Pathology 6 Endocrine, Bone & Repro Endocrine Tumors: The pituitary gland has an adenohypophysis (anterioran epithelial outpouching

ng of the embryonic Rathkes pouch) and a neurohypophysis (posteriorof neural origin). Its located near the optic chiasm, ventricular system, cerebral vessels, and cranial nerves. o pituitary tumors can cause disease by a variety of mechanisms. The anterior pituitary normally has a nested!lobular pattern of gro"th "hich is maintained by a reticulin frame"ork (seen "ith a reticulin stain). It also has several prominent cell types, including aciophils, basophils, and chromophobic (clear looking) cells. #ituitary neoplasms are usually benign and almost al"ays occur in the anterior pituitary. They can be treated by a trans$sphenoidal e%cision. &istologically, neoplastic pituitary tissue sho"s cellular monotony (all acidophils, all basophils, or all chromophobes), immunohistochemical homogeneity, and architectural disorder (looks sheet$like). #ituitary tumors may be hypersecertory, they may compress!destroy pituitary tissue and produce hyposecretory syndromes, or they can impinge on local anatomic strucures. o &ypersecretory states include prolactin adenomas (cause galactorrhea and amenorrhea in young "omen, but are silent in men and older "omen), somatotroph!'& adenomas (cause gigantism in kids, or acromegaly in adultsinsidious enlargement of hands, feet, facial features, etc), and corticotroph!()T& adenomas (causing pituitary )ushings diseasepeople are usually sensitive to very small changes in ()T&, so this may be hard to diagnose). There is often an inverse relationship bet"een tumor si*e and secretory activity, so smaller ones tend to secrete more. o &yposecretory states can include null adenomas (dont produce hormones, usually replace a large percentage of the pituitary gland) or pituitary apople%y (spontaneous hemorrhage into an adenoma that can acutely increase pressure and e%pand it, destroying ad+acent structures). o ,hen the pituitary impinges on ad+acent structures, infrasellar e%tension (do"n"ard) can erode the sella turcica and fill the sphenoid sinus. -ore commonly, suprasellar e%tension (up) can compress the optic chiasm and produce visual disturbances and e%tend into the third ventricle and produce obstruction!hydrocephalus. To distinguish pituitary adenomas from carcinomas, a carcinoma must show metastatic dissemination to extracranial sites. (denomas can sho" invasive gro"th patterns, cellular atypia and necrosis, so none of those things are specific to a carcinoma. Pathology of the terine !orpus and "estational Tropho#lastic $isease: .ndometrial carcinoma is the most common malignancy of the gynecologic tract and the /th most common cancer in "omen. It affects 0. (mericans and .uropeans more. 1f the histological types, the endometrioid type is by far the most common, but the other important type is serous endometrial carcinoma. .ndometrioid endometrial carcinoma is estrogen driven, its precursor lesion is atypical hyperplasia, it begins in pre!perimenopausal "omen, and it is a lo" grade tumor "ith a favorable prognosis. Its associated "ith #T.0, k$ras, - I or beta$catenin mutations.

erous endometrial carcinoma is not estrogen driven, its precursor lesion is endometrial intraepithelial carcinoma (.I)), it begins in post$menopausal "omen, and its a high grade cancer "ith a poor prognosis and p34 mutations. .ndometrial hyperplasia is a proliferation of glands "ith irregular si*e and shape, and "ith an relative decrease in the amount of stroma present compared to the proliferative endometrium. It may be simple or comple% depending on the degree of glandular cro"ding and branching. (nd, it may be categori*ed as atypical or not depending on the cytologic features ("hether glands are normal, pseudostratified "ith basal elongated nuclei or less organi*ed "ith more pink cytoplasm and atypical cells). (typia confers a much higher risk for progression to carcinoma. o Treatment of endometrial hyperplasia is highly dependent on age. ,omen in their reproductive years are treated "ith hormones (progestin) and peri!postmenopausal "omen are treated "ith hysterectomy. .ndometrial hyperplasia can be a precursor of endometrioid carcinoma. This is the most common histologic type of endometrial cancer, but its also the least aggressive. The mean age of patients is 56 years, but theres a "ide range (unlike serous endometrial carcinoma). It presents "ith abnormal bleeding and an enlarged uterus. This cancer is driven by unopposed estrogen stimulation, and this may be related to its association "ith obesity, &T0, diabetes, infertility and polycystic ovarian syndrome. o ,ith endometrioid carcinoma, you often see an e%ophytic mass pro+ecting into the uterine lumen, along "ith uterine enlargement. &istologically theres 7uite a bit of glandular cro"ding, and the glands may look fairly normal. .ndometrial carcinoma is graded "ith stage 2 being "ell differentiated (very glandular) and little solid tumor gro"th, and 4 being poorly differentiated (not glandular, mostly solid) "ith lots of solid tumor gro"th. o The stage of endometrioid carcinoma is the most important prognostic factor. tage 2 is confined to the uterine body (2a is only endometrium, 2b "ith 839: of myometrial thickness, and 2c "ith ;39: of myometrial thickness involved), stage 6 involves the cervi%, stage 4 involves other pelvic structures, and stage / involves distant metastasis. tage I has a <9$<3: 3$year survival. =ut even stage / has /9: survival, so its not too bad. o Treatment in young "omen may be +ust hormones (progestin). In peri!post$ menopausal "omen, they get T(&$= 1 (total abdominal hysterectomy and bilateral salpingo$oophorectomy) and if its a poor prognosis, also radiation. o The pathogenesis involves progression from normal proliferative endometrium to simple hyperplasia to comple% hyperplasia to comple% atypical hyperplasia to carcinoma. erous endometrial carcinoma sho"s a papillary architecture and considerably more cellular atypia. These tumors are higher grade and have a "orse prognosis. The precursor lesion is .ndometrial intraepithelial carcinoma (.I)). Treatment for serous endometrial carcinoma is "ith T(&$= 1 for all patients. >or advanced stages, the operation is follo"ed by ad+uvant chemo. .ndometriosis is ectopic endometrial tissue outside of the uterus. It occurs most commonly in the ovaries and other pelvic sites. It occurs in 2$23: of "omen, mostly of reproductive age. ymptoms include dysmenorrheal, lo"er abdominal!pelvic!back pain, dyspareunia (painful intercourse), abnormal bleeding and infertility (in 49: of cases).

1n gross observation this looks like ?po"der burns "ith irregular, dark, puckered lesions. In the ovaries it may form a cyst that accumulates blood as the endometrial tissue cycles and looks like a ?chocolate cyst. o -icroscopically, you see normal endometrial glands and stroma, often "ith hemorrhage and hemosiderin$laden macrophages. -alignant transformation is rare, but "hen it occurs it produces endometrioid or clear cell carcinomas. mooth muscle tumors include leiomyomas (benign, aka myomas or fibroids) and leiomyosarcomas (malignant). @eimyomas are the most common gynecologic tumor (not cancers, since theyre not malignant). These are estrogen dependent, so they tend to occur in females of reproductive age. #atients usually present "ith pelvic masses, pain, or bleeding. o 'rossly, these tumors may be submucosal (bleed most often), intramural or subserosalbasically any"here in the myometrium. They may be microscopic or very large, and fre7uently multifocal. They are usually "ell circumscribed, but they can be degenerated, hemorrhagic, or calcified. They are usually firm to palapation. o &istologically, they look very similar to normal myometrium, though they can be slightly less organi*ed. o These may be treated "ith surgical removal of the tumor (myomectomy) or the "hole uterus (hysterectomy). 0on$surgical approaches to treatment include 'nR& agonists (reduce the estrogen levels that drive the tumors) and uterine artery emboli*ation (infarct the leiomyoma). @eiomyosarcoma (malignant) occurs in slightly older populations (meanA36) and is relatively uncommon. They present "ith bleeding and!or pelvic mass (much like myoleioma). 'rossly, these are usually solitary, intramural, soft, hemorrhagic, and necrotic. They arent homogeneous like the leiomyomas. o -icroscopically they sho" lots of mitotic figures, tumor cell necrosis and marked atypia. They tend to have bad prognosis and may be treated "ith hysterectomy, surgical e%cision of recurrent tumors and!or chemo. 'estational Trophoblastic BiseaseC The normal placenta sho"s rounded structures (chorionic villi) "hen sampled. )overing the villi should be t"o layers of cells, an inner layer of cytotrophoblasts, and an outer layer of syncitiotrophoblasts. yncitiotrophoblasts can fuse and form multi$nucleated cells. 'enetically abnormal placentasC o )omplete hydatidiform moles sho" enlarged, edematous, chorionic villi. Dou see hyperplasia of the trophoblastic cells around the villi too. ( complete mole occurs in 2!6999 pregnancies and presents "ith vaginal bleeding, passage of grape$like vesicles, and a uterus that is abnormally large for the mothers length of pregnancy. Its often diagnosed early in gestation and may be detected as an absence of fetal heart tones or absence of the fetus itself on ultrasound. E9: of complete moles are benign, 2E: may become invasive, and only 6: progress to choriocarcinoma. Treatment is "ith curettage, monitoring h)' levels, and sometimes chemo. ( complete mole occurs "hen an empty egg is fertili*ed by 2 sperm, then the sperm genome duplicates to produce a /5FF individual "ith t"o identical sets of B0(. This more commonly progresses to genetic trophoblastic disease ("ith recurrent moles or carcinoma) o

( partial hydatidiform mole looks similar (large, edematous villi "ith hyperplastic trophoblastic layers) but is less e%aggerated. ( partial mole occurs "hen 6 sperm fertili*e a normal egg and you get a triploid cell. #artial moles may have a detectible fetus, but its not viable. Trophoblast neoplasmsC )horiocarcinoma is a malignant neoplasm composed of trophoblast cells and chorionic villi. These are very often preceded by a complete mole, abortion, ectopic pregnancy, or normal pregnancy. 'rossly, these appear large, "ell circumscribed, hemorrhagic, and soft. o -icroscopically, no chorionic villi are present but you do see nests of cytotrophoblasts hugged!surrounded by a thin layer of pinker, multi$nucleated syncitiotrophoblasts. These tumors sho" destructive, infiltrative gro"th into surrounding tissue producing necrosis and invading blood vessels (causing hemorrhage). Theses secrete beta$h)', "hich can help identify them via immunohistochemistry o )horiocarcinomas are highly malignant and can spread hematogenously (often to the brain, liver and lungs). It is highly responsive to chemo, so the prognosis is actually 7uite good. It can be monitored "ith h)' levels, because syncitiotrophoblast cells produce it at levels much higher than seen in normal pregnancy. o Pathology of the %&aries and 'allopian Tu#es: The ovaries include surface epithelium, non$specific ovarian stroma, speciali*ed ovarian stromal cells (granulosa and theca cells), and germ cells. )ysts are commonly seen in the ovaries and may be follicular ("ith a developing egg) or a corpus luteum (yello"ish, lots of infoldings inside the cyst). The surface epithelium is normally cuboidal!columnar, and the stroma is usually very spindly. ( normal developing follicle sho"s a germ cells surrounded by granulosa cells (more cytoplasm, rounded nuclei than the surrounding stromal cells). There may also be a layer of theca cells around the follicle, "hich look more spindle$shaped like stromal cells. ( normal corpus luteum has an undulating surface and often a hemorrhagic centerG it may have plump, pink cells "ith round nucleikind of fried$egg looking. ( normal fallopian tube has a muscular "all and mucosa "ith lots of plicae (e%tensive pro+ections into the lumen). (t the fimbriated end of the fallopian tube are finger$like structures. The clinical manifestations of ovarian and fallopian tube pathology include pelvic masses, adne%al masses (involves lateral structures of the uterusso the ovaries and tubes), ovarian masses, and!or pelvic pain. 1varian lesions include non$neoplastic conditions (mostly cysts) and benign!malignant neoplasms. >allopian tube lesions include infectious!inflammatory processes, ectopic pregnancy, and neoplasms (pretty uncommon). 0on$neoplastic lesions of the ovariesC These include surface epithelial inclusions cysts, follicular cysts, corpus luteum cysts, endometriosis!endometriotic cysts and polycystic ovary disease. urface epithelial inclusion cysts are "here the surface epi invaginates and normally find benign cysts that are found incidentally. They are lined by serous type (ciliated) columnar or cuboidal epithelium and are usually in the superficial corte%. They are may be linked to ovarian cancers if they look atypical. >ollicular cysts are usually solitary and thin "alled. They are lined by granulosa and maybe theca cells. They are usually benign and resolve on their o"n. Rupture "ith hemoperitoneum is rare. /

&emorrhagic corpus luteum cysts are benign, physiologic, and usually solitary. They have convoluted yello" tissue. they sho" large, luteini*ed granulosa cells (plump, pink looking cells) and theca interna cells "ith an inner layer of )T. &emorrhage is often seen. .ndometriotic cyst are pretty uncommon. Dou see endometrial tissue in the ovaries (endometrial glands and stroma lining the cyst). They often are filled "ith semi$fluid or chocolate colored material "ith hemosiderin laden macrophages. They are thought to arise either from metastasis or metaplastic processes. #olycystic 1vary Bisease has an unclear etiology but is thought to be due to inappropriate gonadotropin (esp. @&) release, "hich causes production of more androstenedione in the ovary (this is converted to estrone peripherally, you ovarian estrogen production is decreased, causing infertility and anovulation). This often also causes increased peripheral conversion of androgens to estrogen ("hich causes menometorrhagia, endometrial hyperplasia and carcinoma), and hyperandrogenism (hirsuitism). #athologically, you see sclerocystic ovaries "ith cortical fibrosis and multiple follicular cysts. o Dou see enlarged ovaries "ith thickened, "hite corte%. There are numerous, small subcortical cysts and numerous maturing atretic follicles. Dou can also see clusters of luteini*ed stroma cells, cells that look plump and clear!pink in the normally spindly stroma. 1varian 0eoplasmsC These may be surface epithelial neoplasms (most commoncan be benign, atypical proliferative!borderline, or malignant), germ cell (benign or malignant) or se%$cord stromal neoplasms (benign or malignant). urface epithelial neoplasms are 7uite common and can be benign "ith simple, non$ stratified epithelium and no nuclear atypia. These are often cystic (cystadenoma, cystadenofibroma) but they may also be adenofibromas "hich are glandular and fibrotic. urface epithelial neoplasms can be atypical proliferative (borderline) "ith epithelial proliferation!stratification!tufting, lo" levels of atypia, but no stromal invasion. urface epithelial neoplasms can be malignant, "ith stromal invasions, nuclear atypia, and mitotic activity. o urface epithelial tumors are classified as benign!borderline!malignant, but also based on "hat cell type differentiation they sho". They can be serous (fallopian tube epithelium), mucinous ('I or endocervical epi), endometrioid (proliferative endometrium), clear cells (gestational endometrium), or transitional cells (urinary epithelium). o erous cystadenoma (serous and benign) sho"s columnar epithelium "ith cilia, round nuclei and abundant eosinophilic cytoplasm. erous adenofibromas are solid neoplasms "ithin a fibrous stroma, "ith simple serous epithelium as described in the cystadenoma. o (typical proliferative serous tumors are cystic but "ith papillary structures. Dou see epithelial proliferation but no stromal invasion, and you also see bland cytologic features. They may implant other places, but dont invade and have a good prognosis lack of invasion is a key feature. o erous carcinoma (serous, malignant) is the classic ovarian cancer. They may be cystic or solid, and they may sho" a papillary architecture. They may sho" psammoma bodies (concentric microcalcifications that look purple). It sho"s stromal invasion, "hich is an important feature. These may be lo"$grade or high$grade. @o" grade ones 3

are thought to arise from atypical proliferative tumors through a =R(>!H$ras mutation they sho" papillary structure that invades the stroma, but these stay lo" grade and are not the classic ovarian cancer. &igh grade ones arise from p34 mutations from ovarian (possibly in ovarian cysts) or fallopian tube epithelium, and these have no atypical!borderline stage but become very invasive and high grade (lots of mitosis, necrosis, atypical nuclei, etc). These are the classic ovarian cancer. 1varian germ cell neoplasms include mature cystic teratomas (benign, most common) and dysgerminomas. o -ature cystic teratomas are cystic tumors "ith sebaceous, hairy stuff and skin$ like structures. Theyre composed of mature elements derived from all three germ layers (skin, hair, bone, fat, cartilage, mucous glands, nerves, etc). o Bysgerminomas are malignant and grossly they look like a solid fatty mass. -icroscopically they sho" clear cytoplasm, open!translucent nuclei and visible nucleoli. 1varian se% cord$stromal neoplasms include granulosa cell tumors, "hich are some"hat common. These tumors may be cystic or solid, and often hemorrhagic. These tumors all have malignant potential, and they may produce estrogen that can lead to uterine cancer too. -icroscopically they sho" ovoid cells "ith nuclei sho"ing longitudinal grooves (coffee$ bean nuclei). ( characteristic features is )all$.%ner bodies (small cavities filled "ith eosinophilic material) that can look like little flo"ers in the tumor. -etastatic ovarian neoplasms are important to distinguish because they usually have a different treatment and prognosis. )ommon sites of origin include the 'I tract (colorectum, pancreas, stomach, appendi%), female genital tract (endometrium, cervis) and breasts. o #rimary ovarian cancer tend to be unilateral, large in si*e, multi$cystic or solid, and not involve the surface of the ovary (it should still be smooth). -etastatic ovarian neoplasms are often bilateral, smaller, multiple nodules!cysts, and may involve the surface and superficial corte%. o -etastatic carcinomas of the ovary sho" multiple, small, discrete nodules. o 1ne type is metastatic signet ring cell carcinoma (Hrukenberg Tumor) "hich is usually metastatic and bilateral. >allopian Tube #athologyC The fallopian tubes may get infections (acute salpingitis or chronic salpingitis "hich may have tubo$ovarian abscesses), ectopic pregnancies, or neoplasms (tubal intraepithelial carcinoma can be a source of high$grade serous carcinoma in the ovaries). #yosalpin% is "hen you get purulent material in the tubes in acute salpingitis. The tube lumen and plicae!pro+ections are filled "ith #-0s and edematous structures. )hronic salpingitis sho"s more adhesions and congestion!edema developing into fibrosis. The tube structures can get mangled together "ith chronic inflammation and fibrosis, and you can get bilateral tubo$ovarian abscesses. The plicae fuse together and sho" a simplified pattern of invaginations in the fallopian tubes due to this fibrosis, and some cysts may be present near the lumen. Dou see lots of lymphocytes. In chronic salpingitis, you can also get hydrosalpin%, "here the tubes become dilated and filled "ith fluid. Tubal ectopic pregnancy can occur "ith damage to the tubes that causes the blastocytst to get stuck and implant there. <3: of ectopic pregnancies occur here, often preceded by pelvic inflammatory disease. It sho"s dilated tubules filled "ith blood, chorionic villi, and maybe an embryo. 'ro"th and infiltration of trophoblastic cells of the placenta can lead to rupture. Pathology of the !er&ix: 5

The ma+or area "ith cervical cancer is (frica, . (sia, and India. The transformation *one is "here the ma+ority of cervical cancer and its precursor lesions occur here. Its the area of the cervi% initially covered by columnar epithelium and partially or completely replaced by s7uamous epithelium (s7uamous metaplasia). This is most active during embryogenesis, puberty and pregnancy (mainly the first trimester). Theres often a visible +unction bet"een the s7uamous (nearer the vagina) and columnar epithelium (in the endocervical canal, closer to the uterus). o The s7uamocolumnar +unction is not static, and changes throughout life. ,hen it e%tends beyond its original area, its considered (ectopy) or endocervical eversion and produces the original s7uamocolumnar +unction. The region nearer the vagina is a harsher environment (bacteria, etc), so the columnar epithelium becomes covered "ith s7uamous epithelium becoming moving this ne"er ?functional s7uamocolumnar +unction closer to the cervical canal. The area bet"een the old and ne" s7uamocolumnar +unction is the transition *one. o o in the transformation *one, underneath the s7uamous epithelium on the outside you may see ?0abothian cysts of columnar epithelium. Theres cell activity, proliferation and mitotic activity here, "hich predisposes to &#I infection and cervical cancer. The precursors of cervical cancer have changed names several times. ,e currently call them s7uamous intraepithelial lesions ( I@) "hich may be high grade (& I@) or lo" grade (@ I@). They have also been called cervical intraepithelial neoplasias ()I0 2, 6, or 4). They "ere also termed dysplasia and carcinoma in situ (mild, moderate or severe) at some point. o @o" grade I@C Includes "hat "as called )I02, or very mild and mild dysplasia. o &igh grade I@C Includes )I0 6 (moderate dysplasia) and )I0 4 (severe dysplasia or carcinoma in situ). o If theres invasion in any form, its a microinvasive carcinoma. The histology sho"s progressive replacement of the full thickness of the epithelium by immature atypical parabasal cells (higher nucleusCcytoplasm ratio, darker cells more typical of the basal level of the s7uamous epithelium). &#I is a small, circular ds B0( virus encoding 5$J early genes and 6 late genes. There are more than 699 types of &#I (/9 infect the female genital tract). There are 24$23 high risk, oncogenic &#I types (types 25 and 2E cause J9$J3: of cervical cancer) that cause virtually every cervical cancer. .arly genes .5 and .J are transforming genes, and .5 is associated "ith p34 so if its altered itll affect p34. .J is associated "ith R= (involved in the cell cycle). o .5 and .J affect tumor suppressor genes and contribute to cervical cancer development. o @o" risk &#Is (mostly types 5 and 22cause ;<9: of genital "arts) dont cause cancer, but they can cause condylomas and some @ I@. -ost @ I@s are still caused by high risk &#Is. o Ksually &#I associated I@s regress instead of developing into cancer. o o, if you "ant to create a vaccine, you should target at least &#I 25, and probably 2E too. #athology of &#I associated lesions includes Hoilocytotic atypia (empty look of cells, @ I@), "hich represent the cytopathic effect of productive &#I infection that eventually leads to production of viral progeny. The cells have an empty look because of e%pression of

the &#I gene product ./ "hich leads to the destruction of cytokeratin matri%, allo"ing &#I progeny to get out of the cell more easily. 0uclei also look bigger, irregular, and other"ise atypical. Hoilocytotic atypia should mostly be seen at the very surface of the lesion. o gene e%pression of the papilloma correlates "ith cellular differentiation and positioning. o This productive infection is tightly regulated and permitted only in cells that have begun s7uamous maturation. o In the superbasal *one there is e%pression of the early genes (including .5!J) and in differentiated cells (more differentiated, nearer the surface) there is induction of all genes (including late genes @2 and @6) resulting in viral B0( synthesis and production of capsid protein leading to assembly of virions near the surface. This late e%pression produces @ I@. These viral infections are mostly productive and make lots of viral progeny. o o theres lots of &#I infection of cells at the basal area of the epithelium, even though cells higher up are the ones that sho" the @ I@ and lots of viral capsid proteins and gene e%pression. o ,ith microtrauma, the virus gets in and undergoes episomal B0( replication. (s they undergo productive replication, viruses lead to productive infections and condylomas and @ I@. Dou see most &#I B0( synthesis at the surface epithelium, because B0( synthesis is occurring more in the more differentiated cells nearer the surface (but basal cells are still infected). .ventually the virus spreads to other basal cells and you see des7uamation of cells. &#I is 7uite prevalent, and ranges from 29$39: depending on the population youre looking at. 1f those people "ith @ I@, over E9: of people have it. 1ver <9: of people "ith & I@ have &#I. 0early 299: of people "ith invasive cervical caner sho" presence of the &#I genome. &igh risk and lo" risk &#I types do not correspond to @ I@ and & I@ (high risk &#I is associated "ith both). 1ver E9: of @ I@ patients contain high risk virus types. (lmost all & I@ contain high risk type, and the ma+ority are &#I 25. (lmost all genital condylomas ("arts) contain lo" risk &#Is like 5 and 22. &#I B0( is found in all cervical cancers and precursor lesions, but so is the &#I messenger R0( (so gene e%pression is occurring). &#I 25 alone can immortali*e cervical cell lines in culture and prevent cellular differentiation resulting in change that mimic & I@. &igh risk, but not lo" risk, &#I types can transform epithelial cell lines in cooperation "ith an activated cellular oncogene like &$ras. .%pression of .5 and .J is re7uired for maintenance of the malignant phenotype. In & I@, the link bet"een s7uamous differentiation and early viral gene e%pression is lost. Integration into the host genome occurs at random sites in the host chromosome, but almost invariably disrupts .6 of the virus. This is because .6 is a transcription repressor, so in its absence you get e%tra .5 and .J (leads to additional p34 and R= dysfunction and contributing to cancer progression by making cells more susceptible to mutation and increasing unregulated proliferation). o these tend to progress to invasive cancers (sho" invasion in histology). Its not because the virus integrates here more often, but rather selection for cells that have integrated into .6. @o" grade lesions tend to have productive infections "ith the &#I genome still present in the nucleus as lots of episomal (e%trachromosomal). o these @ I@s "ill stain homogenously dark for the viral genome in the nucleus. In high grade lesions, B0( E

integrates into the host genome and @2 and @6 arent "ell e%pressed. o staining for &#I genes isnt homogenous in & I@. &#I infection is associated "ith number of se%ual partners and young age at first intercourse. >emale se%ual promiscuity or monogamous female and a promiscuous partner is also associated "ith &#I. &#I infection precedes and predicts the development of @ I@ and & I@. The highest risk is from &#I 25 and 2E. The relative risk of cervical cancer based on prevalence of &#I is about 299% greater. In multivariate analysis, &#I is the only and very strong independently associated risk factor. o the general consensus is that &#I is a ma+or etiological cause of cervical cancer. )ervical cancer is an TB caused by &#I. (nd, &#I infection is very common. The more se% partners you have, the &#I prevalence by lifetime really increases. &#I is also very infective. &#I negative "omen "ith 4 or more se%ual partners are in / years "ill have about a J9: chance of getting it. -ost &#I infections spontaneously regress, and very fe" persist. (bout E2: of infections regress over 2E months. This is "hy &#I infection is so common and cervical cancer is pretty uncommon. #ersistent infection of a high risk &#I is an important step in the progression from infection to cancer. >actors influencing cervical cancer are dominated by &#I, but &#I alone is insufficient for carcinogenesis. moking, se%ual habits, diet, condom use, and 1)# use also contribute. Buring productive infection, you get @ I@. ,ith persistent infection, you can progress to & I@ and eventually (if untreated) it can become cervical cancer. creening can be done "ith #ap smear. ,ith pap smear screening, incidence of cervical cancer really declines. -any "omen get more pap smears than are needed, often "omen "ho have access to health care, are health conscious and are generally at lo"er risk for developing cervical cancer. This places a pretty big burden on the system. It may lead to overtreatment and really generates high costs. 39 millions #aps are performed a year. 1ver 4 million have either @ I@ or atypical s7uamous cells of undetermined significance (( )K lo" grade cytologic abnormality, less serious than @ I@). 1nly a small portion of these are associated "ith & I@ or invasive cancer. o the dilemma is to identify the undiagnosed & I@ and cancer, but avoid overtreating the common benign lesions. =ecause &#I infection precedes and predicts development of @ I@ and & I@, adding &#I detection test to the #ap smear may enhance sensitivity of detection of cancer precursors. There "as an (@T study to see if &#I testing could help identify "omen "ho could be triaged and not treated. Ksing molecular &#I testing, the sensitivity of detecting & I@ "as <6:. o ince E4: of @ I@s have high risk &#I, its not really useful to test them. =ut only /<: of ( )K cases have high risk &#I. o, "omen "ith ( )K "ho dont have &#I can return +ust for routine follo"$up and the follo"$up interval can be increased. ( negative &#I test implies safety. &#I positive ( )K has the same risk as @ I@ of developing into & I@ or cancer. ,omen "ith normal cytology and are negative for high risk &#I type are at very lo" risk for developing & I@, so the interval of screening may be increased in these "omen (some

<

suggest to as long as E$29 years). ensitivity and specificity of a positive high risk &#I test are very high, so its a pretty reasonable approach. #ersistent high risk &#I infection is a prere7uisite for developing & I@. ,omen "ith any grade of )I0 "ith persistent high risk &#I over 5 months should be evaluated. ,omen "ith negative high risk &#I type can +ust be follo"ed. ome places have considered using &#I testing as the primary screening, not #(# smear. (s this has become cheaper, its more feasible. The goal "ould be to achieve high sensitivity "ith a minimum number of screens. Initially itll probably be used in combination "ith cytology. They may eliminate screening in older "omen "ith negative &#I tests and the appropriate history. &#I prevalence decreases "ith age and cervical cancer increases "ith age. ,ith an abnormal pap smear, you send patients for colposcopy (scope that allo"s you to look at transformation *one of the cervi%). I@ arists from "ithin the transformation *one, then e%tends into the endocervical areaG this sho"s up as "hitish areas. This allo"s for directed biopsy or endocervical curettage. If colposcopy doesnt sho" visible abnormalities, but you sa" high grade cells on pap smear, the lesion may be inside the endocervical canal. Biagnosis begins "ith cytology (#ap smear), then if its pretty abnormal it is follo"ed by colposcopy, and finally you can do loop electroe%cision or cold$knife biopsy to get a definitive diagnosis. In & I@, you can +ust remove all of the abnormal areas "ith loop electroe%cision. ( cone biopsy "ill remove the "hole transition *one, and in e%treme cases hysterectomy may rarely be performed. o If the #ap smear sho"ed ( )K , do an &#I test ne%t. If &#I (L) get colposcopy, if &#I ($) the can +ust get screened in the future. -alignant tumors of the cervi% include s7uamous carcinoma (most common, and these may be microinvasive or frankly invasive), adenocarcionma, adenos7uamous carcinoma, or rarely a sarcoma. 'rossly, they may be e%ophytic (protrude out of the organ) or endophytic (into the uterine canal). They may be necrotic. &istologically, s7uamous carcrinomas of the cervi% sho" anastomosing tongues and islands of s7uamous cells "ith abnormal cytologic features. Dou may see keratin pearls in the affected cells. )linically, cervical s7uamous carcinoma is decreasing in incidence. The age of affected patients ranges from 2J$<2 (mean 32). The epidemiology is the same as I@. They may sho" local e%tension, lymphatic metastasis, or spread to the urinary system. The prognosis depends on stage of the disease. (ll patients together sho" a 59: five$year survival rate. tage I sho"s <9$<3: survival. >or advanced stages, you can do radiation!chemoradiation or radical hysterectomy!lymphadenectomy. The &#I vaccine is against the @2 capsid protein gene. The @2 protein forms virus like particles that induces a virus$neutraili*ing antibody in patients. In animal models, it resulted in nearly complete protection. In a trial in humans, vaccination against type 25 provided complete protection against type 25. o its very protective, although it didnt give any protection against other types. "ardasil protects against (6, (), 6 (protects from lo" risk types that only really cause genital "arts), and (( (lo" risk). )ervari% protects against 25 and 2E. =ut, these are pretty e%pensive, and need to be administered 4%. These re7uire sophisticated storage, etc.

29

o there lots of room for improvement, especially if they are to be used in developing countries. Theres "ork going on here regarding an @6 capsid protein vaccine, "hich "ill be more cross$reactive among &#I types. In the future, "ith continued development, eradication of &#I may be possible "ay do"n the road. &#I testing may also replace cytologic screening.

*agina and *ul&a Pathology: Iulvar cancer can be divided into 6 typesC (n &#I$related type occurring in younger "omen and a 0on$&#I type occurring in older "omen. @ike cervical caner, vulvar cancer develops from intraepithelial precursors. The risk factors are similar to cervical cancer. ,hen diagnosed at an early stage, prognosis is good. Infectious diseases of the vulva include #apillomavirus infection (condylomas acuminatum), &erpes, yphilis, and -olluscum. =ut "ell focus on &#I ones that leads to e%ophytic, cauliflo"er$like, papillary "arts. 1n histology, you see papillary outgro"ths. Dou also koilocytotic atypia, and these are highly contagious. The incidence of vulvar cancer is pretty lo" 4E99 cases per year in the K and E99 deaths. &#I 25 is found in the vast ma+ority of vulva intraepithelial neoplasms (II0). 'rossly, II0s look "hite!red or pigmented, scaly!moist!"arty, and often multicentric. -icroscopically, they have a loss of cellular polarity, abnormal maturation and abnormal nuclear morphology. They may also sho" "art$like papillary morphology. II0 is classified into lo" grade and high grade, much like in the cervi%. These are increasing in fre7uency, and the mean age of patients is about 49 years. Its fre7uently associated "ith condylomas and )I0 and IaI0. They rarely progress to invasive carcinoma. Treatment includes local e%cision or laser treatment. They are similar to s7uamous carcinoma of the cervi%. They fre7uently coe%ist in the same patients. They sho" similar histologic features and similar risk factors (number of partners, smoking, etc). This suggests a common etiology (&#I) =ut, cervical and vulvar s7uamous carincomas are different in that the vulvar s7uamous carcinomas have a much lo"er invasive potential. The proportion of invasive carcinomas "ith ad+acent carcinoma in situ is lo"er in the vulva. ,omen "ith vulvar s7uamous carcinomas are older, and their transit time (from infection to lesion) is longer. The gross features of invasive s7uamous carcinomas of the vulva include unicentric lesions that are often 2!4 ulcerated, 6!4 e%ophytic and three 7uarters of them involve the labia. 7uamous carcinoma of the vulva may be keratini*ing (more like s7uamous carcinoma of the skin "ith keratin and anastomosing tongues and atypical cellsoften in older patients and non$&#I related), basaloid (most similar to cervical cancerhigh nucleusCcytoplasm ratio, no keratin, blue$ish), or "arty (papillary configuration). Dou can lump the basaloid and "arty ones together and look at three types of vulvar cancerC II0 (non$invasivehighly associated "ith &#I, commonly in younger people), =asaloid!"arty (very often associated "ith &#I, often have un$mutated p34, commonly in younger people), and Heratini*ing (not commonly associated "ith &#I, but more often sho" p34 mutation and are more aggressive, in much older people). o o basically keratini*ing s7uamous carcinomas of the vulva are not &#I related, and they have more p34 mutation, they are more aggressive, and occur in older people.

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ince theyre not &#I related, they also lack cervical cancer risk factors and are rarely associated "ith other female reproductive tumors (unlike "arty!basaolid carcinomas). The ones that are &#I positive are mostly type 25. 7uamous carcinoma of the vulva makes of 3: of all female reproductive cancers, and <9: of vulvar tumors. They tend to be slo" gro"ing and spread to regional lymph nodes. They are treated "ith radical vulvectomy and lymphadenoectomy, and more recently "ith radical e%cision "ith selective lymphadenectomy. 3$year survival for all stages is J9:, and if nodes are negative its over <9:. Iaginal cancerC -alignant tumors of the vagina are even less common than in the vulva. These vaginal tumors may be invasive s7uamous carcinomas, clear cell carcinoma (rare), sarcoma botryoides (malignancy of stroma tumor in the youngvery uncommon), endodermal sinus tumors (rare) and melanoma. The key points are that most vaginal cancer is s7uamous cell carcinomas, and like cervical caner, vaginal cancers develop from intraepithelial precursors. The risk factors for &#I related vaginal cancers are similar to those for cervical cancer. The 7uestion isC "ill the development of &#I vaccines have a significant effect in the management of vulvar and vaginal cancerM #robably, yes, at least for a subset of cases. @2 isnt an ok target for a therapeutic vaccineonly for a preventative vaccine. This is because its a capsid protein and stimulates adaptive immunity (humoral). ,hen you give @2, theres no viral genome there. Dou could give inactivated, killed virus (but this could reactivate). ( therapeutic vaccine should use cellular immunity and kill the affected cells, it should not humoral immunity. &umoral immunity and antibodies "ouldnt affect an infected cell. Knless the infection is productive and making ne" particles and lots of capsid proteins, an @2 vaccine that induces antibodies, it "ouldnt be helpful. (n antigen good for a therapeutic vaccine might be .5!.J. These are highly e%pressed in cervical cancer and precursor lesions, and theyre responsible for malignant progression. ome investigators here are "orking on this. It "ould also be useful for patients "ith some head and neck cancers, particularly oral cancers (oral s7uamous cell cancersthese bad a better prognosis than non$&#I cancers "ith better prognosis since they usually dont have mutated p34). It might also be useful for laryngeal papillomas (&#I$5 associated). Prostate !ancer Pathology: The prostate is inferior to the bladder. Biseases of the prostate may block the prostatic urethra and lead to bladder abnormalities. It prostate is also immediately anterior to the rectum, so the rectums is a "indo" for imaging and biopsying the prostate. -ost cancers arise peripherally in the prostate. The urogenital diaphragm is associated "ith the prostate, and in+uring this during treatment of the prostate can lead to urinary incontinence. The prostate has an inner transition *one around the prostatic urethra. This is the area affected by benign hyperplasia of the prostate. There is also a peripheral *one (think of it as the outer prostate), "here most cancers begin. ( healthy prostate looks pretty homogenous "ith a urethra in the middle. ,hen the transition *one is affected by hyperplasia, this *one becomes better demarcated. The prostate is made up of glands that should normally look pretty simple lined by pale cytoplasm and t"o cell layers. The t"o cell layers include secretory cells (have cytoplasm, make prostatic secretions) and flattened cells underneath (basal cellsnot myoepithelial 26

cells, but they are the stem cells of the prostate). The prostate also has a stroma of fibrous tissue and smooth muscle. ( test for diagnosing prostate cancer is a test that labels basal cells selectively. Dou test for high molecular "eight cytokeratin, and this is important because prostate cancers lack basal cells. o this can be important for prostate cancer diagnosis. =ut, there are some benign conditions "ith absent or patchy basal cells. ,ell talk about prostatic cancer and benign prostatic hyperplasia. There are others, but "e "ont talk about them. =#& is probably the most prevalent disease is men. 1ver E9: of men in their seventies have it, at least pathologically but maybe not clinically. They increase "ith age. #ronounced pathologic =#& compresses the urethra a lot (obstructs urinary flo"). Theres also physiologic obstruction due to smooth muscle tone, "hich can occur in the absence of a huge prostate gland. This occurs "ith transition *one e%pansion. =#& sho"s hallmark nodules and less homogeneity (some cysts, some solid areas, some areas of smooth muscle, others of glands). The peripheral *one is often compressed around the outside of the enlarged prostate. &istologically, you see nodules of hyperplastic tissue, a compressed urethra, and a compressed peripheral *one around the outside. 1n microscopy, theres nothing diagnostic of =#& (you cant identify hyperplastic glands). Its never diagnosed by needle biopsy. Nust look for the central area being enlarged and nodules. 1n a cystoscopic e%am through the urethra, you can see the lumen compressed to a slit$like space by hyperplastic regions of prostate. ome hyperplasia is grandular, others may be stromal, and some may be glandular$stromal. This doesnt really matter for our purposes. Dou can do a rectal e%am in a patient and you may feel a fairly small prostate. ometimes, nodules may gro" into the urethra "ithout a huge prostate. This is ?median lobe hypertrophy. o you can still get urinary obstructive symptoms "ith a relatively small overall prostate. #atients have trouble initiating urinary flo", get dribbling, have high fre7uency, and often nocturia (need to get up at night to urinate). Treatment ameliorates symptoms and pre&ents #ladder damage. ,hen you have obstruction, the bladder has to s7uee*e harder and the bladder muscle hypertrophies. Dou can visibly see the muscles under the bladder mucosa (trabeculation). ,hat can happen is that the bladder "ill +ust give up, and the urine "ill flo" back causing hydronephrosis and kidney damage. 1ne treatment is to scoop out obstructive tissues (TKR#) and you get chips out. In 29: of cases, there may be cancer in these chips of prostate tissue. -ost often, prostate cancer is in the peripheral *one, but it can occur in these transition *one segments. #rostate )ancerC This is e%tremely common. In autopsy, 69$/9: of men over J9 "ill have it (maybe even as high as 39: of men in their 59s). =ut its often very indolent. Relatively, its a disease that is increasingly common "ith age. The lifetime risk of developing any prostate cancer is /6:. The lifetime risk of developing clinical cancer is only <.3:. The lifetime risk of dying of prostate cancer is 6.<:. o a lot more people have it than get symptoms or die of it. Its by far the most common cancer in men (nearly 63: of cancers in men), but it doesnt kill a high percentage of them.

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#rostate cancer rates have been changing pretty e%tensively. This is because of changes in detection of prostate cancer. =ut, people found lots of cancers that "erent having an effect. (round the time of ne" tests for prostate cancer, screening contributed in part to screening and advances in treatment. -ost of these cancers are diagnosed in the elderly. =ut it still affects men in their 39s and some in their /9s. #rostate is the second leading cause of death in men in their E9s, but it drops 7uickly do"n in younger people. o it mostly causes mortality in older people. o even "ith diagnosis in the 39s, people still dont die of this for a "hile. # ( is synthesi*ed in the ductal and acinar epithelium, its secreted into the lumen and diffuses into the interstitium. It crosses the vascular basement membrane into the serum. )ancer sho"s higher serum # ( than benign prostates, though its not really clear "hy. In benign forms, its likely +ust lost into the urethra. In prostate cancers, glands may not lead to the lumen necessarily. Its one of the most common reasons for internists to be sued for malpractice. o # ( is a serine protesase that normally li7uefies coagulum (gel$forming proteins) to release sperm. o This is basically a cancer test. @a"suits related to # ( result from # ( tests done and never reported back from the lab, -B never got the results, -B sa" but didnt inform the patient, -B sa" and misinterpreted, etc. (nd, the delay is diagnosis results in allegations of a decreased chance of a cure. o # ( is not a routine lab test, its a cancer test. Dou need a mechanism to make sure that "hen its ordered, you get it back, see it and act on it if its abnormal. If abnormal, consider referring to urology, since its a fairly complicated testyou may not even recogni*e it as abnormal. o Bigital rectal e%am isnt a really great test. Kltrasound isnt that great either (often used to +ust make sure that a biopsy needle hits the prostate). Theres really no good radiology test for prostate cancer. =ut, higher # ( and if rectal e%ams are also abnormal, you see increased risk of cancer. o 1ne of the big problems is that theres no ?normal level of # (, even though a lab test may sho" / as a normal value. @ots of patients "ith no cancer are over /, and lots of cancer (even advanced ones) may have # ( belo" /. =ecause its not a perfect test, you look at other things like # ( density, rate of change, age$specific # (, and freeCbound # (. o # ( density takes into account that benign prostate tissue makes # ( too. =ut cancer produces more. o a large, benign prostate may make a lot. Dou take the # ( and divide by the "eight of the prostate (estimated by ultrasound). o you look at # ( per gram of tissue. o # ( velocity "as developed here. It tracks # ( over time. # ( increases slo"ly in normal men. In =#&, its very slightly faster. ,ith cancer, the "orse it is, the faster your # ( rises. o you look at # ( velocity over a 2.3 to 6 year interval. If # ( is mildly elevated (/$29), an increase of over .J3 per year is abnormal. ,ithout cancer, this type of increase is really rare. If # (8/, the cutoff is a change of .43 per year. It "ould ideally be done "ith three measurements, so its not +ust 2 interval being measured. o (s men age, their prostates get bigger and they produce more # (. o the older you are, more # ( should be ok. This is an age specific # (. 4 may be really high in

2/

somones /9s, but really lo" for someone in their J9s. o # ( in younger people need lo"er cutoffs. o # ( is in the blood, and some is free, some is bound to alpha$2$chymotrypsin and alpha$6$microglobulin. +n cancer, more it the P,- is #ound. In =#&, more if the # ( is free. This is most useful in the moderately elevated # ( cases (/$29). )ancers can be missed commonly on needle biopsy, so this can be used to evaluate if someone should be biopsied again or something. If the free # (829:, theres a pretty high risk of cancer. If the free # (;63:, then cancer is pretty uncommon. o @ots of factors influence serum # ( though. Theres an inter$assay variability of about 29.3:, and biologic variability of 64.3: in a patient. o >actors other than prostate cancer can increase # (. Bigital rectal e%am can elevate it, as can biopsy or e+aculation. #rostatitis (t% "ith ab% and go back do"n to normal), =#&, and cancer can cause elevated # (. =ut, not all men "ith prostate disease have # ( elevations. #rostate cancer occurs in the periphery of the prostate. It is pretty subtle grossly, especially no" that "e detect it earlier. 1n histology, cancer may look dense and blue. #osterolateral is a neurovascular bundle, "hich is re7uired for potency. If a patient doesnt have a rectum, you can sample the prostate for biopsy through the perineal skin. #athologists look for cancer on biopsy. Its difficult to diagnose, because its pretty subtle. =enign prostate has big glands. )ancerous glands tend to be smaller and cro"ded bet"een more normal glands. )ytologically, cancer cells may have central nucleoli. ,ith a basal cell high molecular "eight keratin stain, you can see that cancerous glands lack these basal cells. #rostate cancer is also commonly "rapped around nerves, much more so than benign glands. These cancers arent painful though. (fter the diagnosis of cancer, its graded to identify tumors more likely to be indolent. Its graded on the 'leason grading system (2$3). Its based on architecture, not cytology. @o"er grade patterns have "ell formed glands that are tightly packed together. -ore aggressive cancers lose glands. In this system, you look for the most common pattern and also the second most commonthen add these together so the total score is up to 29. If its 85, then its "ell to moderately differentiated. 5$J is moderate!poor. E$29 is poorly differentiated. ,e "ont have to 'leason grade things. @arge, uniform glands that are pretty back to back, maybe "ith papillary infolding but separated "ith stroma are more normal. The most poorly differentiated ones dont sho" any glands and +ust sheets of cells. @o" grade is often confined to the prostate. =ut once its high, then its more often invaded beyond the prostate and in lymph nodes. This is the best predictor of prognosis. If its 85 vs ;J, it can make the difference bte"en "atching and treating, treating "ith surgery vs radiation, preservation or e%cision of the neurovascular bundle, etc. ,hen it spreads, it goes to the fat around the prostate, to seminal vesicles, pelvic lymph nodes, retroperitoneal nodes, and "hen it spreads distantly its most commonly to the bone (commonly to the a%ial skeleton). ,hen most cancers spread to bone are osteolytic, but prostate cancer is pretty uni7ue in that its osteoblastic. The marro" areas may be mostly filled "ith bone, and this can get really dense. If clinically confined (most cases), prognosis is variable but its uncommon to die "ithin 29 years. ,ith regional node metastases, 29$69: are dead in 3 years, /9$59: in 29 years.

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,ith distant mets, 39: are dead in 3 years, <9: in 29 years. The life e%pectancy of people diagnosed at 33 is 6/ more years, so if these people are diagnosed they should be treated. In people "ho are E3, theyre only e%pected to live 3$5 more years, and prostate cancers might not "arrant treatment since its so indolent. Placenta, Twinning, ,-Bs .spontaneous a#ortion/0: Hno" for the e%amC 2. (bruptioC eparation of the placenta from the site of uterine implantation before delivery of the fetusG can be caused by a short umbilical cord, trauma to the belly, or sudden loss in uterine volume due to loss of amniotic fluid or delivery of the first t"in. 6. #reviaC #lacenta located over the cervical os. Ksually presents "ith bright red blood in the second trimester. ( )$section "ill usually be performed as soon as the baby is mature enough. 4. 1ligohydramniosC Beficiency of amniotic fluid (8 399ml at 46$4E "eeks gestation). #rofound oligohydramnios may result from fetal urinary tract anomalies that include bilateral renal agenesis, posterior urethral valves, and bilateral multicystic dysplastic kidneys. 0onrenal etiologies include intrauterine gro"th retardation, post$term pregnancy, fetal demise, and ruptured membranes. Bue to the lack of amniotic fluid, the lungs can be hypoplastic and neonates "ho survive delivery may die of respiratory failure. evere and prolonged oligohydramnios leads to a constellation of findings that include #otterOs facies (flattened nose, recessed chin, and lo"$set ears) and positional abnormalities (clubbed feet, dislocated hips, and contractures). /. )horoamnionitisC )horioamnionitis is an infection of the placental membranes and amniotic fluid. It occurs in about 2 to 6 percent of all pregnancies, but is much more common in preterm births. )horioamnionitis can cause bacteremia in the mother and may lead to preterm birth and serious infection in the ne"born baby. The organisms usually responsible for chorioamnionitis are those that are normally present in the vagina, including .scherichia coli (.. coli). 'roup = streptococcus may also cause the infection. )horioamnionitis can develop "hen the membranes are ruptured for an e%tended period. This allo"s the vaginal organisms to move up"ard into the uterus. ymptoms include fever, increased heart rate in baby and mom, tender or painful uterus, and foul odor in the amniotic fluid. Treat "ith antibiotics and delivery. 3. #olyhydramniosC #olyhydramnios refers to e%cessive accumulation of amniotic fluid, "hich is associated "ith increased risks of adverse pregnancy outcome. It is typically diagnosed by ultrasound e%amination and may be described 7ualitatively or 7uantitatively by various methods. .%cessive accumulation of amniotic fluid is typically related to decreased fetal s"allo"ing or increased fetal urination. .tiologies include fetal malformations and genetic disorders (E to /3 percent), maternal diabetes mellitus (3 to 65 percent), multiple gestation (E to 29 percent), fetal anemia (2 to 22 percent), and others (eg, congenital viral infection, =artterOs syndrome, hydrops fetalis, neuromuscular disorders, maternal hypercalcemia). 5. (ccretaC #lacenta accreta occurs because the villi penetrate the uterine myometrium. It can result in incomplete e%pulsion of the placenta after birth, hemorrhage, and infection. Risk factors include prior placental abnormality (eg, placenta previa), maternal age ; 43, previous cesarean section or myomectomy, endometrial defects (eg, (shermanOs syndrome), and

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fibroids. Buring delivery, the disorder is suspected if the placenta has not been delivered "ithin /3 to 59 min of the infantOs delivery. In such cases, laparotomy "ith preparation for large$volume hemorrhage is re7uired. &ysterectomy is the safest procedure, but if keeping the uterus is important and hemorrhage is not massive, sometimes hysterectomy can be avoided by resection of the abnormal site (primarily "hen accreta is focal) J. )ircumvalateC )ircumvallate placenta refers to a placenta "ith an unusually small chorionic plate, but "ith gro"th of e%trachorial placental tissue. ( double layer of amnion and chorion, as "ell as necrotic villi and fibrin, form a raised "hite ring around the surface of the placental disk at a variable distance from the umbilical cord insertion siteG the fetal vessels do not e%tend beyond this ring. The e%trachorionic tissue constitutes a small proportion of the placenta and usually does not compromise fetomaternal e%change. &o"ever, these placentas are more prone to premature separation and second trimester bleeding is common. E. >etus papyraceusC ( fetus papyraceus is a fetus in a multiple pregnancy "hich has died and become flattened through mechanical compression in the "omb. The result resembles a scrap of parchment paper. Bepending on the gestational age of the fetus, various developmental features such as limbs may be distinguishable. uch fetuses usually emerge during the process of labor alongside their siblingsG a fetus papyraceus does not usually pose a risk to the other baby or babies involved in the pregnancy. <. T"in perfusion syndromeC This condition occurs only in those identical t"ins that are monochorionic and diamniotic. In almost all of these pregnancies, the single placenta contains blood vessel anastomses bet"een the t"ins. >or reasons that are not clear, the blood flo" through these blood vessel connections becomes unbalanced, resulting in a condition kno"n as t"in$t"in transfusion syndrome (TTT ). This is not an inherited or genetic condition. In TTT , the smaller t"in (often called the donor t"in) does not get enough blood "hile the larger t"in (often called the recipient t"in) becomes overloaded "ith too much blood. In an attempt to reduce its blood volume, the recipient t"in "ill increase the urine it makes. This "ill eventually result in the t"in having a very large bladder on ultrasound, as "ell as too much amniotic fluid around this t"in. This is kno"n as polyhydramnios. (t the same time, the donor t"in "ill produce less than the usual amount of urine. The amniotic fluid around the donor t"in "ill become very lo" or absent. This is kno"n as oligohydramnios. (s the disease progresses, the donor "ill produce so little urine that its bladder may not be seen on ultrasound. The t"in "ill become "rapped by its amniotic membrane (kno"n as a PstuckQ t"in). 29. #lacental infarctsC #lacental infarcts are similar to infarcts observed in any other organ and are the result of obstruction of a uteroplacental artery. mall infarcts are found in about 63: of placentas from uncomplicated pregnancies. Their incidence is significantly increased in pregnancies complicated by preeclampsia or essential hyperand is directly related to the severity of the disease. In maternal hypertensive disorders infarction is usually e%tensive and involves more than 29: of the placental tissue. @arge placental infarcts are also associated "ith e%cess of perinatal mortality and intrauterine gro"th retardation. Recent or acute infarcts appear macroscopically as red lesions composed histologically of congested villi "ith "idely dilated vessels and narro"ed intervillous spaces. 1ld or chronic infarcts are yello"$"hite on macroscopic e%amination and are composed microscopically of necrotic ghost$like villi often "ith fibrin deposition at the periphery of the lesion. tuff >rom (skins (rchived @ecture not on the e%amC

2J

Indications for histological e%amination of the placentaC diabetes, &T0, gestational &T0, pre$eclampsia, eclampsia, rhesus isoimmuni*ation, pyre%ia!fever around labor, prolonged or premature rupture of membranes, small!malformed!stillborn babies, t"o vessels in umbilical cord, unusual placental pathology, history of maternal infection, or history of diagnostic procedure involving placenta. ( term placenta is normally implanted in the uterus. It is usually anterior or posterior. It can implant abnormally, as in placental abruption (separates prematurely from the uterus, and blood fills the gap possibly producing placental hypo%ia). The placenta may invade the myometrium (placenta increta) possibly all the "ay through (percreta), "hich is usually prevented by decidual change in the endometrium. Dou can also get placenta previa, "here it implants over the internal cervical os, so that at delivery the baby e%periences hypo%ia. ( normal placenta may look blue$grey. Dou often see fibrin under the amniotic membrane. The umbilical cord is usually coming out of it slightly off center. The maternal surface of the placenta is divided into lobules (codyledons). Theres often some endometrium stuck on to the maternal side of the placenta "hen its delivered. The placenta invades into the endometrium and into the uterine arteries and dilates them to increase blood flo" into the placenta. The blood flo"s into the space bet"een the placental villi, and o%ygen comes into the placenta from the uterine arteries into lakes of blood "here the villi of the placenta are. 1%ygenated blood is in the veins going to the baby, and deo%ygenated blood is in the umbilical artery. The placenta changes a lot in its development. .arly, the villi of the placenta have very little branching. (s time goes by, these become more e%tensive and complicated. This is seen on microscopy "ith smaller, more numerous branched villi later in pregnancy. (lso, in the early placenta, you see t"o layers of trophoblast, "hereas later you only see syncitiotrophoblasts (the cytotrophoblasts are there, but only visible on .-). The ovum implants on one side of the endometrium, but the fetus gro"s to fill up the "hole uterus. In early gestation, villi are present all the "ay around the placenta. =ut later in the pregnancy, 4!3 of the villi have regressed and leave only membranes. Iilli only remain "here its attached to the uterusM -ost villi have atrophied in the underlying membranes. In the placenta, arteries cross over veinsM ( common finding in a term placenta is a chorionic cyst. They are of no clinical significance, and theyre +ust full of mucous fluid. The baby is in the amniotic cavity. The yolk sac is "here germ cells and red cells come from. Dou can often see remnants of the yolk sac in term placenta, bet"een the amnion and chorion. -icroscopically, it looks a little calcified. Theres fibrin in placentas, usually of no clinical significance. It shouldnt be confused "ith infarcted areas. Iilli around fibrin arent usually collapsed, but around an infarct they are. ,ith enough fibrin deposition, you may impede o%ygenation, but thats pretty unusual. The plate of the placenta forms in the 4!3 of the placenta "here the villi involute and end up as +ust membranes. ometimes the involution isnt complete, and you get abnormal shapes!lobes in the placenta. ( succenturiate(spM) lobe is separated from the main placenta by amnion!chorion "ith an area of no placental villi. 'enerally its +ust a curiosity, but it can be left in the uterus at the time of delivery and might cause a problem "ith bleeding, infection, etc. Dou may see bi$lobed placentas, "hich are like succenturiate ones, but connected. The implantation site is al"ays right underneath the umbilical cord. 2E

#lacenta previa is "hen the placenta is partially or totally covering the cervical os. ,hen the placenta separates from the uterus, the o%ygen flo" to the baby is interrupted and the baby is stuck behind the placenta and cant get out of the uterus. The umbilical cord is implanted either centrally or eccentrically. If the cord terminates on the membranes before it gets to the villous placental areas, and this leaves the vessels unsupported and easily torn. This is a vellimentous insertion of the umbilical cord. .ccentric, marginal or vellimentous insertion of the cord can be associated "ith vasa previa, "here the umbilical cord prolapses into the cervical canal during delivery and interfere "ith blood flo" to the baby. This, like placenta previa, often re7uires cesarean. This occurs commonly "hen the placenta implants near the cervical os and due to ?trophotropism, the placenta gro"s a"ay from the os to"ard more of the uterus, from "hich itll receive more nutrients. #lacental abruption is "hen the placenta prematurely separates and fills "ith a blood clot. =lood clots are common "ith delivery, so to tell if theres an abruption, youd like to see evidence that its been there for a "hile, such as a depression in the placenta filled "ith blood "here the clot is. It could interfere "ith o%ygenation of the placenta. The placenta has 7uite a bit or reserve capacity, so small areas "here o%ygenation is compromised is probably ok. -aternal &T0 or trauma can cause abruption. Infarcts in the placenta may be due to impaired maternal blood supply. ,hen theres infarct, you see villi that are all collapsed together. Dou also see a loss of nuclear staining in areas of infarct. ( )ouvelaire uterus is one "ith e%tensive abruption of the placenta and there may be dissection of blood into the myometrium. It usually re7uires hysterectomy. If you look a placenta, you may see a piece of placenta lateral to the reflection of the membranes, "hich is called e%trachorial placenta. )ircummarginate placentas arent associated "ith fetal!maternal mortality, and it sho"s the amnion connected to the chorion, but the chorion +ust e%tends an e%tra distance beyond the e%tent of the amnion. )ircumvallate placentas (more separation) are "here the amnion and chorion have separated in areas "here they both overlap, and theyre separated so much that the un$overlapped parts have folded over themselves. The space "here the amnion and chorion should be touching is filled "ith fibrin. )ircumvallate placentas are associated "ith increased fetal and maternal mortality. This is related to maternal &T0, diabetes, and trauma. -ultiple gestationC T"ins may be fraternal (from t"o separate ova) or identical (from one ovum that has split). The highest incidence of t"inning in the "orld is in a tribe in 0igeria (Dorba). 1nly mono*ygous t"ins can have a mono$chorionic placenta. They usually have separate amniotic cavities, but can rarely share an amniotic membrane. ,hen this happens, theres a high incidence of mortality due to cords getting intert"ined, etc. ,hen the ovum splits before implantation, you can get either t"o separate placenta or a fused placenta. The tough part is distinguishing a fused placenta from a mono$chorionic placenta. Dou can identify the fused one by the presence of a ridge bet"een the t"o separate placentas that have merged together, and the ridge is still present if you strip all of the membranes off. ( monochorionic placenta "ont sho" any ridge once the membranes are taken off, since all that remains is a single chorion. -onochorionic placentas also have vascular anastomoses, "hich are absent in di$chornionic placentas.

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-ono*ygous t"ins can have any kind of placenta. Bi*ygous t"ins can only have t"o separate placentas, or a fused placenta (that still has 6 chorionic membranes and t"o of everything) depending on "hether the ovum splits early or late. Iellimentous insertion of the cord is common "ith multiple gestations. If mono*ygotic t"ins have their ovum split very early, you can get 6 separate placentas. If they split later, you may get a monochorionic placenta. (nd if much later (after the 29th day) you can get con+oined t"ins. The same ideas apply to triplets, etc. -onochorionic placentas have anastomoses, and theres almost al"ays an imbalanced blood flo" bet"een the t"o kids. o very often, one is larger than the other. These are termed ?t"in$t"in transfusions. Dou cant see these anastomoses, but it occurs in smaller vessels. Dou can even get one fetus develop "ithout a heart, but it gro"s at least a little bit due to blood supply from the other (acardiac t"in). If one t"in dies, it may become almost mummified into a ?fetus papyracius because its flattened like papyrus. Its not uncommon to find loose knots in the cord. Tight ones can obstruct flo" in the cord, and may "arrant inspection for thrombi, etc. -ost knots are not significant. 0ormally there are t"o arteries and a vein in the cord. ometimes there are +ust t"o vessels. If you see it, e%amine the baby for abnormalities, because its often associated "ith severe congenital abnormalities. If they have one, its usually pretty apparent. The placenta may give clues about fetal life. ( patient "ith &T0 sho"s fibrinoid necrosis (decidual vasculopathy) in decidual arteries of the placenta. In patients "ith severe preeclampsia, it may be due to a failure of trophoblast cells to invade the placenta and dilate the uterine arteries, so the placenta gets hypo%emic. (mniotic fluid 826 "eeks is produced by transudation through the amnion. 1ver 26 "eeks its generated by the fetal kidneys. #olyhydramnios is too much fluid (something interferes "ith fetal s"allo"ing). 1ligohydramnios is too little fluid (failure of production of fluid in fetal kidneys). (mnion nodosum is the precipitation of particulates in the amniotic fluid onto the amnion!surface of placenta. 0ear the insertion of the umbilical cord, you may see s7uamous metaplasia. Its of no clinical significance. Dou may see trophoblastic inclusion in the villi. Its likely an artifact of slide preparation, but may be due to a genetic abnormality like trisomy. (mniotic bands may shred off of the surface of the placenta. They may "rap around the baby and cause lots of problems. (mniotic bands are not likely to recur in subse7uent pregnancies. -econium is ingested s7uamous cells, mucous, bile, etc. ,hen the baby is stressed in utero, its often passed. This can be inhaled!aspirated, "hich is not good. It can be recogni*ed grossly as green and slimy. &istologically, if its been there for a "hile it can get into macrophages and you can see the pigment from the bile in the macrophages. It takes 5$26 hours for the pigment to get there. )horoamnionitis is an inflammation of the placenta. In this case, the placenta is opa7ue and bro"n and correlates "ith cellular infiltration. The layers of the placenta are the amnion (nearest the baby), chroion, and chorionic plate. )horoamnionitis is usually due to an ascending infection from the mothers vagina. The first #-0s that appear in the placenta are

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maternal, and first appear in the chorionic plate (nearer the mother). #-0s then progress into the chorion and amnion. Then, the baby starts to participate, and youll see inflammation on the placental surface and umbilical cord. Its important to 7uantify the e%tent of inflammation and if theres fetal participation in the inflammatory response. )hronic amnionitis is lymphocytes and plasma cells in the villi, not the placenta. Its most often of unkno"n etiology. =ut, "hen etiology is found, its often in the T1R)& family (To%oplasmosis, 1ther Rsyphilis, varicella$*oster, parvovirus =2<S, Rubella, )-I, and &erpes infections). )hronic villitis may sho" calcifications. If its )-I, it may have inclusions. (cute villitis is rare, and usually associated "ith listeria. Its associated "ith some cheese from Nalisco, -%. Identifiable causes of intra$uterine gro"th problems include intrauterine infections, chromosomal abnormalities, ingested teratogens, fetal structural abnormalities, and maternal medical complications.

Breast !ancer: 0ormal anatomy and developmentC The breast includes the nipple, large e%cretory ducts, and the terminal duct lobular units. The breast is a mi%ture of stroma "ith fatty (more in older "omen) and fibrous tissue (more in younger "omen). The nipple has large e%cretory ducts that carry milk out to"ard the areola. Dou see skin and large ducts. There are some pink areas of smooth muscle around the ducts that help "ith milk e%cretion. 0ormal large ducts of the breast are large caliber ducts "ith )T around it. The terminal duct lobular units arent present in males, and are only present in females after puberty. They are hormonally responsive. They proliferate and undergo apoptosis "ith the menstrual cycle. This is "here milk is produced. =ecause the epithelium proliferates and regresses, its likely "here cancers arise. o Dou can see the bigger intralobular ducts and terminal ducts!acini. =ut they function the same "ay, so its all called the terminal duct lobular unit. It has speciali*ed stroma (speciali*ed fibrous tissue) that gives rise to fibroadenomas. &istologically you see clusters of acini around a main stem. In a resting (non$pregnant) breast, you may see minor secretions in some terminal ducts. o In a lactating breast, this all changes. @obular units "ill e%pand and undergo hyperplasia!hypertrophy. They are dilated and full of secretions in the lumen "ith vacuoles in the cells. o The epithelium of the breast includes t"o cell typesC a secretory cell and myoepithelial cells. =oth of these are on the basement membrane. These are distinguishable on &T.. 1uter, pale cells are myoepithelial cells. If you cant see them, you can sho" them "ith an actin stain. They contract and push out secretions. (ll breast proliferations e%cept for invasive carcinoma have both secretory and myoepithelial cells in them. The absence of myoepithelial cells is diagnostic of invasive cancer. Inflammatory diseaseC o (cute mastitis usually occurs in a nursing mother "ith fever and a breast mass. It may be due to cracks in the nipple that let bacteria in, then duct obstruction and stasis. Dou see neutrophils infiltrating the breast. Treatment may be treated "ith ab% or even

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+ust a hot pack to increase blood flo". If an abscess forms, that may need to be addressed as "ell. o >at necrosis is often scary, because it forms hard, calcified masses. Its usually due to trauma (often not remembered by patients). #athologically, you see hemorrhage and #-0s early, then macrophages, fibrosis, and calcification later. Dou may see fat cells surrounded by scarring and sometimes multinucleated giant cells. The negatively charged fatty acids may calcify. =enign neoplasmsC o Intraductal papillomas involve the large e%cretory ducts. It usually presents as a mass belo" the nipple or bloody nipple discharge. #athology sho"s large e%cretory ducts, and a papillary lesion (fibrovascular stalks lined by both myoepithelial cells and benign secretory cells). The duct is often markedly dilated. ,ithin it is a papillary proliferation. These may secrete fluid that may be discharged from the nipple. #apillae may t"ist and undergo necrosis, leading to bloody nipple discharge. Its benign, and a minimal risk of cancer. The treatment is to remove it and do the usual follo"$up. o >ibroadenoma is the most common benign neoplasm of the breast. It most often form sin young "omen, but forms a firm, mo&ea#le, rounded mass in the breast. Its usually "ell circumscribed "ith a "horled cut surface. Its a biphasic lesion. Its a neoplasm of the intralobular stroma that induces proliferation of the epithelium. There are little slits!holes in it "ith epithelium. 1n microscopy, its e%aggeration of the intralobular stroma. Dou see more stroma, and its neoplastic but benign (fe" mitoses, little atypical, benign epithelium). These have little risk of carcinoma. Treatment is "ith e%cision (if symptomatic) or +ust "atch it, and +ust the usual follo"$up. =enign fibrocystic changesC 6!4 of "omen over 69 in the K have this. Its the most common cause of a breast mass in the K (. It presents as a firm area, there may be painful areas due to cysts, and the epithelium may calcify. &istologically, you see fibrosis and cystic changes (these cause most of the symptoms) and usual ductal hyperplasia (benign proliferation associated "ith a small increase in risk of breast cancer). 'rossly, you see fibrotic changes and cysts "ith fluid (may look blue, but often have clear fluid). >ibrosis distorts the lobular unit of the breast and may cause dilatation of terminal ducts to form cysts. (ll of the cystic structures are rounded and non$infiltrative. (t high po"er, you can see that some cysts have normal lobular epithelium, and others may sho" apocrine epithelium (pink, granular cytoplasm "ith little ?snouts on the apical surface). This is metaplasia, "hich is +ust change to another type of benign epithelium (here, apocrine metaplasia). These patients have a slightly increased risk of carcinoma, but are +ust treated "ith usual follo"$up. o Intraductal epithelial hyperplasia (same as usual ductal hyperplasia)C This is a benign increase in cell number that leads to an increase in the number of cell layers in some of these glands. The big 7uestion is "hether its hyperplasia or carcinoma in situ distinguishing them is tough. 1verall, the glands and cysts are all rounded. ome sho" more than t"o cells layers (hyperplasia). -itoses, atypical, necrosis, and rounded spaces in the glands "ould be more typical of carcinoma. )arcinoma in situC This is carcinoma cells confined to the lobule units and ducts. They are surrounded by intact myoepithelial cells and basement membrane and cant metastasi*e. There are t"o ma+or typesC Buctal carcinoma in situ (B)I ) and @obular carcinoma in situ (@)I ). They are both derived from the lobular unit and are defined by different

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histopathology, "hich corresponds "ith their clinical behaviors and treatments. =oth impart a 29% increased risk of breast cancer. o B)I C These are mostly detected by mammography as suspicious microcalcifications. It starts in the lobular units, but gro"s into the medium si*ed ducts. It affects local areas of the breast. There are multiple subtypes, includingC #leomorphism and central necrosis (comedo B)I ) and #erfectly round spaces "ithin a duct (cribriform B)I ). )omedo B)I sho"s very malignant$looking secretory cells, and in the middle of a tuft of cells they develop necrosis (calcifies) due to hypo%emia. They look malignant, but are still confined by the basement membrane. )ribriform B)I sho"s pink$looking cells that form really round spaces, and the cells dont have lots of mitoses and are pretty uniform. #agets disease (different from the bone disease) is a crusting and inflammation of the nipple. #athologically, you see B)I cells e%tending up the ma+or ducts to involve the skin of the nipple. It mimics edema. =ut, youll see pleomorphic B)I cells that have gotten into the s7uamous skin at the nipple, and youll also see some inflammation that theyve induced there. This is pretty uncommon. B)I is a direct precursor to invasive cancer (29% increased risk). It can be treated "ith mastecomty, lumptectomy L ad+uvant radiation therapy, and maybe tamo%ifen (blocks estrogen) prophyla%is to prevent recurrence. o @)I is +ust an incidental finding. It doesnt make a mass or calcify. These tend to be multifocal and bilateral. It has small, uniform, discohesive cells. They fill and distend the terminal duct lobular units, they dont form glands or sho" necrosis, and immunostains sho" a loss of .$cadherin. &istologically, you see lobular units "ith too many cells in the lobules due to proliferation. The cells are round!uniform, and some may have mucin in their cytoplasm. To prove "hat it is, do immunohistochemical stain for .$cadherin and itll be more negative than normal tissue. This can help you distinguish it from B)I . This indicates a bilateral risk of breast cancer. ubse7uent cancers are ductal or lobular, and the risk of cancer is increased 29%. Treatment may include observation or bilateral mastectomy (lumpectomy isnt enough here). Tamo%ifen prophyla%is may also be used to block proliferation. (typical proliferative diseaseC This is an incidental finding. #athologically you see eitherC o (typical duct hyperplasia ((B&) "hich sho"s features of both usual duct hyperplasia and B)I in the same duct. o 1r atypical lobular hyperplasia ((@&) "hich sho"s features of @)I but is not sufficiently developed. o .ither of these sho"s /$3% increased risk of carcinoma. (nd, treatment may involve either close follo"$up or tamo%ifen prophyla%is. Invasive =reast )ancerC Tumor cells invade outside of the lobular units into the surrounding stroma, myoepithelial cells are not retained, and these tumor cells have access to the lymphatics and can metastasi*e. o 1ver <<: of cases are in "omen. Its the number 6 cause of cancer death in "omen, ne%t to lung cancer. 2!< of "omen in the K ( "ill develop it.

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o o o

o o

'enetic risk factors include family history (particularly if in young people or bilaterally) and specific gene alterations (=R)(2 has a lifetime risk of J9$<9:, =R)(6, p34). 1ther risk factors are environmental (more common in "estern countries), hormonal (duration of e%posure of epithelium to estrogen), and prior breast pathology (usual duct hyperplasia, aypical hyperplasia, carcinoma in situ), and age (very uncommon under 63). The link bet"een 1)#s and breast cancer is controversial. It presents "ith palpable mass, mammography, or inflammatory breast cancer (usually advanced, "here cells have blocked lymphatics causing edema, redness, s"elling, and has an orange peel appearance). Inflammatory breast cancers "ill be firm and sho" invasive carcinoma cells in the lymphatics, and patients "ith this presentation have systemic metastases and poor prognosis. It can metastasi*e by lymphatics (mostly to a%illary lymph nodes) or hematogenously (bone, brain, lung and liver). 1n pathology, the main type is invasive ductal carcinoma. Theres also invasive lobular carcinoma, but the distinction isnt that important clinically. Invasive ductal carcinoma forms stellate, hard masses that are fi%ed to the surrounding tissue that may be gritty on cut sections due to calcification. There is a prominent stromal fibrosis (desmoplasia) reaction, the tumor cells for ducts to some degree, and in /9: of cases you see B)I (precursor) ad+acent. 1n mammogram, you see a mass "ith a speculated border. Its not very rounded. -icroscopically, it looks irregular, and at high po"er it makes a variable amount of glands. Dou see desmoplastic fibrous response. ome are poorly differentiated and dont form any glands, +ust sheets of cells "ith lots of mitoses. Invasive lobular carcinoma is often less distinct that IB), and its more often bilateral and multicentric. -icroscopically you see an architecture "ith single files of infiltrating cells (Indian filing) and cytology "ith small cells "ith round nuclei (not super malignant looking) and intracytoplasmic mucin (+ust like cells of @)I , may look like signet cells). IB) and I@) have similar prognosis. There are three subtypes of invasive ductal carcinoma that have better prognosesC -edullary carcinomaC These are rare, but grossly look fleshy and circumscribed. -icroscopically they are circumscribed, sho" dense lymphocytic and plasma cell reactions, and have sheets of pleomorphic tumor cells. o cells look really bad, but theyre surrounded by an inflammatory reaction keeping it in check and making the prognosis ok. )olloid carcinomaC This is a slo" gro"ing mass, usually in older "omen. 'rossly, its soft, mucoid and "ell circumscribed. -icroscopically you see bland looking cells floating in lots of mucus. The mucus may keep them a"ay from vessels and prevents metastasis. Tubular carcinomaC These are very small and may be incidentally found. The form small, stellate masses. They are "ell differentiated (lo" grade) and have "ell formed tubules throughout, "ith uniform nuclei. They can be tough to distinguish from benign breast tissue. =ut you see only a single cell layer (no myoepithelial cells) and a desmoplastic response. The main prognositic factor for breast cancer is stage. 1thers include the elston grade (ho" "ell differentiated it is2, 6, or 4), type of tumor, . and # receptors 6/

(presence is a good prognostic factor, and predicts response to tamo%ifensho"n by immunostain for the receptor), and her$6!neu amplification (an oncogene, overe%pression predicts poor prognosis but good response to &erceptin U an anti$&er6 antibody). o tage is the most important thing, "hich is "hy mammography is thought to be good by helping catch them early. Its staged by T (si*e), 0 (node involvement), and (metastases). o Treatment of invasive breast cancer involves local therapy (mastectomy, lumpectomy), a%illary lymph node sampling (a%illary dissection U remove all nodes and usually causes lymphedema, or +ust sentinel node biopsy U sample the first node it drains to) and systemic therapy (tamo%ifen, herceptin, and cytoto%ic chemo).

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