Gupta - Pathology Flashcards

Question

The following gross and microscopic images show what pathology? A. Placenta previa B. Normal placenta C. Abruptio placenta D. Placenta accrete E. Vasa previa

Answer 1

**C. Abruptio placenta** ## Footnote - Retroplacental blood clot in gross image

Answer 2

- **Amnion nodosum**: seen in placentas affected by oligohydramnios, which may be associated with fetal renal agenesis and pulmonary hypoplasia 1. May be due to desquamated skin or membrane injury - GROSS: multiple _yellow-tan superficial amniotic lesions_ (0.2 to 0.4 cm), usually near insertion of the umbilical cord - Not really a bad thing, unless it is associated with oligohydramnios -\> just a collection of squaffed off squamous cells, and maybe some fibroblasts

Answer 3

- **Amnion nodosum**: seen in placentas affected by oligohydramnios, which may be associated with fetal renal agenesis and pulmonary hypoplasia 1. May be due to desquamated skin or membrane injury - MICRO: nodules of _protuberant eosinophilic fibrinous material_ with entrapped squamous cells 1. Associated w/stratified squamous metaplasia - Not really a bad thing, unless it is associated with oligohydramnios -\> just a collection of squaffed off squamous cells, and maybe some fibroblasts

Answer 4

- **Potter's sequence**: clubbed feet, pulmonary hypoplasia, and cranial anomalies - Oligohydramnios experienced in utero

Answer 5

- **Preeclampsia**: HTN and large amount of protein in the urine -\> usually in 3rd trimester of pregnancy and gets worse over time (feared outcome is _eclampsia = seizures_) - Most placentas are smaller than expected - Infarcts and retroplacental hematomas are also more common

Answer 6

- **Placental infarct**: small infarct may be of no consequence to the fetus, but _if \>1/3 or 1/2 of the placental parenchyma is infarcted_ or lost in some fashion, blood supply to fetus can become severely compromised and _fetal demise may occur_ (via utero-placental insufficiency w/multiple infarcts) - Infarcts AND retroplacental hematomas are more common in PREECLAMPSIA - _Bread loafing_ for placenta section: maternal vessels on top, membrane on bottom, and pale area is an infarct

Answer 7

- **Preeclampsia** - LEFT: villi small, and syncytiotrophoblasts have _thinned out_ (as they should) - RIGHT: _villous ischemia_ (increased syncytial knots) in the placenta 1. A little hemorrhage; don’t look as healthy 2. Only some blood vessels, and “nubbins” of syncytiotrophoblasts

Answer 8

- **Fibrinoid necrosis** of the vessel wall: strong eosinophilic staining areas - PREECLAMPSIA - These are maternal vessels in the decidua - _No cell nuclei_, and decidua surrounding it (big, pink, fluffy cells) 1. Pink and amorphous (necrotic)

Answer 9

- Because they are associated with an increased risk of persistent trophoblastic disease (invasive mole) or choriocarcinoma - _Invasive_: trophoblasts go into uterine wall - Attached flow chart is important for pathology (not important for us to know yet) -\> partial moles much more difficult than complete ones because often diagnosed very early

Answer 10

- **Complete**: egg that has lost female chromosomes, so genetic material is completely paternally derived 1. NO fetal parts - **Partial mole**: fertilization of an egg with two sperm - **hCG**: compared to normal levels for gestation 1. Complete mole: very elevated 2. Partial mole: slightly elevated

Answer 11

Gross image of a twin placenta

Answer 12

- **Vasculature problem**: may be b/c trophoblasts don’t sufficiently invade/stimulate the spiral arteries in the uterus -\> _hypoxic state for the fetus_, which is reflected in the gross and micro changes 1. Big, dilated, torturous blood vessels on fetal surface on left (attached image) 2. Right placenta much smaller: _DEC blood supply, nutrients to fetus_ + more likely to get more infarcts and retroplacental hematomas

Answer 13

- **Complete mole**: no embryo, and no normal placenta 1. Marked _villous enlargement_, edema, and circumferential trophoblast proliferation - Villi get very large, and edematous, aka _hydropic_ - _hCG very elevated_ (above what would be normal for that stage of the pregnancy) in these women because way too many syncytiotrophoblasts

Answer 14

- **Snowstorm appearance** of complete mole on US - Buzzword - REMEMBER: no embryo, and no normal placenta 1. Elevated hCG for the corresponding stage of pregnancy

Answer 15

- _Normal first trimester placenta_: chorionic villi are large and covered by two layers of cells: 1. Cytotrophoblast and syncytiotrophoblast (syncytio make hCG) - Blood vessels in the villi are not prominent

Answer 16

- **Partial mole**: some villi appear normal; others are swollen, avascular, and grape-like (though not as large as a complete mole) 1. Minimal trophoblastic proliferation - _hCG won’t be as high_ as with the complete mole - Can be really hard to differentiate these from normal villi microscopically (b/c detected so early) - Will _karyotype if clinical suspicion is very high_ (looking for TRIPLOIDY)

Answer 17

Complete mole: NO normal villi here

Answer 18

- Partial mole: normal villi are pink, fluffy, light tan (vs. grape-like clusters of the molar villi)

Answer 19

- **Gestational choriocarcinoma**: malignant neoplasm of trophoblastic cells from a previously normal or abnormal pregnancy, like an extrauterine ectopic pregnancy or complete mole 1. Complete moles more likely to progress to this than partial, but still only about 2-3% risk - Rapidly invasive and _metastasizes widely_, but once identified _responds well to chemotherapy_ 1. Very hemorrhagic 2. \>50% have metastasized by the time they are identified - _NOTE_: persistent trophoblastic disease does not metastasize, but pieces of it may embolize to lung or other parts of body

Answer 20

- **Choriocarcinoma**: soft, fleshy, yellow-white tumor with large, pale areas of necrosis and extensive hemorrhage - Histo: proliferating syncytio and cytotrophoblasts 1. Mitoses abundant and sometimes abnormal - Invades underlying myometrium, freq penetrates blood vessels, and _in some cases extends out onto the uterine serosa and into adjacent structures_ - Chorionic gonadotropins **(hCG) very high**!!!!

Answer 21

- HISTO: large, avascular villi with trophoblastic proliferation - CLINICAL: occurs when fertilized ovum contains _only paternal chromosomes_ (usually 46, XX karyotype) 1. Marked uterine enlargement 2. "_Snowstorm_" effect w/no fetus on US 3. Some give rise to choriocarcinoma (2-3%)

Answer 22

- HISTO: some villi enlarged, w/minimal trophoblast proliferation - CLINICAL: typically **triploid** (69, XXX or 69, XXY or 69, XYY) 1. _Malformed fetus present_, but rarely goes to term 2. Rarely gives rise to choriocarcinoma

Answer 23

- HISTO: malignant proliferation of syncytio-trophoblast with no villi 1. Often hemorrhagic 2. _NO fetus_ is present - CLINICAL: _hCG levels are often extremely high_ 1. Can metastasize 2. Many are sensitive to chemotherapy

Answer 24

- HISTO: rare, localized proliferation of intermediate trophoblast that can produce a grossly visible nodule - CLINICAL: most are benign, with rare malignant cases

Answer 25

- May give rise to: 1. Neonatal respiratory distress syndrome, also known as hyaline membrane disease 2. Necrotizing enterocolitis (attached image) 3. Sepsis 4. Intraventricular and germinal matrix hemorrhage

Answer 26

- **Necrotizing enterocolitis** (NEC): potential hazard of prematurity - LEFT: entire small bowel markedly distended, with a perilously _thin wall_ (impending perforation) - RIGHT: congested portion of ileum corresponds to areas of _hemorrhagic infarction and transmural necrosis_ microscopically 1. Submucosal gas bubbles (_pneumatosis intestinalis_) can be seen in several areas (arrows on bottom left)

Answer 27

- **Hyaline membrane disease** (neonatal respiratory distress syndrome) in the image on the left 1. Alternating atelectasis and dilation of alveoli 2. Eosinophilic, thick hyaline membranes lining the dilated alveoli - Normal fetal lung on the right

Answer 28

- _Accumulation of edema fluid_ in the fetus during intrauterine growth - CAUSES: CV, chromosomal, fetal anemia (immune, Parvo B19, homo alpha-thalassemia), twin-twin, etc. 1. _Immune hydrops_: major antigens known to induce clinically significant immuno rxns are certain Rh Ags and ABO blood groups a. 2nd and subsequent pregnancies in Rh-(-) mom w/Rh-(+) dad b. O- moms

Answer 29

- **Fetal hydrops**: generalized accumulation of fluid in the fetus - RIGHT image: fluid accumulation is particularly prominent in the soft tissues of the neck, and this condition has been termed **cystic hygroma** 1. Characteristically seen, but not limited to, constitutional chromosomal anomalies such as 45,X karyotypes (_Turner’s syndrome_)

Answer 30

- _Sudden death of infant \<1 year of age that remains unexplained_ after thorough case investigation, incl performance of a complete autopsy, examination of the death scene, and review of the clinical history 1. Aka, sudden unexpected infant death (SUID) - "Triple-risk” model that postulates the intersection of three overlapping factors: 1. Vulnerable infant, 2. Critical devo period in homeostatic control, 3. Exogenous stressor - _NOTE_: babies should sleep on their backs

Answer 31

- XXY - Eunucoid (indeterminate sex) features - Loss of sertoli cells = loss of inhibin and INC FSH 1. _FSH stimulates aromatase in gonads, INC estrogen_ 2. Female secondary sex characteristics at puberty

Answer 32

- XY phenotypic “female;" presents w/amenorrhea - Normal testis: leydig cells make testosterone 1. Loss of testosterone receptor activity 2. No testosterone effect = NO development of male reproductive structures - No conversion of testosterone to DHT = no external developed male genitals - XY means presence of MIF (sertoli cells), inhibits female reproductive organs, however, distal 2/3 forms due to estrogen (also normal breast)

Answer 33

- Female \<40 with amenorrhea - Loss of entire ovarian function - DEC estrogen and inhibin feedback results in increased FSH and LH - Progesterone withdrawal test is negative for bleeding

Answer 34

- Female presents with amenorrhea and hirsutism - INC LH with intact ovary -\> INC testosterone (hirsutism) - INC T converted to estrogen by aromatase, so INC LH (like LH surge) and INH FSH, leading to NO follicle development 1. Follicle becomes a cyst - Progesterone test is positive for bleeding

Answer 35

- 46, XO: monosomy - Short, primary amenorrhea, lymphedema at birth - Shield chest, wide nipples - Webbed neck and low hair line - Coarctation of the aorta - Streak ovaries –\> little estrogen 1. Elevated FSH and LH

Answer 36

- Defect in hypothalamic production of GnRH - Associated with anosmia: inability to perceive odor - Delayed puberty

Answer 37

- Give patient w/amenorrhea medroxyprogesterone acetate (Provera) 10 mg daily for 5-10 days or one IM injection of 100-200 mg of progesterone in oil - If patient experiences bleeding after the progestin, she has estrogen present but is not ovulating (anovulation) - If no withdrawal bleeding occurs, either patient has very low estrogen levels or there is a problem with the outflow tract such as uterine synechiae (adhesions) or cervical stenosis (scarring)

Answer 38

- Cysts - Fibroadenomas - Invasive carcinomas

Answer 39

- About 50% are located in the _upper outer quadrant_ - Some do metastasize, and the majority of those that do will have done so by the time they reach a size that can be palpated -\> _around 2-3cm_ 1. This is why **mammography** has become such a big deal -\> _helps us catch lesions earlier_ - _Note_: ductal and lobular carcinomas come from the same cell type, but *appear different*

Answer 40

- 10% in women younger than age 40 are malignant - 60% are malignant in women over 50 - Breast cancer risk goes starts going back down after age 65 (see attached)

Answer 41

- ABNORMAL MAMMOGRAM

Answer 42

- Benign cyst formation and fibrosis - _Most common abnormality in premenopausal women_ - Cyclic changes with menstrual cycle, especially fibroadenomas 1. Oral contraceptive pills (OCP) seem to DEC risk - Subdivided into proliferative (slightly more risk than non-proliferative to progress to something malignant, but still minimal) and non-proliferative - _IMAGE_: UDH = usual ductal hyperplasia, ADH = atypical ductal H, ALH = atypical lobular H

Answer 43

- Cysts and fibrosis - May have _calcifications picked up on mammography_ - Cysts may undergo apocrine metaplasia

Answer 44

- Gross image of **fibrocystic changes** - Normal breast has a lot of yellow, fatty tissue, but _fibrosis is white and springy_ (going to bounce back if you squish it in) 1. Cancer would be more gritty, and not have the same kind of bounce - Large cyst at the top left - _Blue dome cysts_: no histologic correlation -\> just a gross observation (middle-right of the image)

Answer 45

- **Benign fibrocystic changes**: large, cystic structures - Cystic and _apocrine metaplasia_ near the bottom - Some calcification - Can do stains for _myoepithelial cells_ because these are lost in breast cancer

Answer 46

- **Apocrine metaplasia**: non-proliferative fibrocystic change - Bright, bubblegum pink color to the cells - Fibrosis instead of the typical breast fat and stroma

Answer 47

- **Usual ductal hyperplasia** (UDH): proliferative fibro-cystic change - Lumen filled by a _heterogeneous, mixed population_ of luminal and myoepithelial cell types 1. Two cell layers: NOT DCIS (an invasive cancer that would necessitate lumpectomy or chemo) b/c _myoepithelial layer present_ 2. Cells swarming, hanging out together: all on top of e/o, rather than individualied (as in atypia) - Irregular _slit-like fenestrations_ prominent at periphery

Answer 48

- **Atypical ductal hyperplasia**: proliferative fibrocystic change -\> atypia b/c cells _starting to dissociate from e/o_ rather than be all on top of e/o - Histo resemblance to ductal carcinoma in situ (DCIS), but not classified as such due to its SIZE 1. _\>2mm or 2 ducts = DCIS_ (really ugly cytology or necrosis may also push patho to dx this as DCIS) 2. Still have myoepithelial cells - Relatively monomorphic proliferation of regularly spaced cells, sometimes with _cribriform spaces_ 1. No slit-like spaces, but rather a cookie-cutter appearance (and _Roman bridges_; archways)

Answer 49

- **Atypical ductal hyperplasia**: proliferative fibrocystic change -\> atypia b/c _cells starting to dissociate from e/o_ rather than be all on top of e/o - Histo resemblance to ductal carcinoma in situ (DCIS), but not classified as such due to its SIZE 1. _\>2mm or 2 ducts_ = DCIS (really ugly cytology or necrosis may also push patho to dx this as DCIS) 2. Still have _myoepithelial cells_ - Relatively monomorphic proliferation of regularly spaced cells, sometimes with cribriform spaces 1. No slit-like spaces, but rather a _cookie-cutter appearance_ (and Roman bridges; archways)

Answer 50

- _Atypical lobular hyperplasia_: cells identical to those of lobular carcinoma in situ, but the cells do not fill or distend more than 50% of the acini within a lobule - Can become ductal or lobular carcinoma - Don’t do anything with this right now per standard of care

Answer 51

- **Sclerosing adenosis**: proliferative changes - Involved terminal duct lobular unit enlarged, and acini _compressed and distorted_ by dense stroma 1. Dilated glands - Calcifications present within some of the lumens - Unlike carcinomas, acini are arranged in a _swirling pattern_, and the outer border is _well circumscribed_ - _Myoepithelial marker (+)_ = “good to go” in calling this sclerosing adenosis rather than carcinoma

Answer 52

- _Radiograph_: irregular central mass with long radiodense projections (needle-localized lumpectomy in this image) - _Grossly_: solid and has irregular borders, but not as firm as an invasive carcinoma; tan/yellow instead of grey/gritty of cancer - _Micro_: central nidus of small tubules in a densely fibrotic stroma w/numerous projections containing epithelium with varying degrees of cyst formation and hyperplasia 1. Thick, _keloid-like collagen_ with ducts radiating from central location

Answer 53

- _Minimal to no INC risk_: 1. Non-proliferative changes: cysts, fibrosis, apocrine metaplasia 2. Mild hyperplasia (UDH) - _Slightly INC (1.5-2-fold)_: 1. Moderate to florid hyperplasia (w/o atypia) 2. Ductal papilloma 3. Sclerosing adenosis - _Significant risk_ _(5-fold__)_: ADH, ALH, DCIS, LCIS

Answer 54

- _Acute mastitis_: breastfeeding; staph aureus - _Fat necrosis_: trauma, might calcify and appear abnormal on a mammography (attached image: shriveled and ghost-like, with lipid-laden macros coming in to clean up everything) - _Mammary duct ectasia_: nonbacterial chronic inflammation - _Lymphocytic mastitis_: diabetes, possible autoimmune (not common; incidental finding) 1. Comes in and encircles the ducts - _Granulomatous mastitis_: TB, injections, breast implants, sarcoidosis

Answer 55

- Fibroadenoma - Phyllodes tumor - Intraductal papilloma - Carcinoma

Answer 56

- MOST COMMON benign neoplasm of F breast - Usually relatively small, but can get pretty large 1. Juvenile FA: can rapidly enlarge in teens - _Biphasic_: glands AND stroma, but *only* stroma truly neoplastic - 1-10cm fibroepithelial lesion

Answer 57

- **Fibroadenoma**: usually very well circumscribed - Not fixed (mobile); cancer tends to be more fixed because it can be invasive - BIPHASIC: ducts and stroma (stroma squeezes the ducts closed/down)

Answer 58

- **Fibroadenoma**: usually very well circumscribed - Not fixed (mobile); cancer tends to be more fixed because it can be invasive - BIPHASIC: ducts and stroma (stroma squeezes the ducts closed/down)

Answer 59

- **Phyllodes tumor** (stromal): distinguished from FA's on basis of higher cellularity & mitotic rate, nuclear pleomorphism, stromal overgrowth, and infiltrative borders -\> _leaf-life pattern_

Answer 60

- **Phyllodes tumor**: stromal - Most of these are NOT malignant, but the ones that are will look kind of like a fibrosarcoma with lots of stromal overgrowth and mitotic figures - Cigar-shaped cells

Answer 61

- **Malignant phyllodes tumor**: most of these are NOT malignant, but this one is - \>10 mitotic figures per 10 high per fields AND stromal \> ductal overgrowth - Densely packed anaplastic stromal cells and infiltrative border - Tumor necrosis, heterologous stromal elements, may have cellular stroma only around blood vessels

Answer 62

- Papillary projection inside the duct - _Can present with nipple discharge_, and can rarely induce nipple retraction - _Double layer epithelium_ helps differentiate between papillary carcinoma, but not always so black and white - Have to be really careful with diagnosing these because biopsy may alter the integrity of the sample

Answer 63

- **Intraductal papilloma**: central fibrovascular core extends from the wall of a duct. - The papillae arborize within the lumen and are lined by myoepithelial AND luminal cells (two cell layers distinguishes this from carcinoma) - Fibrovascular stalk - Location is one of the keys: _sub-areolar_

Answer 64

- 12.3% (1 in 8 women) - Most common cancer in women, and 3rd most common cause of death from cancer

Answer 65

We have not made much progress in regards to limiting deaths from breast cancer

Answer 66

- African-americans die at a much higher rate (then Caucasians)

Answer 67

- _Age_: INC through life - _Geographic variations_: environmental, higher in US and Northern Europe - _Race_: AA - _Exogenous estrogens_: shift to combined estrogen + progesterone created drop in new cases - _Radiation_ 1. _Genetics_: ataxia telangiectasia -\> likelihood of breast cancer and radiation - Others include obesity (estrogen), alcohol, and high fat diet

Answer 68

- Tumor size - Lymph node status

Answer 69

- Incompletely understood, but multifactorial: 1. Genetics 2. Hormonal influences 3. Environmental influences

Answer 70

- Genetic profiling can separate the 4 molecular subtypes: 1. _Luminal A_: ER+, Her2(-) -\> better molecular subtype for tx 2. _Luminal B_: ER+, HER2+ -\> more high-grade, so more aggressive 3. _Her2+_: ER-, Her2 over-expressed -\> NOT good (Her2 amplification = more aggressive tumors) 4. _Basal type_: ER-, Her2(-) -\> really difficult to tx, esp. if also progesterone (-)

Answer 71

- **10%** - More likely to be _bilateral_ and to have other cancers, ovarian - More likely to have a family history - To develop _cancer before menopause_ - And belong to certain ethnic groups - _1/3 (of this 10%) have BRCA1 or BRCA2_ - _Other_: Li-Fraumeni (p53), Cowden (PTEN: also endometrial cancer), ataxia-telangiectasia carriers

Answer 72

- Tumor suppressor genes -\> both alleles must be inactivated - _Most carriers devo cancer by age 70_ (30-90%) - 12% of women referred for genetic testing have BRCA1/2 deleterious muts; higher in Ashkenazi Jewish women 1. Pts really need to see a genetic counselor before being tested

Answer 73

- Tumor suppressor gene at 17q21 that may interact with p53; _autosomal dominant_ (DEC penetrance) - BRCA1 muts present in 10% of women with: (a) No family history (b) Breast cancer onset by age 40 years, and (c) High grade, triple negative tumors - Breast cancer usually by ages _40-59_ - Most effective predictor is age of onset \< 50 years, and _triple negative status_ (greater incidence of medullary tumors)

Answer 74

- _Carriers_: close F/U or prophylactic mastectomy - Tamoxifen may prevent bilateral breast cancers in ER(-) tumors - INC risk of recurrence after breast conserving surgery - BRCA1 status _does not appear to affect death rates_, but is associated with resistance to certain chemotherapy agents

Answer 75

- _Medullary tumor of the breast_: greater incidence in BRCA1+ pts 1. If you see this on patho report, test them for BRCA1, even if no family history - Usually _high grade_ (basal-like phenotype) - Abundant intra- and peri-tumoral lymphocytes - Pretty well circumscribed, with pushing border rather than infiltrative

Answer 76

- Usually high grade (_basal-like phenotype_) - Abundant intra- and peri-tumoral lymphocytes - Greater incidence of _medullary tumors_ - High incidence of DCIS

Answer 77

- Tumor suppressor gene at 13q12-13 - Usually get breast _cancer by age 50_ - Pts also have _higher risk of cancers of the ovary (39-63%), bone, pharynx, prostate, pancreas, and other organs_ 1. More incidence of other tumors than with BRCA1 - Slightly more frequent in black (2.6%) versus white (2.1%) American patients

Answer 78

- Usually invasive ductal carcinoma, no special type - _High grade features_ and pushing tumor margin - High incidence of **DCIS** - Don't have same circumscription as BRCA1 tumors

Answer 79

- Estrogen/hormone imbalance play significant role - _Long duration of reproductive life, nulliparity, and late age at birth of first child_ - All INC estrogen unopposed by progesterone - Functional ovarian tumors

Answer 80

- _Noninvasive_: still have myoepithelial cells 1. Ductal carcinoma in-situ (DCIS) 2. Lobular carcinoma in-situ (LCIS) - _Invasive_ 1. Invasive Ductal Carcinoma (NOS) 2. Invasive lobular carcinoma 3. Medullary Carcinoma 4. Colloid/Mucinous Carcinoma 5. Tubular Carcinoma

Answer 81

- _Many patterns_: solid, comedo, cribriform, papillary, micropapillary 1. Comedo type: central necrosis (\>50%) and high grade nuclei; more likely to progress to invasion (atypical cytology) - _Calcifications_ frequent - _Good prognosis_: can take a long time for these to progress to full-blown carcinoma - Current tx options include lumpectomy, radiation and anti-estrogenic agents like Tamoxifen

Answer 82

DCIS: cribriform pattern

Answer 83

- High-grade DCIS: comedo type - These cells are huge, prominent nuclei - Easy to pick out mitotic figures - Pyknotic

Answer 84

- Uniform, low grade monotonous cells - _Intracellular, “targetoid” mucin_ - Treatment either chemotherapy OR close F/U - _Loss of e-cadherin_: come from same cell as DCIS, but this loss of e-cadherin makes it different - _Morphological keys_: tend to be much simpler cytology than DCIS 1. Look kind of like lymphos 2. Round nuclei

Answer 85

- _70-80% of tumors_ fall into this category - Can be associated with DCIS - **NO myoepithelial cell layer** - Arises from terminal duct lobular unit (as does lobular carcinoma), not ductal epithelium, so nomenclature is not actually accurate

Answer 86

- **Invasive ductal carcinoma**: atypical cells - Some ducts - Tumor cells infiltrating into and *through the stroma* and collagen - _NO myoepithelial cells_ here (single cell layer)

Answer 87

Invasive ductal carcinoma

Answer 88

- **Invasive ductal carcinoma** with desmoplastic response - Lighter, purple kind of stroma in the background - High N/C ratios

Answer 89

Invasive ductal carcinoma with desmoplastic response

Answer 90

- _Loss of expression of CDH1_, gene that encodes E-cadherin -\> (-) for E-cadherin, while ductal will be (+) - Males and females w/heterozygous germline muts in CDH1 _also have a greatly INC risk of gastric signet ring cell carcinoma_ (image attached) 1. Lamina propria with cells with mucin pushing nuclei out to the edge 2. Form of adenocarcinoma that produces mucin - Start to fall apart because they have lost their E-cadherin - She said this was IMPORTANT to remember

Answer 91

- **Lobular carcinoma**: infiltrates with lines in the stroma -\> caterpillars (or indian file)

Answer 92

- _Lobular carcinoma_ - Targetoid mucin droplet pushing mucin to the side

Answer 93

- Lobular carcinoma - Indian file infiltration: cells line up (loss of adhesion due to loss of E-cadherin)

Answer 94

- _Medullary carcinoma_: rare subtype w/strict criteria - Unclear whether good or poor prognosis according to current research - Minority of cases may be associated with germ line _BRCA1 mutations_ - Recurrences are very rare more than 5 years post detection

Answer 95

- **Medullary breast carcinoma**: indistinct cell borders (syncytial growth) - Large pleomorphic tumor cells containing large nuclei, prominent nucleoli, numerous mitotic figures - Prominent _lymphoplasmacytic infiltrate at periphery_ - Pushing borders, but well circumscribed

Answer 96

- **Colloid carcinoma**: 10-yr survival for pure form \>90% (much better than ductal carcinoma NOS) - Slow growing - Usually older women, around 70: _good prognosis_ - _Tumor cells floating in huge pools of mucin_ - \*NOS = not otherwise specified

Answer 97

- **Tubular carcinoma**: favorable prognosis - Composed of: 1. Distinct, well-differentiated _angular tubular structures_ (90%+ according to WHO) with 2. Open lumina, 3. Lined by a single layer of epithelial cells - Can be more difficult because can look like sclerosing adenosis - Tadpole angles, gland looking

Answer 98

Micropapillary variant carcinoma

Answer 99

- **Micropapillary variant carcinoma** - Very aggressive with poor prognosis - 95% have lymph node metastases at presentation - 70% recur, 50% die of disease - Clinicians need to know this is what it is because it needs to be treated more aggressively

Answer 100

- **Paget disease of the nipple**: extension up the lactiferous duct and into skin of nipple - Produces crusted nipple and skin - _In almost all cases, have underlying carcinoma_ - DDx: melanoma

Answer 101

- Clinically defined - Enlarged swollen erythematous breast with no palpable mass (red, inflammatory) - Underlying carcinoma usually poorly differentiated and diffusely infiltrative - _5-year survival \<50%_, and even lower if metastatic - Gone to dermal lymphatics under skin -\> huge chunks of carcinoma in dermal lymphatics

Answer 102

- _Peau d’orange_: thickened skin due to lymphatic congestion

Answer 103

- _Gynecomastia_: hormone influence, typically estrogen excess 1. Causes include: cirrhosis (liver can't metabolize estrogen), Klinefelter syndrome, anabolic steroids, and drugs 2. Physiologic, and can occur in puberty and old age - _Cancer_ is rare, but it does occur! (especially if BRCA or Li Fraumeni)

Answer 104

- **Gynecomastia**: men do NOT have lobules - _INC ducts and prominent stroma_: may be edematous with INC cellularity, and late phase may have fibrosis (pale areas around ducts)

Answer 105

- EPI: abnormal urethral orifice on dorsal aspect of penis - HYPO: ventral aspect; can result in obstruction, and may be associated with other abnormalities, like _inguinal hernia and undescended testes_

Answer 106

- Local inflammation of the glans penis and of the overlying prepuce, respectively - Agents: *Candida albicans*, anaerobic bacteria, *Gardnerella*, pyogenic bacteria - Most cases a consequence of poor local hygiene in uncircumcised males

Answer 107

- _Germ tube_: outgrowth produced by spores of spore-releasing fungi during germination - Think about Candida

Answer 108

- Condition in which the prepuce cannot be retracted easily over the glans penis - Inflammation or congenital

Answer 109

- _Squamous cell carcinoma of the penis_: associated with HPV infection (16, 18) 1. Cellular atypia, parakeratosis, and mitotic figures -\> carcinoma in situ 2. Can also get condylomas (HPV 6 and 11) - _Ulceration_ on the glans or shaft of the penis - Can spread to inguinal nodes and rarely to distant sites - Most cases occur in _uncircumcised_ males: SCC of the scrotal skin one of the first that was linked to hygiene

Answer 110

- Failure of testicular descent into the scrotum - Diagnosis after 1 year of age (1%) - Unknown cause - Associated with infertility, and 3-5-fold risk of testicular cancer - _Orchiopexy_: surgery to remove the cryptorchid testicle -\> reduces risk of sterility and cancer 1. Often infertile, even if they move the testicle down to where it is supposed to be; also still have a risk of cancer

Answer 111

- _More common in testis_ than epididymis, and often sexually transmitted; other causes of testicular inflam include: 1. **Non-specific epididymitis and orchitis**: 1^o UTI that spreads to testis via vas deferens or lymphatics of the spermatic cord -\> chiefly _neutrophilic infiltrate_ 2. **Orchitis -\> mumps** infection: 20% males, but rarely in children; _lymphoplasmocytic infiltrate_ 3. **TB**: granulomatous inflam and caseous necrosis

Answer 112

- **Torsion**: obstruction of testicular veinous drainage, but thick-walled and more resilient arteries remain patent 1. NEONATAL: in utero or shortly after birth; lacks any associated anatomic defect 2. ADULT: typically sudden onset of testicular pain; results from a _bilateral anatomic defect_ whereby the testis has increased mobility - One of the few **urologic emergencies** – if fixed in 6 hours, there is a good chance that the testis will remain viable - Histo: residual testicle on left and hemorrhage on right

Answer 113

- Overall, not very common (6 per 100,000 males); peak in **15-34-y/o** age group - Unknown cause; _whites \> blacks_ - Seminoma (**95%**) from germ cells in post-pubertal males, and are _malignant_ - Non-seminoma 1. Embryonal carcinoma 2. Yolk sac tumor 3. Choriocarcinoma 4. Teratoma - Neoplasms from Sertoli or Leydig cells (sex cord–stromal tumors) uncommon and usually benign - Can't shine a light through a cancerous protuberance, unlike hydrocele - _Don’t needle these_ because they don’t want to spread them; just take them out -\> **assumed to be malignant**

Answer 114

- **Seminoma**: sheets of polygonal cells with lymphos in the stroma (20-30-y/o) 1. Delineated, large cells w/prominent nucleoli, lymphos in background, and clearing around the nucleus - Syncytiotrophoblasts in 15%: minimally elevated serum hCG concentrations (NO bearing on prognosis) - Also looks like germinoma that happens in brain or mediastinum

Answer 115

- Non-seminoma **embryonal carcinoma**: primary can be small, but metastatic - Pure cases rare, typically mixed - Sheets of undifferentiated cells and _primitive gland-like structures_ - Nuclei are large and hyperchromatic -\> more high-grade than the seminoma, and much more anaplastic-looking - With chemo, these cells can actually start to differentiate, and look more like a teratoma

Answer 116

- **Yolk sac tumor**: children **\<3**; good prognosis - Often have eosinophilic hyaline globules with α-1-antitrypsin and alpha fetoprotein (**AFP**) - Areas of loosely textured, microcystic tissue and papillary structures resembling a developing glomerulus (_Schiller-Duval bodies_: circled on attached image)

Answer 117

- **Yolk sac tumor** (non-seminoma): children **\<3**; good prognosis - Often have eosinophilic hyaline globules with α-1-antitrypsin and alpha fetoprotein (**AFP**) - Areas of loosely textured, microcystic tissue and papillary structures resembling a developing glomerulus (_Schiller-Duval bodies_: circled on attached image -\> vessel surrounded by anaplastic cells and a space)

Answer 118

- **Choriocarcinoma**: _cytotrophoblastic_ cells with central nuclei (arrowhead, upper right) and _syncytiotrophoblastic_ cells with multiple dark nuclei embedded in eosinophilic cytoplasm (arrow, middle) are present - Hemorrhage and necrosis are prominent - _hCG_ in syncytiotrophoblasts can be identified by IHC staining and is _elevated in the serum_ - **Invasive**: go to vessels quickly and metastasize -\> may be small, and already have metastasized

Answer 119

- INFANTS/KIDS: pure forms fairly common, second in frequency only to yolk sac tumors - ADULTS: pure teratomas are rare; 2-3% of germ cell tumors, and most are seen in combo with other histologic types (like with embryonal carcinomas) - Elements may be _mature_ (resembling various tissues within the adult) or _immature_ (sharing histologic features with fetal or embryonal tissues) - ANY AGE: prepubertal males -typically benign, _postpubertal males are malignant_

Answer 120

- **Teratoma**: mature cells from endodermal, mesodermal, and ectodermal lines - Four different fields from same tumor specimen contain: 1. Neural (ectodermal; ganglion cells) (A), 2. Glandular (endodermal) (B), 3. Cartilaginous (mesodermal) (C), and 4. Squamous epithelial (D) elements

Answer 121

- Prostatitis - BPH (nodular hyperplasia): TZ 1. Symptoms: hesitancy, dribbling - Carcinoma: PZ

Answer 122

- Note the intraluminal secretions -\> helpful for ID'ing this tissue - _Two layers of cells_: when basal layer is lost, this is malignancy 1. _Glands also get more simple when they become carcinoma_: nice and round, rather than tortuous

Answer 123

- **Bacterial prostatitis** - May be acute or chronic - Responsible organism usually is E. coli or another gram-negative rod - Can also be STI’s in younger men - Can still see 2 cell layers, so not a neoplasm

Answer 124

- Proliferation of benign _stromal_ and glandular elements -\> _DHT_ (androgen derived from T) is the major hormonal stimulus for proliferation 1. Normal proliferation rate, but NOT dying at a normal rate -\> growth factors keep them alive - BPH nodules can compress the prostatic urethra - _Clinical symptoms_: hesitancy, urgency, nocturia, and poor urinary stream 1. Chronic obstruction predisposes to recurrent UTI's (can cause pyelonephritis, but would likely come in before that) - **NOT pre-malignant**

Answer 125

- **BPH** - Nodular, mostly in the central transition zone - Still has the 2 cell layers (see attached image), so this is a benign process: a lot more stroma - Really fibrous

Answer 126

- Men **\>50-y/o** - 25% of cancer in men in the US, but only 9% of deaths ( - Clinical and experimental observations suggest pathogenic roles of: 1. Androgens 2. Heredity 3. Environmental factors 4. Acquired somatic mutations - Low-grade take a long time to progress to high-grade

Answer 127

- **Adenocarcinoma** of the prostate - Carcinomatous tissue on posterior aspect (lower left) - Note the _solid whiter tissue of cancer_, in contrast w/the spongy appearance of the benign peripheral zone on the contralateral side

Answer 128

- _Prostate adenocarcinoma_: normal gland at bottom left, but the rest are carcinoma glands -\> small, simple, round, invading stroma - This is low-grade: grade 3

Answer 129

- **Prostate adenocarcinoma** -\> loves to invade nerve tissue (_perineural invasion_ shown here)

Answer 130

- Grading system of prostate cancer -\> correlates with _pathologic stage_ and prognosis - Pathologists start reporting at 3 1. 4: cribriforming; glands start fusing together 2. 5: single cells infiltrating the stroma - Biopsy done in systematic way to get an idea of the _volume of the tumor_ (volume + grade is what determines whether it stays or goes) 1. _2 grades_: most commonly seen pattern + 2nd most commonly seen -\> 4 + 3 in younger patient getting surgery; grade 5 definitely getting surgery

Answer 131

- Prostate cancer - Normal glands have more cytoplasm and 2 cell layers; carcinoma glands DO NOT 1. Both types of glands shown in these two images

Answer 132

- PROSTATE CANCER - **IHC stains** showing normal basal cells (brown) in a benign gland and NO _basal cells_ in the malignant glands on the right side (no brown staining) - Malignant glands show increased expression of _racemase_ (AMCAR; red cytoplasmic stain) -\> stains malignant glands in the prostate - _Perinueural invasion_ in the image on the left (this is a common feature of prostate cancer)

Answer 133

- T2: tumor confined within prostate - T2c: tumor involving both lobes - T3a: extra-capsular extension (uni- or bilateral) - T3b: tumor invading seminal vesicle(s) - Don't need to memorize, but just realize that you are _looking for invasion, extracapsular extension and tumor involving both lobes_ - When you are concerned about something being a metastatic prostate cancer, you can stain for PSA, but this staining is NOT used for prostate samples

Answer 134

- **Urothelium**: composed of 5-6 layers of cells with oval nuclei, often with linear nuclear grooves 1. Surface layer of large, flattened, umbrella cells with abundant cytoplasm - Found in renal pelvis, ureters, bladder, and urethra (except terminal portion) - Aka, transitional epithelium - Think about this like a specialized squamous epithelium: mucosal surface - NO mitotic figures or atypia

Answer 135

- Defining whether or not there is invasion into the muscular layer is important -\> determines prognosis

Answer 136

- **Double/bifid ureters**: most are unilateral, and of NO CLINICAL SIGNIFICANCE - Congenital

Answer 137

- **Hydronephrosis** (cystic spaces): ureteropelvic junction (UPJ) obstruction is the most common cause in infants and children - Males, bilateral (20%); often associated with other congenital anomalies - _Abnormal organization of smooth muscle bundles_ at the UPJ, to excess stromal deposition of collagen between smooth muscle bundles, or rarely to congenitally extrinsic compression of the UPJ by renal vessels - Congenital, and can be associated with other congenital abnormalities

Answer 138

- **Diverticula**: saccular outpouchings of the ureteral wall - Uncommon: may be congenital or acquired - Typically asymptomatic, but _urinary stasis with recurrent infections_ possible

Answer 139

- **Low-grade papillary urothelial carcinoma**: 1^o malignant tumors of the ureter resemble those arising in the renal pelvis, calyces, and bladder 1. Papillary lesion: fibrovascular core, too many cell layers (\>6-7) - Majority are urothelial carcinomas -\> this example is _low grade_ 1. If there is any area of high-grade, the whole lesion is high-grade: more pleomorphism, hyperchromatic, mitotic figures - Occur most frequently in 6-7th decades of life and cause _obstruction of the ureteral lumen_ - Can be multifocal; _commonly occur concurrently w/similar neoplasms in bladder or renal pelvis_ 1. Can be hard to get control of; like to come back, esp. in the bladder

Answer 140

- INTRINSIC: calculi, strictures, tumors, blood clots, neurogenic - EXTRINSIC: pregnancy, periureteral inflammation, endometriosis, tumors - CONSEQUENCES: hydroureter, hydronephrosis, pyelonephritis 1. Kidney involvement is a major consequence

Answer 141

- **Sclerosing retroperitoneal fibrosis**: uncommon, and can cause ureteral narrowing or obstruction - Middle to late age males - Subset related to _IgG4-related disease_: associated w/elevated serum IgG4 and fibroinflammatory lesions rich in **IgG4**-secreting plasma cells 1. Reidel's thyroiditis association (woody, fixed thyroid) - Tubulointerstitial with _fibrous and prominent infiltrate of lymphocytes_, plasma cells (frequently IgG4-positive), and eosinophils

Answer 142

- Most common and serious _congenital anomaly_ - Major contributor to _renal infection and scarring_ - NOTE: diverticula also possible in the bladder

Answer 143

- **Exstrophy of the bladder**: developmental failure in the anterior wall of the abdomen and the bladder - Bladder either communicates directly through a large defect with the surface of the body or lies as an opened sac

Answer 144

- Urachus (canal that connects fetal bladder with the allantois) is normally obliterated after birth, but it _sometimes remains patent in part or in whole_ 1. Totally patent: fistulous urinary tract _connects the bladder with the umbilicus_ 2. Only central region of the urachus persists: **urachal cysts**, lined by urothelium or metaplastic glandular epithelium -\> may lead to _carcinomas_, mostly glandular tumors

Answer 145

- **Cystitis** of the bladder: malakoplakia (raised mucosal plaques) - Filled with _foamy macrophages_, occasional multinucleate giant cells, and lymphocytes - Macros have abundant granular cytoplasm due to phagosomes stuffed w/particulate & membranous _debris of bacterial origin_ - Mineralized concretions resulting from deposition of calcium = **Michaelis-Gutmann bodies** (circled in the attached image)

Answer 146

- **Cystitis** of the bladder: malakoplakia (raised mucosal plaques) - Filled with _foamy macrophages_, occasional multinucleate giant cells, and lymphocytes - Macros have abundant granular cytoplasm due to phagosomes stuffed w/particulate & membranous _debris of bacterial origin_ - Mineralized concretions resulting from deposition of calcium = **Michaelis-Gutmann bodies** (circled in the attached image) - Repeated bacterial infections: macros don’t eat up and destroy the bacterial particulate correctly - Yellow-white, plaque-like lesions

Answer 147

- **Squamous cell carcinoma of the bladder** - CAUSES: cigarette smoking, various occupational carcinogens (hair dyes), and Schistosoma haematobium (blood drop; see attached image) 1. Schistosoma: Japonicum (Japanese flag), Mansoni (man); young, middle eastern men

Answer 148

- PUNLMP: papillary urothelial neoplasm of malignant potential - LGUC: low-grade urothelial carcinoma - HGUC: high-grade urothelial carcinoma

Answer 149

- _Bladder carcinoma in situ_: umbrella cells gone or falling off -\> can clue you in to carcinoma of the bladder - Mitotic figure - Whole urothelium is affected - _FLAT lesion_ (NOT papillary): these can be a little more difficult to see, and may progress faster than some of the papillary lesions

Answer 150

- _Low-grade papillary urothelial carcinoma_ (LGUC): \>5-6 cell layers - Mitotic figures - Some atypia

Answer 151

- _High-grade urothelial carcinoma_: HGUC - Lots of atypia - Cells falling off the top - Very large cells

Answer 152

- _High-grade invasive urothelial carcinoma_: FLAT lesion - Not an INC # of cell layers, but hyperchromatic and have very _high N/C ratios_ - Can even have areas that undergo metaplasia to squamous cells, and keratinize - A little bit of desmoplasia

Answer 153

- _High-grade invasive urothelial carcinoma_ - BM-like division between the stroma and the papillary lesion - Necrosis, apoptotic cells, large, prominent nucleoli, high N/C ratios, lots of mitotic figures

Answer 154

- Aka, lues: chronic venereal infection caused by the spirochete *Treponema pallidum* - Like all other ulcerative genital diseases, syphilis _promotes transmission of HIV_, and HIV stimulates the progression of syphilis

Answer 155

- **Syphilis spirochetes** are readily demonstrable in histologic sections of early lesions with the use of standard silver stains (e.g., _Warthin-Starry stains_) 1. *T. pallidum* - Pathognomonic micro lesion is a _proliferative endarteritis_ with an accompanying _inflammatory infiltrate rich in plasma cells_ - Lg areas of parenchymal damage in 3^osyphilis result in formation of **gumma**, an irregular, firm mass of necrotic tissue surrounded by resilient connective tissue (see attached image)

Answer 156

- LEFT: **syphilitic chancre** of the scrotum 1. These lesions are typically are painless despite ulceration, and heal spontaneously - RIGHT: histologic features of the chancre include a _diffuse plasma cell infiltrate_ beneath squamous epithelium of skin 1. Plasma cells: perinuclear hof, like to hover around the blood vessels

Answer 157

- **Syphilis gumma**: central zone of coagulative necrosis (tertiary syphilis) - Surrounded by a _mixed inflammatory infiltrate_ of lymphocytes, plasma cells, activated macrophages (epithelioid cells), occasional giant cells - Peripheral zone of _dense fibrous tissue_

Answer 158

- Trichomoniasis - Pear-shaped organisms with flagella

Answer 159

- Genital herpes simplex - Margination of the chromatin, multi-nucleation, nuclear viral inclusions (with molding)

Answer 160

- _Inflammation_: gonococcal and nongonococcal causes - _Benign epithelial tumors_: squamous and urothelial papillomas, inverted urothelial papillomas, and condylomas - _Primary carcinoma_: uncommon lesion; depending on area of origin, are urothelial or squamous

Answer 161

- **Urethral caruncle**: inflammatory lesion that presents as a small, red, painful mass about the _external urethral meatus_ - Typically in OLDER FEMALES - Inflamed _granulation tissue_ covered by an intact, but extremely friable urothelial mucosa, which may ulcerate and bleed with the slightest trauma - _Surgical excision_ affords prompt relief and cure

Answer 162

- _High-grade urothelial carcinoma_: invasion of the detrusor muscle - Up to half of people that have this invasion can have occult metastatic disease

Answer 163

- In the fallopian tubes, and they metastasize to the ovary

Answer 164

- _Inflammation_: gonococcus, chlamydia, TB - _Benign paratubal cysts_ - Tumors are uncommon (\*except it is believed serous carcinomas of the ovary arise here, and met there)

Answer 165

- **Non-neoplastic**: 1) cysts: follicular and luteal, and 2) PCOS - **Neoplastic**: 1. _Surface epithelial tumors_: serous, mucinous, clear cell, Brenner, MMMT, metastatic 2. _Sex cord stromal tumors_: granulosa cell, fibromas/fibrothecomas, Sertoli-Leydig 3. _Germ cell tumors_: teratoma, dysgerminoma, yolk sac tumor, mixed

Answer 166

- _Follicular cyst_: granulosa lining cells are present if the intraluminal pressure has not been so great as to cause their atrophy - Outer theca cells may be conspicuous due to INC amounts of pale cytoplasm - Mostly just see a space because granulosa and theca cells squeezed out to the edge

Answer 167

- **Corpus luteal cyst**: present in normal ovaries of women of reproductive age - Lined by a _rim of bright yellow tissue containing luteinized granulosa cells_ -\> occasionally rupture and cause a peritoneal reaction - HISTO: luteinized granulosa cells (top arrow) bright yellow grossly and thecal cells (bottom arrow) - Can hemorrhage and cause abdominal pain

Answer 168

- _Benign_: cystadenoma - _Borderline_: malignant, but low malignant potential; don’t see invasion, so don’t know exactly how it is going to behave - MMMT and metastatic do NOT have this classification system

Answer 169

- STIC: serous tubal intraepithelial carcinoma; early malignant cells break off fimbriae, get into ovary somehow, and develop into _high-grade serous_ - _Low-grade serous_ develop in the ovary proper - **NOTE**: endometrioid tumor looks like endometrial carcinoma, but arises in ovary 1. Can have an endometrioid tumor, and endometrial carcinoma at the same time: _arise independently, not metastatically_

Answer 170

- _Most common malignant ovarian tumors_; 40% of all cancers of the ovary 1. 70% benign or borderline, 30% malignant: not too worried about malignant tumors until pts get into their 60's - Inherited germline mutations in both **BRCA1** and **BRCA2** increase susceptibility - **Bilaterality** common: 20% cystadenomas, 30% of borderline, and 66% of serous carcinomas 1. Bilateral doesn’t necessarily mean malignant

Answer 171

- **Serous cystadenoma** (left): stromal papillae with a columnar epithelium - Not a lot of cytoplasm, and no atypia - No architectural complexity

Answer 172

- **Serous cyst adenofibroma**: like a cystadenoma, but with a fibrous component - Not a lot of cytoplasm, and no atypia - No architectural complexity

Answer 173

- **Serous borderline**: INC architectural complexity and epithelial cell stratification

Answer 174

- LEFT: **low-grade serous carcinoma** -\> complex micropapillary growth (pseudo-papillary appearance) - RIGHT: **high-grade serous carcinoma** -\> invasion of underlying stroma 1. Distinguished from low-grade tumors by more _complex growth patterns & widespread infiltration_, or frank effacement of underlying stroma - PRESENTATION: usually really late with abdominal pain and INC abdominal girth: **ascites** because bits of tumor will seed abdominal cavity

Answer 175

- **Mucinous tumor** of the ovary: mutation of KRAS oncogene a consistent genetic alteration in these - Looks like colon adenocarcinoma, which likes to metastasize to the ovary - Can get very large: tenacious, gross mucous - MALIGNANT: serosal penetration and solid areas of growth -\> architectural complexity, incl. areas of growth, cellular stratification, cytologic atypia, and stromal invasion 1. When you get one of these, you will tell the surgeon to check the appendix too (to make sure it is not a met) - BENIGN: nice and smooth a good indicator

Answer 176

- *Psudomyxoma peritonei*: clinical condition with extensive mucinous ascites, cystic epithelial implants on the peritoneal surfaces, adhesions, and _frequent involvement of the ovaries_ - Recent evidence points to the source being, in almost all cases, extraovarian (usually **appendiceal**) 1. Mucinous neoplasms of the appendix can look pretty benign, and still cause this 2. Always tell surgeon to check the appendix - ASCITES

Answer 177

- **Endometrioid adenocarcinoma**: 15-20% of cases coexist with endometriosis - Some have PTEN mutation, similar to endometrial carcinoma

Answer 178

- **Brenner** (transitional cell) **tumor**: neoplastic epithelial cells resembling urothelium - Usually benign; characteristic epithelial nests (or islands of cells) in the ovarian stroma - NOTE: also a cystic teratoma on the left in the gross image

Answer 179

- _Tumors of müllerian origin_ -\> uterus, fallopian tube, contralateral ovary, or pelvic peritoneum 1. These are MOST COMMON - _Extra-müllerian tumors_: breast and GI tract (see attached image) 1. Rare cases of pseudomyxoma peritonei, derived from appendiceal tumors

Answer 180

- Ovarian tumors **seed locally** - Choriocarcinoma is the exception to this rule bc it invades blood vessels, and spreads hematogenously, i.e., to lungs

Answer 181

- **Krukenberg tumor**: classic metastatic GI carcinoma involving the ovaries - Characterized by bilateral metastases composed of mucin-producing, **signet-ring** cancer cells, most often of _gastric origin_ (diffuse variant gastric carcinoma from the stomach) - _Signet rings_: plump cells with lots of cytoplasm, and mucin pushing the nucleus to the side; see attached image (look for this on exam)

Answer 182

- **Granulosa cell tumo****r** of the ovary: arranged in sheets punctuated by small, follicle-like structures (_Call-Exner bodies_; image attached) - Right image shows strong IHC positivity for _Inhibin_ - CLINICAL IMPORTANCE: 1) may elaborate large amounts of _estrogen_, and 2) may behave like _low-grade_ malignancies (not a high-grade behaving malignancy) - Make little circles because they are trying to recapitulate the follicles - Little grooves on cells -\> look like coffee beans

Answer 183

- **Fibroma/fibrothecoma/thecoma** in ovary: benign, white fibrous bands grossly - Loose syncytium of stromal cells - _Meig's syndrome_: combo of findings -\> ovarian tumor, hydrothorax, and ascites; genesis unknown - Also associated with basal cell nevus syndrome - REMEMBER: hydrothorax is a pleural effusion when pleural fluid collects in the pleural cavity

Answer 184

- **Sertoli-Leydig cell tumor** in the ovary: often functional, and commonly produce masculinization or defeminization - Few have estrogenic effects - \<5% metastasze

Answer 185

- **Teratoma** in the ovary: most common - 3 categories: 1) mature (benign), 2) immature (malignant), and 3) monodermal/highly specialized - Teeth, skin, hair, nails - Right image: brain, hair follicles, skin - Key is to _make sure there are no malignancies here_, like SCC (most common) or melanoma - Germ cell tumor

Answer 186

- **Immature tissue in teratoma**: resemble embryonal and immature fetal tissue (neural most common) - Found in _pre-pubertal adolescents, young women_ - Risk for subsequent extra-ovarian spread is histo grade of tumor (I through III), which is based on the proportion of tissue containing immature neuroepithelium 1. _This determines how they behave_: the more of this they have, the worse they behave - Always want to ask: Are there immature tissue variants inside? (when you find a teratoma)

Answer 187

- **Monodermal teratoma** in ovary: thyroid tissue - Struma ovarii

Answer 188

- **Dysgerminoma**: ovarian counterpart of testicular seminoma - Also present in: mediastinum, pineal gland in brain (germinoma), retroperitoneum - Express _receptor tyrosine kinase, KIT_ and about one third have activating mutations in the KIT gene (IHC staining attached) - All malignant, but only 1/3rd aggressive and spread; all radiosensitive; _80% cure rate_ - HISTO: _fried egg appearance_ to the cells, with prominent nucleoli 1. Lymphocyte infiltration seals the deal

Answer 189

- **Yolk sac tumor**: α-fetoprotein - Schiller-Duval body: glomeruloid shape; vessel with malignant cells crowding around it - Hyaline droplets - Aka, endodermal sinus tumor

Answer 190

- Elevated in the sera of 75-90% of women with epithelial ovarian cancer - Undetectable in up to 50% of women with cancer limited to the ovary - Often elevated in a variety of benign conditions and no-ovarian cancers - Primarily used as a **MONITORING TOOL** (NOT for screening)

Answer 191

- Fibroma/fibrothecoma/thecoma in ovary: - Combo of findings (ovarian tumor, hydrothorax, and ascites) is designated Meigs syndrome. Its genesis is unknown.

Answer 192

- _Functional_: grows thicker in response to estrogen and is shed during menstruation - _Basal_: forms the foundation from which the functional layer develops -\> is NOT shed

Answer 193

- _Proliferative_: mitotic figure at the arrow (can also see these in the stroma sometimes, but may be difficult to find)

Answer 194

- _Proliferative_: simple, columnar epithelium with tubular glands -\> multiplying, but not tortuous yet

Answer 195

- _Proliferative_: nice, round glands

Answer 196

- _Secretory_: nice tubes have become squiggly glands with secretions inside them - Vacuolization: from basilar to luminal side in early to late - There will be a question about this on the exam

Answer 197

- _Early secretory_: vacuoles on basilar side of the glands

Answer 198

- _Late secretory_: vacuoles on the apical side of the glands

Answer 199

- _Menstruation_/breakdown: clumps of cells with blood in between them - Breakdown typically associated with menstruation

Answer 200

- _Menstruation_/breakdown: clumps of cells with blood in between them - Breakdown typically associated with menstruation

Answer 201

- Functional endometrial disorders

Answer 202

- **Anovulation** (failure to ovulate): due to subtle hormonal imbalances, which are most common at _menarche and in the perimenopausal_ period 1. Usually too much estrogen, and/or not enough progesterone -\> proliferative phase, but no normal secretory phase, so glands big and dilated, encroach on stroma (normally a 1:1 ratio); **disordered endometrium** -\> prone to breakdown and abnormal bleeding - Less commonly, anovulation is the result of: 1. _Endocrine disorders_: thyroid disease, adrenal disease, or pituitary tumors 2. _Ovarian lesions_: functioning ovarian tumor (granulosa cell tumors) or polycystic ovaries 3. Generalized _metabolic disturbance_: obesity, malnutrition, or o/chronic systemic diseases - _Attached image_: menstruation/breakdown stage of endometrium -\> glands, stroma in clumps, and bleeding in between

Answer 203

- _Endometrial polyp_: can cause anovulatory bleeding - Cervix on the left and uterus on the right

Answer 204

- _Endometrial polyp_: polypoid shape with dilated glands - Cystic change, large thick walled blood vessels, fibrous stroma

Answer 205

- _Endometrial polyp_: cystic change, large **thick walled blood vessels**, fibrous stroma

Answer 206

- Endometrial polyps in association w/admin of tamoxifen (anti-estrogenic activity on the breast) - Tamoxifen has weak _pro-estrogenic effects in the endometrium_ - Link between estrogen and endometrial changes, including _hyperplasia and carcinoma_ - Not very common, but they do happen -\> can look a little different than normal polyps (normal polyp attached)

Answer 207

- **Acute endometritis**: not very common - Usually retained _products of conception_ (POC) - Removal of the retained gestational fragments by _curettage_, accompanied by _antibiotic therapy_, promptly clears the infection

Answer 208

- **Chronic endometritis** -\> occurs in assoc with: 1. Pelvic inflammatory disease (_PID_) 2. Retained gestational tissue, postpartum or post-abortion 3. Intrauterine contraceptive devices 4. _TB_: from miliary spread or, more often, from drainage of tuberculous salpingitis -\> both are rare in Western countries - **Plasma cell** is what you want to find: perinuclear hof and clock-face chromatin

Answer 209

- Actinomyces -\> sulfur granulomas

Answer 210

- **Disordered endometrium** histo: due to ovulatory failure - Regardless of cause, ovulatory failure results in _excess of estrogen relative to progesterone_ 1. Endo goes through proliferative phase NOT followed by normal secretory phase 2. Endo glands may devo mild cystic changes or appear disorderly 3. Endo stroma, which requires progesterone for growth, may be scarce -\> this combo of abnormalities makes endo _prone to breakdown and abnormal bleeding_

Answer 211

- Defined by presence of **"ectopic" endometrial tissue** at a site outside of the uterus (see attached image -\> brown-grey discoloration on surface) - Almost always contains functioning endometrium, which undergoes _cyclic bleeding_ (adenomyosis does NOT do this)

Answer 212

- Endometrial tissue in the myometrium - Does NOT undergo cyclic bleeding like endometriosis typically does

Answer 213

- _Endometriosis_: endo glands, stroma, and hemosiderin - Image of chocolate cyst attached: ovarian cyst rupture

Answer 214

- Endometriosis of the sigmoid colon

Answer 215

- Cause of abnormal bleeding and a frequent precursor to the most common type of endometrial carcinoma - Associated with prolonged _estrogenic stimulation_ of the endometrium unopposed by progesterone - _Inactivation of the PTEN tumor suppressor gene_ is a common genetic alteration in both endometrial hyperplasias and endometrial carcinomas

Answer 216

- Hyperplasia without atypia: 1. Simple hyperplasia without atypia 2. Complex hyperplasia without atypia - Endometrioid intraepithelial neoplasia: 1. Simple hyperplasia with atypia 2. Complex hyperplasia with atypia - Endometrial carcinoma

Answer 217

- _Simple endometrial hyperplasia with no atypia_: mild glandular crowding and cystic glandular dilation - Loss of organization, but NO cytologic atypia in these glands - Normal proliferative phase endometrium attached

Answer 218

- **Complex endo hyperplasia with no atypia**: INC glandular crowding w/areas of back-to-back glands and cytologic features similar to proliferative endo - _Loss of stroma_, but carcinoma would have NO stroma, and be a larger SIZE (needs to be a certain # of cm) - Glands still look the same (no atypia), but they are _more crowded_ - Image of normal proliferative phase endometrium attached

Answer 219

- _Complex endo hyperplasia with atypia_: very little intervening stroma - Cancer would have NO STROMA - Prominent nucleoli, cells bigger, less cytoplasm, likely to have necrosis - Normal proliferative endo image attached

Answer 220

- _Complex endo hyperplasia with atypia_: clumpy chromatin (arrow) - Elongated cells with apoptotic debris - High-power view

Answer 221

- Most common invasive cancer of F genital tract - **Type I**: micro-satellite instability (MSI) -\> lynch syndrome association (HNPCC) 1. Depth of invasion usually \<0.5 endometrium 2. Defects of DNA mismatch repair genes in about 20% of sporadic tumors (esp. prevalent in HNPCC pts) - **Type II**: serous -\> think HIGH-GRADE (p53)

Answer 222

- **Endometrioid carcinoma** (FIGO): grading based on pattern, and amount of glandular crowding 1. _Grade 1_ (top right): non-squamous solid growth pattern 5% or less 2. _Grade 2_ (bottom left): 6% to 50% non-squamous solid growth pattern 3. _Grade 3_ (bottom right): 50% non-squamous solid growth pattern - Will often have squamous differentiation (almost a metaplastic change within the cancer)

Answer 223

- Big difference often going to be between pT1a and pT1b -\> from less than 1/2 the myometrium to \>+1/2

Answer 224

- **Serous endometrial carcinoma**: grade 3, regardless of histologic pattern - Despite relatively superficial endo involvement, may be assoc w/extensive peritoneal disease 1. Can be metastatic, even if it is a small lesion - p53(+) nuclear stain - Pseudo-papillary projections with small balls of cells that break off

Answer 225

- **Malignant mixed mullerian tumors** (MMMT's): aka, carcinosarcomas -\> mitotic figures, big cells (only epi components may metastasize) - _Epithelial AND stromal components_ appear to be derived from the same cell - Tumors that have heterologous mesenchymal components (bone, cartilage) do worse - _Poor outcomes_

Answer 226

- **Uterine leiomyoma**: (commonly called fibroids) - Perhaps the most common tumor in women

Answer 227

- **Leiomyosarcoma**: DIFFERENT than leiomyomas (NOT a malignant transformation of them)

Answer 228

- Common and involves, in order of frequency, the cervix, vagina, and vulva - Eearliest lesions usually red papules that progress to vesicles and then to _painful coalescent ulcers_ - High transmission rate during active infection - Migrates to regional _lumbosacral nerve ganglia_, and establishes a LATENT INFECTION - Gravest consequence of is transmission to the _neonate during birth_ is she is having an outbreak (usually do a C-section to avoid this) -\> can cause _conjunctivitis and encephalitis_

Answer 229

- _Herpes_: margination, molding (cells all being squished together like "play-doh"), multinucleation - Glassy look; not clear chromatin because the virus has marginated the chromatin, "pushing it out"

Answer 230

- _Molluscum contagiosum_: poxvirus - Common in young children between 2-12 yrs of age -\> transmitted through direct contact or shared articles (e.g., towels) - Sexually transmitted in adults, but not always - Always looks like this -\> pink volcano exploding up towards the surface - Bright pink, eosinophilic inclusions

Answer 231

- **Candida**: extremely common - Typically a result of a disturbance in the patient's vaginal microbial ecosystem, i.e., via douching or lubricant - RISK FACTORS: diabetes, antibiotics, pregnancy (due to immunocompromised state), and conditions resulting in a compromised immune system - _Semi-branching appearance w/pseudohyphae_ - Tend to cluster: SHISH KEBAB'ING

Answer 232

- **Trichomonas vaginalis**: protozoan - Asymptomatic OR may complain of _yellow, frothy vaginal discharge_, vulvovaginal discomfort, dysuria (painful urination), dyspareunia (painful intercourse) - Marked dilatation of cervical mucosal vessels results in characteristic colposcopic appearance of “_strawberry cervix_” (attached image) - _Arrow_: little falling leaves or heart-like look with red granules

Answer 233

- **Gardnerella vaginalis**: G(-) bacillus; main cause of bacterial vaginosis - Microbial balance is off - Patients typically present with thin, green-gray, malodorous (fishy) vaginal discharge - Small nuclei and abundant cytoplasm - _CLUE CELLS_

Answer 234

- **Chlamydia trachomatis**: mainly cervicitis - One of the causes of PID: ascending infection (can also cause tubo-ovarian abscesses and other peritoneal infections) - Histology non-specific - Diagnosis is based on molecular tests (_NAAT_)

Answer 235

- Begins in the vulva or vagina and spreads upward to involve most of the structures in the female genital system, resulting in pelvic pain, _adnexal tenderness_, fever, and vaginal discharge - Causes: Neisseria gonorrhoeae (G- diplococcus) and Chlamydia (intracellular organism) - _Chandelier sign_: extreme pain on bimanual exam

Answer 236

- **Acute salpingitis**: dilated lumen and edematous tubal plicae (folds) expanded by inflammatory cell infiltrates - Pus fills the center of the fallopian tube - Whole tube can be inflamed, and you _can get abscesses between the fimbriae and the ovary_ - Normal tubal histo attached here; showing fimbriae, delicated finger-like projections

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- **Chronic salpingitis**: scarring and fusion of plicae - Scarring may cause infertility, or ectopic tubal pregnancy - Whole tube can be inflamed, and you can get abscesses between the fimbriae and the ovary - Normal tubal histo attached here; showing fimbriae, delicated finger-like projections

Answer 238

- _Fitz-Hugh-Curtis syndrome_: perihepatitis due to fibrous ADHESIONS to the liver from PID - Generally, presents with righ upper quandrant pain and minimal (or no) pelvic pain or cervical motion tenderness

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- Obstruction of the Bartholin's glands in the vulva - Common - Affects all ages, including little girls

Answer 240

- **Lichen sclerosis**: marked _thinning_ of epidermis, _sclerosis_ of superficial dermis, and chronic _inflam_ cells deeper (normal VULVA histo on the right) 1. Normal ridges dipping into the dermis are gone, and the dermis is now pale - CLINICAL: white patch, atrophy of skin, vaginal stenosis -\> squamous cell carcinoma can also look like this, so these often get biopsied - Can get stenosis of the vagina too

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- **Condyloma accuminatum**: benign genital warts on VULVA via low oncogenic risk HPVs -\> 6 and 11 - Very rarely, if ever, progress to carcinoma, so treated as BENIGN - Velvety, undulating, pedunculated - Hyper-granular squamous cells that aren’t completely normal: viropathic effect -\> can have binucleation, halos (_koilocytic change_), and wrinkly nuclear membrane

Answer 242

- Older women (60's); not as common as cervical 1. Younger pts: HPV-16 2. Older patients: keratinizing, not HPV-related; often long-standing lichen sclerosis - Pts w/_lesions \< 2 cm_ in diameter have _90% 5-year survival_ after tx w/vulvectomy + lymphadenectomy 1. Larger lesions with lymph node involvement have poor prognosis

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- **HPV(+) VIN**: whole entire surface looks the same - Everything looks like a blue, basal cell -\> _SCC in situ_ on the left because has not crossed the BM - _Invasive_ on the right: pink/red is necrosis too

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- **HPV(-) VIN**: keratinizing SCC on the right -\> most likely developed from lichen sclerosis - In situ lesion on the left, but it looks like there may be some microscopic invasion

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- **Paget disease**: distinctive intraepithelial proliferation of malignant cells -\> abundant clear cells in epi that are malignany, abnormal - Typically NOT associated with underlying cancer, and is _confined to the epidermis of vulvar skin_ - Red, plaque-like clinical appearance - Big differential going to be a melanoma bc they look the same, but clinical impression is important here -\> can also do staining to help (keratin should not be + in a melanoma, but is + here -\> **K7**) - _NOT in the dermis_

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- Vaginal intraepithelial neoplasia (VAIN) and SCC - Virtually all 1^o carcinomas of the vagina are _SCC's associated with high risk HPVs_ 1. Very RARE 2. Nomenclature is like that of the cervix

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- **Embryonal rhabdomyosarcoma**: aka, sarcoma botryoides -\> uncommon malignant vaginal tumor most frequently found in infants, children _\< 5-y/o_ - Tend to _invade locally_ and cause death by penetration into peritoneal cavity or by obstruction of the urinary tract - Conservative _surgery coupled with chemotherapy_ offer best hope, esp. in cases dx'd sufficiently early - Cluster of grapes at the vaginal opening 1. _Cambium layer_: cluster of cells right underneath the epithelium

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- 3rd most common cancer in women, with an estimated 530,000 new cases in 2008, of which _more than half are fatal_ - High-risk HPV's the most important factor - **HPV-16 (SCC)** accounts for almost 60% of cervical cancer cases - **HPV-18 (adenocarcinoma)** accounts for another 10%

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- LACK OF SCREENING: accessibility of the cervix and slow progression make it amenable for screening, detection, and prevetive treatment 1. Most pts w/advanced cervical cancer die of the consequences of local tumor invasion (e.g., ureteral obstruction, pyelonephritis, and uremia), rather than distant metastases 2. Survival really high with localized cancer - REMEMBER: transformation zone is the area you want to look at, and sample

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- _E6_: dysregulation of p53 - _E7_: promotes degradation of RB - Also prevents cell cycle arrest, and _INH p21 and p27_, 2 important cyclin-dependent kinase inhibitors - Removal of these controls: 1. Enhances cell cycle progression and 2. Impairs ability of cells to repair DNA damage - Something else has to happen for these to progress, i.e., weakened immune system, genetics, hormonal changes, etc.

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- _Cervical cancer_: can be fungating (exophytic) or infiltrative masses - Transition zone a little more granular in appearance

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- All HSIL's are considered at-risk for progression to carcinoma - SIL terminology is current - Severe dysplasia and carcinoma in situ are the same thing

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- Normal cervical epithelium - BM and nice maturation of the cells

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- **CIN I**: koilocytic change, with halos and raisin-like nuclei, bi-nucleation in lower 1/3rd of the epithelium - Highest viral load at top, maturing cells -\> high proliferation at surface

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- **CIN II**: still have a little bit of maturation, with para-keratotic cells on top - Higher mitotic figure (in middle) is a giveaway for these - Highest viral load at top, maturing cells- high proliferation at surface - 20% can develop without LSIL

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- **CIN III**: NO maturation, and may start looking for invasion - Highest viral load at top, maturing cells -\> high proliferation at surface - 20% can develop without LSIL

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- **Ki-67 and p53**: can really help in older women because their cervix can become atrophic A. LSIL B. In-situ hybridization for HPV DNA -\> dark granular staining (typically most abundant in the koilocytes) C. Ki-67 (brown nuclear staining): abnormal expansion of the proliferating cells D. Upregulation of CDK INH p16 (brown stain) characterizes high-risk HPV infections - p16: has to be _strong AND diffuse_ to be (+), i.e., staining every cell (will often see a _block of brown_ cells next to “normal-appearing” cells)

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- **Invasive SCC**: this is what you are looking for in CIN III - A little bit of keratinization in the bottom right

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- Most women clear the HPV in 12-30 months

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- **Cervical adenocarcinoma**: AIS on the left and invasive adeno on the right - _Adeno in situ_: have lost mucin-containing cells at the top (normal gland at the bottom) - **_Invasive_**t: back to back glands with cribriform architecture, hyperchromatic, necrotic debris because turning over very fast, loss of maturation - 2nd most common tumor type in the cervix: 15% of cervical cancer cases and devo from a precursor lesion called adenocarcinoma in situ - Caused by _high-risk HPV;s_ - _Note_: adenosquamous and neuroendocrine tumors exist, very rare, and typically aggressive

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- Risk of metastasis INC from \<1% for tumors under 3mm in depth to \>10% once the invasion exceeds 3mm (stage 1a1 to 1a2)

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- Normal in top left - _LSIL_: nuclear membranes are wrinkly (top right) - _HSIL_: punctuated nuclear membrane and hyperchromatic (bottom)