Morphology
- More than half of the gastrin-producing tumors are locally invasive or show metastasis at the time of diagnosis (hepatic metastasis)
Characteristic features
- Marked gastric acid secretion, results in peptic ulceration
- Multiple duodenal and gastric ulcers, which are unresponsive to therapy
- Ulcers can also be seen in unusual locations such as the jejunum
Clinical features
- Similar to symptoms of peptic ulcer disease
- More than 50% of patients present with diarrhea
Question 19. Write a note on Addison’s disease.
Answer:
Addison’s disease (primary chronic adrenocortical insufficiency)
Pathogenesis
1. Autoimmune adrenalitis
- The most common cause of primary adrenal insufficiency in developed countries
- Includes autoimmune polyendocrine syndrome type 1 (APS1) and APS2
2. Infections
Tuberculosis (most common in India), Histoplasma capsulate and Coccidioides immunity and in HIV patients (MAC bacteria, CMV infections
3. Metastatic neoplasms
- The most common sources include lung and breast carcinomas
Question 20. Discuss pheochromocytoma.
Answer:
Pheochromocytoma
- Neoplasms composed of chromaffin cells, which synthesize catecholamines
Rule of 10s
- Ten percent of pheochromocytomas are extra-adrenal, called paragangliomas
- Ten percent of sporadic adrenal pheochromocytomas are bilateral
- Ten percent of adrenal pheochromocytomas are malignant
- Ten percent of adrenal pheochromocytomas are not associated with hypertension
Genetics
- Associated genetic mutations: RET, NF1, VHL, SDHD, SDHC, SDHB (succinate dehydrogenase)
Morphology
- Gross
- Small, circumscribed lesions confined to the adrenal gland to large hemorrhagic masses, which can weigh between 1 gm and 4000 gm (average: 100 gm)
- Cut surface: Appears tan brown to hemorrhagic
- Incubation of fresh tissue with potassium dichromate solution turns the tumor a dark brown color, due to oxidation of stored catecholamines
Microscopy
- Clusters of polygonal to spindle-shaped chromaffin cells, that are surrounded by sustentacular cells, creating small nests or alveoli (zell-Ballen)
- Cells are supplied by a rich vascular network
- Nuclei are round to ovoid, with a stippled “salt and pepper” chromatin
- IHC markers: Chromaffin cells show chromogranin and synaptophysin positivity, and peripheral sustentacular cells show S-100 positivity
Question 21. Write a note on MEN-I and MEN-II syndromes.
Answer:
Multiple endocrine neoplasias, type 1 (MEN-1, or Wermer syndrome)
Etiology
- MEN-1 syndrome is caused by germline mutations in the MEN1 tumor suppressor gene, which encodes a protein called menin
Characteristic features
Abnormalities of parathyroid, pancreas, and pituitary glands
1. Parathyroid
- Primary hyperparathyroidism: A most common manifestation of MEN-1
- Due to parathyroid hyperplasia and adenomas
2 Pancreas
- Endocrine tumors of the pancreas are commonly seen in MEN-1
- Pancreatic polypeptide is the most commonly secreted product
3. Pituitary
- Prolactinoma is the most frequent anterior pituitary tumor
Note:
- In individuals with MEN-1, the duodenum is the most common site of gastrinomas
Multiple endocrine neoplasia, type 2
Genetics
- MEN-2A and MEN-2B are caused by germline gain-of-function mutations in RET proto-oncogene
- Three distinct syndromes: MEN-2A, MEN-2B, and familial medullary thyroid cancer
MEN-2A, or Sipple syndrome
- Characterized by pheochromocytoma, medullary carcinoma of the thyroid, and parathyroid hyperplasia
MEN-2B
- Characterized by medullary carcinoma of the thyroid, pheochromocytoma, ganglioneuromas (involving the skin, oral mucosa, eyes, respiratory tract, and gastrointestinal tract), and marfanoid habitus
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