Gupta - Pathology Flashcards

Question

What are the clinical manifestations of acute adrenal insufficiency?

Answer 1

- Predominant manifestation of adrenal crisis **SHOCK**, but pts often have non-specific symptoms: 1. Anorexia, weakness, fatigue, lethargy 2. N/V, abdominal pain 3. Fever, confusion or coma - Hypoglycemia is a RARE manifestation of primary acute adrenal insufficiency

Answer 2

- **Charcot joint** (neuropathic arthropathy): PROGRESSIVE (slow or rapid), DESTRUCTIVE variant with large amounts of dead bone and cartilage particles embedded in synovium 1. Severe subluxation or dislocation of joint with extreme deformity 2. Fibroblastic proliferation, reactive new bone formation

Answer 3

Give tx within few days of birth

Answer 4

- Hypothyroidism (Hashimoto's) - Facial/preorbital myxedema -\> resolved with successful treatment

Answer 5

- _Anterior pituitary_: basophils, acidophils, and chromophobes - Epithelial cells derived from developing oral cavity - Release is controlled by the hypothalamus

Answer 6

- **von Hippel Lindau**: 10-20% of patients - Cysts of kidney, liver and epididymis - Renal cell carcinoma (clear cell type) - _Pheochromocytoma_ - Angiomas - Cerebellar hemangioblastoma

Answer 7

- Autoimmune manifestation of _Graves' disease_ (also occurs in Hashimoto's thyroiditis) - Lesions are usually _asymptomatic_ and have only cosmetic importance, but are associated with relatively _severe opthalmopathy_ 1. Usually ophthalmopathy appears first and dermopathy much later. - High serum concentrations of TSH-receptor Abs, indicating the severity of the autoimmune condition - Occurrence in areas other than pretibial skin indicates a systemic process -\> TSH-receptors in CT may be the Ag responsible for the immune process. 1. Humoral + cellular immune mechs involved in stimulation of fibroblasts and production of large amounts of **glycosaminoglycans** 2. Localization in the pretibial area relates to mechanical factors and dependent position - _Diagnosis_ based on signs and typical pretibial skin lesions in association with a history of Graves' hyperthyroidism and ophthalmopathy

Answer 8

- TSH has receptors on more cells than just those in the thyroid; they may bind with fibroblasts of tissue in various locations and cause receptor increases the deposition of glycosaminoglycan - TSH receptor protein expression by normal dermal fibroblasts raises possibility that TSH-receptor antibodies and/or antigen specific T cells initiate the inflammatory response, which stimulates the production of glycosaminoglycans by these cells as seen in the accompanying Graves’ orbitopathy - Cytokines like **TNF-alpha and gamma interferon induce GAG release from fibroblasts**, and may be secreted by Th1 type T cells activated by TSH receptor antigen

Answer 9

- Elaborate more than one hormone, i.e., mammo-somatotroph adenomas (5% incidence; GH and PRL release, and effects) - These tumors are usually aggressive

Answer 10

- BENIGN: follicular adenomas - MALIGNANT: papillary carcinomas

Answer 11

- Malignant neoplasm of postganglionic sympathetic neurons that is most common in kids **\<5** years old 1. 3rd most common cancer in children, and mean age of onset: 18 months - Primarily in adrenal medulla; commonly metastasize to skin and bones (**70% have mets** at time of dx -\> hematogenous) 1. Skin mets and \<1-y/o = GOOD PROGNOSIS - Amplification of **N-MYC** oncogene: indicator of a POOR PROGNOSIS - Clinical and laboratory findings: (1) Palpable abdominal mass (2) Diastolic HTN (3) INC urine **VMA and HVA** (90-95% sensitivity)

Answer 12

- Exogenous administration of steroids - Followed by: 1. Pituitary adenoma 2. Primary adrenal neoplasm 3. Paraneoplastic, ACTH-producing tumors

Answer 13

- Three lesions: (1) **glomerular lesions**: most important of these are cap BM thickening, diffuse mesangial sclerosis, and nodular glomerulosclerosis (2) renal vascular lesions, principally **arteriolosclerosis**; and (3) **pyelonephritis**, including necrotizing papillitis - _NOTE_: renal failure 2nd only to MI as a COD from this disease

Answer 14

- **ACROMEGALY** due to INC GH secretion - Lab values: ↑GH, IGF-1, glucose (secondary DM) - Most common COD: cardiomyopathy

Answer 15

- **INC glucocorticoids** - Flushed face, acne - Buffalo hump, bruisability - Immunosuppression, mental changes, insomnia - Hunger, truncal and facial obesity, "diabetes," gastric ulcers - HTN, edema, hypokalemia - Osteoporosis, muscle wasting, thinning skin

Answer 16

Papillary thyroid cancer: orphan-annie eyed nuclei

Answer 17

- PRIMARY: autonomous overproduction of aldosterone; DEC plasma renin activity 1. Bilateral idiopathic hyperaldosteronism 2. Adrenocortical neoplasm (Conn syndrome) 3. Rarely: familial hyperaldosteronism - SECONDARY: aldosterone release due to activation of renin-aldosterone system -\> **WAY MORE COMMON** 1. DEC renal perfusion 2. Arterial hypovolemia 3. Pregnancy

Answer 18

- Solid arrow: optic nerve and its proximity to the sella turcica (dotted white arrow) - While pituitary adenomas are BENIGN, they can produce problems either from **mass effect** (usually _visual problems_ from pressing on the optic chiasm and/or _headaches_) or from production of hormones like prolactin or ACTH

Answer 19

- Granulomatous (de Quervain) thyroiditis (PAINFUL) - Subacute lymphocytic thyroidits (PAINLESS) - Struma ovarii: ovarian teratoma w/ectopic thyroid - Factitious thyrotoxicosis: exogenous thyroxine intake

Answer 20

- **Bilateral cortical hyperplasia** (can be nodular) - This could be due to: 1. _Pituitary adenoma_ secreting ACTH (Cushing's disease), or 2. Cushing's syndrome from _ectopic ACTH_ production, or 3. _Idiopathic adrenal hyperplasia_ - Normal adrenals on top (medulla is brown center)

Answer 21

- ANAPLASTIC CARCINOMA - Large, pleomorphic **giant cells**, including occasional osteoclast-like multinucleate giant cells - **Spindle cells** with a sarcomatous appearance

Answer 22

- Pheochromocytomas: commonly gray, pink, or red (hemorrhage)

Answer 23

- For all 3 tests, w/in the prediabetes range, the higher the test result, the greater the risk of diabetes

Answer 24

- Parathyroid adenomas - Typically associated with: hypercalcemia and a # of clinical symptoms involving neuromuscular, skeletal, renal, and CV

Answer 25

- **Multinodular goiter**: note the _ABSENCE OF A PROMINENT CAPSULE_, a distinguishing feature from follicular neoplasms - GROSS: coarsely nodular gland with areas of fibrosis and cystic change - MICRO: hyperplastic nodule with compressed residual thyroid parenchyma on the left

Answer 26

- _Subacute granulomatous (de Quervain) thyroiditis_ - Uncommon; **diffuse pain**; 40-60 F - Thought to be viral-induced -\> activation of CTLs - Marked ACUTE INFLAM: lymphos, macros, giant cells - Follicle destruction - Most pts fully **recover in 6-8 wks** (don't see many biopsies for these people)

Answer 27

- _Metastatic tumor_: leading to chronic adrenal insufficiency - Blue arrow: tumor - Purple arrow: residual cortex - NOTE: TB and HIV are also important causes of chronic adrenal insufficiency

Answer 28

Hashimoto thyroiditis

Answer 29

- People w/**hemoglobin variants** like SICKLE CELL (hemoglobin S) will have DEC amt of hemoglobin A, which may limit usefulness of A1c test in dx and/or monitoring this pt's diabetes, depending on method - _Anemia, hemolysis, or heavy bleeding_: A1c test results may be falsely low - _Iron-deficient_: A1c level may be increased - _Recent blood transfusion_: A1c may be inaccurate and may not accurately reflect glucose control for 2 to 3 months

Answer 30

- _TUMORS_: pituitary, adenoma, craniopharyngioma, cerebral tumor - _HYPOTHALAMIC DISORDERS_: tumor, functional disturbance (e.g., anorexia), isolated GH, GnH secretion due to impaired secretion of hypothal releasing hormones - _MISCELLANEOUS_: sarcoidosis - _VASCULAR DS_: necrosis (Sheehan's), infarction, severe hypotension, cranial arteries - _TRAUMA_ - _INFECTION_: meningitis, esp. TB, syphilis - _IATROGENIC_: sx, irradiation, prolonged Rx with glucocorticoid or thyroid hormones -\> isolated TSH or ACTH suppression

Answer 31

- Insulinoma: hypoglycemia - Glucagonoma: necrolytic migratory erythema - Gastrinoma: peptic ulcers, diarrhea - Somatostatinoma: diabetes, cholelithiasis, steatorrhea - VIPoma: watery diarrhea, achlorhydria (no HCl production in stomach)

Answer 32

- **Adrenocortical** **adenoma**: distinguished from nodular hyperplasia by solitary, circumscribed nature 1. Atrophy of normal adrenal tissue, if functional, but can't really tell from gross image 2. Many incidental, and weigh \<30g 3. 10% secrete cortisol, 2% secrete aldosterone - _Histologic features_: neoplastic cells are **vacuolated** because of the presence of intracytoplasmic lipid 1. Mild nuclear pleomorphism 2. Mitotic activity and necrosis are **NOT** seen 3. Cells similar to those in normal zona fasciculata (see attached image) - _Note_: func status of adrenocortical adenoma can **NOT** be predicted from gross or micro appearance

Answer 33

- _Pancreatic beta-cell tumors_: most common type of pancreatic neuroendocrine tumor (1,200/yr) - Generally **INDOLENT**: 87% single benign, 7% multiple benign, \<10% malignant (most likely to metastasize bc most common, but most often indolent) - 8% part of **MEN1** syndrome: more likely to be synchronous (multiple occurring at same time) and metachronous (coming up at different times) - Patients will come in with **episodic hypoglycemia**

Answer 34

- **Necrolytic migratory erythema**: NOT specific to glucagonomas - Erythematous, _painful, pruritic rash_ that begins as macules that coalesce and develop central bullae, then erode, leaving _hyperpigmentation and crusting_ of the periphery - Usually begins in _perirectal area_ with subsequent spread to the perineum, thighs, buttocks and legs

Answer 35

- **Diffuse hyperplasia**: of the adrenal on the bottom vs. normal adrenal on the top 1. Cortex yellow and thickened, with a subtle nodularity - This abnormal gland was from a patient with ACTH-dependent Cushing syndrome, in whom both adrenals were diffusely hyperplastic

Answer 36

- Can cause seizures or cardiac arrhythmias, both of which can kill - Thought to account for 3-4% of deaths in insulin-treated diabetics

Answer 37

- **Follicular carcinoma**: 5-15% of 1^o thyroid cancers; more frequent in areas w/dietary iodine deficiency (25-40% of thyroid cancers) - More common in WOMEN (3 : 1) - Present more often in OLDER PTS (40-60) than do papillary carcinomas - Follicular adenoma vs. carcinoma = _capsular invasion or **vascular** invasion_ (and this invasion must be capsular or outside of the lesion) 1. One of few carcinomas that _spreads hematogenously_ -\> important bc even if you don’t see capsule being breached, this could be from how you cut/sectioned the tumor (but, if you have vessel invasion outside of the tumor, you can still call it follicular carcinoma)

Answer 38

- Most comm cause of chronic adrenal insufficiency in the Western world - Part of 2 autoimmune polyendocrine syndromes: 1. **APS1** (_AIRE_ gene): chronic mucocutaneous candidiasis + abnormalities of skin, dental enamel, and nails (ectodermal dystrophy) in assoc w/combo of organ-specific autoimmune disorders (autoimmune adrenalitis, autoimmune hypoparathyroidism, idiopathic hypogonadism, pernicious anemia) 2. **APS2**: combination of adrenal insufficiency and autoimmune thyroiditis or type 1 diabetes - NOTE: we do NOT need to know the specifics of these two mutations

Answer 39

- Usually small; stain w/PAS due to accumulation of glycosylated ACTH (incidence: 10-15%) - Can be clinically silent or cause hypercortisolism, this manifests as **CUSHING DISEASE** (the syndrome will be discussed with the adrenal) 1. ACTH stimulates the adrenal - Because ACTH is part of the larger prohormone that includes melanocyte-stimulating hormone (**MSH**), patients may have **hyperpigmentation**

Answer 40

- _α -cell tumors_ associated with INC serum levels of glucagon and a syndrome consisting of: 1. Mild diabetes mellitus, 2. Characteristic skin rash (necrolytic migratory erythema -\> smaller lesions that coalesce), and 3. Anemia - Occur most frequently in _perimenopausal and postmenopausal women_ and are characterized by extremely high plasma glucagon levels

Answer 41

- 85% in patients with **MEN-1** - Can also occur in: 1. Von-Hippel Lindau 2. Neurofibromatosis-1 3. Tuberous sclerosis

Answer 42

- _Rare_ (3,000/year in the US) - Most sporadic, and in middle-aged patients - Most (up to 75%) _non-functioning_, i.e., no assoc hormonal syndrome - All MALIGNANT unless microadenoma ( - _Liver_ is the most common site of metastases - **Serum chromogranin A** elevated in about 70% of pts with pancreatic NETs (functioning and non-functioning), but specificity is poor

Answer 43

- PAPILLARY CARCINOMA - Black: _intranuclear grooves_ - Blue: _pseudoinclusions_ (invaginations of the cytoplasm that cover up parts of the nucleus) - Green: _optically clear_ - This is an FNA: cells in a fluid, not tissue

Answer 44

- Papillae having a fibrovascular stalk covered by a single to multiple layers of cuboidal epithelial cells. - **Nuclear features**: 1) optically clear or empty, 2) intranuclear grooves, and 3) pseudoinculsions 1. _Dx can be made based on nuclear features_, even in absence of papillary architecture - PSAMMOMA BODIES (can happen in multiple contexts; not *always* an indicator for malignancy) - Foci of lymphatic invasion by tumor often present - **Metastases** to adjacent cervical lymph nodes occur in up to 50% of cases

Answer 45

Typically due to surgical interventions (but less common then hyperparathyroidism)

Answer 46

- Cortex: 1. Adrenal cortical adenoma 2. Adrenal cortical carcinoma - Medulla: 1. Pheochromocytoma 2. Neuroblastoma

Answer 47

- 2nd most common functional pituitary adenoma; effects can be subtle (incidence: 10-15%) - Persistent **GH** secretion stimulates hepatic release of **IGF-1** (somatostatin C), stimulating _bone, cartilage, soft tissue growth_ (clinical manifestations) 1. Gigantism (children), acromegaly (adults) - **Prolactin** can be produced in sufficient quantities to produce signs and symptoms - GH excess can also be associated with a variety of _other disturbances_, including: gonadal dysfunction, DM, generalized muscle weakness, HTN, arthritis, CHF, and INC risk of GI cancers - **Hyperglycemia** (diabetes): GH INH of peripheral glucose uptake and INC hepatic glucose production 1. Compensatory hyperinsulinism -\> insulin resistance -\> DM

Answer 48

- TRABECULAE - Non-neoplastic pancreas on the left - Tumor on the right (these don't all have capsules, but this one has a little one)

Answer 49

- _Auto-immune adrenalitis_: extensive mononuclear infiltrate - Most common cause of primary adrenocortical insufficiency in Western world - Autoantibodies to key steroidogenic enzymes **APS1 and APS2** - Irregular shrunken glands, but medulla preserved - Scant residual cortical cells in a collapsed network of connective tissue

Answer 50

CAH: suspect in neonates with ambiguous genitals

Answer 51

- **Metastatic adrenal neoplasms**: bilateral and multi-focal tumors *almost always* metastatic - Common sites of the primary tumors: LUNG, BREAST, KIDNEY - Most common malignancies in the adrenals, BY FAR = metastases

Answer 52

- Guanine nucleotide-binding protein (G-protein) mutations encoded by the **GNAS1 gene** - Lead to unchecked CELLULAR PROLIFERATION - _40% of GH-secreting somatotroph cell adenomas_ and a minority of ACTH-secreting adenomas bear GNAS1 mutations

Answer 53

- Left: pituitary ADENOMA -\> cellular monomorphism and **absence of a reticulin network** (reticulin stain highlights this) - Right: normal pituitary

Answer 54

- **Nephrosclerosis**: in a pt w/long-standing diabetes - Kidney has been bisected to show: 1. _Diffuse granular transformation_ of the surface (left), and 2. _Marked thinning of the cortical tissue_ (right) - Also some irregular depressions, the result of _pyelonephritis_, and an incidental cortical cyst (far right)

Answer 55

- Somatic muts of TSH receptor signaling pathway in toxic adenomas and toxic multinodular goiter; most often: 1. Gene encoding TSH receptor (**TSHR**) or α-subunit of G_s (**GNAS**) —\> cause follicular cells to secrete thyroid hormone independent of TSH stimulation (_“thyroid autonomy”_) a. Rare in follicular carcinomas - Leads to symptoms of hyperthyroidism and produces a functional **“hot” nodule** on imaging - Minority (\<20%) of nonfunctioning follicular adenomas have _RAS or PIK3CA muts_, genetic alterations that are shared with follicular carcinomas

Answer 56

Accidental removal of PTHs in surgery

Answer 57

- Small, bean-shaped structure at base of brain, in the confines of the _sella turcica_ - Intimately related to hypothalamus -\> connected by a stalk - Two morphologic and func distinct components: 1. Anterior 2. Posterior

Answer 58

- Thyroid – **medullary carcinoma** in the first two decades of life 1. Stain with calcitonin (C cells) - Adrenal medulla – 50% get **pheochromocytomas** - Parathyroid – 10-20% get hyperplasia and manifestations of primary hyperparathyroidism - _NOTE_: also familial medullary thyroid cancer (variant of 2A medullary cancer w/o clinical manifestations)

Answer 59

Normal adrenal histo

Answer 60

- **Hypothyroidism** in older children/adults - General apathy and mental sluggishness –\> can mimic depression - _Mucopolysaccaride-rich edematous fluid_ builds up broad, coarse facial fxs -\> large tongue, deep voice 1. GAGs build up in the tissue (more like a clay than a watery texture, unlike fluid edema) - Bowel slowing, causing constipation and _pericardial effusions_ are common - Cold intolerant and often overweight - **Measurement of serum TSH level is most sensitive screening test for this disorder**

Answer 61

**Hurthle cell adenoma**: enlarged epi cells w/abundant eosinophilic, granular cytoplasm as a result of altered mito (follicular in origin)

Answer 62

- Cushing syndrome - Hyperaldosteronism - Adrenogenital or virilizing syndromes

Answer 63

- Inherited diseases of **_multiple_** endocrine organs - Typically occur in **_younger_** patients (i.e., 30s) - Multifocal -\> can be synchronous or metachronous - Typically have **_hyperplasia_** of cell before neoplasm - Typically more **_aggressive and recur_** (vs. sporadic)

Answer 64

- Long-loop: 3rd hormone going back up - Short-loop: 2nd hormone - Ultra-short loop: auto-INH

Answer 65

- **Craniopharyngioma**: thought to arise from vestigial remnants of Rathke pouch 1. Slow-growing tumors that account for 1 - 5% of intracranial tumors 2. Bimodal age distribution: children and adults in 50s-60s - Pts come to attention due to _headaches and visual disturbances_ (bitemporal hemianopsia); children sometimes present with _growth retardation_ due to pituitary hypofunction and GH deficiency - Abnormalities of **WNT signaling pathway**, incl. activating muts of gene encoding **β-catenin**, have been reported in craniopharyngiomas in children - Note the **wet keratin** (NOT squamous cell carcinoma) and stellate reticulum (edema)

Answer 66

- Cavernous hemangiomas (port-wine spots) of trigeminal nerve (cranial nerve V) - Pheochromocytoma

Answer 67

- PAS stain of **nodular glomerulosclerosis** (Kimmelstiel-Wilson disease) in a pt with long-standing diabetes mellitus - Note also the markedly thickened arteriole at the lower right which is typical for the **hyaline arteriolosclerosis** that is seen in diabetic kidneys as well

Answer 68

- Autosomal recessive; F may have masculinization, and M have precocious puberty - Enzyme deficiencies, so no cortisol synthesis, and precursors shunted into excess androgen production - Most common form: **21-hydroxylase deficiency** (wastes sodium -\> hypotension) - 11-hydroxylase deficiency: retains sodium (HTN) bc DOC is a potent mineralocorticoid

Answer 69

- **ACTH-independent hyperplasia** (primary cortical hyperplasia) -\> very uncommon - _Micronodular_ hyperplasia: 1-3mm - Darkly pigmented (_lipofusion_) nodules with intervening atrophy

Answer 70

- **Diabetic neuropathy**: varies, depending on the duration of the disease - Up to 50% of diabetics overall have peripheral neuropathy clinically, and up to 80% of those who have had the disease for more than 15 years

Answer 71

- Any condition or treatment that destroys part or all of the pituitary gland - _PRIMARY TYPE_: **anatomic defect** in child 1. Subarachnoid space herniates into sella turcica and fills w/**CSF -\> pressure** compresses gland 2. INC in pressure on pituitary gland causes it to flatten out and undergo atrophy 3. Questions often include _obese patients with HTN_ and a history of multiple pregnancies - _SECONDARY TYPE_: **mass**, i.e., pituitary adenoma, enlarges sella and is then either **surgically removed** or undergoes infarction -\> loss of pituitary function

Answer 72

- Mesodermal origin - Glomerulosa: mineralocorticoids - Fasciculata: glucocorticoids - Reticularis: estrogens and androgens

Answer 73

- Pancreatic histo in **T1D**: leukocytic infiltrates in islets (**insulitis**) are principally composed of T-lymphos - Also seen in animal models of autoimmune diabetes - Reduction in the # and size of islets

Answer 74

- Ant pituitary loss: panhypopituitarism - Post pituitary loss: deficiency of ADH -\> diabetes insipidus

Answer 75

- **Subacute lymphocytic thyroiditis** (aka, painless thyroiditis -\> variant of Hashimoto) - Fine needle aspiration biopsy NOT typically part of the evaluation of painless thyroiditis - Lymphos and macros, normal thyroid epithelial cells, a _few damaged thyroid follicles_, and masses of colloid - During recovery, lymphocytic infiltration persists, may be mild fibrosis, but the thyroid follicles are normal - These findings _differ from those of chronic auto-immune thyroiditis_ in that there is: 1. More follicular disruption, but 2. Fewer lymphocytes, 3. Fewer germinal centers, and 4. Less fibrosis in painless thyroiditis

Answer 76

- Hypothyroidism that develops in infancy or early childhood - RARE now that iodine is supplemented in food - _Clinical features_: severe mental retardation 1. Short stature 2. Coarse facial features 3. Protruding tongue (and abdomen) 4. Umbilical hernia

Answer 77

- Typically incidental, discovered on imaging - _Non-functioning_ adenomas, with 2 exceptions: 1. 10% secrete cortisol (Cushing syndrome) 2. 2% secrete aldosterone (HTN + hypokalemia, aka, Conn syndrome) - Usually a yellow (or gold) color, like butter, bc lots of CHOLESTEROL

Answer 78

- Insulinoma - Hypoglycemia - Note: pancreatic neuroendocrine tumors are RARE

Answer 79

- **Catecholamine**-secreting tumor of adrenal medulla - Rare: 2,400/year in US (most comm in _middle age_) - _SYNDROMES_: up to 20% in pts with MEN-2, von Hippel-Lindau (VHL) syndrome, or Li-Fraumeni - _CLASSIC TRIAD_: 1) Episodic headache, 2) Sweating, 3) Tachycardia - Hypertension (+/- paroxysmal)

Answer 80

- Release of **vasoactive intestinal peptide** (VIP) 1. Watery diarrhea 2. _Hypokalemia_, hypovolemia, and acidosis 3. Achlorhydria (absent or reduced production of HCl in stomach) 4. _Severe diarrhea_ -\> VIP assay should be done on all pts w/severe, secretory diarrhea - Some are locally invasive and metastatic - _Neural crest tumors_, such as neuroblastomas, ganglioneuroblastoma, and ganglioneuromas and pheochromocytomas can also be associated with the VIPoma syndrome

Answer 81

- **Pheochromocytoma**: typically composed of cells in clusters (“Zellballen”) - Tumor cells often have abundant _BASOPHILIC cytoplasm_ -\> compare the pheo cells to the adrenal cortical cells in the lower right (in the right-hand image)

Answer 82

- Electron micrograph of a **β cell** shows the characteristic membrane-bound granules, each containing a _dense, often rectangular core and distinct halo_ - Portions of an **α cell** (left: _dense, round center_) and a **δ cell** (right) also show granules, but with closely apportioned membranes

Answer 83

- Chronic lymphocytic thyroiditis: breakdown in self-tolerance -\> AUTO-IMMUNE disease 1. Auto-Abs against **thyroglobulin** and **thyroid peroxidase** (lympho-mediated destruction) - 45-65 F; HLA-DR3, HLA-DR5 - Strong genetic component: most significant **CTLA-4** - Progressive depletion of thyroid epi cells, with replacement by inflam and fibrosis - Risk of developing _B-cell lymphoma_

Answer 84

- **Adrenal cortical adenoma**: looks a lot like normal zona glomerulosa, with mild pleomorphism - Abundant lipid - Really need to have the gross nodule to be able to tell that this is not normal

Answer 85

- **Diffuse mesangial sclerosis**: diffuse INC in mesangial matrix 1. INC in mesangial matrix, a slight INC in mesangial cellularity, and capillary BM thickening -\> will eventually become sclerotic - As disease progresses, expansion of mesangial areas _can extend to nodular configurations_ 1. Progression correlates with measures of deteriorating renal function -\> _INC proteinuria_

Answer 86

- Stress = bodily response to disturbances of homeostasis - Mediated by CATECHOLAMINES (acute) or CORTICOSTEROID hormones (chronic) - Causes tachycardia, HTN, hyperventilation and hyperglycemia

Answer 87

- 25-30% of all pituitary tumors (50% of adenomas) - Typically present w/**mass effect** symptoms - May compromise residual anterior pituitary sufficiently to cause **hypopituitarism**, which may appear slowly due to gradual enlargement of the adenoma or abruptly because of acute intra-tumoral hemorrhage (**pituitary apoplexy**)

Answer 88

- Hypersecretion of trophic hormones - Typically from an **anterior pituitary** adenoma - Adenomas are classified based on the hormone produced by the neoplastic cells: 1. Can be functional or non-functional 2. Most are **sporadic**; 5% are inherited 3. Arbitrary designation based on size (\<1cm = microadenoma; \>1cm macroadenoma) - _Non-functioning_ more likely to be macroadenomas and may cause hypopituitarism 1. **Mass effects**, e.g., bitemporal hemianopsia

Answer 89

- Adenomas - Pituitary adenomas may be hormonally inactive or produce excess prolactin, growth hormone, ACTH, thyrotropin, or gonadotropins

Answer 90

**Low glucose, low sodium, high potassium** ## Footnote - Tuberculosis used to be the most common cause of chronic adrenal insufficiency; now, idiopathic (presumably autoimmune) Addison's disease is much more often the cause for chronic adrenal insufficiency - **Lack of cortisol** leads to hypoglycemia, hyponatremia, and hyperkalemia

Answer 91

- Normal parathyroid on the right - **Parathyroid adenoma** on the left -\> major cause of 1^o hyperparathyroidism (the most common cause of asymptomatic hypercalcemia) 1. Most important distinction is the LACK OF FAT in the adenoma

Answer 92

- Renal atherosclerosis/arteriolosclerosis in diabetes - Thickening of renal arteriolar wall -\> "**onion skin**" appearance to the media - The thickening has left a tiny lumen

Answer 93

- **ADH deficiency**: excessive urination (polyuria) due to inability of kidney to resorb water properly from the urine -\> can occur in a variety of conditions - Clinical manifestations: _excretion of large volumes of dilute urine_ w/lower than normal specific gravity - Serum Na+, osmolality INC by excessive renal loss of free water -\> _thirst and polydipsia_ - Pts who can drink water generally compensate for urinary losses, but pts who are obtunded, bedridden, or limited in their ability to obtain water may develop life-threatening dehydration

Answer 94

- Biopsy in pt w/**chronic renal failure** -\> yields little useful information - TOP ARROW: _atherosclerosis & arteriolosclerosis_ severely affect the kidney in DM - NEXT ARROW: cortex is fibrotic, glomeruli are sclerotic, the arteries are thickened, and there are scattered _chronic inflammatory cell infiltrates_ - BOTTOM ARROW: _sclerotic glomeruli_ - CIRCLE: tubules often dilated and filled with pink casts -\> "**thyroidization**"

Answer 95

- Patient with adrenal atrophy due to: 1. Long-standing Addison's, or 2. Long-term corticosteroid therapy

Answer 96

- **Diffuse thickening of BMs**: most evident in skin caps, skeletal muscle, retina, renal glomeruli, and renal medulla 1. May also be seen in nonvascular structures like renal tubules, Bowman capsule, peripheral nerves, and placenta 2. Underlies devo of _nephropathy, retinopathy, and some forms of neuropathy_ - Despite iINC in thickness of BMs, **diabetic caps are more leaky than normal** to plasma proteins - An indistinguishable microangiopathy can be found in aged nondiabetic patients, but rarely to the extent seen in patients with long-standing diabetes

Answer 97

- **Nelson's Syndrome**: 20-30% of these cases - Hyperpigmentation - Visual field defects (bilateral hemianopsia) or cranial nerve symptoms

Answer 98

- Essence of DM - Causes excess glucose stuck to everything (**GLYCOSYLATION**), but especially basement membranes - Excess IC glucose can go down **sorbitol pathway** to fructose, even more potent glycosylator than glucose

Answer 99

Presence of small amounts of albumin (**microalbuminuria**) of up to 200 mg/24hr in the urine

Answer 100

- LH-producing and FSH-producing (35% incidence): gonadal regulation of germ-cell devo and sex steroid hormones - Can be difficult to recognize bc **typically non-functioning** (or can cause hypogonadism) 1. _Mass effects_ and hypopituitarism can occur w/any tumor when large, but more characteristic of this type of tumor - If deficiency, most often impaired secretion of LH - FSH is usually the predominant secreted hormone

Answer 101

- ANAPLASTIC CARCINOMA - Large, pleomorphic **giant cells**, including occasional osteoclast-like multinucleate giant cells - **Spindle cells** with a sarcomatous appearance

Answer 102

- Silent, or painless, thyroiditis: think about this when pt presents w/in 1 year of delivery - Thyrotoxicosis, then hypothyroidism; only about 1/3rd of women show evidence of both phases - _Thyrotoxic phase_ 1-4 mos post-delivery and lasts 1-3 mos: anxiety, insomnia, palpitations, fatigue, weight loss, irritability -\> often missed - Much more common for women to present in the _hypothyroid phase_: 4-8 mos post-delivery and may last up to 9-18 mos 1. Symptoms: fatigue, weight gain, constipation, dry skin, depression, poor exercise tolerance - Most women will have return of thyroid function, but 20% of those that go into a hypothyroid phase will remain hypothyroid - If therapy is needed, it will be tapered

Answer 103

Goiter caused by thyroid follicular hyperplasia

Answer 104

- **Nelson syndrome**: large, destructive pituitary adenomas that devo after sx removal of the adrenal glands (to tx Cushing's) - Loss of INH effect of adrenal corticosteroids on a _preexisting corticotroph (ACTH) microadenoma_ 1. Because adrenals are absent in persons with this disorder, hypercortisolism does NOT devo - Hyperpigmentation possible bc stimulatory effect of **MSH** on melanocytes (o/product of ACTH precursor)

Answer 105

- Group of metabolic disorders: common feature is HYPERGLYCEMIA - Defect is typically with _insulin secretion and action_ in combination - Almost **7% of population** is effected by diabetes; up to 1/3 might not even be diagnosed - Leading cause of: END-STAGE **RENAL** DIAEASE, ADULT-ONSET **BLINDNESS**, and NONTRAUMATIC LOWER EXTREMITY **AMPUTATION**

Answer 106

- Normally, there are 4 parathyroids, but **up to 8** can occur - Normally located posterior to thyroid at upper and lower poles, but _sometimes reside in the thyroid, or below it, even as low as in the mediastinum_ - NOTE: these anatomic variations are very important for SURGEONS

Answer 107

- HASHIMOTO THYROIDITIS - Chronic inflam of _T-lymphos_, incl follicle formation 1. Germinal center in top right 2. Hyper -\> Eu -\> Hypothyroid - Remaining tissue can become atrophic, and undergo _Hurthle cell change_ (follicular cells get more abundant pink cytoplasm) - Risk of developing _B-cell lymphoma_

Answer 108

- 5% of cases of hyperthyroidism (2^o to thyroid tissue damage) - Middle-aged F - _Mild goiter or hyperthyroidism_ -\> most recover, but some progress to hypothyroidism - AUTO-IMMUNE: **anti-thyroid peroxidase Abs** 1. Thyroid peroxidase oxidizes iodide ions to form iodine atoms for addition onto tyrosine residues on thyroglobulin for the production of thyroxine (T4) or triiodothyronine (T3) -\> image attached - Excludes women who have a painless thyroiditis syndrome w/in 1 yr of delivery, abortion, or miscarriage (silent can be associated w/pregnancy, per Dr. Steinberg)

Answer 109

- Multiple insulinomas in a patient with Type 1 Multiple Endocrine Neoplasia (**MEN1**) - Tumors are a brown color - Remember: tumors in the context of a syndrome more likely to be synchronous and metachronous

Answer 110

- Stores antidiuretic hormone (**ADH**) 1. ADH controls total body water 2. Presence of ADH induces concentration of urine 3. Absence of ADH produces dilution of urine 4. _SYNDROMES_: *Diabetes insipidus, SIADH* - Releases **oxytocin** after suckling 1. Causes milk ejection and uterine contractions

Answer 111

- Normal adrenal gland histology: 1. Capsule 2. Zona glomerulosa 3. Zona fasciculata 4. Zona reticularis 5. Medulla - Lot of fat is going to clue you in this is the adrenal

Answer 112

- **Addison disease**: 90% caused by auto-immune disease, AIDS, infection, or cancer - 90% of tissue has to be destroyed for clinical manifestations, which include: 1. Fatigue, weakness, GI disturbances 2. 1^o adrenocortical insufficiency also has high ACTH levels and skin pigmentation - ACTH stimulation test: improvement w/ACTH admin suggests secondary (pituitary/hypothalamic) disease

Answer 113

- LSH, FH - Hypogonadism, mass effect and hypopituitarism

Answer 114

- Malignant OR benign - More likely _malignant in kids_ –\> Li-Fraumeni (p53) and Beckwith-Wiedemann - Functional adenomas or carcinomas of the adrenal cortex are _NOT morphologically distinct_ from non-functioning adrenal neoplasms 1. **Carcinomas are more likely to be functional** and virilizing (masculinizing)

Answer 115

Congenital Adrenal Hyperplasia

Answer 116

- **Pyelonephritis**: acute or chronic inflammation of the kidneys (more common in diabetics, and tends to be more severe involvement) - Usually begins in interstitial tissue, then spreads to affect the tubules - One special pattern of acute pyelonephritis, _necrotizing papillitis_ (or papillary necrosis), is much more prevalent in diabetics than in nondiabetics

Answer 117

- BENIGN neoplasms outnumber carcinomas 10 : 1 1. Most are indolent; \>90% of affected patients are alive 20 years after being diagnosed - **Solitary nodules**, in general, are more likely to be neoplastic than are multiple nodules 1. Nodules in YOUNG PTS more likely neoplastic 2. Nodules in MALES are more likely neoplastic - Hx of **radiation tx to head and neck** region assoc with an INC incidence of thyroid malignancy (higher risk w/radiation if pt has hereditary telangiectasias) - Functional nodules that take up radioactive iodine in imaging studies (**hot nodules**) are **much more likely to be BENIGN than malignant**

Answer 118

- 10% extra-adrenal - 10% malignant (presence of metastases) - 10% of sporadic pheos are bilateral - NOTE: 25% of pheos are familial (germline mutation)

Answer 119

- _Subacute (de Quervain) granulomatous thyroiditis_ - Self limited; symptomatic treatment - Often after flu-like symptoms - Acute phase may be associated with mild hyperthyroidism, which is usually followed by a period of hypothyroidism - GRANULOMAS and lymphoplasmacytic (chronic) inflitrate - Note: memory tool -\> vain = pain

Answer 120

- **T1D**: ABSOLUTE deficiency of insulin secretion due to AUTOIMMUNE pancreatic beta cells destruction - **T2D** (80-90% of diabetics): combo of peripheral resistance + inadequate beta cell response (genetic component) - Despite different causes, **end results are similar**: complications in kidneys, eyes, and blood vessels - _NOTE_: there can be o/causes, including infections, pancreatitis, drugs, etc.

Answer 121

- Upregulates **CD11b** on neutrophils - Also upregulates **ICAM-1, VCAM-1,** and **E-selectin** on endothelial cells - Creates an “ADHESIVE PHENOTYPE” - This all impairs neutrophil exodus from blood vessels to sites of infection

Answer 122

- This tumor is an INSULINOMA - However, stains often do NOT correlate with secretion - NOT helpful when really needed

Answer 123

- _Persistent hyperglycemia_ (“glucotoxicity”) seems to be responsible for the long term complications of diabetes - Morbidity associated with longstanding diabetes of either type is due to: 1. Damage induced in large- and medium-sized muscular arteries (**diabetic macrovascular disease**) 2. Small vessels damage (**diabetic microvascular disease**) 3. Both by chronic hyperglycemia

Answer 124

- GH and prolactin - Combined features of prolactin and GH excess

Answer 125

- IHC calcitonin stain - Identifies the C (parafollicular) cells, which secrete CALCITONIN

Answer 126

- Impairs hepatic _gluconeogenesis_ - Does NOT impair hepatic glycogenolysis, but liver glycogen stores average around 8 hours - 1 day of binge drinking w/o eating is unlikely to cause hypoglycemia, but a 2-3 day binge is much more likely to do so

Answer 127

- Renal cortex showing **thickening of tubular basement membranes** in a diabetic patient (left image; PAS stain) - Microangiopathy

Answer 128

- PRIMARY: adrenal disease 1. _Acute_: adrenal crisis, acute hemorrhagic necrosis 2. _Chronic/Addison_: lots of causes -\> **auto-immune**, infection (TB, fungal), amyloid, sarcoid, metastatic carcinoma - SECONDARY: DEC stimulation of adrenals due to deficiency of ACTH 1. _Pituitary neoplasm_ or inflammation 2. _Long-term steroids_ - **NOTE**: bc of blood supply, metastatic carcinoma LOVES to go to the adrenals (much more common than other cancers in the adrenals, if multiple nodules -\> especially from the lung)

Answer 129

- **Parathyroid adenoma**: cause 85-95% of HYPER- PARATHYROIDISM - Tumors _usually found on routine blood tests_ when they reveal elevated blood calcium and PTH levels 1. In more serious cases, bone density will diminish and kidney stones can form 2. Other non-specific symptoms include depression, muscle weakness, and fatigue - Clinical triad: **moans, bones, and stones** - Red arrow: _rim of normal parathyroid tissue_

Answer 130

- **Neuroblastoma**: small cell tumor composed of malignant neuroblasts; well-circumscribed - Arrows: Homer-Wright rosettes -\> neural appearing center with cells wrapped around it - See attached image for gross appearance

Answer 131

- Expanded zona reticularis in adrenal hyperplasia

Answer 132

- GH - Gigantism in children - Acromegaly in adults

Answer 133

- **Spironolactone bodies** in aldosterone-producing adenoma: eosinophilic, laminated cytoplasmic inclusions (characteristic feature) - Found after treatment with the antihypertensive agent spironolactone, which is the drug of choice in primary hyperaldosteronism - NOTE: in contrast to cortical adenomas associated with Cushing syndrome, those associated with hyperaldosteronism do NOT usually suppress ACTH secretion -\> _adjacent adrenal cortex and that of the contralateral gland are NOT atrophic_

Answer 134

- Glucose production by the liver - Glucose uptake and utilization by peripheral tissues -\> insulin's principal job is to INC rate of glucose transport into cell to become ATP - Actions of insulin and counterregulatory hormones (glucagon) responsible for both of the above - REMEMBER: brain is NOT dependent on insulin

Answer 135

- Top row: pt w/_adrenal atrophy_ -\> either Addison's disease or long-term corticosteroid therapy - Middle: NORMAL - Bottom row: _bilateral cortical hyperplasia_; could be due to pituitary adenoma secreting ACTH (Cushing's disease), Cushing's syndrome from ectopic ACTH production, or idiopathic adrenal hyperplasia

Answer 136

Adrenal cortical adenoma (lipid-rich, like normal zona glomerulosa)

Answer 137

- ACTH and other POMC-derived peptides (i.e., MSH) - Cushing syndrome - _Nelson syndrome_: rapid enlargement of a pre-existing ACTH-secreting pituitary adenoma after removal of the adrenals due to lack of negative feedback from cortisol on ACTH production 1. Signs/symptoms: muscle weakness, skin hyperpigmentation (rare syndrome now)

Answer 138

- **Amyloid deposition** in islets in **T2D**: begins in and around capillaries, and between cells - May be a subtle reduction in islet cell mass - At advanced stages, the islets may be virtually obliterated; fibrosis may also be observed - Similar lesions may be found in older nondiabetics, as part of normal aging

Answer 139

- Physiologic expansion of pituitary gland during pregnancy -\> NOT accompanied by INC in blood supply from low-pressure venous system, so there is relative **hypoxia** - _Posterior pituitary usually NOT affected_: receives blood directly from arterial branches, so it is much less susceptible to ischemic injury - Can get empty sella from this -\> first thing mom will notice is that she **cannot lactate** - Can get some GENITAL HAIR LOSS as well

Answer 140

- **Aldosterone-producing adenoma**: almost always solitary, small (\<2 cm diameter), well-circumscribed lesions - Characteristic feature is presence of eosinophilic, laminated cytoplasmic inclusions -\> _spironolactone bodies_ 1. Found AFTER tx w/antihypertensive agent spironolactone, the drug of choice in primary hyperaldosteronism

Answer 141

- Most common cause of primary hyperaldosteronism - Diffuse and focal hyperplasia of cells resembling normal glomerulosa - Often wedge shaped

Answer 142

- **Necrotizing papillitis**, complicating acute pyelonephritis 1. Much more prevalent in diabetics than in non-diabetics - Infarct-like papillary necrosis (blue arrow) with surrounding cellular exudate (red arrow)

Answer 143

- MEN-1, MEN-2A, MEN-2B, Sturge Weber, VHL, von-Recklinghausen (neurofibromatosis type 1) - Probably **10% of cases** - Usually _younger_ age of onset: 10-20-y/o vs. 40-60 - _Bilateral_: 70% vs. 10% of sporadic - Multicentric - Associated with other neoplasms, male gender

Answer 144

- Prolactin - FEMALES: galactorrhea, amenorrhea - Sexual dysfunction and infertility (M and F)

Answer 145

- Acute adrenal insufficiency - Typical "bag of blood" appearance of hemorrhagic adrenals

Answer 146

- Occurs in areas where the _environment is low in naturally occurring iodine_ (Albania, Bangladesh, Ethiopia examples provided in class) - "Endemic” if **\>10% of the population** has goiter - Other causative factors (diet, genetics) contribute - Starts as diffuse thyroid enlargement, but generally progresses (through multiple episodes of regression and enlargement) to **multinodular state**

Answer 147

- **ADH excess**: resorption of excessive amounts of free water, resulting in _hyponatremia_ - Most frequent causes of SIADH are secretion of ectopic ADH by malignant neoplasms (particularly _small-cell carcinoma_ of the lung) - Clinical manifestations: hyponatremia, _cerebral edema_, and resultant neurologic dysfunction - While total body water is INC, blood volume normal, and **NO peripheral edema**

Answer 148

- Based on **mitotic figures and Ki-67** staining: 1. LOW grade (G1): \<2 mitoses / 10 hpf AND \<3% Ki67 index 2. INTERMEDIATE grade (G2): 2-20 mitoses / 10 HPF OR 3%-20% Ki67 index 3. HIGH grade (G3): \>20 mitoses / 10 hpf OR \>20% Ki67 index - _High grade = higher propensity to metastasize_, but this does not mean that it has, or will (can’t really tell based on histology many times) - **BONA FIDE CARCINOMAS DX'D ON BASIS OF LOCAL INVASION AND DISTANT METASTASES** - Don't need to memorize these numbers, but know there is a grading system

Answer 149

- Gliomas and craniopharyngiomas (the latter are mostly in kids, but can also be in adults in 50s, 60s) - Neoplasms in this location _may induce hypo- or hyperfunction of the anterior pituitary, diabetes insipidus_, or combinations of these manifestations

Answer 150

- MEN1 –\> associated with MEN syndrome type 1 - CDKN1B –\> subset of “MEN-like” abnormalities - PRKAR1A - AIP –\> GH adenoma pts younger at presentation - _ATYPICAL ADENOMAS_: muts of p53 in pituitary adenomas associated w/more **aggressive** behavior (invasion/recurrence)

Answer 151

- THYROID GLAND - Left image: 1. **Hurthle cells**: enlarged epi cells with abundant eosinophilic, granular cytoplasm as a result of altered mito (follicular in origin) 2. Lymphocytes - Right Image: follicular cells in a follicular adenoma

Answer 152

- **Graves disease**: tall, columnar appearance with small clear vacuoles that create SCALLOPED EDGE - Lab: 1. TSH decreased in the serum 2. Free T3 and T4 are elevated

Answer 153

- Shakiness - Sweatiness - Nervousness - Hunger - Weakness - Visual disturbances - Palpitations - Pallor - Mental status changes (patient may not remember)

Answer 154

- SUPPORTS lipogenesis (glucose storage as lipid in adipose) - PREVENTS lipolysis - Does the same with protein

Answer 155

- Graves - Pretibial myxedema

Answer 156

- GH: pituitary dwarfism - Gonadotropin: amenorrhea, infertility in F; DEC libido, impotence, loss of pubic/axillary hair in M - TSH: hypothyroidsim - ACTH: hypoadrenalism and pallor - Prolactin: postpartum lactation failure

Answer 157

- Low dose at 12pm suppresses 8am cortisol = NORMAL - High dose at 12pm suppresses cortisol = ACTH-producing pituitary adenoma only - Neither of these suppresses cortisol = look outside of the pituitary (i.e., adrenals or paraneoplastic syndrome)

Answer 158

- _Glucagonoma_: anemia, diabetes, necrolytic migratory erythema - _Insulinoma_: hypoglycemia, confusion, blurred vision, muscle weakness, sweating, palpitations - _Gastrinoma_: Zollinger-Ellison syndrome -\> parietal cell hyperplasia, peptic ulcers - _VIPoma_: vasoactive intestinal peptide -\> achlorhydria (no HCl production), severe diarrhea, hypokalemia, acidosis, hypovolemia - _Somatostatinoma_: achlorhydria, cholelithiasis, diabetes, steatorrhea

Answer 159

- Painless goiter - Peripheral edema - Headache and joint ache - Anovulation (women) - Anti-thyroid Abs that block and destroy thryoid function

Answer 160

- Hashimoto thyroiditis - Granulomatous (de Quervain) thyroiditis - Subacute lymphocytic thyroiditis

Answer 161

- **Pancreatic NET**: small, bland, uniform, monotonous, benign-looking cells - Arranged in nests or cords - Round-to-oval nuclei and inconspicuous nucleoli - Stippled chromatin pattern sometimes called “salt and pepper," and scant pink eosinophilic granular cytoplasm 1. Note: salt and pepper chromatin does NOT make these cells malignant

Answer 162

- **Pancreatic NET**: small, bland, uniform, monotonous, benign-looking cells - Arranged in nests or cords - Round-to-oval nuclei and inconspicuous nucleoli - Stippled chromatin pattern sometimes called “salt and pepper," and scant pink eosinophilic granular cytoplasm - These all look the same, regardless of the organ

Answer 163

- **Enlargement of the thyroid**: typically from a dietary iodine deficiency 1. **INC TSH** = hypertrophy/plasia of follicular cells 2. Creates MASS EFFECT - Minority of pts may devo hyperthyroidism (toxic multi-nodular goiter) -\> _PLUMMER SYNDROME_ 1. NOT accompanied by infiltrative opthalmopathy and dermopathy of Graves - **Endemic** type is geographic; **sporadic** type is rare, and typically in F where there is INC physiologic demand for T4

Answer 164

- **Adrenal cortical carcinoma**: INVASION (into vein here) and METASTASES are most reliable indicators of malignancy - Closely resembles normal adrenal cortex; difficult to determine malignancy in endocrine neoplasms based on cytology alone - Most endocrine neoplasms are benign adenomas

Answer 165

- 2nd most comm pancreatic neuroendocrine tumor - _Zollinger-Ellison syndrome_: 1. Unrelenting peptic ulcer disease, 2. Hypersecretion of acid, and 3. Pancreatic islet cell lesion - Just as likely to arise in the duodenum and peri-pancreatic soft tissues as in the pancreas (so-called _gastrinoma triangle_) - 25% are in pts with **MEN-1** - _Treatment-resistant_ -\> do not go away (definitive tx is removal of the tumor) - Cells still really monotonous, w/trabecular pattern

Answer 166

- **Neuroendocrine** tumor derived from parafollicular (C cells) -\> secrete CALCITONIN - Approx. 5% of thyroid neoplasms - 70% of tumors sporadic, others associated with: 1. _MEN syndrome 2A or 2B_: younger pts (may even arise during 1st decade of life) a. MEN = multiple endocrine neoplasia 2. Familial tumors w/o assoc MEN syndrome (familial medullary thyroid carcinoma, or FMTC) - Activating point mutations in **RET proto-oncogene** play an important role in the development of both familial and sporadic medullary carcinomas - Sporadic and familial medullary carcinomas are _lesions of adulthood_: peak incidence in 40s, 50s

Answer 167

- **Follicular adenoma** - Follicular growth pattern usually quite distinct from the adjacent nonneoplastic thyroid - Neoplastic cells show little variation in cell size, cell shape, or nuclear morphology

Answer 168

- Tighter control of blood sugar (hypoglycemic episodes especially likely during sleep) - Missed meals - Exercise - Weight loss - Renal failure: DEC insulin clearance

Answer 169

Hyperparathyroidism

Answer 170

- CLINICAL: usually adult onset; INC incidence in childhood and adolescence 1. Vast majority are obese (80%) 2. INC blood insulin (early); normal or moderate decrease in insulin (late) 3. No islet autoantibodies 3. **Nonketotic hyperosmolar coma** more common than DKA - GENETICS: candidate diabetogenic and obesity-related genes (**TCF7L2**, PPARG, FTO); NO HLA link - PATHOGEN: insulin resistance in peripheral tissue, and failure of compensation by β-cells 1. Multiple **obesity-assoc factors** (circulating nonesterified FAs, inflammatory mediators, adipocytokines) linked to insulin resistance - PATHOLOGY: NO insulitis; **amyloid deposition** in islets, mild β-cell depletion

Answer 171

- Transverse CT and MR images in a 35-year-old woman with VHL syndrome and pancreatic NET - Left: contrast-enhanced CT scan shows a 2.0 x 1.8-cm **mass in the pancreatic head** (arrows) that is homogeneously enhancing - Right: T1-weighted spoiled gradient-echo MR image of same mass (arrows) 7 months later -\> well defined, low in signal intensity, and has increased slightly in size (2.2 x 2.0 cm)

Answer 172

- **Tall cell variant** of papillary carcinoma: cells twice as tall as wide comprise 50% of tumor - Abundant eosinophilic cytoplasm and papillary nuclear features - Aggressive behavior

Answer 173

- CLINICAL: usually childhood, adolescence onset; marked by triad of **polyuria, polydipsia, polyphagia** 1. Normal weight or weight loss preceding diagnosis 2. Progressive DEC in insulin levels 3. Circulating islet autoantibodies (anti-insulin, anti-GAD, anti-ICA512) 4. **DKA** in absence of insulin therapy - GENETICS: MHC class II genes (**HLA-DR3 or HLA-DR4**), polymorphisms in **CTLA4** and PTPN22 (INH T-cell response), and insulin gene variable number tandem repeats (VNDRs) - PATHOGEN: dysfunction in T cell selection and regulation, leading to breakdown in self-tolerance to islet autoantigens - PATHOLOGY: **insulitis** (inflam infiltrate of T cells and macrophages), β-cell depletion, islet atrophy

Answer 174

- _Pituitary/hypothalamus_: e.g., a tumor, aka, Cushing disease - _Adrenal_: nodular hyperplasia, adenoma, or carcinoma - _Paraneoplastic_: lung (most often small cell) or other neuroendocrine cancer that makes ACTH - _Iatrogenic_: via corticosteroids - MNEMONIC: **A**drenal, **C**ushing disease, **T**umor secreting ACTH, **H**ormone therapy

Answer 175

- _δ -cell tumors_: high plasma somatostatin levels are required for diagnosis - Somatostatinoma syndrome (only **10% of pts** with the tumor have this syndrome): 1. _Diabetes mellitus_: INH insulin release from beta cells 2. _Cholelithiasis_: gall stones bc INH release of cholecystokinin, delaying gallbladder emptying 3. _Steatorrhea_: INH pancreatic secretion and lipid absorption - Smelly, greasy diarrhea due to fat malabsorption

Answer 176

- **Reidel thyroiditis**: rare, unknown etiology 1. Young women; will describe as "_woody_" - **Extensive fibrosis** that may be associated with idiopathic fibrosis in other parts of the body - HISTO: 1) Fibrosis, 2) Lymphocytes, 3) Hyperplastic germinal centers - _Infiltrative_: surgeon goes in, and has a really hard time getting everything out - Main thing is to be able to distinguish this from a carcinoma, in which you would be able to see the cells, not just this kind of diffuse fibrosis

Answer 177

- Substances that interfere with thyroid hormone syn at some level when they are ingested - Examples: vegetables belonging to the **Brassicaceae (Cruciferae) family** (e.g., cabbage, cauliflower, brussel sprouts, turnips)

Answer 178

- Sites of paraganglia in which neoplasms may form: 1. Branchiomeric 2. Intra-vagal 3. Aortico-sympathetic - Paragangliomas can be thought of as extra-adrenal pheochromocytomas - Looks the same as pheo histologically

Answer 179

- Most common cause of hyperthyroidism - Autoimmune disease with **autoantibodies to TSH receptors** (thyroid-stimulating immunoglobulin and thyroid growth-stimulating immunoglobulins) - Association with **HLA-DR3** - Thyroid hyperplasia characterized by papillary infoldings

Answer 180

- Diffuse enlargement of thyroid gland - Infiltrative **opthalmopathy**: inflam cells + accumulated extracellular matrix components + fatty infiltration - Infiltrative **dermatopathy** (sometimes caller pretibial _myxedema_): if present is from glycosaminoglycans and lymphocytes

Answer 181

- Undifferentiated tumors of thyroid follicular epi - \< 5% of thyroid tumors - **AGGRESSIVE** -\> almost 100% mortality - Found in _older patients_, _rapid enlargement_ - Often have a history of a well-differentiated thyroid carcinoma, or harbor concurrent well-differentiated tumor in the resected specimen

Answer 182

- Diabetic ocular complications: 1. Flame-shaped and dot-blot hemorrhages 2. Cotton-wool spots: soft exudates, e.g., microinfarcts 3. Microaneurysms

Answer 183

- MEN2a signs/symptoms: 100% medullary thyroid carcinoma, 30-50% pheochromocytoma, (+) mucosal neuromas and ganglioneuromas 1. May lack parathyroid hyperplasia - Autosomal dominant or sporadic

Answer 184

- Small group of uncommon diseases due to excess aldosterone production - Clinically characterized by: **HTN and hypokalemia** (BP high and potassium low) - Most common primary: aldosterone-secreting cortical adenoma -\> _CONN SYNDROME_

Answer 185

- MEDULLARY CARCINOMA - _Polygonal to spindle-shaped_ cells, which may form nests, trabeculae, and even follicles - **Calcitonin** is readily demonstrable in cytoplasm of the tumor cells - Acellular **amyloid** deposits derived from calcitonin polypeptides present in the stroma in many cases 1. Amyloid is the pink, amorphous, anuclear part

Answer 186

- Electron micrograph of a renal glomerulus showing markedly **thickened glomerular basement membrane** (left) in a diabetic (MICROANGIOPATHY)

Answer 187

Caseating TB granuloma in the adrenal gland ## Footnote - _Note_: histoplasma, coccidioides, and HIV can also cause chronic adrenal insufficiency

Answer 188

- Can be caused by focal or diffuse hyperplasia of the islets -\> found occasionally in adults, but more commonly in **congenital hyperinsulinism** with hypoglycemia in neonates and infants - Several clinical scenarios may cause islet hyperplasia (aka, nesidioblastosis), including: 1. **Maternal diabetes**: fetal islets respond to hyperglycemia by INC size/# -\> in postnatal period, hyperactive islets may cause serious episodes of hypoglycemia (usually transient) 2. _Beckwith-Wiedemann syndrome_ (complex syndrome: nevus flammeus + macroglossia + other developmental abnormalities), and 3. Rare _mutations_ in the β-cell K + channel protein or sulfonylurea receptor

Answer 189

- MEDULLARY CARCINOMA - _Polygonal to spindle-shaped_ cells, which may form nests, trabeculae, and even follicles - **Calcitonin** is readily demonstrable in cytoplasm of the tumor cells - Acellular **amyloid** deposits derived from calcitonin polypeptides present in the stroma in many cases 1. Amyloid is the pink, amorphous, anuclear part

Answer 190

- **Thyroglossal duct cyst** - Usually MIDLINE, between isthmus of thyroid and hyoid bone - Usually apparent at _birth or in childhood_ - Tend to get repeated INFECTIONS - NOT hormonally active

Answer 191

- PRIMARY: 1. Diffuse hyperplasia (Graves) a. Neonatal thyrotoxicosis assoc w/maternal Graves 2. Hyperfunctioning toxic multinodular goiter 3. Hyperfunctioning toxic adenoma 4. Iodine-induced hyperthyroidism - SECONDARY: 1. TSH-secreting pituitary adenoma (rare)

Answer 192

- BETA CELLS: **insulin** -\> proteolytically cleaved in the Golgi complex to gen the mature hormone and the byproduct, C-peptide 1. Both are then stored in secretory granules, and secreted in equimolar quantities after physiologic stimulation - ALPHA CELLS: **glucagon** - DELTA CELLS: **somatostatin** - See attached image for relative distribution of these 3 types of cells and their contents (immunoperoxidase stains w/dark rxn products)

Answer 193

- HYPER: Graves - HYPO: Hashimoto's thyroiditis (in iodine-sufficient parts of the world)

Answer 194

- Slowly enlarging **painless** nodule - Typically “**cold**” on scintigrams - PROGNOSIS depends largely on extent of invasion and stage at presentation 1. _Widely invasive_: often presents w/systemic metastases; as many as half of affected pts succumb to their disease within 10 years 2. _Minimally invasive_: 10-year survival rate of greater than 90%

Answer 195

- Initially leads to a painless enlargement of the gland - Atrophy follows years later -\> this will lead to a HIGH level of TSH

Answer 196

- Papillary: \>85% of cases - Follicular carcinoma: 5% to 15% of cases - Medullary carcinoma: 5% of cases - Anaplastic (undifferentiated): \<5% of cases

Answer 197

- 4 parathyroid glands (2 superior, 2 inferior) devo from the 3rd and 4th branchial pouches - _Inferior -\> 3rd branchial pouch_; also gives rise to the thymus (DiGeorge) - _Superior -\> 4th branchial pouch_

Answer 198

- DEC insulin: kicks in at glucose \< about 80 or so - INC glucagon: glucose \< 70 - INC epinephrine: glucose \<70 - INC cortisol: glucose \< 70 (but not rapidly helpful) - Symptoms: glucose \< 50

Answer 199

- Beta subunit - These hormones are alpha-beta dimers, and the alpha subunits of all 3 are quite similar - BIOLOGICAL ACTIVITY DETERMINED BY THE BETA SUBUNIT

Answer 200

- **DEC secretion of pituitary hormones** -\> can result from diseases of hypothalamus or the pituitary 1. About _75% of parenchyma is lost_ or absent 2. Partial or complete loss of secretion of one or more hormones - 3 most common causes: 1. _Nonfunctioning adenoma_: compression 2. _Sheehan’s syndrome_: infarction during parturition 3. _Empty sella syndrome_: any condition or tx that destroys all or some of the pituitary

Answer 201

- **Diabetic macrovascular disease**: takes the form of an amorphous, hyaline thickening of the wall of the arterioles, which causes narrowing of the lumen - HYALINE ARTERIOSCLEROSIS, the vascular lesion associated with HTN is both _more prevalent and more severe in diabetics than in nondiabetics_

Answer 202

- Left: pancreatic NET -\> sheets of uniform cells with "salt and pepper" chromatin - Right: normal pancreatic islet

Answer 203

- MOST COMMON type of hyperfunctioning pituitary adenoma (incidence: 35%) - IHC shows prolactin in neoplastic cell cytoplasm - HYPERPROLACTINEMIA causes: 1) amenorrhea 2) galactorrhea 3) loss of libido, and 4) infertility - _NOTE_: any mass in the area can disturb prolactin secretion, so called “**stalk effect**” -\> mild elevations in serum prolactin (\<200 ug/L) do not necessarily indicate a prolactin secreting neoplasm

Answer 204

- **Acute adrenal insufficiency** - Causes include: 1. Waterhouse-Friderichson syndrome 2. Sudden withdrawal of exogenous steroids 3. Sudden stress in a patient w/chronic adrenal insufficiency

Answer 205

- **Lateral aberrant thyroid**: embryonic rests in lateral neck, sometimes in lymph nodes 1. Lymph node with ectopic thyroid: _metastatic until proven otherwise_ - Beware, especially in adults: what seems to be lateral aberrant thyroid is _most likely metastatic follicular thyroid carcinoma_ - NOTE: in paratracheal musculature (left-hand image) and outer cervical musculature (right-hand)

Answer 206

- ADENOMA: derived from FOLLICULAR epithelium, so called **follicular adenoma** - Typically SOLITARY and ENCAPSULATED - Not considered a forerunner to carcinoma, but there are shared genetic alterations - Most are NONFUNCTIONAL; a small minority are toxic adenomas - REMEMBER: only difference b/t follicular adenoma and carcinoma is that the _carcinoma will breach the capsule_ (have to take it out and look at it)

Answer 207

- **Neovascularization** with diabetic proliferative retinopathy -\> note the _proliferation_ (arrow) of small vessels near the optic disc - These are _prone to bleed_, producing vitreal hemorrhages that obscure vision - Always perform fundoscopy (opthalmoscopy) on these patients (refer to opthalmologist, if necessary)

Answer 208

- GROSS: marked thickening of adrenal w/enlarged, **cerebriform appearance** (see attached image) 1. Cut surface would be more brown than yellow - HISTOLOGY: diffuse **cortical hyperplasia**, esp. involving the zona reticularis; cortical cells are lipid depleted - ADDITIONAL FXS: many also have **hyperplasia of corticotrophs** (ACTH secreting cells) in the pituitary 1. May have **tumors in testes** hilus due to increase ACTH

Answer 209

- _Primary_: the most common cause of asymptomatic hypercalcemia 1. Most cases are from an adenoma (most important distinction from normal parathyroid tissue is lack of fat) - _Secondary_: most commonly from renal failure - Parathyroid carcinoma is exceedingly rare

Answer 210

- TSH - Hyperthyroidism

Answer 211

- Two groups of disorders – type 2A and 2B - **Gain of function mutation of RET** - Strong genotype-phyenotype correlation - MEN-2 is _AUTOSOMAL DOMINANT_

Answer 212

- Diabetic patients have **impaired innate immune** **systems** (also a little acquired) due to numerous mechanisms -\> underlying problem is TOO MUCH GLUCOSE 1. Neutrophil function (visible phagocytosis) impaired by adding diabetic serum or sugar - This dysfunction leads to more numerous and more severe infections in: 1. Skin 2. Feet (bone, soft tissue) 3. Lungs 4. Urinary tract

Answer 213

_Graves disease_: thyroid hyperplasia characterized by papillary infoldings (this is a pathognomonic histo slide for Graves)

Answer 214

- Minority of pts with _goiter who devo hyperthyroidism_ (toxic multi-nodular goiter) - NOT accompanied by infiltrative opthalmopathy and dermopathy of Graves

Answer 215

- **Hashimoto's** thyroiditis: NONTENDER - Can be hyperthyroid due to early attack, and follicle rupture - HYPOTHYROID in long-term - Follicles, lymphocytes, and Hurthle cell change

Answer 216

- A: _duodenal peptic ulcer_ in pt with Zollinger-Ellison Syndrome -\> punched-out lesion - B: _pancreatic gastrinoma_ that caused it 1. White/tan color to the tumor (can get hemorrhage if they get big enough)

Answer 217

- Painless = silent - Mild hyperthyroidism - Middle-aged women - Most recover, and do NOT progress to hypothyroidism

Answer 218

- **B**uffalo hump - **U**nusual behavior (depression, personality changes, and fatigability) - **F**acial features (moon face, hirsutism in women) - **F**at accumulation (obesity) - **A**CTH (and cortisol) in blood ↑; ACTH and dexamethasone test abnormalities - **L**oss of muscle mass (thin legs and arms; protruding abdomen due to weak abdominal muscles) - **O**verextended skin (striae with easy bruisability due to weak vessels) - **H**ypertension - **U**rinary cortisol ↑ and 17-hydroxycorticosteroids ↑ - **M**enstrual irregularities - **P**orosity of bones (osteoporosis)

Answer 219

- ACTH reduced due to **hypothalamus or pituitary insult** - _Hyperpigmentation is absent_ because melanotropic hormone levels are low - LOW ACTH with prompt rise in cortisol with ACTH administration

Answer 220

- **ACTH-dependent**: bilateral diffuse or nodular hyperplasia of the adrenals 1. _Cushing disease_ (anterior pituitary): 70%; young adult F w/microadenoma (bc functioning) 2. _Ectopic corticotropin syndrome_: non-pituitary tumors (i.e., small cell carcinoma of lung with crush artifacts -\> see attached image) - **ACTH-independent**: adrenal adenoma (10%) or adrenal carcinoma (5%) 1. Cortisol high, ACTH low

Answer 221

- Advanced glycation end products (**AGE**): formed from glucose precursors and proteins 1. Bind, _induce inflam cells on endo and sm m_ 2. Proinflam state, ROS, procoagulant activity, crosslinks o/proteins, and traps o/proteins in vessel walls (i.e., LDL, albumin) - Activation of protein kinase C (**PKC**): downstream effects of PKC incl _proangiogenic_ molecules (VEGF) 1. Implicated in neovascularization seen in RETINOPATHY - Disturbances in **polyol** pathways: in tissues that do NOT use insulin, cells have high IC glucose 1. Excess glucose metabolized by aldose reductase to **sorbitol** (a polyol), and eventually to **fructose** 2. Uses **NADPH**, which is also required by the enzyme glutathione reductase in a reaction that regenerates reduced glutathione (GSH) 3. **GSH** is important in antioxidant mechanisms; any reduction in GSH INC cellular susceptibility to ROS (“**oxidative stress**”) 4. Sorbitol accumulation in the lens contributes to CATARACT FORMATION

Answer 222

- **Adrenal cortical adenoma**: mid-size cells arranged in nests and cords 1. Tumor cells have mid-size, round-oval nuclei, and abundant granular eosinophilic cytoplasm - 29-y/o female with VIRILIZING (masculinization) symptoms, in this case

Answer 223

- **Struma ovarii** = monodermal TERATOMA of ovary, composed mainly (\>50%) of _adult thyroid tissue_ (see histo image on the right) - May functionally cause _thyrotoxicosis_ - Adenomas are COMMON; 5% are malignant - All different parts look different, so all different types of tissue

Answer 224

Conn Syndrome

Answer 225

- On the basis of local invasion and distant metastases

Answer 226

- Need for cortisol will go up - Need to cover patients with adrenal atrophy for excess stress of surgery (even if that atrophy was caused by corticosteroid administration)

Answer 227

- **ACTH-independent hyperplasia** (primary cortical hyperplasia) -\> very uncommon - _Macronodular_: typically \>3mm -\> almost entirely replaced by prominent nodules of various sizes - Typically _sporadic_, but association with McCune-Albright (GNAS mutations) - Cortisol is regulated by non-ACTH hormones - Mix of lipid poor and lipid rich cells b/t nodules have _microscopic nodularity_ (vs diffuse hyperplasia which does not)

Answer 228

- **Pituitary infarct**: high power view of _coagulative necrosis_ of all the pituitary parenchymal cells 1. Only viable cells are erythrocytes, leukocytes and a few endothelial cells - Really really pink celss are RBCs - Inflam cells are there to help clean up the mess

Answer 229

- RETICULARIS (top): estrogens and androgens - MEDULLA (bottom): epinephrine and NE 1. Neuroectodermal origin

Answer 230

- TSH producing (2% incidence) - **Uncommon**: approx 1% of all pituitary adenomas - RARE cause of hyperthyroidism

Answer 231

- **P**ituitary tumors - **P**arathyroid hyperplasia or adenoma - **P**ancreatic hyperplasia or adenoma - Carcinoid tumors

Answer 232

- REDUCES the production of glucose in the liver

Answer 233

- 1-5% of patients - Neurofibromatosis, schwannoma, meningioma, glioma and _pheochromocytoma_ - Composite tumors with neuroblastoma, ganglioneuroma or ganglioneuroblastoma may be associated with neurofibromatosis 1

Answer 234

- **Adamantinomatous craniopharyngioma** - Squamous epithelium - Compact, lamellar “WET KERATIN” - Dystrophic calcification - Cholesterol-rich, thick brownish-yellow fluid (“MACHINE OIL”) in cysts

Answer 235

- **Nodular glomerulosclerosis**: Kimmelstiel-Wilson lesion - Nodules of pink, hyaline material form in regions of glomerular capillary loops in the glomerulus - Due to a marked _INC in mesangial matrix_ from damage as a result of **non-enzymatic glycosylation** of proteins

Answer 236

- Thyroid – **medullary carcinoma** in the first two decades of life - Adrenal medulla – get **pheochromocytomas** - Difference from MEN-2A: _NO HYPER-PTH_ 1. Extra-endocrine manifestations: ganglioneuromas, **marfanoid habitus** (long axial skeleton, and hyperflexible joints) - Histo of ganglioneuroma attached: ganglion cells and schwann cells

Gupta - Pathology Flashcards

(266 cards)