Endocrine Pathology 1 Flashcards
pituitary adenomas - overview
*benign epithelial neoplasm arising from anterior pituitary gland
*most common cause of HYPERpituitarism
pituitary adenomas - classifications
*pituitary adenomas are classified based on:
1. size: micro-adenomas (small, < 1 cm) vs. macro-adenomas (large, > 1 cm)
2. hormone production:
-functional = cause clinical syndromes related to overproduction of hormone(s)
-nonfunctional = cause mass effect due to growing to larger size before detection
pituitary adenomas - clinical features
*systemic: dependent on excess or deficiency of pituitary hormones
*local: dependent on mass effects:
-visual field abnormalities (bitemporal hemianopsia) due to compression of optic chiasm
-headache, N/V are signs of elevated intracranial pressure
pituitary adenomas - pathogenesis
- sporadic/acquired somatic mutations:
-growth hormone releasing hormone receptor (GHRHR)
-ubiquitin-specific protease 8 (USP8) - familial/inherited: MEN1 germline mutations
pituitary adenomas - pathologic features
*solitary, well-circumscribed lesions
*monotonous cells with decreased or no supporting reticulin stroma
*immunohistochemical stains identify the hormones
subtypes of pituitary adenomas: lactotroph adenoma
*hormone = prolactin
*associated syndrome = galactorrhea & amenorrhea (in females); sexual dysfunction, infertility
subtypes of pituitary adenomas: somatotroph adenoma
*hormone = growth hormone (GH)
*associated syndrome = gigantism (children), acromegaly (adults)
subtypes of pituitary adenomas: mammosomatotroph adenoma
*hormone = prolactin, GH
*associated syndrome = combined features of growth hormone and prolactin excess
subtypes of pituitary adenomas: corticotroph adenoma
*hormone = ACTH and other POMC-derived peptides
*associated syndrome = Cushing syndrome, mass effect
subtypes of pituitary adenomas: thyrotroph adenoma
*hormone = TSH
*associated syndrome = hyperthyroidism
subtypes of pituitary adenomas: gonadotroph adenoma
*hormone = FSH, LH
*associated syndrome = hypogonadism (most are silent with mass effect)
craniopharyngioma - overview
*epithelial neoplasm arising from Rathke pouch remnants
*proliferation of squamous cells
craniopharyngioma - clinical features
*bimodal distribution: children 5-15 years; elderly > 65
*headaches and visual disturbances
*suprasellar (may induce hypo- or hyper-function of pituitary, diabetes insipidus; children may have growth retardation)
craniopharyngioma - pathologic features
*keratinizing squamous cells, calcifications, cholesterol crystals, fibrosis
*associated mutations:
1. BRAF mutations → papillary architecture
2. beta-catenin mutations → compact, lamellar (“wet”) squamous epithelium with peripheral palisading
thyroid gland - overview
*2 lobes united by an isthmus
*only endocrine organ which stores secretory product
*synthesizes hormones:
-thyroxine (T4) and tri-iodothyronine (T3) = controls basal metabolic rate in cells
-calcitonin = inhibits osteoclast activity
thyroid gland - cell types
- follicular cells:
-simple cuboidal epithelium, under the control of TSH
-exocrine function = thyroglobulin (colloid) production; sufficient stored hormone to supply body ~3 months
-endocrine function = iodination of thyroglobulin with subsequent secretion of T4 and T3 - parafollicular (C) cells:
-neuroendocrine cells which secrete calcitonin
-triggered by elevated blood Ca2+
-inhibits osteoclast activity
goiter - overview
*enlargement of the thyroid
*most common clinical manifestation of thyroid disease
goiter - pathogenesis
*defective synthesis of T3 and T4 from relative iodine deficiency
*endemic = dietary iodine deficiency
*sporadic goiter = most common in adolescent/young adult women; dietary goitrogens
goiter - pathology
*diffuse goiter evolves into multinodular goiter
1. initial diffuse goiter (TSH-induced proliferation of follicular cells → cells involute as demand for thyroid hormones goes down)
2. cycles of proliferation/involution → irregular enlargement
goiter - clinical features
*usually functionally silent (euthryoid)
*neck mass may become so large it compresses other structures → airway obstruction, dysphagia, and vascular compromise
pathogenesis of thyroid enlargement in Graves’ Disease
- IgG antibodies to TSH receptor →
- bind to follicular cells →
- thyroid hypertrophy/hyperplasia →
- increased secretion of T3 and T4
Graves Disease - overview
*most common cause of hyperthyroidism
*most prevalent in women of childbearing age
*associated with HLA-DR3
*caused by autoantibodies against TSH receptor, which bind to and stimulate thyroid follicular cells
Graves Disease - clinical features
- diffuse goiter - due to constant TSH stimulation
- hyperthyroidism (note - thyroid storm is a potentially fatal complication)
-
exophthalmos and/or pretibial myxedema
-fibroblasts behind the orbit express the TSH receptor
-TSH activation → glycosaminoglycan build-up, inflammation, and edema in soft tissues
Graves Disease - pathology & labs
*diffuse hyperplastic thyroid follicles
*labs: hyperthyroidism = increased total and free T4, decreased TSH
*positive thyroid stimulating immunoglobulins (TSIs)
Hashimoto’s Thyroiditis - overview
*most common cause of hypothyroidism
*most prevalent in women of childbearing age
*associated with HLA-DR5
*caused by thyroid destruction by T-cell immune response against thyroid antigens
Hashimoto’s Thyroiditis - clinical features
-
hypothyroidism (follicle damage)
-fatigue, weight gain, feeling cold
-joint and muscle pain
-dry and thinning hair - lobular goiter: thyroid enlargement from lymphocytic infiltration and fibrosis
pathogenesis of thyroid enlargement in Hashimoto’s Thyroiditis
*inflammatory process: thyroid enlargement from lymphocytic infiltration and fibrosis
Hashimoto’s Thyroiditis - pathology & labs
*lymphocytic infiltration → nodular thyroid fibrosis → progressive thyroid failure
*labs: decreased T4, increased TSH
thyroid neoplasms - overview
*usually present as distinct, solitary nodule/mass; vast majority are benign
*radioactive iodine scan is useful:
-HOT nodules = toxic adenomas, rarely malignant
-COLD nodules = ~10% are malignant
clinical characteristics of MALIGNANT thyroid neoplasms
- solitary nodule
- nodule in male
- age: < 20 or > 70
- radiation exposure history
- cold nodule: failure to take up radioactive iodine in imaging studies
- evidence of extrathyroidal extension or enlargement of cervical lymph nodes
thyroid neoplasm: follicular adenoma - overview
*benign, solitary neoplasm derived from follicular epithelium
*somatic mutations that lead to constitutive activation of the TSH receptor signaling pathway (e.g. gain-of-function mutations of TSH receptor)
thyroid neoplasm: follicular adenoma - clinical features
*typically painless, incidental thyroid nodule
*vast majority are nonfunctional (euthyroid)
*function “toxic” adenomas cause hyperthyroidism
thyroid neoplasm: follicular adenoma - pathology
*solitary lesion composed of colloid-filled follicles lined with uniform-appearing epithelial cells
*thin fibrous capsule:
-evaluation of capsule integrity critical
-diagnosis of malignancy would require demonstration of capsular invasion
thyroid neoplasm: papillary carcinoma - overview
*malignant neoplasm derived from follicular epithelium
*most common malignant thyroid neoplasm
*risk factors: ionizing radiation, particularly during the first 2 decades
thyroid neoplasm: papillary carcinoma - clinical features
*neck masses: within thyroid and/or metastatic deposits in draining cervical lymph nodes
*nonfunctional (euthyroid)
*indolent
thyroid neoplasm: papillary carcinoma - pathogenesis
*activating MAP kinase pathway:
1. RET gene rearrangements
2. BRAF activating mutations
thyroid neoplasm: papillary carcinoma - pathology
*solitary or multiple
*infiltrative
*papillary growth
*cells with empty chromatin (Orphan Annie eyes)
*Psammoma bodies
thyroid neoplasm: follicular carcinoma - overview
*malignant neoplasm derived from follicular epithelium
*RAS or PI3K/AKT activating mutations
thyroid neoplasm: follicular carcinoma - clinical features
*solitary, cold nodules
*distant hematogenous metastases
thyroid neoplasm: follicular carcinoma - pathology
*resemble follicular adenomas, but with capsular invasion
*vascular invasion and/or metastases present
thyroid neoplasm: medullary carcinoma - overview
*malignant calcitonin-producing neuroendocrine C-cells
thyroid neoplasm: medullary carcinoma - pathogenesis
*majority are sporadic
*familial = RET activating mutations
thyroid neoplasm: medullary carcinoma - clinical features
- neck mass (sporadic = adults; MEN2A/B = children)
- hypocalcemia
- increased serum calcitonin
thyroid neoplasm: medullary carcinoma - pathology
*small round blue cells
*deposits of pink amyloid
endocrine pancreas - overview
*composed of “Islets of Langerhans:” round endocrine cell group in acinar exocrine tissue
*concentrated in narrow tail region of pancreas
endocrine pancreas - cell types
- alpha cells: produce glucagon - acts on several tissues to make energy stored in glycogen and fat available through glycogenolysis and lipolysis; increases blood glucose content
- beta cells: produce insulin - acts on several tissue to cause entry of glucose into cells and promotes decrease of blood glucose content
- delta cells: produce somatostatin: inhibits release of other islet cell hormones through local paracrine action; inhibits release of GH and TSH in anterior pituitary and HCl secretion by gastric parietal cells
- PP cells: produce pancreatic polypeptide - stimulates activity of gastric chief cells; inhibits bile secretion, pancreatic enzyme and bicarbonate secretion, and intestinal motility
type 1 diabetes mellitus - pathogenesis
*autoimmune disease
*type 4 hypersensitivity reaction: CD4 and CD8 T cells attack and destroy beta cells, resulting in insulin deficiency
*susceptibility: HLA-DR3 or DR4 haplotypes; environmental influences / “molecular mimicry”
*insulitis: islets “invaded” by T-lymphocytes; beta-cell destruction
type 1 diabetes mellitus - pathology
*insulitis - infiltration by T lymphocytes
*decreased number/size of the islets of Langerhans (due to autoimmune destruction)
type 1 diabetes mellitus - clinical features
*commonly presents in childhood
*triad: polyuria, polydipsia, polyphagia
*can present in diabetic ketoacidosis
type 2 diabetes mellitus - pathogenesis
*complex genetic, environmental, inflammatory disease
1. insulin resistance → decreased response of peripheral tissues
2. beta cell dysfunction → inadequate insulin secretion
*susceptibility: inheritable risk present; environmental factors (obesity, lifestyle, sleep disorders)
type 2 diabetes mellitus - pathology
*islet AMYLOID DEPOSITION
type 2 diabetes mellitus - clinical features
*older patients (generally)
*obesity
*typically asymptomatic, following routine bloodwork
diabetes complications: vascular lesions
*pathogenesis: atherosclerosis/hyalinization of small/medium arteries; deposition of AGEs
*examples:
1. myocardial infarctions
2. ischemic necrosis of the legs (gangrene)
3. small-vessel disease (microangiopathy)
-diffuse thickening of the capillary basement membranes underlies lesions; kidneys, eyes, nerves
diabetes complications: diabetic nephropathy
*nephrotic syndrome
*glomerulosclerosis: nodular glomerular scarring (Kimmelstiel-Wilson lesions) & capillary basement membrane thickening
*renal hyaline arteriosclerosis (markedly thickened, tortuous afferent arterioles)
diabetes complications: diabetic retinopathy
- nonproliferative: thickened capillaries, aneurysms, hemorrhages; edema/exudates of leaked plasma proteins & lipids
- proliferative: local production of VEGF induces neoangiogenesis
-extensive retinal/vitreous hemorrhages; fibrosis place traction on retina leading to detachment - cataracts, glaucoma
diabetes complications: diabetic neuropathy
*microangiopathy affecting vessels supplying nerves; may also have component of direct axonal damage
1. symmetric peripheral neuropathy:
-affects mainly SENSORY nerves of legs but may also impair motor function
-upper extremities may be involved, thus “stocking-and-glove” pattern
2. autonomic neuropathy:
-bowel & urinary disturbances; erectile dysfunction
3. diabetic mononeuropathy:
-manifests as sudden foot drop, wrist drop, or isolated cranial nerve palsies
