10/21- Pathology of the Adrenal Glands and Thymus Flashcards
What are the layers of the adrenal glands?
- Cortex: more hormonally active
- Zona glomerulosa: mineralocorticoids (aldosterone)
- Zona fasciculata: glucocorticoids (cortisol)
- Zona reticularis: sex steroids (estrogen, androgen)
- Medulla: fight/flight hormones
What is seen here?
Layers of adrenal gland
- Cortex: more hormonally active
- Zona glomerulosa: mineralocorticoids (aldosterone)
- Zona fasciculata: glucocorticoids (cortisol)
- Zona reticularis: sex steroids (estrogen, androgen)
- Medulla: fight/flight hormones
IMPORTANT
What is seen with adrenocortical hyperfunction (syndromes)?
Hyperadrenalism: syndromes with overlapping clinical features
- Hypercortisolism (Cushing’s)
- Hyperaldosteronism
- Adrenogenital (virilizing) syndromes
What are clinical features of Hypercortisolism (excess glucocorticoids)?
- Hypertension
- Easy bruisability
- Weight Gain
- Menstrual irregularity
- Central obesity
- Hirsutism
- Decreased muscle mass
- Mood swings/psychosis
- Osteoporosis
- Immunosuppression
- Diabetes
- Cutaneous striae
- Thin skin
- Poor wound healing
- “Cushingoid” appearance
What are causes of hypercortisolism?
Exogenous steroid use
- Steroid treatment for autoimmune diseases or post-organ transplants
- Weight lifters, athletes, etc. (rare)
Endogenous:
- ACTH hypersecretion (hypothal-pit), 70-80%
- Cortisol hypersecretion (adrenal), 10-20%
- Ectopic ACTH secretion (paraneoplastic), 10%
- Common in small cell tumors of the lung
What are causes of ACTH hypersecretion?
- Lab values
- Epidemiology
Labs:
- High ACTH
- High cortisol
Causes:
- Pituitary (Cushing Disease)
- 5x more in females; 20s-30s
- Microadenoma, adenoma (>1cm)
- Primary corticotrophic cell hyperplasia
- Hypothalamic
- CRH producing tumor (2’ cortioctrophic cell hyperplasia in pituitary)
- Secondary adrenocortical hyperplasia
What are causes of cortisol hypersecretion?
- Lab values
Labs:
- ACTH-independent, so low ACTH
- High cortisol
Seen in:
- Adrenocortical adenoma (#1)
- Adrenocortical carcinoma
- Primary adrenocortical hyperplasia (uncommon)
What are causes of ectopic ACTH production?
- Lab values
- Epidemiology
Paraneoplastic syndrome
Labs:
- High ACTH
- High cortisol
Epidemiology:
- More males
- 40s-50s
Causes:
- Small cell carcinoma of lung (#1)
- Carcinoid tumor (typ small intestine/colon), Medullary thyroid CA, Islet cell tumor of pancreas
- Ectopic CRH secretion also possible (rare)
What is seen here?
Adrenal hyperplasia
What is seen here?
Tumor of the adrenal cortex
- Much fat (medulla will look different; different tissue composition)
Microscopically, see very different cell size/morphology
- Hard to tell benign vs. malignant with adrenal tumors - Even benign may look scary
What is the pathology of Cushing’s syndrome on the pituitary?
Crooke hyaline change
What is the pathology of Cushing’s syndrome on the adrenal?
- Atrophy: if low ACTH (exogenous steroids, functioning tumor)
- Diffuse hyperplasia: if high ACTH (hypothalamic-pituitary)
- Nodular hyperplasia: if high ACTH (hypthalamic pituitary)
- Mass
How do you make the lab diagnosis of Cushing’s syndrome?
- 24 hour urine free cortisol level increased due to loss of normal diurnal pattern of cortisol secretion
- Serum ACTH level
- Dexamethasone suppression test
- Urinary 17-hydroxycorticosteroid level
- After low dose and high dose dexamethasone
What is seen in the various causes of Cushing’s (pituitary disease, ectopic ACTH, and adrenal disease) for:
- ACTH levels
- Cortisol levels
- Response to low and high dose Dex
Pituitary disease: high ACTH, high cortisol
- Low dose dex -> no suppression of 17OH-CCS
- High dose dex -> suppression of 17OH-CCS
Ectopic ACTH: high ACTH, high cortisol
- Low dose dex -> no suppression
- High dose dex -> no suppression
Adrenal disease: low ACTH, high cortisol
- Low dose dex -> no suppression
- High dose dex -> no suppression
What are clinical and lab features of hyperaldosteronism (excess mineralocorticoids)?
Sodium retention and potassium excretion
- Hypernatremia (increased fluid volume)
- Hypokalemia (weakness, paresthesia, visual disturbance, tetany)
- Hypertension
- EKG changes, cardiac decompensation
Primary (adrenal)
- Suppression of renin-angiotensin system
- Low renin
Secondary (extra-adrenal)
- Activation of renin-agniotensin system. High renin
What are causes of secondary hyperaldosteronism?
RAAS system
- Decreased renal perfusion
- Renal artery stenosis
- Arteriolar sclerosis
- Arterial hypovolemia and edema
- CHF
- Cirrhosis
- Nephrotic syndrome
- Pregnancy
- Estrogen-induced increase in plasma renin
What are causes of primary hyperaldosteronism?
Adrenocortical neoplasm
- Most often adenoma (Conn syndrome)
Primary adrenocortical hyperplasia
- Idiopathic
- May be genetic
- Cells resemble ZG
Glucocorticoid-remediable hyperaldosteronism
- Uncommon
- Genetic in some families
What is Conn syndrome?
- Epidemiology
- Gross appearance
- Histo features
Adenoma (causing primary hyperaldosteronism)
Epidemiology
- Adults, 2x more females
- 30s-40s
Features:
- Small bright yellow nodule.
- May have spironolactone bodies.
- May be multiple adenomas.
- No associated cortical atrophy due to normal ACTH
What are adrenogenital syndromes
Excess androgens causing virilization
What is broad pathway for androgen production?
Dehydroepiandrosterone (DHEA) and androstenedione produced by adrenal cortex
- Converted to testosterone in peripheral tissues
- Production regulated by ACTH
What are causes of adrenogenital syndromes?
- Adrenocortical neoplasms
- More often carcinomas
- Often association with Cushing syndrome
- Congenital Adrenal Hyperplasia (CAH)
What is Congenital Adrenal Hyperplasia
- Sporadic or genetic
- Mechanism
Inherited AR metabolic disorders of steroid biosynthesis (CYP21B gene defect)
Deficient or absent activity of enzymes:
- 21-hydroxylase (90%)
- Other: 17-hydroxylase, 11-hydroxylase
Decreased cortisol (+/- aldosterone) production
- Alternate pathway of steroidogenesis results in excess androgens
- Increased ACTH – Adrenocortical hyperplasia
Describe the genital defect in CAH
Inherited AR metabolic disorders of steroid biosynthesis (CYP21B gene defect)
- Abnormal recombination with non-functional CYP21A, a neighboring “pseudogene”
- Highest carriers: Hispanic, Ashkenazi Jewish
What happens with 21-hydroxylase deficiency in CAH (congenital adrenal hyperplasia)?
- Defective conversion of progesterone to 11-deoxycorticosterone (aldosterone pathway)
- Defective conversion of 17-OH progesterone to 11-deoxycortisol (cortisol pathway)
What are the clinical features of Congenital Adrenal Hyperplasia?
Variable; Mild to Severe (life-threatening)
- Androgen excess
- Ambiguous genitalia at birth: masculinization in females and precocious puberty in males
- Variable aldosterone and glucocorticoid deficiency
- Salt-wasting (if low aldosterone production)
What are the different CAH syndromes?
- Salt-wasting (classic) form
- Simple virilizing form
- Late-onset (non classic) form
What is seen with salt-wasting (Classic) form of CAH?
- Absent activity: most severe disease; seen at birth.
- Ambiguous genitalia
- More easily recognized in girls
- Salt-wasting
- Hyponatremia, hyperkalemia, hypotension, vomiting, dehydration, acidosis, cardiovascular collapse, death
- Also, impaired catecholamine production
What is seen with simple virilizing form of CAH?
- Decreased activity; less severe disease
- Ambiguous genitalia, but no salt-wasting
What is seen with Late-onset (non-classic) form of CAH?
- Most common
- Mildest disease
- Recognized late in life
What is the pathology seen in CAH?
Bilateral adrenocortical hyperplasia
- 10-15 x normal weight
- Diffusely thick and nodular cortex
- May be tan-brown due to decreased lipid.
- Secondary hyperplasia of ACTH-producing corticotroph cells in pituitary
What may cause adrenocortical insufficiency?
Primary hypoadrenalism
- Loss of cortex
- CAH, Adrenoleukodystrophy, Autoimmune adrenal insufficiency, infection, amyloidosis, sarcoidosis, hemochromatosis, metastasis
- Metabolic failure
- CAH, Drug and steroid-induced inhibition
Secondary hypoadrenalism
- Hypothalamic-Pituitary disease
- Neoplasm, inflammation
- Hypothalamic-Pituitary suppression
- Long-term steroid administration, steroid-producing neoplasms
What is adrenal crisis? What causes it?
Acute adrenocortical insufficiency
Caused by:
- Stress crisis in patients with chronic adrenal insufficiency
- Rapid withdrawal of exogenous steroids
- Massive adrenal hemorrhage
What may result in massive adrenal hemorrhage and constitute and adrenal crisis (acute adrenocortical insufficiency)?
- Neonate after prolonged delivery, trauma, hypoxia
- Anticoagulation therapy
- DIC
- Waterhouse-Friderichsen Syndrome (bacteremia): picture below
- Neisseria meningitidis (Meningococcemia)
- Other: Pseudomonas, S. pneumoniae, H. flu, Staphylococcus
What is Addison disease?
Primary chronic adrenal insufficiency
What are clinical features of Addison disease?
- Insidious onset
- Progressive weakness, fatiguability, GI disturbance (anorexia, N/V/D, weight loss), Skin hyperpigmentation, hyperkalemia, hyponatremia, volume depletion, hypotension, hypoglycemia
- Acute adrenal crisis
- Triggered by stress (infection, trauma, surgery)
- Life-threatening
What are causes of primary chronic adrenal insufficiency (Addison disease)?
- Autoimmune adrenalitis (60-70%)
- Tuberculosis (historically, 90%)
- Fungal (histoplasma, coccidioides)
- AIDS (CMV, MAI, KS)
- Metastatic cancer (Lung, breast)
- Also: GI, lymphoma, melanoma
- Genetic disorders
- Adrenoleukodystrophy
- Congenital adrenal hypoplasia
What is seen here?
Progressive destruction of adrenal glands
- Very small and atrophic with few residual cortical cells
- Lymphocytes
What is Autoimmune Adrenalitis
- Epidemiology
- Types
Epidemiology:
- More in Caucasian women
- Autoantibodies to 21OH-ase, 17OH-ase
Types
- Isolated autoimmune Addison disease
- Autoimmune polyendocrinopathy syndrome type I (APS1)
- Chronic mucocutaneous candidiasis, skin/nail/enamel abnormalities, hypoadrenalism, hypoparathyroidism, hypogonadism, pernicious anemia
- AIRE gene
- Autoimmune polyendocrinopathy syndrome type II (APS2)
- Early adulthood; May be HLA-related
- Adrenal insufficiency, autoimmune thyroiditis, type I diabetes
What are causes of secondary hypoadrenalism? ACTH level?
- Hypothalamic- Pituitary cause
- Low ACTH
What are clinical features of secondary hypoadrenalism?
- Similar to Addison Disease
BUT:
- Normal or near-normal aldosterone
- No evidence of skin hyperpigmentation
ACTH administration causes increase in cortisol
- No response to ACTH in primary adrenal disease due to loss or non-function of adrenal cortex
T/F: There is no morphologic distinction between functioning and non-functioning adrenocortical neoplasms
True
What are broad features of adrenocortical adenomas?
- Often incidental and asymptomatic
- Well-circumscribed, yellow to yellow-brown (2.5cm)
- May have “endocrine atypia”
What are broad features of adrenocortical carcinomas?
- RARE, adults and children.
- Larger mass, often necrosis and hemorrhage.
- Malignancy defined by vascular invasion or mets!
What is seen here?
Benign adrenocortical adenoma
- Circumscribed, yellow, sitting in surface
What is seen here?
Benign adrenocortical adenoma ?
What is seen here?
Adrenocortical carcinoma
What is seen here?
Adrenocortical carcinoma
What is seen here?
Adrenocortical carcinoma
What is a pheochromocytoma?
- Cell type
- Lab values
- Clinical presentation
- Chromaffin cells
- Release catecholamines
- Elevated urinary VMA, HVA
Clinical presentation
- Hypertension
- Paroxysmal BP elevation with tachycardia, HA, sweating, tremor, apprehension. May be life-threatening.
- Chronic sustained hypertension with some lability
- Amenable to surgical cure
What condition does the rule of 10s apply to?
Pheochromocytoma
What is the rule of 10s for a pheochromocytoma?
Familial, extra-adrenal, bilateral, malignant, childhood
- 10% familial
- MEN2A/2B
- NF1
- VHL, SW
- 10% extraadrenal
- Paraganglioma
- 10% bilateral
- 10% malignant
- 10% childhood
Describe the appareance/characteristics of a pheochromocytoma
- Size
- EM
- Variable size, avg 100g
- Often hemorrhagic
- Dark brown in Zenker’s fixative (potassium dichromate) – oxidation of catecholamines
- “Zellballen”; vascular
- Stippled chromatin and nuclear pleomorphism
- Neural markers (chromogranin, synaptophysin)
- EM: electron dense granules
Are pheochromocytomas more commonly benign or malignant?
- Histologic distinction
Benign
- No reliable histological criteria to differentiate
- Defined by mets
What is seen here?
Pheochromocytoma
What is seen here?
Pheochromocytoma
What is seen here?
Pheochromocytoma
What is Multiple Endocrine Neoplasia?
- Associations?
Endocrine hyperplasia, adenomas, carcinomas
Associated with:
- Younger age
- Multiple organ sites (synchronous or metachronous)
- Multifocality
- Asymptomatic stage of hyperplasia
- More aggressive course (recurrence)
What are the features/conditions of MEN1?
3Ps:
- Pituitary adenomas
- Parathyroid (hyperplasia, adenomas)
- Pancreas (endocrine tumors: gastrinoma, insulinoma)
Also, gastrinomas in duodenum, carcinoid tumors, thyroid and adrenal adenomas, lipomas
What are the features/conditions of MEN2A?
- Gene involved?
MEN2A = RET gene
- Medullary thyroid CA (100%)
- Pheochromocytoma (40-50%)
- Parathyroid hyperplasia (10-20%)
- Also, Familial Medullary Thyroid CA syndrome
What are the features/conditions of MEN2B?
- Gene involved?
MEN2B = RET gene
- Medullary thyroid CA
- Pheochromocytoma
- Mucosal neuromas
- Skin, oral, eyes, respiratory, GI
- Marfanoid features
What is seen here?
?
What are the most common extracranial solid tumors of childhood?
Neuroblastic tumors
- Often in infants and kids under 5
What is the spectrum of differentiation with neuroblastic tumors?
- Neuroblastoma
- Ganglioneuroblastoma
- Ganglioneuroma
Where can neuroblastic tumors occur?
- Adrenal gland
Also:
- Retroperitoneal
- Posterior mediastinal
What is seen here?
Neuroblastoma of adrenal gland?
What is seen here?
Neuroblastoma of adrenal gland?
Embryology of the thymus?
Derived from 3rd (and 4th) pharyngeal pouches
What cell types are found in the thymus?
- Thymic epithelial cells
- Lymphocytes
- Few B cells, macrophages, DCs
- Rare neutrophils and eosinophils
What immune organ has Hassal’s corpuscles?
Thymus
What is seen here?
Thymus..?
Describe the structure of the thymus (micro)
- Has lobes and lobules
- Encapsulated
- Reticulum of epithelial cells
- Cortex with blood-thymus barrier
- Medulla
- Hassall’s corpuscles
What is seen here?
Normal thymus structure
What is seen here?
Thymus: Hassal’s corpuscles (?)
SINCE LECTURE WASN’T FINISHED IN THE STREAM, THYMUS PATHOLOGY WILL NOT BE COVERED ON THE TEST
SINCE LECTURE WASN’T FINISHED IN THE STREAM, THYMUS PATHOLOGY WILL NOT BE COVERED ON THE TEST
Describe the development of the thymus
Growth during childhood, followed by involution
- 10-35 g at birth
- 20-50 g at puberty (maximum)
- 5-15 g in adults, replaced by fatty tissue
What can cause rapid involution of the thymus?
- Histologic features?
Stress/illness
- Blurred corticomedullary junction
- “Starry-sky” appearance
- Lymphocyte depletion
Where is the thymus located?
Inferior to thyroid gland; more in the thorax
What are the different types of thymic hyperplasia?
- Histologic characteristics?
True thymic hyperplasia
- Increased size and weight
- Histologically normal
Follicular hyperplasia
- Lymphoid follicles (germinal centers)
What can cause follicular hyperplasia?
- Associated with myasthenia gravis (65-75%)
- Other chronic inflammatory conditions
- Grave’s disease
- SLE
- Scleroderma
- RA
What is seen here?
Thymic hyperplasia??
What are the different thymic neoplasms?
- Subtypes
Thymoma
- Benign
- Medullary type (spindled)
- Mixed med-cortical
- Malignant
- Malignant thymoma type 1 (invasive)
- Malignant thymoma type 2 (thymic carcinoma)
Describe thymoma
- Cells involved
- Epidemiology
- Location
- DDx
- Clinical features
- Tumor of thymic epithelium
Also lymphocytes in the background
Epidemiology:
- Adults > 40 yo
- Equal genders
Location: superior mediastinum
DDx:
- Lymphoma
- Germ cell
- Carcinoid
Clinical features:
- Local mass effect (40%)
- Myasthenia (30-45%)
- Incidental
- Paraneoplastic phenomena (acquired hypogram, pure red cell aplasia, Grave’s, pernicious anemia, DM-PM, Cushing’s); possibly with abnormal T cell selection in tumor environment
What is malignant thymoma type 1?
- Benign or malignant
- Cells involved
- Prognosis
Invasive thymoma
- Cytologically benign
- Mostly cortical (epithelial)
- Locally invasive; prognosis related to invasion:
- >90% minimal invasion
- 50% extensive invasion
What is malignant thymoma type 2?
- Histology
- Prognosis
- Subtypes
Thymic carcinoma
- Cytologially malignant
- Biologically aggressive
May be:
- Squamous
- Lymphoepithelioma-like
- Sarcomatoid
- Basaloid
- Clear cell
What is seen here?
Medullary ?
What is seen here?
Cortical ?
