Midterm Flashcards
(739 cards)
1
Q
What is the name for the anterior vs posterior pituitary
A
Anterior: adenohypophysis
Posterior: neurohypophysis
2
Q
How do chromophobe cells stain
A
Poorly
3
Q
What are the cell types of the anterior pituitary
A
- somatotrophs: GH
- mamosomatotrophs: GH and prolactin
- lactotrophs: prolactin
- corticotrophs: ACTH, POMC, MSH (melanocytes-stimulating hormone)
- thyrotrophs: TSH
- Gonadotrophs: FSH and LH
4
Q
What are somatotrophs, mamma somatotrophs and lacctotrophs derived from
A
Stem cells that express pituitary transcription factor (PIT-1)
5
Q
What is required for gonadotroph differentiation
A
Steroidogenic factor 1 (SF-1) and GATA-2
6
Q
What are causes of hyperpituitarism
A
Pituitary adenoma, secretion of hormones by nonpituitary tumors, hypothalamic disorder
7
Q
What are causes of hypopituitarism
A
Ischemic injury, surgery, radiation, inflammatory reactions, non functional pituitary adenomas
8
Q
What are the mass lesion effects on the sella turcica
A
Stellar expansion, bony erosion, disruption of diaphragm sella
9
Q
Is pituitary apoplexy an emergency
A
Yes; can cause sudden death
10
Q
What is the most common cause of hyperpituitarism
A
Adenoma in anterior lobe
11
Q
What is the most common combination in adenomas that secrete 2 hormones
A
GH and prolactin
12
Q
Who are pituitary adenomas most commonly found in
A
Adults 35-60
13
Q
How are adenomas classified
A
- microadenomas: < 1 cm
- macroadenomas: > 1 cm *non functional more likely to be macro
- most are clinically silent (pituitary incidentaloma)
14
Q
What syndromes do lactotrophs cause
A
Galactorrhea and amenorrhea, sexual dysfunction and infertility
15
Q
What syndromes do somatotrophs produce
A
Gigantism and acromegaly
16
Q
What syndrome do mammosomatotrophs produce
A
Combined features of GH and prolactin excess
17
Q
What syndrome do corticotrophs produce
A
Cushing and Nelson syndrome
-subtypes: densely granulated, sparsely granulated, silent
18
Q
What syndrome do thyrotrophs produce
A
Hyperthyroidism
19
Q
What syndrome do gonadotrophs produce
A
Hypogonadism, mass effect, hypopituitarism
20
Q
What are “null cell”
A
Silent gonadotroph adenomas
21
Q
What is the most common mutation alterations seen in pituitary adenomas
A
G protein mutations; GNAS encodes Gsalpha - in basal state is inactive *seen in somatotroph cell adenomas - aberrant GTPase activity leading to constant activation; also in som corticotrophs adenomas *ABSENT in thyrotroph, lactotrophs, and gonadotrophs b/c do not act via cAMP dependent pathways
22
Q
Are most pituitary adenomas genetic or sporadic
A
Sporadic
23
Q
What genes are involved in genetic pituitary adenomas
A
MEN1, CDKN1B, PRKAR1A, AIP
24
Q
What mutation is seen in pituitary carcinomas
A
HRAS
25
What does PRRKAR1A encode for
Negative regulator of PKA -> LOF leads to inappropriate cAMP activity; present in AD carney complex; associated with GH and prolactin adenomas
26
What pituitary tumors are associated with LOF in MEN
(Tumor suppressor) GH, prolactin and ACTH adenomas
27
What is a LOF in CDKN1B associated with
ACTH adenomas
28
What is a LOF mutation in Aryl hydrocarbon receptor interacting protein (AIP) associated with
GH adenomas *especially if <35
29
What is the morophology of a typical pituitary adenoma
Soft and well circumscribed; large lesions can extend superiority through diaphragm to suprasellar region; can invade sinuses (invasive adenomas); sparse mitosis * cellular monomorphism and absence of reticulum distinguishes pituitary adenomas from nonneoplastic ant pituitary parenchyma
30
What are atypical adenomas
Has elevated mitotic activity and nuclear p53 expression (TP53 mutations); aggressive behavior
31
What is the most common type of hyperfunctioning pituitary adenoma
Prolactin secreting lactotrophs
32
What is the morphology of lactotroph adenomas
Chromophobic cells with localization of PIT-1 - known as sparesely granulated lactotroph adenomas; rarer: acidophilic denely granulated lactotroph adenomas with diffuse PIT-1 expression; have a propensity to undergo calcification - psammoma bodies or pituitary stone formation; serum prolactin correlates to size of adenoma
33
What can a mass in the suprasellar compartment do
Disrupt normal inhibitory influence of hypothalamus on prolactin secretion
34
How are lactotroph adenomas treated
Surgery or bromocriptine (dopamine receptor agonist)
35
What is the morphology of somatotroph adenomas
Densely granulated: acidophilic cells
| Sparesley granulated: chromophobe cells with pleomorphic mood and weak staining for GH
36
What does persistently elevated levels of GH stimulate
Hepatic secretion of insulin like GF-1
37
What are the features of acromegaly
Growth seen in skin, soft tissues, viscera (thyroid, heart, liver, adrenals), bones of face hands and feet; bone density can increase (hyperostosis) in spine and hips; prognathism (protruding jaw)
38
What can GH excess be associated with
Gonadal dysfunction, DM, generalized m weakness, HTN, arthritis, CHF and increased risk for GI cancer
39
How do you dx a somatotroph adenoma
Elevated levels of GH and IGF-1; failure to suppress GH with oral glucose (sensitive for acromegaly)
40
What is the morphology of corticotroph adenomas
Usually microadenomas; most often basophilic (Densely granulated) and occasionally chromobphobic (sparse); both stain with periodic acid Schiff (contain POMC)
41
What is Cushing disease
When excess ACTH is produced by the pituitary
42
What is Nelson syndrome
When corticotroph adenomas form after removal of adrenals for treatment of Cushing syndrome; hypercorticolism doe not develop b/c dont have adrenals; mass effect and hyperpigmentation
43
What are the features of gonadotroph adenomas
Produce LH and FSH; most frequent in mild aged omen and men when they become large; pituitary deficiencies can be seen - most commonly impaired secretion of LH; stain for Beta-LH and FSH; FSH usually predominantly secreted; express steroidogenic factor 1 and GATA-2
44
What do pituitary carcinomas most commonly secrete
Prolactin and ACTH; Mets occur late following multiple local recurrences
45
What is Sheehan syndrome
Postpartum necrosis of the anterior pituitary; during pregnancy, ant pituitary grows but blood supply remains the same so relative hypoxia
46
What are rathke cleft cysts lined by
Ciliated cuboidal epithelium
47
What is empty sella syndrome
Any condition or treatment that destroys part or all of the pituitary gland can results in this syndrome;
- primary: defect in diaphragm allows CSF to herniate and compress pituitary ; occurs in obese women with hx of multiple pregnancies; visual ducts and hyperprolatinemia presentation
- secondary: mass enlarges sella and is either removed or undergoes infarction leading to loss of pituitary function
48
What are craniopharyngiomas
Benign hypothalamic tumor
49
What are most malignant tumors in the hypothalamus
Met from breast and lung
50
What are congenital causes of hypopituitarism
Mutation in PIT-1; deficient in GH, prolactin and TSH
51
What does hypopituitarism lead to
- dwarfism
- amenorrhea, infertility, decreased libido, impotence, loss o pubic and axillary hair
- TSH and ACTH def lead to hypothyroidism and hypoadrenalism
- failure of postpartum lactation
- pallor due to loss of MSH
52
What are the most common hypothalamic suprasellar tumors
Gliomas and craniopharyngiomas (arises from remnants of rathke’s pouch)
53
What are the features of craniopharyngiomas
Bimodal age distribution: 5-15 and 65; sx: headaches and visual disturbances or growth retardation; abnormalities of WNT pathway has Ben reported; can bulge into floor of 3rd ventricle
54
What is the morphology of craniopharyngiomas
```
2 histo variants: adamantinomatous (children; most commonly has calcifications); nests of strat squamous embedded in spongy reticulum; palisading; lamellar keratin is diagnostic feature; cholesterol rich cysts (machine oil)
and papillary (adults); squamous; lack keratin, calcification and cysts
Good prognosis
```
55
What is the function of thyroid follicular epithelial cells
Converts thyroglobulin into thyroxine (T4) and triiodothyronine (T3)
56
What are T3 and T4 bound to in circulation
Thyroid binding globulin and transthyretin
57
What kind of receptor does T3 have
Nuclear -> results in assembly of multiprotein hormone-receptor complex on thyroid hormone response elements (TREs) in target genes; stimulates carb and lipid catabolism and protein synthesis; brain development in neonate
58
What can inhibit the thyroid
Goitrogens; propylthiouracil inhibits oxidation of iodide and blocks production of T3 and 4; iodide blocks release of thyroid hormones by inhibiting proteolysis of thyroglobulin
59
What does calcitonin do
Promotes absorption of calcium by bones and prevents resorption of bone by osteoclasts
60
What is thyrotoxicosis
Hypermetabolic state caused by elevated circulating levels of free T3 and 4; hyperthyroidism is one cause
61
What are the most common causes of thyrotoxicosis
Diffuse hyperplasia of the thyroid associated with graves dz, hyperfunctional multinodular goiter, hyperfunctional thyroid adenoma
62
What hormones do the hypothalamus release
TRH, CRH, GHRH, GnRH, somatostatin, dopamine
63
What does the skin of thyrotoxicosis patients look like
Soft warm, and flushed (increased blood flow and peripheral vasodilation), increase heat loss, heat intolerance
64
What is thyrotoxic (hyperthyroid) cardiomyopathy
Left ventricular dysfunction and low output heart failure caused by hyperthyroidism
65
What is thyroid myopathy
Proximal m weakness and decreased m mass caused by hyperthyroidism
66
What are the ocular changes associated with hyperthyroidism
Wide staring gaze and lid lag (overstimulation of tarsal m - Muller’s m) proptosis only in grave’s dz
67
How is the skeletal system affected by hyperthyroidism
Stimulate bone resorption, increasing porosity of cortical bone and reducing volume of trabecular bone; atrophy of skeletal m with fatty infiltration and focal interstitial lymphocytic infiltrates; lymphoid hyperplasia nad LAD in graves dz
68
What causes thyroid storm
Graves dz; excess of catecholamines in asso with infection, surgery, cessation of antithyroid meds, any form of stress; patients fertile and tachycardia out of proportion to fever *medical emergency
69
What is apathetic hyperthyroidism
Thyrotoiosis in older adults in whom advanced age blunts features of thyroid hormone excess
70
What are the primary diseases associated with hyperthyroidism
Diffuse hyperplasia (graves), hyperfunctioning multinodular goiter, hyperfuncioning adenoma, iodine induced hyperthyroidism, neonatal thyrotoxicosis assoc with maternal graves
71
What are the secondary causes of hyperthyroidism
TSH-secreting pituitary adenoma
72
What are the diseases not associated with hyperthyroidism
Granulomatous thyroditis (painful), subacute lymphocytic thyroidtis (painless), strums ovarii (ovarian teratoma with ectopic thyroid), fictitious thyrotoxicosis (exogenous thyroxine intake)
73
What is the most useful test for dx of hyperthyroidism m
TSH levels (decreased); confirm with measurement of T4
74
How do you confirm a dx of secondary hyperthyroidism
Inject TRH; if normal rise in TSH - exclude secondary hyperthyroidism
75
After confirming dx of hyperthyroidism, how do you determine the etiology
Radioactive iodine uptake measurement (if diffuse uptake - graves, if uptake in solitary nodule - toxic adenoma, if decreased uptake - thyroiditis)
76
How do you treat hyperthyroidism
Beta blocker, thionamide to block new hormone synthesis, iodine solution to block release of thyroid hormone, and agents that inhibit peripheral conversion of T4 to T3; or radioiodine
77
What is the most common cause of congenital hypothyroidism
Endemic iodine deficiency in diet
78
What are other causes of congenital hypothyroidism
Inborn errors of thyroid metabolism (dyshormogenetic goiter), thyroid agenesis, thyroid hypoplasia
79
What mutations can cause defects in thyroid development
PAX8, FOXE1, TSH receptor
80
What mutation causes thyroid hormone resistance syndrome
THRB
81
What drugs can cause hypothyroidism
Lithium, iodides, p-aminosalicylic acid
82
What is the most common cause of hypothyroidism in iodine sufficient areas
Autoimmune
83
What abs are seen in hashimotos
Anti microsomal, antithyroid peroxidase and antithyroglobulin
84
What can autoimmune hypothyroidism occur in conjunction with (but not always)
Autoimmune polyendocrie syndromes (APS) types 1 and 2
85
What is cretinism
Hypothyroidism that develops in infancy or early childhood; impaired development of skeletal system and CNS, severe mental retardation, short stature, coarse facial features, protruding tongue, umbilical hernia; depends on iodine intake by mother
86
What is myxedema
Hypothyroidism developing in older children or adults; slowing of physical and mental activity - initially generalized fatigue, apathy, and mental sluggishness; speech and intellectual functions slowed; cold intolerance, overweight, constipation, decreased sweating, skin cool and pale, SOB, reduced exercise capacity; decreased transcription of calcium ATPases and beta adrenergic receptor -> low CO, increase in LDL, nonpitting edema, broadening and coarsening of facial features, enlargement of tongue and deepening of voice due to accumulation of matrix substances
87
What is the most sensitive test for dx of hypothyroidism
TSH - increased in primary
88
What is strums lymphomatosa
Lymphocytic infiltration of thyroid - seen in hashimotos
89
What is the profile for people affected typically by hashimotos
45-65 women
90
What is the pathogenesis of hashimoto thyroiditis
Breakdown in self tolerance to thyroid autoantigen; genetic mutations: CTLA4, PTPN22 (protein tyrosine phosphatase 22)
91
What contributes to thyroid cell death in hashimoto
CD8 mediated cell death, cytokine mediated cell death (activation of CD4 cells), binding of antithyroid abs followed by ab-dependent cell mediated cytotoxicity
92
What is the morphology of hashimoto
Infiltration of mononuclear cells containing small lymphocytes, plasma cells, well-developed germinal centers; hurthle cells; no invasive fibrosis beyond the capsule
93
What is the clinical presentation of hashimoto
Painless enlargement of gland; hypothyroidism develops gradually
94
What is hashitoxicosis
When hypothyroidism is preceded by transient thyrotoxicosis caused by disruption of thyroid follicles; T3 and 4 elevated, TSH decreased, radioactive iodine uptake decreased
95
What are people with hashimotos at increased risk for
Autoimmune diseases and extranodal marginal zone B cell lymphomas within the thyroid
96
What is subacute lymphocytic thyroiditis
Painless thyroiditis; comes to attention because of mild hyperthyroidism, goitous enlargement of the gland or both; more common in middle aged women *subset: postpartum thyroiditis - circulating antithyroid peroxidase abs or family hx of autoimmune dz; can turn into hashimotos
97
What is the morphology of subacute lymphocytic thyroiditis
Lymphocyte infiltration; but o fibrosis or hurthle cell metaplasia
98
What is the pathogenesis of granulomatous thyroiditis
Aka dequervain; thought to be triggered by virus; seasonal incidence (peak in summer)
99
What is the morphology of granulomatous thyroiditis
Gland is uni or b/l enlarged and firm; intact capsule that can adhere to surrounding structures; multinucleated giant cells; fibrosis later on
100
What is the clinical course of granulomatous thyroiditis
Pain (most common cause); enlargement; transient hyperthyroidism (diminishes over weeks even if not treated); radioactive uptake is diminished
101
What is riedel thyroiditis
Extensive fibrosis of thyroid and adjacent structures; associated with fibrosis of other sites (retroperitoneum) *IgG4 related disease
102
What is the triad found in Graves’ disease
Hyperthyroidism, infiltrative opthalmopathy, and localized infiltrative dermopathy (pretibial myxedema)
103
What population is graves seen in
Women 20-40
104
What abs are found in Graves’ disease
Anti TSH receptor ; TSI (thyroid stimulating immunoglobulin) - mimics TSH -> stimulates adenyly Cyclase and releasing hormones
105
What genetics are involved in graves
Mutations in CTLA4 and PTPN22; and HLA-DR3
106
What is the morphology of graves
Thyroid symmetrically enlarged due to diffuse hypertophy and hyperplasia of thyroid follicular epithelial cells; tall cells that are crowded and form papillae that lack fibrovascular cores; colloid has scalloped margins germinal centers
107
What extrathyroidal changes can occur to tissue in graves dz
Lymphoid hyperplasia, especially enlargement off thymus; hypertrophied heart, ischemic changes, orbital edema
108
What features of thyrotoxicosis are unique to graves
Diffuse hyperplasia of the thyroid, opthalmopathy and dermopathy
109
What happens to the blood flow to the thyroid in graves
Can increase and cause a bruit
110
What happens to radioiodine uptake in graves
Increases
111
What causes goiter
Impaired synthesis of thyroid hormone; leads to increase in TSH which causes hypertrophy and hyperplasia of thyroid -> euthyroid
112
What is diffuse nontoxic goiter
Enlargement of thyroid w/o nodularity; aka colloid goiter
113
What are the 2 types of diffuse nontoxic goiter
- endemic: geographic areas with low level o iodine; also can be caused by goitrogens (broccoli,cabbage, Brussels sprouts, cassava)
- sporadic: less frequent; more in females in puberty; can be an inherited condition (AR)
114
What is the clinical course of diffuse nontoxic goiter
Euthyroid; mass effect; in kids, dyshormonogenetic goiter can cause cretinism
115
What are multinodular goiters
Recurrent episodes of hyperplasia of thyroid; produce most extreme thyroid enlargements and are mistake for neoplasms; derive from simple goiter; can lead to rupture of follicles or vessels leading to hemorrhage, calcification and scarring
116
What is an intrathoracic goiter
Aka plunging goiter; multinodular goiter that grows behind sternum and clavicle
117
What is the clinical course of multinodular goiter
Mass effects - airway obstruction, dysphagia, compression of large vessels (SVC syndrome) most are euthyroid
118
What is toxic multinodular goiter
If it has an autonomous nodule that produces hyperhtoidism; known as Plummer syndrome - not accompanied by exopthlamos or dermopathy
119
What does a radioiodine scan show in multinodular goiters
Uneven take up with hot spots; FNA is helpful
120
What distinguishes multinodular goiter from follicular neoplasms
Multinodular goiter lacks a capsule
121
What kind of thyroid nodules are most likely to be neoplastic
Single, younger patients, males
122
Are follicular adenomas functional
Not usually
123
What mutations are seen in toxic adenomas and toxic multinodular goiters
TSH receptor signaling pathway (GNAS and TSHR)
124
What mutations are seen in non functional follicular adenomas
PAX8-PPARG fusion gene
125
What is the morphology of a follicular adenoma
Capsule *does not invade past capsule
126
How do follicular adenomas present
Painless mass; non functioning take up less iodine
127
Who does thyroid carcinoma occur in
Females; but in kids equal in males and females
128
What are most thyroid carcinomas derived from
Follicular epithelium; except medullary
129
What mutations are even in papillary carcinomas of the thyroid
GOF in RET (fusion with PTC)- seen in cancers arising from radiation
or NTRK1
or BRAF- correlates with extrathyroidal extension
130
What mutations are seen in follicular carcinomas
RAS or PI-3K/AKT; PAX8-PPARG
131
What mutation is seen in anaplastic carcinoma of the thyroid
P53
132
What do familial medullary thyroid carcinomas occur in
MEN2; assoc with RET mutation
133
What is the major risk factor for thyroid cancer
Radiation exposure
134
What is the most common thyroid cancer
Papillary carcinoma
135
What is the morphology of papillary carcinoma of the thyroid
Branching papillae with dense fibrovascular cores*, optically clear or empty appearance of nuclei (orphan Annie eye nucleus) - can make dx based on this, psammoma bodies; blood invasion not common; met to cervical LN
136
What is the follicular variant of papillary carcinoma of the thyroid
Features of papillary carcinoma but with follicular architecture; can be encapsulated (favorable prognosis) or poorly circumscribed (more aggressive); higher propensity to angioinvade and lower LN Mets
137
What is the tall-cell variant of papillary carcinoma
Tall columnar cells; tend to occur in older individuals and have higher frequencies of vascular invasion, extrathyroidal extension and cervical and distant mts
138
Who does the diffuse sclerosing variant of papilary carcinoma occur in
Younger individuals; contains nests of squamous metaplasia; extensive diffuse fibrosis;; LN met almost always
139
What is papillary microcarcinoma
< 1 cm
140
Where does papillary carcinoma most likely met
Lung
141
How do papillary carcinomas show up on radionuclide scanning
Cold
142
What is the prognosis of papillary thyroid cancer
Excellent
143
What does the prognosis of someone with papillary thyroid cancer depend on
Age, presence of extrathyroidal extension, and presence of distant Mets
144
How do follicular carcinomas present
Slowly enlarging painless nodules; most are cold nodules; dont usually involve lymphatics; vascular spread common - Mets to bone, liver, lung; prognosis based on extent of invasion
145
How are follicular carcinomas treated
Thyroidectomy with administration of radioactive iodine
146
What is the morphology of anaplastic carcinoma
Contain giant cells, spindle cells, and mixed; positive for cytokeratin but negative for thyroglobulin
147
What is medullary carcinoma of the thyroid
Neuroendocrine neoplasms derived from parafollicular cells; secrete calcitonin; can sometimes elaborate serotonin, ACTH or VIP; either sporadic or with MEN2A or 2B or familial medullary thyroid carcinoma
148
What is the morphology of medullary carcinoma
If b/l more likely to be familial; *amyloid deposits; in familial lesions - C cell hyperplasia seen
149
Is hypocalcemia a feature of medullary thyroid carcinoma
No
150
What is a useful bio marker for medullary carcinoma
Carcinoembryonic antigen
151
What is true of medullary carcinoma associated with MEN2B
It is more aggressive and met more frequently (offered prophylactic thyroidectomy)
152
What are the parathyroid glands composed of
Chief and oxphil cells
153
What are the actions of PTH
Increases Neal tubular reabsorption of calcium, increases conversion of vit D to active form, increases urinary phosphate excretion, augments GI calcium absorption
154
What is tertiary hyperparathyroidism
Persistent hypersecretion of PTH even after the cause of prolonged hypocalcemia is corrected (ie after renal tx)
155
Who is primary hyperparathyroidism common in
Women adults; most common cause is adenoma
156
What genetic defects cause sporadic parathyroid adenomas
Cyclin D1 gene inversions
| MEN1 mutations
157
How can you preoperatively distinguish parathyroid adenomas from hyperplasia
Technetium sestamibi radionuclide scan
158
What genetic syndromes are associated with familial parathyroid adenomas
MEN 1 and 2 (MEN and RET mutations, respectively), familial hypocalciuric hypercalcemia (AD caused by LOF in CASR)
159
What is the morphology of parathyroid adenomas
Almost always solitary; composed of chief cells; uncommonly composed entirely of oxphil cells (oxphil adenomas); loss of adipose tissue
160
What is the morphology of primary parathyroid hyperplasia
Mostly of chief cells; loss of fat
161
What is the only reliable criteria for diagnosis of parathyroid carcinomas
Invasion of surrounding tissue
162
What are the skeletal manifestations of primary hyperparathyroidism
Osteoporosis (affects cortical bone more than medullary bone) - in medullary bone creates appearance of railroad tracks -> dissecting osteitis; can lead to fractures and hemorrhage high create a mass of reactive tissue known as a brown tumor (generalized osteitis fibrosis cystica)
163
What is the effect of primary hyperparathyroidism on the urinary tract
Nephrolithiasis an calcification of renal interstitium and tubules (nephrocalcinosis)
164
Is primary hyperparathyroidism usually symptomatic
No; usually caught before sx
165
What are the GI sx of hyperparathyroidism
Constipation, nausea, peptic ulcer, pancreatitis, gallstones
166
What are the CNS sx of primary hyperparathyroidism
Depression, lethargy, seizures
167
What are the neuromuscular features of primary hyperparathyroidism
Weakness and fatigue
168
What are the cardiac manifestations of primary hyperparathyroidism
Aortic or mitral valve calcifications
169
What are causes of hypercalcemia with decreased PTH
Malignancy, vit D toxicity, immobilization, thiazides, granulomatous dz (sarcoidosis)
170
What are causes of secondary hyperparathyroidism
Renal dz, vit d deficiency, steatorrhea
171
How does chronic renal failure lead to hyperPTH
Decreased phosphate excretion -> binds to calcium -> sensed as low -> increases PTH; also renal failure means cannot synth vit D and cannot absorb calcium
172
What is renal osteodystrophy
Skeletal abnormalities seen as a result of renal failure from hyperparathyroidism
173
What effect can secondary hyperparathyroidism have on the skin
Can cause calcification and lead o ischemia - calciphylaxis
174
How do you treat secondary hyperparathyroidism
Dietary vit d supplementation, phosphate binders
175
What is autoimmune hypoparathyroidism associated with
Chronic mucuocutanous candidiasis and primary adrenal insufficiency known as autoimmune polyendocrine syndrome type 1 (APS1) caused by mutation in AIRE; presents in childhood
176
What is AD hypoparathyroidism
Caused by GOF in CASR; senses low calcium as sufficient and suppresses PTH resulting in hypocalcemia and hypocalcuria
177
What is familial isolated hypoparathyroidism (FIH)
Rare; either AD (caused by mutation in PTH precursor peptide) or AR (LOF of glial cells missing-2 GCM2)
178
What can congenital absence of the parathyroid occur in
Digeorge (chrom 22)
179
What are the sx of hypoparathyroidism
Numbness, paresthesias, carpopedal spasm, laryngospasm, seizures, mental status change, calcifications of basal ganglia, parkinsonian-like movement, increased ICP, ocular disease (calcification of lens and cataract formation), prolongation of QT, dental hypoplasia, defective enamel
180
What is pseudohypoparathyroidism
Occurs because of end organ distance to actions of PTH; PTH normal or elevated; defect in G proteins; presents as hypocalcemia, hyperphosphatemia, and PTH
181
What does somatostatin do to insulin and glucagon
Inhibits their release
182
What does pancreatic polypeptide do
Stimulation of secretion of gastric acid and intestinal enzymes and inhibition of intestinal motility
183
What do D1 cells secrete
VIP. - induces glycogenolysis and hyperglycemia; stimulates I fluid secretion and causes secretory diarrhea
184
What do the enterochromaffin cells synthesize
Serotonin; source of pancreatic tumors that cause carcinoid syndrome
185
What is normal blood glucose
70-120
186
What is the diagnostic criteria for diabetes
Fasting plasma glucose >126, random plasma glucose >200, 2 hour plasma glucose >200 during oral glucose tolerance test with 75 load, HgbA1C >6.5
187
What is prediabetes defined as
Fasting glucose btw 100-125, 2 hour plasma glucose btw 140-199 with 75gm OGTT, HbA1c btw 5.7-6.4
188
What mutations cause maturity onset diabetes of the young (MODY)
Hepatocytes nuclear factor (HNF4A), MODY1, glucokinase, MODY2
189
What exocrine pancreatic defects cause diabetes
Chronic pancreatitis, pancreatic trauma, neoplasia, CF, hemochromatosis, fibrocalculous pancreatopathy
190
What endocrinopathies cause diabetes
Acromegaly, Cushing syndrome, hyperthyroidism, pheochromocytoma, glucagonoma
191
What infections can cause diabetes
CMV, Coxsackie B, congenital rubella
192
What drugs can cause diabetes
Glucocorticoids, thyroid hormone, IFNalpha, protease inhibitors, beta agonists, thiazides, nicotinic acid, phenytoin
193
What genetic syndromes are associated with diabetes
Down syndrome, klinefelter, turner, prader-willi
194
What abs are seen in T1DM
Anti-insulin, anti-GAD, anti-ICA512
195
Instead of DKA, what are people with T2DM at risk for
Nonketotic hyperosmolar coma
196
What is the genetic diff in T1 vs T2DM
T1: HLA linked; also polymorphism in CTLA Nd PTPN22
T2: no HLA; links to candidate diabetognic and obesity relate genes
197
Which type of diabetes has amyloid deposition in the islets
T2DM
198
How does glucose enter the pancreatic beta cells
GLUT 2
199
How is insulin released
Metabolism of glucose generates ATP which inhibits te activity of the ATP sensitive K channel leading to depolarization and influx of Ca2+ which stimulates the secretion of insulin
200
What are the 2 incretins
Glucose dependent insulinotropic polypeptide (GIP) secreted by K cells and glucagon like peptide (GLP-1) secreted by L cells
201
What happens to the incretin effect in ppl with T2DM
Blunted; reason why treated with GLP-1 agonist and DPP 4 inhibitors (DPP 4 breaks down GLP)
202
What are the actions of insulin
- adipose tissue: increase glucose uptake, lipogenesis and decrease lipolysis
- striated m: increase glucose uptake, glycogen synthesis and protein synthesis
- liver: decreased GNG, increased glycogen synthesis and lipogenesis
203
What pathway translocates GLUT 4 to the membrane
AKT and CBL
204
Which genes are seen with T1DM
HLA-DR3 or 4, CTLA4 and PTPN22
205
How does obesity lead to insulin resistance
Adipocytes release adipokines, FFA, and inflammation
206
What are the results of insulin resistance
Failure to inhibit GNG in the liver (leads to high fasting glucose levels), failure to uptake glucose (high post prandial glucose), an failure to inhibit hormone sensitive lipase which leads to excess triglyceride breakdown and excess circulating FFAs
207
How does exercise improve insulin sensitivity
Increased translocation of GLUT 4 to membrane of m cells
208
How do excess FFAs lead to insulin resistance
Overwhelm intracellular FA oxidation pathways leading to accumulation of diacylglycerol which can attenuate inhaling through the insulin receptor
209
What is not released from adipose tissue in obesity
Adiponectin
210
How does inflammation lead to insulin resistance
FFA in macrophage activate inflammasome -> IL-1beta
211
How does beta dysfunction occur in T2DM
- excess FFA compromise beta function
- chronic hyperglycemia
- abnormal incretin effect leading to reduced GIP and GLP
- amyloid exposition in islets
- genetics
212
What is type A insulin resistance
Mutation in the insulin receptor; hyperisulinemia and diabetes; acanthosis Nigricans; females typically have polycystic ovaries and increased androgen levels
213
What is lipoatrophic diabetes
Hyperglycemia with loss of adipose tissue in subcutaneous fat; insulin resistance, diabetes, hypertriglyceridemia, acnthosis nigricans and abrnomal fat deposition in the liver
214
What can poorly controlled gestational diabetes lead to
Excessive birth weight (macrosomia), obesity and diabetes in child
215
What is the triad of type 1 diabetes
Polyuria, polydipsia, polyphagia
216
What hormones are increased in diabetes
Glucagon, growth hormone, epi
217
What kind of diuresis is seen in diabetes
Osmotic
218
How are ketones produced in DKA
Insulin def stimulates hormone sensitive lipase -> FFA to liver Nd are oxidized to Ketone bodies (acetoacetic acid an beta hydroxybutyric acid)
219
What are the manifestations of DKA
Fatigue, N/V, severe ab pain, fruity odor and Kussmaul breathing
220
How do you treat DKA
Insulin, correction of acidosis Nd treatment of underlying factors
221
What is hyperosmolar hyperosmotic syndrome
Seen with T2DM; due to severe dehydration resulting from sustained osmotic diuresis - occurs in ppl unable to maintain water intake; impaired mental status *hyperglycemia more severe than in DKA
222
What is the most common acute metabolic complication in either type of diabetes
Hypoglycemia - sx: confusion, sweating, palpitations, tachycardia
223
Where is microvascular dz related to diabetes seen
Kidneys, retina, peripheral nerves
224
What is the goal of HbA1C in diabetics
<7
225
What are advanced glycation end products
AGEs; formed as a result of freactions tw intracellular glucose precursors with amino groups; formation accelerated in presence of hyperglycemia bind to RAGE receptor on inflammatory cells, endothelium and smooth m causing lease of cytokines high leads to deposition of BM, VEGF, ROS, increased procoagulants, and proliferation of vascular smooth mm
226
How is atherogenesis accomplished in diabetes
AGE cross links and prevents efflux of LDL from vessel wall
227
What does hyperglycemia do to PKC
Increases its activation -> leads to production of VEGF, TGF-beta and procoagulants (PAI-1); contributes to microangiopathy
228
How does hyperglycemia affect tissues that do not require insulin for glucose transport
Metabolized by aldose reductase to sorbitol and polygon and eventually to fructose i a reaction that uses NADPH which compromises GSH regeneration and increases suceptibility to oxidative stress
229
What are the long term complications of diabetes
Microangiopathy, CVA, hemorrhage in brain, retinopathy, cataracts, glaucoma, MI, HTN, atherosclerosis, PVD, nephrosclerosis, pyelonephritis, peripheral and autonomic neuropathy
230
What is diabetic macrovascular dz
Atherosclerosis of aorta and large-medium sized arteries
231
What are the features of diabetic microangiopathy
Diffuse thickening of BM;; capillaries are more leaky than normal to plasma proteins; *involvement includes nephropathy, retinopathy Nd neuropathy
232
What is the morphology of diabetic nephropathy
Diffuse mesangial sclerosis, cap BM thickening, nodular glomerulosclerosis
233
What are the features of nodular glomerulosclerosis
Aka kimmelstiel-Wilson dz; nodules are PAS positive; usually accompanied by prominent accumulations of hyaline in cap loops (fibrin caps) or adherent to bowman capsules (capsular drops)
234
What is a unique feature of renal arteriosclerosis not seen in non-diabetics
Arteriosclerosis in efferent arterioles
235
What special form of pyelonephritis is seen in diabetics
Necrotizing papillitis
236
What are the most common causes of mortality in long standing diabetes
Macrovascular complications (CVA, MI, renal vascular insufficiency)
237
What CV risks are seen in diabetics
HTN, dyslipidemia, elevated levels of PAI-1 (inhibitor of fibrinolysis and is therefore procoagulant)
238
What population of diabetics is at higher risk of developing renal dz
non-whites
239
What is the earliest manifestation of diabetic nephropathy
Low albumin in the urine (microalbuminuria) - if see this should then be screened for macrovascular dz
240
What is the most frequent pattern of involvement of diabetic neuropathy
Distal symmetric polyneuropathy of the lower extremities; affects both motor and sensory; over time upper extremity may become involved - glove and stocking pattern
241
What is autonomic neuropathy
Produces disturbances in bowel and bladder function
242
What is diabetic mononeuropathy
Can manifest as footdrop, wristdrop, or isolated CN palsies
243
What infections are diabetics at increased risk for
Pneumonia and TB
244
What causes the long term complications of diabetes
Formation of advanced glycation end product (AGEs), activation of PKC, disturbance in polyol pathways, and overload of hexosamine pathway
245
What mutations (besides MEN1) are seen in pancreatic neuroendocrine tumors
Alpha-thalassemia/mental retardation syndrome, X-linked (ATRX) and death domain associated protein (DAXX)
246
What are the features of insulinomas
Most common; cause hypoglycemia (glucose <50); contusion, loss of consciousness; precipitated by fasting or exercise and relieved by feeding; benign with exception of bona fide carcinomas *deposition of amyloid
247
What are the features of gastrinomas
Most have already met or locally invaded at time of diagnosis; MEN1 associated are multifocal while sporadic are single; *when intractable jejunal ulcers are found, consider zollinger Ellison
248
What are the clinical manifestations of gastrinomas
Most have diarrhea, tx: H/K ATPase inhibitors and excision; if met to liver, short life expectancy
249
What are the features of alpha cell tumors (glucagonomas)
Diabetes, necrolytic migratory erythema, anemia; occur mostly in peri or post menopausal women
250
What are delta cell tumors (somatostatinomas)
Diabetes, cholithiasis, steatorrhea, hypocholrhydria
251
What are the feature of VIPomas
Watery diarrhea, hypokalemia and achlorhydria); some are locally invasive and met; causes severe secretory diarrhea
252
What are pancreatic carcinoid tumors
Produce serotonin
253
How do pancreatic polypeptide secreting tumors present
Mass effect
254
What is the most common cause of Cushing syndrome
Exogenous administration of glucocorticoids
255
Who does Cushing disease mostly affect
Women and younger adults
256
What causes Cushing disease most often
ACTH producing pituitary microadenoma
257
What is the most common cause of ectopic ACTH secretion
Small cell carcinoma; ectopic causes of Cushing more common in men
258
Do adrenal adenomas or carcinomas produce more hypercorticolism
Carcinomas
259
If the adrenal adenoma or carcinoma is unilateral, what happens to the other gland
It atrophied
260
What are the ACTH independent causes of cushing syndrome
Adrenal adenomas or carcinoma, macronodular hyperplasia, primary pigmented nodular adrenal dz, McCune Albright syndrome (GNAS mutation)
261
What is the morphology of cushing syndrome
Pituitary always shows change - crooke hyaline change (resulting from exogenous source) - becomes paler
262
What is the morphology of the adrenal glands in Cushing
Either become atrophic (exogenous), diffuse hyperplasia (ACTH dependent), macronodular or micronodular hyperplasia, or an adenoma/carcinoma
263
Who are adrenal adenomas/carcinomas more prevlanent in
Women in 30s-50s
264
What are the clinical features of cushing
Obesity, facial plethora, rounded face, thin skin, rebased libido, decreased linear growth in kids, menstual irregularity, HTN, hirsutism, depression, easy bruising, glucose intolerance (secondary diabetes), weakness, osteopenia or fracture, nephrolithiasis, proximal limb weakness, increased risk of infections
265
How do you dx cushing
24 hour urine free cortisol concentration is increased, loss of normal diurnal pattern of cortisol secretion
266
What happens to renin in primary hyperaldoseteronism
Decreases
267
What is b/l idiopathic hyperaldosteronism
B/l nodular hyperplasia of adrenal glands; tend to be older and have less severe HTN than those with adrenal neoplasms
268
What causes conn syndrome
Aldosterone producing tumor; more common in women
269
What is glucocorticoid remediable hyperaldosteronism
Cause of primary familial hyperaldosteronism; rearrangement in chrom 8; *suppressible by dexamethasone
270
What causes secondary hyperaldosteronism
Decreased renal perfusion (arteriolar nephrosclerosis, renal a stenosis)
Arterial hypovolemia and edema (CHF, cirrhosis, nephrotic syndrome)
Pregnancy
271
What is the morphology of aldosterone producing adenomas
More common on left in women; often do not produce visible enlargement; *spironolactone bodies found after treatment; NOT atrophic adjacent cortex
272
What are the long term complications of hyperaldosteronism
Left ventricular hypertrophy and reduced diastolic volumes
273
How is primary hyperaldosteronism diagnosed
Elevated ratios of aldosterone:renin activity; if positive, confirm with aldosterone suppression test
274
What is congenital adrenal hyperplasia
Stems from AR inherited metabolic errors -> dont produce cortisol -> shifts to androgen production; if also can’t make aldosterone, will have salt wasting; b/c not making cortisol, ACTH will increase and cause hyperplasia
275
What is salt wasting syndrome
Complete deficiency of 21 hydroxylase; cant make mineralocorticoids or cortisol; salt wasting, hyponatremia, hyperkalemia, acidosis, hypotension, CV collapse, virilization
276
What is simple virilizing adrenogenital syndrome without salt wasting
Presents as genital ambiguity; 21 hydroxylase deficiency; generate sufficient mineralocortoid but not enough cortisol; virilization
277
What is nonclassic or late onset adrenal virilism
Most common; only partial deficiency in 21 hydroxylase; mild manifestations such as hirutism, acne, or menstrual irregularities
278
What effect do adrenogenital syndromes have on the medulla
Cortisol is required to facilitate medullary catecholamines synthesis; so with severe salt wasting syndrome, causes adrenomedullary dysplasia which disposes people to hypotension and collapse
279
How do you treat congenital adrenal hyperplasia
Glucocorticoids; mineralocorticoids if salt wasting
280
What are the patterns of adrnocortical insufficiency
Primary acute adrenocortical insufficiency (adrenal crisis), primary chronic adrenocortical insufficiency (addisons), or secondary adrenocortical insufficiency
281
What can cause primary acute adrenocortical insufficiency
- crisis in individuals with chronic insufficiency precipitated. By stress
- in patients on exogenous corticosteroids whom rapidly withdraw treatment
- as a result of massive adrenal hemorrhage (patients on anticoagulants, post surgical with DIC, Waterhouse friderichsen)
282
What are the features of Waterhouse friderichsen syndrome
Overwhelming bacterial infection, rapidly progressive hypotension leading to shock, DIC with widespread purpura, rapidly developing adrenocortical insufficiency
283
What diseases most commonly affect the adrenal cortex
Autoimmune adrenalitis, TB, AIDS, or metastatic cancers
284
What is autoimmune polyendocrine syndrome type 1
APECED; chronic mucocutaneous candidiasis and abnormalities of the skin, dental enamel and nails (ectodermal dystrophy), autoimmune adrenalitis, hypoparathyroidism, hypogonadism, pernicious anemia; mutation in AIRE; develop abs against IL-17 and IL-22 (reason for development of fungal infections)
285
What is autoimmune polyendocrine syndrome type 2
Combination of adrenal insufficiency and autoimmune thyroiditis or type 1 diabetes
286
What are genetic causes of adrenal insufficiency
Congenital adrenal hypoplasia (X linked), adrenoleukodystrophy
287
What is the morphology of TB adrenalitis
Granulomatous
288
What are the clinical symptoms of addisons
Progressive weakness and fatigue, GI disturbances (anorexia, nausea, vomiting, weight loss, diarrhea), hyperpigmentation of skin (only in primary); hyperkalemia, hyponatremia volume depletion, hypotension
289
Do you see hyponatremia or hyperkalemia with secondary adrenocortical insufficiency
NO because aldosterone regulated separately
290
Are adrenal adenomas or carcinomas more common
Equal in adults; carcinomas more common in kids
291
What 2 syndromes carry an increased risk of adrenal carcinoma
Li-frumpiness syndrome (TP53) and beckwith wiedemann syndrome
292
Are carcinomas or adenomas of the adrenal most likely to be functional
Carcinomas
293
What is the prognosis for adrenal carcinoma
Poor; invades veins and lymphatics
294
What are adrenal myelolipomas
Benign lesions composed of fat and hematopoietic cells
295
What are the rules of 10 of pheochromocytomas
10%:
- are extra adrenal - paragangliomas
- of sporadic adrenal pheochromocytomas are b/l
- are biologically malignant (defined by Mets) - more common in paragangliomas
- are not associated with HTN
296
What genes are involved in pheochromocytomas
RET, NF1, VHL, SDHB,C,D
297
How can you stain pheochromocytomas
Potassium dichromate
298
How do the nuclei of neuroendocrine tumors stain
Salt and pepper
299
What is the other name for MEN1
Wermer syndrome
300
What is the most common kind of pancreatic tumor in MEN1
Pancreatic polypeptide
301
What is the most common pituitary tumor in MEN1
Prolactinoma
302
What is the other name for MEN2A
Sipple syndrome
303
Does thyroid cancer in the setting of familial medullary thyroid cancer have a better or worse prognosis than MEN2
Better
304
What does the pineal gland secrete
Melatonin
305
What are tumors off the pineal gland called
Germinomas; embryonal carcinomas, choriocarcinoma, teratoma (usually benign)
306
What are Gardner duct cysts
Failure of mesonephric ducts to regress in female - form cysts in cervix and vagina
307
What is the epithelial lining of the female genital tract and ovaries?
Mesothelium
308
What infections are implicated in preterm deliveries
Mycoplasma hominis and ureaplasma urealyticum
309
What part of the female genital tract does HSV affect in order of frequency
Cervix, vagina, and vulva (lower genital tract)
310
What are lesions of HSV associated ith
Fever, malaise and tender inguinal LN; cervical or vaginal lesions present with severe purulent discharge and pelvic pain; lays dormant in lumbo-sacral nerve Angelia
311
What is the morphology of HSV ulcers
Epithelium is desquamated; histo shows multinuclated squamous cells containing viral inclusions with a ground glass appearance
312
Are women or men more susceptible to STIs
Women
313
Previous infection with HSV 1 _____ the chance of infection with HSV 2
Decreases BUT HSV 2 increases risk for HSV 1
314
What must be done in a pregnant woman with HSV
C section
315
What is detection of anti_HSV abs indicative of
Recurrent or latent infection
316
What is Molluscum contagiosum
Skin or mucosal lesion cause by poxvirus; 4 types of MCVs (1 most prevalent and 2 is most often sexually transmitted); common in children btw 2-12 and transmitted through direct contact; most common on trunk, arms and legs; in adults, most commonly isn’t genital, lower abdomen, butt and inner thighs *pearly, dome shaped papules with a dimpled center - central waxy core has cytoplasmic vial inclusions
317
What increases the risk of vaginal fungal infection
Diabetes, abx, pregnancy, compromised neutrophil or Th17 peons
318
How do vaginal fungal infections present
Vulvovaginal pruritis, erythema, swelling and curdlike vaginal discharge; severe infection may result in mucosal ulceration
319
How are fungal infections of the lower genital tract diagnosed
Inning pseudospores or filamentous fungal hyphae in wet KOH mounts of the discharge or Pap smear; not STI
320
What is trichomonas vaginalis
Flagellated ovoid protozoan transmitted sexually and develops within 4 days to 4 weeks; yellow, frothy vagina discharge, vulvovaginal discomfort, dysuria, dyspareunia (painful intercourse); vaginal and cervical mucosa has fiery red appearance with marked dilation of cervical mucosal vessels *strawberry cervix
321
What is gardnerella vaginalis
Gram negative bacillus; main cause of bacterial vaginosis/vaginitis; thin, green-grey malodorous discharge Pap smear reveals superficial and intermediate squamous cells covered with shaggy coating coccobacilli; in pregnant patients, leads to premature labor
322
What are ureaplasma urealyticum and mycoplasma hominis implicated in
Vaginitis, cervicitis, chorioamnionitis and premature delivery
323
What is the main manifestation of chlamydia trachomatis
Cervicitis
324
What are the symptoms of pelvic inflammatory disease
Pain, adnexal tenderness, fever, vaginal discharge
325
What is the most common cause of PID
Neisseria gonorrhea
326
Besides chlamydia and gonorrhea, what are other causes of PID
Infections after spontaneous or induced abortions and deliveries (puerperal infections) - typically polymicrobial and aused by staph, strep, coliorms, and clostridium perfringens - spread via lymphatics or venous rather than mucosal surfaces; tend to produce more inflammation within deeper layers than gonococcal infections
327
What is the morphology of gonococcal infection
Acute inflammation of mucosal surfaces; smears show phagocytosed gram negative diplococci within neutrophils; endometrium usually spared but within Fallopian tubes, acute suppurative salpingitis occurs -> spread to ovary (scalping-oophoritis); pus can accumulate and form tubo-ovarian abscess or pyosalpinx; over time, tubal plicae fuse and scar (chronic salpingitis) or hydrosalpinx
328
What is a more frequent complication of strep or staph PID than gonococcal
Bacteremia
329
What are the acute complications of PID
Peritonitis, bacteremia which can lead to endocarditis, meningitis and suppurative arthritis
330
What is a bartholin cyst
Infection of bartholin gland produces acute inflammation (adenitis) and may result i abscess; relatively common; occurs at all ages; lined by transitional or squamous epithelium; can become large and produce pain and discomfort; either excised or opened permanently (marsupialization)
331
What can cause leukoplakia
Inflammatory dermatoses (psoriasis, chronic dermatitis), lichen sclerosis and squamous hyperplasia, neoplasia such as vulvar intraepithlial neoplasia (VIN), Paget dz, and invasive carcinoma
332
What is lichen sclerosus
Presents as smooth, white plaques or macules that can enlarge or coalesce producing a porcelain or parchment surface; when entire vulva affected, labia become atrophic and agglutinated and vaginal orifice constricts
333
What is the histo of lichen sclerosus
Thinning of epidermis, degeneration of basal cells, hyperkeratosis, sclerotic changes of superficial dermis and bandlike lymphocytic infiltrate in underlying dermis; most common in post menopausal women autoimmune suggested *slightly increased change of developing SCC of vulva
334
What is squamous cell hyperplasia of the vulva
Caused by rubbing or scratching presents as leukoplakia and histo release thickening of epidermis (acanthosis) and hyperkeratosis; no atypia; sometimes present at margins of vulvar cancer
335
What is condyloma acuminatum
Papilloma induced lesion (HPV 6 and 11) aka genital wart; mostly multiple; can affect vulvar, perineal, perianal, vagina, cervix; papillary exophytic treelike cores of stroma covered by thickened squamous cells; *koilocytic atypia (nuclear enlargement, hyperchromasia, and cytoplasmic perinuclear halo)
336
What is condyloma Latum
Caused by syphilis
337
What are vulvar fibroepithelial polyps
Skin tags
338
What are vulvar squamous papillomas
Benign exophytic proliferation’s covered by nonkeratinized squamous cells; can be numerous (papillomatosis)
339
Who does vulvar carcinoma occur in
Women > 60
340
What are the types of vulvar SCC
- basaloid and warty related to infection with high risk HPVs (mostly 16); less common and occur at younger ages
- keratinizing SCC unrelatedly to HPV; more common and occur in older women
341
What is the precursor lesion for basaloid and warty carcinomas
Classic vulvar intraepithlial neoplasia (VIN); occurs mainly in reproductive age women - CIS or Bowen dz; risk: young age at first intercourse, multiple sexual partners, male partner with multiple sexual partners; can spontaneously regress; risk of cancer higher in those > 45
342
Who does keratinizing SCC of the vulva most commonly occur in
Long standing lichen sclerosus or squamous cell hyperplasia; peak occurrence is 8th decade; arises from differentiated vulvar intraepithlial neoplasia (differentiated VIN) or VIN simplex
343
What is the morphology of classic VIN
Discrete white hyperkeratosis pigmented lesions; epidermal thickening nuclear atypia, increased mitosis and lack of cellular maturation; basaloid has nests and cords; warty is exophytic and papillary with koilocytic atypia
344
What is the morphology of differentiated VIN
Marked atypia of basal layer of squamous epithelium an normal appearing superficial layers
345
What does the risk of cancer development in VIN depend on
Duration and extent of disease and immune status of the patient
346
Where can vulvar cancer spread
Inguinal, pelvic, iliac, periaortic LN; then to lungs, liver
347
What is the prognosis for vulvar cancer
Small lesions: good
| Larger lesions w/ LN involvement: poor
348
What is papillary hidradenoma
Presents as sharply circumscribed nodule most commonly on labia majora or interlabial folds; tends to ulcerate; histo: identical to intraductal papilloma of the breast - pap projection covered with 2 layers (upper layer of columnar secretory cells with deeper layer of flattened myoepithelial cells)
349
What is extramammary paget dz
Presents as pruritic, red, crusted maplike area usually on labia majora; proliferation of malignant cells; pale cytoplasm containing mucopolysaccharide that stains with PAS, Alcian blue or mucicarmine stains; express cytokeratin 7; apocrine, eccrine and keratinocytes differentiation
350
Is vulvar paget associated with underlying cancer
No; confined to epidermis of vulvar skin; treat with excision; rarely will invade and suggests poor prognosis
351
What is septate vagina
Double vagina; failure of Müllerian duct fusion; accompanied by double uterus (uterus didelphys); can be manifestation of genetic syndromes or in utero exposure to diethylstilbestrol (DES)
352
What is vaginal adenosis
When vagina is not completely replaced by squamous cells and still has some remaining columnar cell; presents as red granular areas; seen with exposure to DES; rarely will lead to clear cell carcinoma
353
Where are gartner cysts located
Lateral walls of vagina; submucosal
354
What age do most benign tumors of the vagina occur in
Reproductive age women; include stromal tumors (polyps), leiomyomas, and hemangiomas
355
What is the most common malignant tumor to involve the vagina
Carcinoma spreading from the cervix
356
What are primary carcinomas of the vagina
All are SCC associated with high risk HPVs; greatest risk factor is previous carcinoma of cervix or vulva; premalignant lesion: vaginal intraepithelial neoplasia; mostly affects upper vagina posterior wall; lesions in lower 2/3 met to inguinal nodes and upper met to iliac nodes
357
What is embryonal rhabdoyosarcoma
Aka sarcoma botryoides; found in infants and children <5 ears. Grow as polyploid rounded bully masses (grapelike clusters); tumor cells resemble tennis racket; sometimes can see striations; tumor cells are in cambium layer or within loose fibroyxomatous stroma; invades locally and causes death hby penetration into peritoneal cavity or obstruction of urinary tract; tx: surgery with chemo
358
What is the main flora of the cervix
Lactobacilli -> produce lactic acid and maintains vaginal pH <4.5; also produce bacteriotoxic H2O2; if pH becomes alkaline due to bleeding, sex, or douching, H2O2 producing decreases; abx therapy can also cause pH to rise
359
What are endocervical polyps
Common benign exophytic growths that arise within endocervical canal; composed of loos fibromyxomatous stroma covered by mucus secreting endocervical glands; source of vaginal spotting; tx: simple curettage or surgical excision
360
What cells does HPV infect
Immature basal cells of the squamous epithelium; but viral replication occurs in maturing squamous cells
361
What are the roles of E7 and E6
E7 binds to activated Rb and degrades it and binds and inhibits p21 and 27
E6 binds to p53 an promotes its degradation; also upregulates telomerase
362
What is the classification system for squamous cervical precursor lesion
- mild dysplasia: CINI; Low grade SIL
- moderate: CINII; high grade SIL
- severe: CINIII; high grade
- carcinoma in situ: CINIII; high grade
363
What are the features of LSIL
Productive HPV infection; high level of viral replication but only mild alterations in growth of host cells; doesn’t progress directly to invasive carcinoma; *most regress spontaneously
364
Are all HSILS at high risk for progression to carcinoma
Yes
365
What is the morphology of squamous intraepithelial lesion (SIL)
```
Nuclear atypia (nuclear enlargent, hyperchromasia, coarse chromatin granules, variation in nuclear size and shape); cytoplasmic halos - koilocytic atypia
-low vs high grade: low is if immature cells confined to lower 1/3 of epithelium
```
366
What is the histo of LSIL
- upper portion of epithelium express Ki-67 (normally confided to basal layer)
- overexpression of p16
367
What is the average age for cervical carcinoma
45
368
What other kinds of cancer (besides SCC) can present in the cervix
Adenocarcinoma, adenosquamous, and neuroendocrine; all assoc with HPV; all have less favorable prognosis than SCC
369
What is the morphology of invasive cervical carcinoma
Fungating or infiltrative mass; SCC: nests and tongues of malignant epithelium; adeno: glandular epith. Mucin depleted cytoplasm resulting in dark appearance; adenosquamous: glandular and squamous; neuroendocrine: looks like small cell
370
How does cervical carcinoma spread
Direct extension; lymphovascular - liver, lungs, bone marrow
371
How are microinvasive vs invasive cervical cancers treated
Microinvasive: cone
Invasive: hysterectomy with LN dissection; radiation and chemo
372
What do people with cervical cancer die of
Ureteral obstruction, pyelonephritis, uremia
373
What is the screening guideline for cervical cancer
First pap at age 21 and every 3 years; after age 30 if normal cytology, every 5 years; if test positive for HPV DNA, every 6-12 months
374
What are the parts of the uterus
Myometrium: smooth m that forms the wall
Endometrium: internal cavity; composed of lands
375
What is shed during menses
Superficial layer of endometrium (functionalis)
376
What are the phases of the menstrual cycle
- proliferative: growth of glands and stroma arising from basalis; glands are straight lined by pseudostratified columnar no mucus secretion; endometrial stroma composed of spindle cells
- ovulation: proliferation stops differentiation in response to progesterone
- postovulation: secretory vacuoles beneath nuclei in glandular epithelium; glands tortuous (saw toothed)
- late secretory: impt for dating endometrium spiral arterioles; stromal hypertrophy and increased cytoplasmic eosinophilia (predicidual change)
377
What is the most common cause of abnormal uterine bleeding
Dysfunctional uterine bleeding; lacks an underlying structural abnormality; disturbances in hormones
378
What are the prepubertal causes of abnormal uterine bleeding
Precocious puberty
379
What are the causes of abnormal uterine bleeding in adolescents
Anovulatory cycle, coagulation disorders
380
What are the causes of abnormal uterine bleeding in reproductive years
Complications of pregnancy (abortion, trophoblastic dz, ectopic), anatomic lesions (leiomyoma, adenomyosis, polyps, endometrial hyperplasia, carcinoma), dysfunctional uterine bleeding (anovulatory cycle, ovulation dysfunctional bleeding)
381
What are the causes of abnormal uterine bleeding in perimenopausal women
Dysfunction uterine bleeding (anovulatory cycle), anatomic lesions (carcinoma, hyperplasia, polyps)
382
What are the causes of abnormal uterine bleeding in postmenopausal women
Endometrial atrophy, anatomic lesions (carcinoma, hyperplasia, polyps)
383
What is the most common cause of dysfunctional bleeding
Anovulation - most common at menarche and postmenopausal period
Less common causes: endocrine disorders (thyroid, adrenal, pituitary), ovarian lesions (granulosa cell tumors or PCOS), generalized metabolic disturbances (obesity, malnutrition)
384
How does anovulation cause bleeding
Results in excessive endometrial stimulation by estrogens unopposed by progesterone; repeat anovulation - biopsy shows stromal condensation and eosinophilic epithelial metaplasia; lacks progesterone dependent features (glandular secretory changes)
385
What are the manifestations of inadequate luteal phase
Infertility associated with increased bleeding or amenorrhea; inadequate progesterone during post ovulation period
386
What is acute endometritis
Uncommon; limited to bacterial infections after delivery or miscarriage; group A strep, staph
387
What causes chronic endometritis
Chronic PID, retained gestational tissue, IUD, TB (miliary sprea or drainage of tuberculous salpingitis)
388
How is the dx of chronic endometritis made
Plasma cells in stroma
389
What are the most common sites of endometriosis
Ovaries, uterine ligaments, rectovaginal septum, cul de sac, pelvic peritoneum, large and small bowel and appendix, mucosa of cervix, vagina, and fallopian tubs, laparotomy scars
390
What does endometriosis cause
Infertility, dysmenorrhea (painful menstruation), pelvic pain
391
What is the regurgitation theory
Endometrial tissue implants at ectopic sites due to retrograde flow of menstrual endometrium
392
What is the benign metastasis theory
Endometrial tissue can spread to distant sites via bv and lymph
393
What is the meta plastic theory
Endometrium arises directly from coelomic epithelium (mesothelium of pelvis or abdomen)
394
What is the extrauterine stem/progenitor cell theory
Bone marrow can differentiate into endometrial tissue
395
When can endometriosis occur in men
Treated with estrogens for prostate cancer
396
What do the endometria of women with endometriosis show that is not seen in normal endometria
- Release of PGE2, IL-1beta, TNFalpha, IL-6 and 8, NGF, VEGF, MCP-1, MMPs, TIMPs
- increased estrogen production by endometriotic stromal cells *high levels of aromatase (inhibitors of this used as treatment)
397
What cancer has endometriosis been associated with
Ovarian cancer of the endometrioed and clear cell types; mutations in PTEN and ARID1A
398
What is the morphology of endometriotic lesions
Bleed; produces nodule with red-blue to yellow-brown appearance on or just beneath the mucosa or serosa; organizing hemorrhage can cause fibrous adhesions; ovaries can become distorted by cystic masses (chocolate cysts or endometriomas)
399
How do you make a diagnosis of endometriosis
Need glands and stroma or just stroma; if only glands, need to consider other causes
400
What is atypical endometriosis
Precursor to endometriosis-related ovarian carcinoma
401
What is adenomyosis
Presence of endometrial tissue within the uterine wall (myometrium); sx: menometrorrhagia (heavy menses), colicky dysmenorrhea, dyspareunia, and pelvic pain; can coexist with endometriosis
402
What are endometrial polyps
Exophytic masses that project into endometrial cavity; can cause bleeding; neoplastic; have been observed in association with administration of tamoxifen (therapy for breast cancer) - has pro-estrogen affect on endometrium; atrophic polyps occur in postmenopausal women; rarely adenocarcinoma can result
403
What is endometrial hyperplasia
Cause of abnormal bleeding; frequent precursor to most common typ of endometrial carcinoma; *increased proliferation of glands in ratio to stroma; assoc with prolonged estrogenic stimulation (anovulation, exogenous or endogenous)
404
What associated conditions can cause endometrial hyperplasia
- obesity (peripheral conversion of androgens to estrogens)
- menopause
- PCOS
- functioning granulosa cell tumors of the ovary
- excessive ovarian cortical function (cortical stromal hyperplasia)
- prolonged administration of estrogenic substances
405
What genetic mutation is seen in endometrial hyperplasia
PTEN (LOF); encodes lipid phosphatase that is negative regulator of PI3K/AKT pathway *Cowden syndrome
406
What is the morphology of non-atypical endometrial hyperplasia
*increased gland to stroma ratio; rarely progress to adenocarcinoma; can evolve into cystic atrophy when estrogen is withdrawn
407
What is the morphology of atypical endometrial hyperplasia
Aka endometrial intraepithelial neoplasia; complex patterns of proliferating glands displaying atypia; sometimes cannot distinguish from adenocarcinoma without hysterectomy
408
How is atypical hyperplastia of the endometrium managed
Hysterectomy or in young women who desire fertility, trial of progestin therapy and close follow up
409
What is the most common invasive cancer of the female genital tract
Endometrial carcinoma
410
What is type I endometrial carcinoma
Most common; well differentiated; endometrioid carcinoma; assoc with obesity, diabetes, HTN, infertility, and unopposed estrogen; mutation in PTEN, PIK3CA (GOF - plays a role in invasion), KRAS, LOF in ARID1A (regulator of chromatin structure - also mutated in ovarian endometrioid and clear cell carcinomas)
411
What is the age of onset of type I vs type II endometrial carcinoma
- type I: 55-65
| - type II: 65-75
412
What is the clinical setting of type I vs type II endometrial carcinoma
- type I: unopposed estrogen, obesity, HTN, diabetes
| - type II: atrophy, thin physique
413
What is the morphology of type I vs type II endometrial carcinoma
- type I: endometrioid
| - type II: serous, clear cell, mixed mullerian tumor
414
What is the precursor of type I vs type II endometrial carcinoma
- type I: hyperplasia
| - type II: serous endometrial intraepithelial carcinoma
415
What is the mutation of type I vs type II endometrial carcinoma
- type I: PTEN, ARID1A, PIK3CA, KRAS, FGF2, MSI, CTNNB1, TP53
- type II: TP53, aneuploidy, PIK3CA, FBXW7, CHD4, PPP2R1A
416
What is the behavior of type I vs type II endometrial carcinoma
- type I: indolent, spread via lymphatics
| - type II: aggressive, intraperitoneal and lymphatic spread
417
Who are endometrial cancers with mismatch repair genes mutations more common in
HNPCC (hereditary nonpolyposis colorectal carcinoma)
418
What is the order of mutations for serous carcinoma of the endometrium
Atrophic endometrium -> TP53 and aneuploidy -> serous endometrial intraepithelial carcinoma -> FBXW7, PPP2R1A, CCNE1 mutations -> serous carcinoma
419
What is type II serous carcinoma of the endometrium
Occur in women about 10 years older than type I;; arise in setting of endometrial atrophy; poorly differentiated (grade 3); mutations in TP53 (most missense); poorer prognosis b/c propensity to exfoliate and travel through Fallopian tubes and implant on peritoneal surfaces
420
What is the clinical presentation of endometrial carcinoma
Bleeding with excessive leukorrhea
421
Who does serous carcinoma of the endometrium occur more often in
African Americans
422
What are malignant mixed mullerian tumors (MMMTs)
Aka carcinosarcomas; endometrial adenocarcinomas with a malignant mesenchymal component (can be stromal sarcoma, leiomyosarcoma or rhabdymyosaroma or chondrosarcoma); mutations PTEN, TP53 and PIK3CA
423
What is the morphology of MMMTs
Bulky and can protrude through os; histo adenocarcinoma mixed with sarcomatous elements; *mets only contain epithelial components
424
Who do MMMTs present in
Postmenopausal women; present with bleeding; prognosis based on depth of invasion, stage, and differentiation of mesenchymal component (those with heterologous mesenchymal components do worse)
425
What are adenosarcomas of the endometrium
Malignant appearing stroma with benign but abnormally shaped glands; predominate in women btw 4th and 5th decade; low grade malignancy; estrogen-sensitive and responds to oophorectomy*
426
What mutations are seen in low grade endometrial stromal sarcomas
Translocations in which portions of JAZF1 is fused to SUZ12
427
Do stromal sarcomas recur
Yes
428
What are uterine leiomyomas
Benign smooth m neoplasms; more often multiple; rearrangements involving HMGIC and HMGIY; mutations in MED122
429
What is the morphology of leiomyomas
Sharply circumscribed; found within myometrium of the corpus; can occur within myometrium (intramural), beneath the endometrium (submucosal) or beneath the serosa (subserosal); *whorled pattern of smooth m; low mitotic index
430
What is benign metastasizing leiomyoma
Uterine leiomyoma that extends into vessels and spreads hematogenously (mostly to the lung); benign
431
What is disseminated peritoneal leiomyomatosis
Multiple small peritoneal nodules benign
432
What are sx of leiomyomas
Bleeding, urinary frequency, sudden pain from infarction, impaired fertility; increased risk of spontaneous abortion, fetal Malpresentation, uterine inertia (failure to contract), and postpartum hemorrhage
433
What are leiomyosarcomas
Arise from myometrium and endometrial stromal precursors; MED12 mutation; complex karyotypes; grow in 2 patterns bulky fleshy masses or polyploid that project into the lumen
434
Who do leiomyosarcomas develop in
Both before and after menopause; 40-60; often recur following surgery and most met to lungs bone and brain
435
What is the most common primary lesion of the Fallopian tube
Paratubal cysts (serous filled); larger varieties found near the fibrates end or in the broad ligaments (hydatids of Morgagni); arise from remnants of Müllerian duct
436
What are the tumors of the Fallopian tube
Benign: adenomatoid (mesothelioma)
Malignant: primary adenocarcinoma
437
What are cystic follicles of the ovary
Originate from unruptured Graafian follicles or in follicles that hav ruptured and immediately sealed; usually multiple; filled with serous fluid;
438
What are luteal cysts
Present in normal ovaries of women of reproductive age; lined by bright yellow tissue containing luteinized granulosa cells; occasionally rupture and cause peritoneal reaction
439
What is PCOS
Hyperandddrognism, menstrual abnormalities, polycystic ovaries, chronic anovulation and decreased fertility; assoc with obesity, T2DM, premature atherosclerosis; show insulin resistance; at risk for endometrial hyperplasia and carcinoma
440
What is stromal hyperthecosis
Disorder of ovarian stroma seen in postmenopausal women but can overlap with PCOS in younger women; uniform enlargement of ovary; usually b/l and shows hypercellular stroma and luteinization of stromal cells; virilization may be more striking than PCOS
441
What is theca lutein hyperplasia of pregnancy
Response to pregnancy hormones (gonadotropins), theca cells proliferate and the perifollicular zone expands; as follicles regress, May appear nodular
442
What do most tumors of the ovary arise from
- surface/Fallopian tube epithelium and endometriosis
- germ cells (migrate from yolk sac)
- stromal cells, including sex cords
443
What are the surface epithelial stromal tumors of the ovary
- serous (cystadenoma, cystadenofibroma, serous borderline, serous adenocarcinoma)
- mucinous
- endometrioid
- clear cell
- transitional cell
- epithelial-stromal
444
What are the sex cord stromal tumors of the ovary
Granulosa, fibromas, fibrothecomas, thecomas, sertoli-leydig cell tumors, steroid cell tumors
445
What are the germ cell tumors of the ovary
Teratoma, dysgerminoma, yolk sac tumor, mixed germ cell tumor
446
What are the metastatic cancers that affect the ovary
Colonic, appendiceal, gastric, pancreaticobiliary, breast
447
What is the most common type of malignant ovarian tumor
Serous
448
Where do most primary ovarian neoplasms arise from
Mullerian epithelium - 3 subtypes: serous, mucinous and endometrioid
449
What are the types of ovarian carcinomas
Type I: low grade arise in associated with borderline tumors or endometriosis; type II: high grade serous carcinomas that arise from serous intraepithelial carcinoma
450
What are the most common malignant ovarian tumors
Serous; can be benign, borderline (20-45) or malignant (later in life)
451
What are the risk factors for malignant serous tumors of the ovary
Nulliparity, family hx, heritable mutations (BRCA1 and 2)
452
What are the types of serous ovarian carcinoma
Low grade (well diff) - arise in assoc with serous borderline tumors and high grade - arise from in situ lesions in Fallopian tube fimbriae or serous inclusion cysts within the ovary
453
What do women with BRCA mutation undergo
Salpingo-oophorectomy
454
What mutations are seen in low grade vs high grade serous ovarian carcinomas
- low grade: KRAS, BRAF, ERBB2; usually have wildtype TP53
| - high grade: TP53 and lack KRAS or BRAF mutation; PIK3CA, RB, BRCA1/2 (but rare in sporadic)
455
What is the morphology of serous tumors
Benign: smooth glistening cyst wall with no epithelial thickening
Borderline: increased papillary projections
Most are b/l especially if malignant
456
What kind of invasion are ovarian serous tumors (both low and high grade) capable of
Spread to peritoneal surfaces and omentum; assoc with presence of ascites
457
What is the prognosis of low vs high grade serous ovarian tumors
Low grade, even if mets progresses slowly; high grade usually has wide Mets at time of diagnosis
458
Who do mucinous tumors of the ovary occur in
Mid life; rare before puberty and after menopause; most are benign or borderline
459
What is the pathogenesis of mucinous tumors of the ovary
Mutations of KRASS
460
How do mucinous tumors differ from serous
Mucinous rarely involve the surface and are not usually b/l; produce bigger masses
461
What is the histo of mucinous tumors of the ovary
- benign: most demonstrate gastric or intestinal differentiation; some show endocervical
- borderline: distinguished from cystadenomas from epithelial stratification, tufting and papillary intraglandular growth
- carcinomas: glandular growth (expansile invasion); non-invasive outside ovary - excellent prognosis; if spread beyond ovary, usually fatal
462
What is pseudomyxoma peritonei
Mucinous ascites, cystic epithelial implants on peritoneal surfaces, adhesions and involvement of ovaries; can result in intestinal obstruction
463
What are endometriod ovarian tumors
Distinguished from serous and mucinous tumors by presence of tubular glands resembling benign or malignant endometrium; can arise with endometriosis or borderline tumor; seen in conjunction with carcinoma of the endometrium but arise independently rather than spread
464
What is the pathogenesis of endometrioid carcinoma of the ovary
Assoc with endometriosis (occurs early than not associated with); mutations in PTEN, PIK3CA, ARID1A, KRAS, CTNNB1
465
What does b/l endometrioid carcinoma of the ovary usually suggest
Extension beyond the genital tract
466
What are cystadenofibromas
Uncommon; more pronounced proliferation of fibrous stroma that underlies the columnar lining; benign; simple papillary processes; may contain mucinous, serous, endometrioid, and transitional (Brenner) epithelium
467
What are transitional cell tumors
Contain neoplastic epithelial cells resembling urothelium and are usually benign; Brenner tumors; usually unilateral; if >50% of malignant cells, considered transitional cell carcinoma of ovary
468
What serum marker is used to measure disease recurrence in ovarian cancers
CA-125
469
What are the most common germ cell tumors of the ovary
Benign cystic teratoma
470
What are the features of mature benign teratomas
Most are cystic and referred to as dermoid cysts; lined by skin structures; found in young women urging reproductive years; assoc with paraneoplastic syndromes - inflammatory limbic encephalitis
471
1% of dermoids undergo malignant transformation t o what kind of cancer
Usually squamous cell; but can to thyroid or melanoma as well rarely
472
What is the karyotype of most benign ovarian teratomas
46, XX
473
What are the most common monodermal or specialized teratomas
```
Struma ovarii - mature thyroid tissue (can cause hyperthyroidism)
and carcinoid (may also be functional - if >7cm can produce enough 5-hydroxytryptamine to cause carcinoid syndrome in the absence of liver mets b/c ovarian v leads to systemic circulation; can meet) *always unilateral although contralateral teratoma may be present
```
474
What are immature malignant teratomas
Rare; resemble embryonal and immature fetal tissue found in prepubertal adolescents and young women; grade depends on about of immature neuroeptihelium; grow rapidly and spread; Stage I has excellent prognosis; high grade confined to ovary treated with chemo
475
What are dysgerminomas
Ovarian counterpart of seminoma; most occur in 2nd to 3rd decade; some occur in patients with gonadal dysgenesis or pseudohermaphroditism; a few produce chorionic gonadotropin (presence of syncytiotrophoblastic giant cells); express OCT3,4, NANOG,KIT
476
What is the morphology of dysgerminomas
Most are unilateral; composed of vesicular cells having clear cytoplasm and regular nuclei; grows in sheets or cords
477
Are all dysgerminomas malignant
Yes; if unilateral and has not broken through capsule excellent prognosis after salpingooophorectomy; responsive to chemo
478
What are yolk sac tumors
Aka endodermal sinus tumor; derived from malignant germ cells differentiating along the extraembryonic yolk sac lineage; elaborate alpha fetoprotein; *glomerulus like structure on histo with central blood vessel enveloped by tumor cells within a space lined. By tumor cells (Schiller-Duvall body); most are children or young women who present with ab pain and rapidly growing mass in single ovary; good prognosis with chemo
479
What is choriocarcinoma
More commonly of placental origin; extraembryonic differentiation of germ cells; prepubertal; most exist in combo with other germ cell tumors; aggressive in the ovary and met to lungs, liver bone by hematogenous route; elaborate chorionic gonadotropins; *unresponsive to chemo when in the ovary
480
What is embryonal carcinoma
Highly malignant tumor of primitive embryonal elements
481
What is polyembryoma
Malignant tumor containing embroid bodies
482
What is mixed germ cell tumor
Contains combo of dysgerminomas,teratomas, yolk sac. Tumor and choriocarcinoma
483
What are granulosa cell tumors
Composed of cells that resemble granulosa cells of developing ovarian follicle; adult and juvenile forms; most occur in postmenopausal women; usually unilateral; if hormonally active, have yellow coloration to surface
484
What is the histo of granulosa cell tumors
Can have small cuboidal to polygonal cells growing in cords, sheets or strands; can have glandlike structures filled with acidophilic material called call-exner bodies *staining with ab to inhibin
485
What are the manifestations of granulosa tumors
In prepubertal girls -> precocious puberty
In adults: proliferative breast dz, endometrial hyperplasia, endometrial carcinoma; can produce androgens and masculinize the patient
All are potentially malignant (tumors composed predominantly of theca cells are almost never malignant)
486
What is elevated as a result of granulosa Ellis
Inhibin
487
What mutation is seen in granulosa cell tumors
FOXL2(only in adult type)
488
What are fibromas and thecomas
Fibromas: composed of fibroblasts; hormonally inactive; unilateral
Thecomas: composed of plump spindle cells with lipid droplets
combo: fibrothecomas
*present as painful mass, ascites, hydrothorax usually on the right - Meigs syndrome; also associated with basal cell nevus syndrome
489
What mutations are seen in sertoli-leydig tumors
DICER1 - encodes enonuclease that processes microRNAs
490
What is the morphology of sertoli-leydig tumors
Usually unilateral; resemble granulosa tumors; does not usually recur or met; can block normal female sexual development or defeminization (atrophy of breasts, amenorrhea, sterility, and loss of hair)
491
What are Hilus cell tumors (pure leydig cell tumors)
Derived from clusters of polygonal cells arranged around hilar vessels; unilateral; *reinke crystalloids; masculization (hirsutism, voice changes, and clitoral enlargement, but milder than sertoli-leydig); produce testosterone; benign
492
What is pregnancy luteoma
Rare resembles corpus luteum of pregnancy; produce virilization in pregnant patients and their female infants
493
What is gonadoblastoma
Uncommon; tumor composed of germ cells and sex cord stroma derivative resembling immature stroll and granulosa cells; occurs in individuals with abnormal sexual development and in gonads of indeterminate nature; most of phenotypic females, and the rest are phenotypic males with undescended testicles and female internal secondary organs; *coexistant dysgerminoma occurs in half of cases prognosis is excellent if excised
494
what are the most common places that cancers metastasize from to the ovary
Mullerian origin: uterus, Fallopian tube, contralateral ovary, pelvic peritoneum
495
What are the most what are the extra-mullerian sites that have ovarian mets
Breast, GI, pseudomyxoma peritonei
| *krukenberg tumor - b/l met composed of mucin producing, signet ring cancer cells
496
What is spontaneous abortion defined as
Pregnancy loss before 20 weeks gestation (most occur before 12 weeks)
497
What are some causes of spontaneous abortion
- fetal chromosome anomalies: aneuploidy, polyploidy, translocations
- maternal endocrine factors: luteal-phase defect, poorly controlled diabetes
- physical defect of uterus: submucosal leiomyomas, uterine polyps, or uterine malformations
- systemic disorders affecting maternal vasculature: antiphospholipid ab syndrome, coaulapathies and HTN
- infections with Protozoa (toxoplasma), bacteria (mycoplasma, listeria), ascending infection tends to occur in 2nd trimester loss
498
Where is the most common site of ectopic pregnancy
extrauterine Fallopian tube (intrauterine is called cornual pregnancy)
499
What is associated with increased risk of ectopic pregnancy
IUDs
500
What is diagnosis of tubal pregnancy based on
Presence of chorionic gonadotropin, pelvic sonography, endometrial bx (shows deciduous without chorionic villi or implantation sites) and/or laparoscopy
501
What are the types of twin placentas
Diamnionic dichorionic, diamnionic monochorionic, and monoamnionic monochorionic; monochorionic = monozygotic twins; dichorionic = either mono or dizygotic
502
What is a complication of monochorionic twin pregnancy
Twin-twin transfusion syndrome; contain av shunts and if increases blood flow to one twin over another, one twin will be anemic and the other will be fluid overloaded
503
What is placenta Previa
When placenta implants in lower uterine segment or cervix; complete covers internal cervical os and requires delivery via c section
504
What is placenta accreta
Caused by partial or complete absence of decidua such that the placental villous tissue adheres directly to the myometrium which leads to allure of placental separation at birth; cause of severe postpartum bleeding ; disposing factor is placenta previa and previous c section
505
How do placental infections occur
Either through ascending infection through the birth canal (most. Common - always bacterial) or hematogenous (transplacental) infection; causes preterm delivery; amniotic fluid many be cloudy; histo of corionamnion contains infiltrate of neutrophils with edema and congestion of vessels; elicited Vasculitis of umbilical and fetal chorionic plate vessels
506
What are the TORCH infections
Toxoplasmosis, syphilis, TB, listeriosis, rubella, CMV, herpes; hematogenous; cause chronic villlitis
507
What is preeclampsia
Widespread maternal endothelial dysfunction that presents with HTN, edema, and proteinuria; more common in primiparas (first pregnancy); can be complicated by hypercoagulability, acute renal failure, and pulm edema, microangiopathy hemolytic anemia, elevated liver enzymes, and low platelets (HELLP)
508
What is the pathogenesis of preeclampsia
Diffuse endothelial dysfunction, vasoconstriction, and increased vascular permeability mediated by placental derived mediators
- abnormal trophoblastic implantation and failure of remodeling of maternal vessels (trophoblastic cells don’t invade maternal decidua and destroy the vasclar smooth mm)
- ischemic placenta releases factors (FMS-like tyrosine kinase - sFltl) and endoglin antagonize VEGF and TGFbeta - leads to endothelial dysfunction and vasoconstriction)
509
Where are clots most likely to form in women with preeclampsia
Liver, kidneys, brain, pituitary; related to reduced production of PGI2 (because requires VEGF to be released)
510
What is the morphology of the placenta in preeclampsia
Infarcts, exaggerated ischemic changes in villi nad trophoblastic consisting of incrased syncytial knots, retroplacental hematomas, abnormal decidua vessels
511
What are the liver lesions seen in preeclampsia
Subcapsular and intraparenchmal hemorrhages fibrin thrombi in portal capillaries and hemorrhagic necrosis
512
What are the kidney lesions seen in preeclampsia
Glomeruli show swelling of endothelial cells, amorphous dense deposits and mesangial cell hyperplasia; fibrin in glomeruli; can cause b/l renal cortical necrosis
513
What are the clinical features of preeclampsia
Occurs most commonly after 34 weeks (occurs earlier in women with hydatidiform mole, preexisting kidney dz, HTN, or coagulopathies); for term infants, delivery is treatment regardless of disease severity; in preterm, monitor, but inf eclampsia, severe preeclampsia with maternal end organ dysfunction, HELLP, or fetal distress are indications for delivery
514
What are long term consequences of preeclampsia
Some women develop HTN and microalbuminuria; increase in risk off vascular dz of heart and brain
515
What are hydatidiform moles
Cystic swelling of chorionic villi with trophoblastic proliferation; diagnosed during early pregnancy by pelvic sonogram; higher risk at 2 extremes of reproductive life; more common in SE Asia
516
What is a complete mole
Fertilization of egg that has lost its female chromosomes (46 XX - called androgenesis) or fertilization of empty egg by 2 sperm (46 XX or 46 XY); risk of choriocarcinoma and invasive mole
517
What is a partial mole
Result from fertilization of an eg with 2 sperm (Triploid - 69 XXY or tetraploid - 92 XXXY); fetal tissue present; increased risk of persistent molar disease but NOT associated with choriocarcinoma
518
What is the morphology of hydatidiform moles
Delicate, friable mass of thin-walled translucent cystic grapelike structures consisting of woolen edematous villi; complete: chorionic villi enlarged scallops w/ central cavitation (cisterns); partial: only fraction of ili are enlarged
519
What is true of the HCG elaborated by complete moles
Higher. Than those of a normal pregnancy of similar gestational age; monitor level even after removal to see if persistent or invasive mole (seen more with complete rather than partial moles)
520
What is an invasive moles
Penetrates or perforates the uterine wall; hydropic villi can embolize to distant sites such as lungs and brain but do not grow here as true mets and will regress; manifested by vaginal bleeding nad uterine enlargement; responds well to chemo but may result i uterine rupture
521
What is gestational choriocarcinoma
Malignant neoplasm of trophoblastic cells derived rom previously normal or abnormal pregnancy; rapidly invasive and mets widely but responds well to chemo
522
What is the morphology of gestational choriocarcinoma pale
Large pale areas of necrosis and extensive hemorrhage; histo: no chorionic villi; only proliferating syncytiotrophoblasts and cytotrophoblasts; mitosis abundant invades underlying myometrium, penetrate bv and extended onto uterine serosa
523
What are the clincial features off gestational choriocarcinoma
Irregular vaginal spotting of bloody-brown fluid; high propensity for hematogenous spread (most common to lungs, vagina, brain, liver, bone and kidney)
524
What is placental site trophoblastic tumor (PSTT)
Neoplastic proliferation’s of extravillous trophoblastic (intermediate trophoblasts); normally produce human placental lactogen and found in implantation site; presents as uterine mass accompanied by uterine bleeding or amenorrhea and moderately elevated HCG; can follow normal pregnancy (half of cases), spontaneous abortion, or hydatidiform mole; localized = good prognosis; disseminated - can die
525
What happens to the breast after ovulation
Cell proliferation increases and the number of acini per lobule also increases; intralobular stroma becomes edematous
526
When does the breast become completely mature
During pregnancy; lobules increase (by end of pregnancy hardly any stroma left), immediately after pregnancy, lobules produce colostrum (high in protein) and change to milk (higher in fat and calories)as progesterone levels drop; permanent changes explains reduction in breast cancer risk observed in those who gave birth to children at young ages
527
What happens during the 3rd decade to the breast
Lobules and specialized stroma start to involute and the interlobular stroma converts from radiodense fibrous stroma to radiolucent adipose tissue
528
What lesions occur in lobules and terminal ducts
Cysts, sclerosing adenosis, small duct papilloma, hyperplasia, atypical hyperplasia, carcinoma
529
What lesions occur in large ducts
Duct ectasia, squamous metaplasia of lactifferous ducts, large duct papilloma, paget dz
530
What lesions occur in intralobular stroma
Fibroadenoma and phyllodes tumor
531
What lesions occur in interlobular stroma
Fat necrosis, lipoma, fibromatosis, sarcoma
532
What are milk line remnants
Supernumerary nipples or breasts result from persistence of epidermal thickening along milk line (extends from axilla to perineum); heterotopic, hormone responsive foci - come to attention because of painful prementual enlargements
533
What is accessory axillary breast tissue
In some women, normal ductal system extends into subcutaneous tissue of the chest wall or axillary fossa (axillary tail of Spence); because you may not be able to remove breast tissue from these areas, prophylactic mastectomies do not eliminate the risk for breast cancer in these people
534
What is congenital nipple inversion
Failure of nipple to evert during development; common and may be unilateral; *acquired nipple retraction is of concern bc may be indicative of invasive cancer or inflammatory nipple dz
535
What is mastalgia or mastodynia
Pain in the breast
536
What are the most common palpable lesions of the breast
Cysts, fibroadenomas, invasive carcinomas
537
Where are most malignancies located in the rest
Upper outer quadrant
538
What aspect of nipple discharge makes it worrisome for carcinoma
When it is spontaneous and unilateral
539
What is galactorrhea associated with
Pituitary adenoma, hypothyroidism, endocrine anovulatory syndromes, OCPs, tricyclic antidepressants, methyldopa, phnothiazines; not associated with malignancy
540
What causes bloody or serous discharge from the nipples
Large duct papillomas and cysts; during pregnancy bloody discharge can result on rapid growth and remodeling of the feast; risk of malignancy assoc with discharge increases with age
541
What are the mammographic signs of breast carcinoma
Densities
Calcifications: calcifications assoc with malignancy are usually small, irregular, numerous and clustered *ductal carcinoma in situ (DCIS) detected as calcifications
542
What are some reasons carcinomas are not detected on mammogram
Presence of surrounding radiodense tissu, small size, diffuse infiltrative pattern with little or no desmoplastic response, location close to chest wall or in periphery of breast
543
What is the use of US in breast masses
Can distinguish between cystic and solid lesions
544
What is inflammatory breast cancer
Mimics inflammation by obstructing dermal vasculature with tumor emboli; always consider in women with erythematous swollen breast
545
What is acute mastitis
Typically occurs during 1st month of breastfeeding caused by local bacterial infection (staph or strep); breast is erytheatous and painful and fever present; only one duct system or sector fo breast is involved -> if not treated, spread to entire breast; staph form abscesses strep forms cellulitis
546
What is squamous metaplasia of lactiferous ducts
Aka recurrent subareaolar abscess, periductal mastitis, zuska dz; woman and sometimes men present with painful erythematous subareolar mass that appears to be an abscess; in recurrent cases, fistula can form under smooth m of the nipple and opens onto the skin; many have inverted nipple; *most are smokers (vit A def)
547
What is the morphology of squamous metaplasia of lactiferous ducts
Keratinizing squamous metaplasia of the nipple ducts; keratin plugs ductal system causing dilation and rupture of the duct; chronic granulomatous response develops once keratin spills into surrounding periductal tissue
548
How do you treat squamous metaplasia of lactiferous ducts
Incision to drain; recurrence is common; can do surgical removal of duct and contiguous fistula
549
What is duct ectasia
Presents as palpable periareaolar mass assoc with thick white nipple secretions and skin retraction; pain and erythema uncommon; occurs in 5th-6th decade usually in multiparous women NOT assoc with smoking *mammogram mimics invasive carcinoma
550
What is the morphology of duct ectasia
Dilated ducts filled with inspissated secretions and lipid laden macrophages; can rupture; granulomas can form; fibrosis produces irregular mass with skin and nipple retraction
551
How does fat necrosis present
Can mimic cancer; painless palpable mass, skin thickening or retraction, mammographic densities or calcifications; *half have hx of breast trauma or prior surgery
552
What is the morphology of fat necrosis
Acute lesions may be hemorrhagic and contain central areas of liquefactive necrosis with neutrophils and macrophages; then proliferation fibroblasts and chronic inflammatory cells come; then giant cells, calcifications and hemosiderin; replaced by scar tissue; film gray-white nodules containing small white foci are seen grossly
553
What is lymphocytic mastopathy (sclerosing lymphocytic lobulitis)
Single or multiple hard palpable masses or mammographic densities; difficult to obtain needle bx b/c dense collagenized stroma; atrophic ducts and lobules have thickened BM and are surrounded by prominent lymphocytic infiltrate; *most common in women with T1DM or autoimmune thyroid dz
554
What is granulomatous mastitis
Granulomatous lobular mastitis; uncommon; occurs ONLY in porous women; closely assoc with lobules (may be caused by hypersensitivity reaction); tx w/ steroids sometimes affective
555
What causes cystic neutrophilic granulomatous mastitis
Corynebacteria
556
What are the groups of benign epithelial lesions
Non proliferative breast changes, proliferative breast dz, atypical hyperplasia
557
What are nonproliferative breast changes (fibrocystic changes)
Not associated with increased risk of breast CA; 3 kinds of change - cystic (often with apocrine metaplasia), fibrosis, and adenosis
558
What is the morphology of cystic change
Dilation of lobules; contain turbid, semi-translucent fluid of brown or blue color (blue dome cysts); liked by atrophic epithelium or metaplastic apocrine cells (resemble sweat glands); calcifications common; concern when solitary and firm to palpation;; *dx confirmed if disappears after FNA
559
What are fibrotic changes
Cysts rupture and release material into stroma; chronic inflammation and fibrosis occur; leads to nodularity
560
What is adenosis of the breast
Increase in number of acini per lobule *normal feature of pregnancy; calcifications present within lumens; acini lined by columnar cells (flat epithelial atypia) assoc with del of chrom 16q - earliest recognizable precursor of low grade breast cancer, but ones not increased cancer risk
561
What are lactational adenomas
Present as palpable masses in pregnant or lactating women; normal-appearing breast tissue with lactational changes; not neoplastic
562
What is proliferative breast disease w/o atypia
Lesions characterized by proliferation of epithelial cells; assoc with small increase in risk of carcinoma in either breast
563
What is the morphology of epithelial hyperplasia of the breast
Normal breast ducts and lobules lined by double layer of myoepithelial cells and luminal cells; distend ducts
564
What is sclerosing adenosis of the breast
Type of proliferative breast dz w/o atypia; increased number of acini that are compressed and distorted in central portion; stromal fibrosis can compress the lumens to create appearance of solid cords or double strands of cells lying within dense stroma; palpable mass, radio density or calcification is presentation
565
What is a complex sclerosing lesion of the breast
Proliferative dz w/o atypia; components of sclerosing adenosis, papillomas, and epithelial hyperplasia; *one member = radial sclerosing lesion (radial scar) can mimic invasive carcinoma; central Indus of entrapped glands in hyalinizd stroma surrounded by radiating projections; not assoc with prior trauma or surgery
566
What is a papilloma
Proliferative dz w/o atypia; grow within dilated duct; composed of multiple branching fibrovascular cores;large duct papillomas found in lactiferous sinuses of the nipple and usually solitary - produce discharge sometime bloody if undergoes torsion; small duct commonly multiple and located deeper in ductal system - no discharge
567
What is the morphology of gynecomastia
Subareaolar enlargement; uni or b/l; increase in dense collagenous connective tissue assoc with epithelial hyperplasia of duct lining with tapering micropapillae; *no lobule formation
568
What is the histo diff btw sclerosing adenosis and invasive carcinoma
In sclerosing, acini are arranged in swirling pattern and outer border wall is well circumscribed
569
What drugs can cause gynecomastia
Alcohol, weed, heroin, antiretroviral, anabolic steroids
570
What syndrome causes gynecomastia
Klinefelter (XXY)
571
Does gynecomastia increase risk for breast cancer
Yes
572
What are the forms of proliferative breast dz with atypia
Atypical ductal hyperplasia (distinguished from DCIS by only partially filling involved duct) and atypical lobular hyperplasia (cells do not distend >50% of acini within a lobule) ; has some but not all features of CIS;
573
What does atypical lobular hyperplasia show a loss of
E cadherin
574
What are most breast malignancies
Adenocarcinomas; also most are based on expression of HER2
575
What are the 3 groups of adenocarcinomas of the breast
Estrogen receptor positive, HER2 negative (most common)
HER2 positive
ER negative HER2 negative
576
What is the correlation btw ER positive cancers and age
Increase with age; ER negative and HER2 positive remain the same across age groups
577
Who is invasive breast cancer more common in
White women; but AA women have an earlier onset and higher mortality rate; also ER positive cancers have lower rate in non-white women
578
What are the risks for breast cancer
Germline mutation, first degree relative (unless postmenopausal mother), race, age, age of menarche (<11 increases risk), late menopause, age at first live birth (<20 decreases risk), benign breast dz, estrogen exposure, oophretomy decreases risk, increased breast density, radiation to the chest, carcinoma of contralateral breast or endometrium, diet (alcohol increases risk), obesity (<40 decrease risk, postmenopausal increased risk), exercises decreases risk, breastfeeding reduces risk,
579
What are the genes assoc with familial breast cancer
BRCA1/2, TP53, CHEK2 - all are tumor suppressor
580
Which BRCA gene increases risk for ovarian carcinoma
1; 2 is seen more with male breast cancer; 1 and 2 at risk for prostatic and pancreatic cancer
581
What are the features of BRCA1 assoc breast cancers
Poorly differentiated, have medullary features (syncytial growth pattern with pushing margins and lymphocytic response) basal like, have TP53 mutations; biologically similar to ER-neg/HER2 positive
582
What are the features of BRCA2 cancers
Poorly differentiated but are more often ER positive; seen in prostate, stomach, melanoma, gallbladder, bile duct and pharynx cancers; can cause fanconi anemia as well
583
What does mutation in STK11 cause
Peutz-jeghers; can cause familial breast cancer
584
What other cancers are TP53 mutations seen in
Sarcoma, leukemia, brain tumors, adrenocortical carcinoma
585
What other cancers are seen with CHEK2 mutations
Prostate, thyroid, kidney, colon; it is a checkpoint kinase; may increase risk for breast cancer after radiation
586
What is the pathway of ER-positive HER2 negative cancers
Dominant pathway; most common in ppl with BRCA2; asoc with gain of chrom 1q, loss of chrom 16q and activating mutations in PIK3CA, precursors: atypical ductal hyperplasia and flat epithelial atypia “Luminal” b/c resemble normal breast luminal cells
587
What is the pathway of HER2 positive cancers
Assoc with amplifications in HER2 on chrom 17q; most common in ppl with TP53 mutations; precursor: atypical apocrine adenosis
588
What is the pathway of ER negative HER2 negative cancers
No precursor lesions; most common seen in BRCA1 mutations and AA; sporadic tumors of this type have TP53 mutations; have a basal like pattern of mRNA expression
589
What are the most common DRIVER mutations of breast cancer
PIK3CA, HER2, MYC, and CCND1, TP53, BRCA1/2
590
What has been shown to increase the risk of tumor invasion and facilitated the transition of CIS to invasive carcinoma
Remodeling of the breast during post pregnancy involution
591
What are the features of DCIS
Myoepithelial cells intact although may be diminished in #; can be detected by mammography; calcifications
592
What is the best predictor of local recurrence and progression of DCIS
Nuclear grade and necrosis rather than architectural subtype
593
What are the subtypes of DCIS
- comedo: detected on mammography as clustered or linear and branching areas of calcification; define by* tumor cells with pleomorphic, high grade nuclei and areas of central necrosis
- noncomedo: lacks either high grade nuclei or central necrosis; cribriform DCIS may have rounded (cookie cutter like) spaces within ducts;; micropapillary produces bulbous protrusions within a fibrovascular core
594
What is paget dz of the nipple
Rare manifestation of breast cancer; presents as unilateral erythematous eruption with a scale crust; pruritus common; malignant cells extend from DCIS within ductal system via lactiferous sinuses into nipple skin w/o crossing BM; almost all have underlying invasive carcinoma (usually poorly differentiated, ER negative, and HER2 positive*)
595
How do you treat DCIS
Surgical excision with radiation - curative; mastectomy also curative
596
What are the major risk factors for recurrent of DCIS
High nuclear grade and necrosis, extent of dz, and positive surgical margins
597
What is lobular carcinoma in situ (LCIS)
Grow in discohesive fashion due to loss of E cadherin (mutation in CDH1); expand but do not distort involved spaces; *always an incidental bx finding; more b/l than DCIS; identical morphology to atypical lobular hyperplasia and invasiv lobular carcinoma
598
What is the morphology of LCIS
Uniform cells; mucin-positive signet ring cells present lack of e-cadherin results in round shape w/o attachment to adjacent cells cannot form cribriform spaces or papillae (seen in DCIS); pagetoid spread seen but does not involve nipple skin; necrosis and calcifications not seen; almost always expresses ER and PR; no HER2 overexpression
599
What is different about the risk of cancer with LCIS vs DCIS
In LCIS, risk is almost as high in contralateral breast as in ipsilateral breast
600
What is the most common typ of invasive breast cancer
ER positive, HER negative (luminal)
601
What are the 2 groups of ER positive HER negative breast cancers
- low proliferation (more common): older women and men; most common detecte by mammogram and in women with hormonal therapy; lowest incidence of recurrence and cured by surgery; typically met to bone; respond well to hormone tx; incomplete response to chemo
- high proliferation: *most common type assoc with BRCA2; 10% show complete response to chemo; met to bone
602
Who are HER2 positive cancers more common in
Young non white women; TP53 (HER positive, ER positive); met early usually to viscera and brain
603
Which kind of breast cancer has the best response to chemo
ER negative, HER2 negative
604
Who do ER neg, HER2 neg occur in
Young, BRCA1, AA, Hispanic
605
What are the histo types of ER neg HER2 neg cancer
Medullary, adenoid cystic, secretory, metaplastic
606
What proteins are stained for in ER negative HER2 negative cancers
Basal keratin
607
What chrom is HER2 located on
17q
608
What is the prognosis for HER2 positive cancers
With ab therapy (trastuzumab - herceptin) to HER2, excellent
609
Can recurrence of ER neg HER neg occur even after mastectomy
Yes; also some express ER and HER2 so need to test to target treatment
610
What is the morphology of invasive breast carcinoma
Hard, irregular radiodense mass; *grating sound when cut (cutting chestnut) due to foci or streaks of chalky-white desmoplastic stroma and calcification
611
What can larger carcinomas present as
Invasion of pectoralis m or dermis and cause dimpling of skin; if involves central portion of breast, nipple retraction;
612
How are carcinomas graded
Tubule formation, nuclear pleomorphism, mitotic rate; Grade I to III
Grade I: tubule pattern or cribriform pattern; monomorphic nuclei
Grade II: some tubule formation but solid clusters or single infiltrating cells also present; mitotic figures present; pleomorphic nuclei
Grade III: invade as ragged nests or solid sheets; central necrosis
613
What is the morphology of ER positive, HER2 negative carcinoma
Can be poor or well diff; mucinous, papillary, cribriform, and lobular all seen
614
What is the morphology of HER2 positive cancer
Most are poorly differentiated; some apocrine, some micropapillary
615
What is the morph of ER negative HER2 negative
Almost all poorly differentiated
616
What is lobular carcinoma
Clearest assoc of phenotype and genotype; most show balletic loss of CDH1; fail to incite desmoplastic response; *met to peritoneum and retroperitoneum, leptomeninges (carcinomatous meningitis), GI, and ovaries and uterus; also have increased risk of gastric signet ring carcinoma
617
What is medullary carcinoma
*BRCA associated (NOT mutation, but hypermethylation), good prognosis; lymphocytic infiltrates within tumor assoc with better outcome and response to chemo
618
What is micropapillary carcinoma
*anchorage independent growth is characteristic; express E cadherin but are not adherent to the stroma
619
What is the morph of lobular carcinoma
Almost always ER positive; forms irregular masses, but can hav e diffuse infiltrative pattern difficult to palpate; signet ring cells containing intractoplasmi mucin; no tubule formation
620
What is the morph of mucinous (colloid) carcinoma
Almost always ER positive; soft or rubbery and has consistency and appearance of pale grey-blue gelatin; borders are pushing or circumscribed; arranged in clusters and small islands of cells within large lakes of mucin
621
What is tubular carcinoma
Almost always ER positive consists only of well formed tubules; cribriform may also be seen; apocrine snouts seen; assoc with flat epithelial atypia, atypical lobular hyperplasia, LCIS and low grade DCIS
622
Which 2 histo types of breast carcinoma overexpress HER2
Apocrine and micropapillary
623
What are the features of inflammatory carcinoma
Extensive invasion within lymph channels causing swelling; usually of high grade but dont belong to any molecular subtype *poor prognosis
624
What are male breast cancers assoc with
Klinefelter and testicular dysfunction, BRCA2; *ER positivity more common - usually presents as palpable subareolar mass
625
What is the most important prognostic factor for invasive carcinoma in the absence of distant mets
Axillary LN involvement; drain first to sentinel nodes (identified with radiotracer or color dye) - if negative don’t need to do axillary LN bx
626
When is size not an important prognostic factor for breast cancer
HER2 positive and ER negative
627
What is peau d’orange
Seen in inflammatory carcinoma; when breast cancers presents with breast erythema and skin thickening; edematous skin tethered to breast by cooper ligaments - caused by dermal lymphatics filled with meet carcinoma that blocks lymph drainage *higher risk in AA and young women; most are ER neg HER2 pos
628
What breast cancer histo types have a good vs poor prognosis
Tubular, mucinous, lobular, papillary, adenoid cystic - better than no special type
Metaplastic or micropapillary - poor
*in adenoid cystic, low grade adenosquamous, and secretory in young women histo subtype is more predictive of prognosis than molecular type
629
What is the best vs worst molecular subtype for prognosis
Best: well diff ER positive, HER2 negative
Worst: poor diff ER negative and/or HER2 positive
630
What is the staging for breast cancer
0: DCIS or LCIS
1: invasive carcinoma <2cm no mets
2: > 2cm w/1-3 positive LN, o >5 0-3 positive LN; no d instant mets
3: >5 cm w/ neg or pos LN & no distant mets; >4 positive LN, invasive of skin or Chet wall
4: distant met
631
What type of breast carcinoma is proliferation rate an important prognostic factor
ER positive HER2 negative
632
How is estrogen and progresterone receptors used as a prognostic factor in breast cancer
If positive in both, respond better to hormonal manipulation; strongly ER pos less likely to respond to chemo; dont have either, respond better to chemo than hormones
633
What is carcinoma en cuirasse
Carcinoma of the breastplate; complication of breast cancer
634
What are the 2 types of stroma in the breast
Inter and intralobular
635
What are the stromal tumors of the breast
Intralobular: fibroadenoma and phyllodes tumor
Interlobular: lipomas and angiosarcomas; pseudoangioatous stromal hyperplasia, myofibroblastomas and fibrous tumors
636
What is the most common benign tumor of the female breast
Fibroadenomas; multiple and b/l; younger present with palpable mass and older present with density or calcification; hormonally responsive (increase during pregnancy which can be complicated by infarction); absence of adipose tissue; *assoc with cyclosporin A; proliferative change w/o atypia
637
What is phyllodes tumor
Present mostly in 6th decade; palpable masses;; sometimes called cystosarcoma phyllodes; gains in chrom 1q; overexpresion o HOXB13 assoc with more aggressive clinical behavior; *bulbous protrusions of large (leaflike); more mitotically active than fibroadenomas; ax LN dissection contraindicated - if met, only stromal portion mets
638
What is unique about myofibroblastoma
Only tumor of the breast that is equally common in males
639
What can fibromatosis be assoc with
Familial denomatous polyposis, hereditary Desmoid syndrome, Gardner syndrome
640
What are the malignant stromal tumors of the breast
(All interlobular) angiosarcoma, rhabdomyosarcoma, liposarcoma, leiomyosarcoma, chondrosarcoma, osteosarcoma; *angiosarcoma only one to be of concerned with in breast - result of therap; poor prognosis
641
What type are most primary breast lymphomas
B cell; rare T cell can arise in scar capsule assoc with breast implants; young with Burkitt lymphoma can present with b/l breast involvement and are often pregnant or lactating
642
What cancers form mets to breast
Melanomas or ovarian
643
What are the 3 classes of hormones
- proteins and peptides: store in secretory vesicles until released; water soluble
- amines: derived from tyrosine
- steroids: synthesized from cholesterol; lipid soluble; not stored
644
Which hormones use a phospholipase C mechanics m
GnRH, TRH, GHRH, oxytocin
645
What part of the hypothalamus contains the cell bodies of the axons in the posterior pituitary
Supraoptic nucleus (SON - secretes mostly ADH) and Paraventricular nucleus (PVN - mostly oxytocin)
646
What are primary vs secondary vs tertiary endocrine disorders according to phys
Primary: peripheral
Secondary: pituitary
Tertiary: hypothalamus
647
What hormone can increase the release of prolactin
TRH
648
What patterns is growth hormone released in
Pulsatile; during sleep
649
How is growth hormone negatively regulated
Somatomedins (IGF) inhibits release from ant pituitary and hypothalamus; and growth hormone increases release of somatostatin from hypothalamus
650
What are the effects of growth hormone
Diabetogenic effect; insulin resistance; decreased glucose uptake; increased lipolysis in adipose tissue increased blood insulin levels; increased protein synthesis and organ growth (mediated by IGF); increased linear growth (mediated by IGF)
651
Who is GH secretion increased in
Subjects who are malnourished or fasting
652
What does hyperprolactinemia suppress
Release of GnRH (low FSH and LH0
653
What receptors does ADH bind to
In the kidney: V2
| In the blood vessels: V1 (vasoconstriction)
654
What is the water deprivation test
Weigh the patient after allowing no fluid if patient drops weight or plasma osmolarity high, DI
655
What is 3 beta hydroysteroid DH used for
Convert pregnenolone to progesterone ->>> aldosterone; also convert 17 OH pregnenolone to 17 OH progesterone _>>> cortisol; also converts DHEA -> androstenedione
656
What is 17 alpha hydroxylase used for
Convert pregnenolone to 17 OH pregnenolone -> lead to cortisol or androgens
657
What products do you get an increase of if you inhibit 21 beta hydroxylase
Progesterone, 17 OH progesterone and shunted to androgens
658
What happens if you block 11 beta hydroxylase
Increased deoxycorticosterone and 11 deoxycortisol; still get some mineralocorticoids
659
What enzyme deficiency leads to increased mineralocorticoids
17 alpha hydroxylase; increased BP, decreased potassium, decreased androstenedione; undescended tests, lack of secondary sexual characteristics
660
What does 11 beta hydroxylase deficiency present with
Increased BP, decreased K+, virilization, decreased cortisol
661
What are the effects of cortisol
Immune suppression, GNG in liver, protein catabolism in m, lipolysis in adipose tissue
662
What time of day is cortisol released
Early morning (8 am)
663
How do sulfonylurea drugs work
Promotes closing of ATP dep K+ channel; increases insulin secretion
664
What conditions are assoc with T1 vs T2DM
Type I: autoimmune thyroid dz, celiac dz, addisons dz
| Type II: obesity, lipid abnormalities, PCOS, NAFLD
665
What can influence the calcium concentration
Changes in plasma proteins concentration (increases total calcium, no change in ionized), changes in anion concentration (decrease ionized), acid base abnormalities (changes fraction bound to albumin - more bound when alkalemia)
666
What are the effects of PTH
Bone resorption
Kidney: decreases phosphate reabsorption, increases calcium reabsorption, increases urinary cAMP
Intestine: increases calcium absorption (indirect via vit D)
667
What does vit D do to PTH
Increases its secretion
668
Where are PTH receptors located on the bone
Osteoblasts - bone formation
Long term actions of PTH is bone resorption by indirect action on osteoclasts mediated by cytokines released from osteoblasts
*regulates M-CSF, RANKL, OPG production
669
Where is calcium reabsorbed in the kidney
Thick ascending limb and distal tubule
670
What are the actions of vit D on calcium and phosphate
Increases absorption of both from GI tact; sensitized osteoblasts to PTH, promotes phosphate reabsorption by proximal tubule (stimulates NPT2a); inhibits PTH gene expression and stimulates CASR gene sxpression
671
what is the difference between secondary hyperparathyroidism caused by renal failure and vit d deficiency
Renal failure: phosphate will be increased
| Vit D: phosphate will be decreased
672
What is Albright hereditary osteodystophy
Pseudohypoparathyroidism; PTH receptor doesn’t function; hypocalcemia, hyperphosphatemia, decreaed vit D; increased PTH; short stature, obesity, subcutaneous calcifications, shortened metatarsal and metacarpals
673
What happens to vitamin D level with hypercalcemia of malignancy
Decreased
674
What are the types of congenital vitamin D deficiency rickets
- pseudovitamin D deficienct rickets or vitamin D deficiency rickets type I: decrease in 1 alpha hydroxylase
- pseudovitamin D defilement rickets or vit D dependent rickets type II: decreased vitamin D receptor
675
What are the values you would see with vitamin D deficiency
Increased PTH, decreased calcium, decreased phosphate, increased urine phosphate and cAMP, decreased vit D, osteomalacia increased resorption
676
How is T4 converted to T3
Deiodinase
677
What do perchlorate and thiocynate do
Inhibit iodine trapping in follicular cells of thyroid; treatment for hyperthyroidism
678
What is the effect of high levels of iodine on the thyroid
Inhibit orgnification and synthesis of thyroid hormones (Wolff chaikoff effect)
679
What does PTU do
Inhibits peroxidase which inhibits several steps of thyroid hormone formation
680
What are the main binding proteins for thyroid hormone.
Thyroxine binding protein (TBG) -synthesized in liver (higher affinity for T4)
Transthyretin (TTR)
Albumin
681
What is the effect of liver failure on the thyroid
Increases free T4 which will inhibit release of thyroid hormone
682
How does pregnancy affect thyroid
Increases TBG levels; increases bound thyroid hormone; causes increase in secretion of T3 and 4; but are euthyroid
683
What initiates puberty
Pulsatile secretion of GnRH *needs to be pulsatile
684
What are the seminiferous tubules
Forms by Sertoli cells with germ cells; spermatogonia most immature located near periphery; spermatozoa: mature located near lumen of tubule
685
What are the functions of sertoli and leydig cells
Sertoli: nutrients to sperm; form tight junctions creation blood testis barrier; secrete acqueous fluid into lumen which helps to transport sperm through tubules
Leydig: synth and secretion of testosterone
686
What enzyme do the testes have that converts androstenedione to testosterone
17 beta hydroxystoid
687
What does testosterone bind to in the lumen of the seminiferous tubules
Androgen binding protein (ABP)
688
What tissue is responsive to DHT rather than testosterone
Prostate; external genitalia of male fetus, skin, liver
689
Where is estrogen produce in the male
Conversion from testosterone to estradiol by aromatase in Sertoli cells; role in spermatogensis
690
What is the rate limiting step in the synthesis of testosterone
Conversion of cholesterol to pregnenolone
691
What is testosterone bound to in the peripheral circulation
SHBG and albumin
692
What stimulates the conversion of cholesterol to pregnenolone
LH; regulates rate of testosterone synthesis; *increases affinity for P450scc enzyme for cholesterol, stimulates synthesis of P450sc enzyme (long term) P450scc = cholesterol desmolase
693
What does presence of testosterone in the embryo lead to
Development of penis and scrotum; fetal diff of internal tract; descent of testes into scrotum during last 2-3 months of pregnancy
694
What are the actions of testosterone at puberty
Increased muscle mass, pubertal growth spurt, closure of epiphyseal plate, growth of penis and seminal vesicles, deepening of voice, spermatogenesis, libido
695
What does a deficiency of 5alpha reductase result in
Ambiguous external genitalia
696
What are the actions of DHT
Fetal differentiation of external genitalia; male hair distribution and male pattern baldness, sebaceous gland activity, growth of prostate
697
What stimulates the Sertoli cells
Testosterone and FSH (cAMP PKA pathway) results in protein synthesis and production of inhibin, ABP, aromatase
698
What does FSH stimulate the Sertoli cells to do
Secrete ABP into the lumen of the seminiferous tubules; provides local testosterone supply for developing spermatogonia
699
What is the exocrine and endocrine function of Sertoli cells
Exocrine: production of fluid, production o ABP, determination of release of sperm from seminiferous tubule
Endocrine: expression of ABP, Testosterone and FSH receptors, production of anti mullerian hormone (AMH), aromatiation of testosterone to estradiol 17 beta; production of inhibin to regulate FSH levels
700
What are the phases of spermatogenesis
Mitotic division (results in primary spermatocytes), meiotic division (haploid gamete - spermatids), spermiogenesis (spermatids undergo spermiogenesis and mature into spermatozoa)
701
What stimulation is needed for spermiogenesis to occur
FSH
702
What is the effect of growth hormone on spermatogenesis
Needed for metabolic function of testes;; promotes early division of sperm; without it spermatogenesis is deficient
703
What nerves cause ejaculation
Somatic b.c need striated mm to ejaculate
704
What changes occur during capacitation
Uterine and Fallopian tube wash away inhibitory factors, cholesterol loss around the acrosome, membrane of sperm more permeable to Ca+ which increases motility
705
What is the sperm acrosome reaction
Hyaluronidae and proteolytic enzymes are stored in acrosome; hyaluronidase depolymerizes hyaluronic acid polymers in cement that hold the ovarian granulosa cells together; proteolytic enzymes digest proteins in structural elements of tissues that adhere toe ovum
706
What are the different types of gonadal dysfunction in the male
- if testosterone def in 2n-3rd month o gestation: ambiguity in male genitalia
- if def in 3rd trimester: cryptorchidism and micropenis
- if def in puberty: poor secondary sex development; eunuchoidism(persistence of prepubertal characteristics)
- if def post puberty: decreased libido, erectile dysfunction, decreas in hair, low energy, infertility
707
What is kallman syndrome
Genetic; GnRH neurons fail to migrate to hypothalamus; delayed or absent puberty and impaired sense of smell; *hypogonadotropic hypogonadism; more common in males
708
What is Klinefelter syndrome
Males with extra X chromosome; normal at birth; androgen production low; gonadotropins high; primary hypogonadism; seminiferous tubules destroyed
709
What is increased in men with benign prostatic hyperplasia
DHT receptors
710
Which gonadotropin is released more in infancy and childhood vs puberty
Infancy and childhood: FSH more
puberty and reproductive years: LH
Menopause: FSH
711
What does LH and FSH stimulate in the female
LH -> theca cells (secrete androgens and progestin)
| FSH -> granulosa cells (secrete progestin, estrogens, inhibins and activins)
712
What do inhibins and activins do in the female
Inhibins inhibit FSH secretion and activins activate it
713
When do granulosa cells acquire LH receptors
Just before ovulation
714
What is the prominent estrogen produced in the nonpregnant female
Estradiol
715
What do the ovaries contain that is important for formation of estrogens
Can synthesize their own cholesterol; have aromatase, 17 beta hydoxysteroid DH which can. Convert estrone to estradiol
716
What is the ovarian vs endometrial cycle
Ovarian follicular phase coincides with proliferative phase of endometrial cycle; ovarian luteal coincides with secretory endometrial
717
What happens during the follicular phase
FSH stimulates a follicle; ends on day of LH surge; granulosa cells produce estradiol which stimulates endometrium to undergo growth
718
What happens during the luteal phase
Follicle transforms into corpus luteum; luteal cells produce progesterone and estrogen which stimulate endometrial growth
719
What cause the LH surge
Positive feedback from estrogens, progestin and activins
720
How do estrogens and progestins assert negative feedback
Estrogens at any concentration, progestins only at high concentration
721
What causes a change in basal body temperature during the menstrual cycle
High level of estrogen before ovulation lowers it; high levels of progesterone after ovulation raise it
722
What does progesterone do in the late follicular phase
Opposes action of estrogen on epithelial cells; promotes proliferation of stroma of endometrium stimulates 17 beta HSD and sulfotranferase which converts estradiol to weaker compound
723
What dos progesterone do in the secretory phase
Promotes differentiation of stromal cells into predecidual cells
724
What is reduced during menopause
Estrogen and inhibins
725
What are the hormone levels seen in PCOS
High LH, low FSH, elevated testosterone
726
How does fertilization occur
Sperm head attaches to zone pellucida (sperm ZP3 interaction), acrosomal reaction (increase in calcium triggers fusion of outer acrosomal membrane with sperm cells plasma membrane and results in exocytosis of acrosomal contents), sperm penetrates zona pellucida, cell membrane of sperm fuses with cell membrane of oocyte, oocytes 2nd meiotic division and cortical reaction (increase in Ca2+), sperm nucleus decondenses and forms male pronucleus which fuses with female pronucleus
727
What day is the embryo a morula
3 days; 16 cells
728
When does the embryo reach a blastocyst stage
Day 4-5; implantation occurs day 6-7
729
Which trophoblastic cell is adhesive and invasive
Syncytiotrophoblasts; cadherin; makes HCG (so corpus luteum can survive); makes progesterone to sustain pregnancy independent of corpus luteum
730
When do HCG levels peak
Week 10; cause of morning sickness
731
What are the features of human placental lactogen
Similar to growth hormone and prolactin; detected in serum 3 weeks of gestation; *antagonistic action to insulin contributing to diabetogenicity of pregnancy
732
What is estrogen production dependent on during pregnancy
Healthy fetus; functions during pregnancy: increase uteroplacntal blood flow, enhance LDL receptor expression in syncytiotrophoblasts, induce prostaglandin and oxytocin receptors, increase growth of mammary glads
733
What are the effects of estrogen on parturition
Increases degree of uterine contraction, stimulates oxytocin receptor synthesis
734
Which prostaglandins initiate labor
PGF2alpha and PGE2
735
What does oxytocin do after delivery
Causes uterus to contract to limit blood loss
736
What is the role of relaxin during labor
Softens and dilates cervix
737
What positive feedback mechanisms are seen during labor
Uterine contractions stimulate prostaglandin release; stretch of cervix stimulates oxytocin release (Ferguson reflex)
738
What inhibits the effects of prolactin during pregnancy
Estrogen and progesterone
739
What is the effect of oxytocin on breast feeding
Enhances milk ejection (galactokinetic)
