1. Functional EndometrialDisorders (DysfunctionalUterine Bleeding)

*most common gynecological problem during reproductive life = EXCESSIVE BLEEDING during orbetween menstrual periods-most common etiology is DYSFUNCTIONAL UTERINE BLEEDING (DUB) defined as bleeding in theabsence of an organic lesion--> HYPERESTROGENIC STATES are the most common basis for DUB, although other endocrinedisorders or generalized metabolic disturbances can be causal

2. Hyperestrogenic states *Anovulatory cycle-lack of ovulation causes prolonged, excessive estrogen without the counteractive progestational phase-most anovulatory cycles have no obvious explanation and are attributed to subtle hormonal imbalances-DUB associated with menopause may be related to ovarian insufficiency and anovulatory cycles

*Inadequate luteal phase-inadequate CORPUS LUTEUM function --> low progesterone output with early menses and is oftenassociated with infertility

3. Endometritis *Acute endometritis-uncommon-usually caused by BACTERIAL INFECTIONS occurring after delivery or miscarriage and is related toretained products of conception-Curetage and antibiotics are usually sufficient therapy

*Chronic endometritis-can be present with abnormal bleeding, pain, discharge, and/or infertility-Histo: endometrial plasma cell and macrophage infiltration-Occurs in patients with: Chronic PID (Chlamydia most common), Retained gestational tissue post-abortion or postpartum, Intrauterine contraceptive devices, Disseminated TB (rare), 15% have noobvious cause

4. Endometriosis *the presence of endometrial tissues OUTSIDE THE UTERUS-involves (in descending order): ovaries, uterine ligaments, rectovaginal septum, cul de sac, pelvicperitoneum, GI tract, mucosa of the cervix, vagina, fallopian tube, and laparotomy scars-these ectopic foci are under influence of ovarian hormones and therefore undergo cyclic menstrualchanges with periodic bleeding (formation of CHOCOLATE CYSTS), but hey have no means ofsloughing externally like normal endometrial lining-manifests as severe menstrual-related pain-often results in painful intercourse and infertility-menorrhagia*Uterus is NORMAL-SIZED

*Leading theory:-retrograde menstruation through the fallopian tubes allow diffuse seeding of endometrial tissue-in rare cases, the endometrial foci may arise by coelomic epithelial metaplasia-endometriotic tissue differs from normal endometrium by exhibiting marked activation of inflammatorycascades and increased stromal aromatase activity (and thus estrogen production)-overproduction of prostaglandins and estrogen (and relative progesterone resistance) enhances thesurvival and persistence of endometriotic foci

5. Adenomyosis -related disorder characterized by nests of endometrial tissues in the uterine myometrium (middle layer)-these are continuous with the endometrial lining, suggesting that they form by down-growth; 20% ofwomen are affected -the symptomatology is similar to endometriosis*Uterus IS ENLARGED

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6. Morphology ofEndometriosis

*Gross:-manifests as red-blue and yellow-brown mucosal or serosal nodules-extensive disease can be marked by organizing hemorrhage and fibrosis

*Micro:-foci classically exhibit endometrial glands and stroma, with or without hemosiderin

7. Clinicalfeatures

-primarily affects women during their rep. years (10% of women affected), and can present with severe dysmenorrheal(painful menses), pelvic pain, and/or infertility (30-40%)-uncommonly, malignancy can dev. from the foci

8. EndometrialPolyps

-exophytic masses of endometrial glands and stroma that project into the endometrial cavity-they may be associated with elevated estrogens or tamoxifen therapy-these polyps are usually benign and manifest primarily with abnormal bleeding, but they occasionally develop intoadenocarcinoma

9. Endometrialhyperplasia

*defined as INCREASED PROLIFERATION of endometrial glands RELATIVE TO STROMA-an important cause of abnormal uterine bleeding-also clinically important as a precursor lesion in the continuum to endometrial carcinoma-lesions is associated with prolonged estrogen stimulation of the endometrium

*Causes:-range from exogenous estrogen administration to anovulation, obesity, polycystic ovarian disease, and functioningestrogen-producing tumors-often associated with INACTIVATION of the PTEN tumor suppressor gene (20% of cases), leading to enhanced AKTphosphorylation with increased proliferation and diminished apoptosis

10. Morphology *simple hyperplasia without atypia (cystic or mild hyperplasia) exhibits benign cystically dilated glands; these rarelyprogress to adenocarcinoma

*simple hyperplasia with atypia is uncommon; besides cystically-dilated glands, it exhibits cytologic atypia (e.g. loss ofpolarity, prominent nucleoli) and 8% progress to malignancy

*complex hyperplasia without atypia shows closely apposed glands of varying size crowded together into clusters; theepithelium remains cytologically normal and only 3% progress to cancer

*complex hyperplasia with atypia shows gland crowding and cytologic changes; there is substantial overlap withendometrial adenocarcinoma, and 23% to 48% of patients with such changes have concurrent malignancy

11. Carcinoma oftheEndometrium

-accounts for 7% of all invasive cancers in women-peak incidence of 55-65 years

12. Type 1 -the most common (80%)-well differentiated (endometrioid carcinoma)-typically arise in the setting of ENDOMETRIAL HYPERPLASIA (with the same overall risk associations)*PTEN mutations are seen in 30-80% of endometrioid carcinomas; in addition, tumors often exhibitMICROSATELLITE INSTABILITY, as well as mutations involving components of the PI3 kinase complex, and KRASor B-catenin-p53 mutations may be late events

*Morphology-Gross - localized polypoid tumors or diffuse spreading lesions-Micro - most (85%) are endometrioid (resembling endometrial tissues) adenocarcinomas with epithelium resemblingnormal endometrium; grading depends on the mix of well-differentiated glands and more poorly differentiated solidtumor. Foci of squamous differentiation are seen in 20% of cases

13. Type II -typically arise a DECADE LATER than type 1-occur in setting of ENDOMETRIAL ATROPHY-POORLY DIFFERENTIATED tumors-most common subtype is SEROUS CARCINOMA, so-called due to biologic overlaps with similar ovarianlesions; p53 mutations present in at least 90% and appear to be early oncogenic events -Endometrial intraepithelial carcinoma (EIC) without invasion is a precursor to serous carcinoma

*Morphology:-Gross - tumors are usually LARGE and BULKY as DEEPLY INVASIVE-Micro - invasive lesions exhibit a papillary or glandular growth pattern with marked cellular atypia

*Clinical Course:-pts. present with UTERINE BLEEDING or an abnormal Pap smear-prognosis depends largely on disease stage and grade-excellent (90% 5 year) when cancer is confined to uterine corpus and is well differentiated-However, serous tumors have a propensity for extensive extrauterine spread even when apparently confinedto the endometrium

14. Malignant MixedMullerian Tumors(MMMT)

-endometrial adenocarcinomas associated with concurrent malignant stroma changes attributable to acommon neoplastic precursor for both lineages-the stromal component tends to differentiate into a variety of malignant mesodermal components-MMMT are highly malignant-5 year survival rates = b/w 25-30%

*Morphology-Gross - tumors are bulky, fleshy, and polypoid-Micro - lesions consist of malignant glandular and stromal elements; $$ the stromal sarcomatous elements may show muscle, cartilage, and osteoid differentiation

15. Adenosarcomas -estrogen sensitive tumors-exhibit STROMAL NEOPLASIA WITH BENIGN GLANDS-Gross: large, polypoid growths, generally considered LOW-GRADE MALIGNANCIES

16. Stromal tumors *BENIGN STROMAL NODULES - are discrete lumps of stromal neoplasia within the myometrium

*Endometrial stromal sarcomas - lesions composed of malignant stroma interposed b/w myometrial bundles;they are distinguished by diffuse infiltration and/or lymphatic invasion-a recurrent t(7;17) translocation --> formation of a fusion transcript with anti-apoptotic features-five year survival approaches 50%

17. Leiomyomas -myometrial tumors-commonly called FIBROIDS - benign masses of uterine smooth muscle cells**they are the most common tumor in women

-while most have a normal karyotype, some 40% have a balanced t(12;14) translocation, partial deletions ofchromosome 7q, trisomy 12, or rearrangements of 6p, 3q, or 10q

-may be asymptomatic or can present with abnormal uterine bleeding, pain, urinary bladder disorders, andimpaired fertility

**Malignant transformation is extremely rare

18. Morphology *Gross:-tumors are sharply circumscribed, discrete, round, firm, gray-white nodules that occur within themyometrium (intramural), beneath the serosa (subserosal), or immediately beneath the endometrium(submucosal)

*Mico:-lesions show characteristically whorled bundles of relatively uniform smooth muscle cells with rare mitoses-variants can exhibit increased cellularity or atypical, bizarre cells

19. Leiomyosarcomas -uncommon malignancies that form bulky, fleshy masses in the uterine wall or project into the lumen

*Histo:-wide range of atypia; increased numbers of mitoses (5-10 per 10 high power fields), particularly whenaccompanied by cellular atypia and/or necrosis

*these tumors disseminate throughout the abdominal cavity and aggressively metastasize-the overall 5 year is 10-15%

20. Fallopian tubeInflammations

*Suppurative salpingitis - typically a component of PID-gonococcal infections account for 60% of cases, although any of the pyogenic organisms can beinvolved-Chlamydia is less often a factor

*Tuberculous salpingitis -rare in the United States but is an important cause of infertility worldwide

21. Tumors and Cysts offallopian tubes

*most common primary lesions are benign PARATUBAL CYSTS (1-2 mm translucent cysts filled withserous fluid); larger version near the fimbria are called HYDATIDS OF MORGAGNI

*Benign neoplasms include ADENOMATOID TUMORS, comprising small nodules of mesothelial cells

*Primary tubal adenocarcinoma is rare and can be associated with germline BRCA mutations. Even earlystage tumors have a 40% 5 year mortality-prognosis worsen with higher stages

22. Follicle and Luteal Cysts *EXTREMELY COMMON findings-typically multiple and usually less than 2 cm-they are lined by follicular or lutenized cells with a clear, serous fluid-cysts derive from unruptured Graafian follicles, or follicles that have resealed after rupture-while typically asymptomatic, they can rupture with ensuing peritoneal inflammation and pain

23. Polycystic Ovarian Diseaseand StromalHyperthecosis

*PCOD (Stein-Leventhal Syndrome)-affects 3-6% of reproductive-age women-presents with numerous cystic follicles, often with associated oligomenorrhea, persistent anovulation,obesity, hirsuitism, and insulin resistance-disturbances in ANDROGEN BIOSYNTHESIS are causally implicated -deranged steroid synthesis bytheca cells-Increased LH production and decreased FSH; increased estrogen from testosterone aromatization)-ovaries are ENLARGED with CORTICAL FIBROSIS; innumerbale subcortical cysts (i.e. up to 1 cm)exhibit theca interna hyperplasia

*Stromal hyperthecosis-disorder of ovarian stroma typically in POSTMENOPAUSAL WOMEN-reflected by stromal hypercellularity and luteinization visible as discrete nests of cell with vacuolatedcytoplasm-the clinical manifestations are similar to PCOD, although virilization can be profound

24. Ovarian tumors -can arise from the epithelium, germ cells, or sex cord stroma-overall, 80% are benign, and most occur in women aged 20-45 years-malignant tumors typically occur in older women (45-65) and rep. 3% of all female cancers; b/c mostare detected only after spreading beyond the ovary, they account for a dipropotionate number of cancerdeaths

25. Tumors of Surface(Mullerian) Epithelium

cont. below

*Most primary ovarian neoplasms fall into this category*Classification - based on the proliferation and differentiation of the epithelium; greater proliferationgenerally connotes greater malignant potential-most of these tumors ultimately derive from transformed COELOMIC EPITHELIUM-the serous, mucinous, or endometrioid varieties speak to the plasticity of the original cells

26. Seroustumors

-account for 30% of all ovarian tumors-70% are benign or borderline-serous carcinomas are the most common ovarian malignancy (40% of total)-Prognosis is linked to stage and tumor grade-grow slowly if low grade

27. Pathogenesis -nulliparity-gonadal dysgenesis-family hx-hereditable mutations

*BRCA1 and -2 mutations incur a risk of ovarian cancer developing by age 70 years in 20% to 60%; most are high grade

*low grade tumors tend to arise in serous borderline tumors and have KRAS and BRAF mutations; conversely, high gradetumors have a high frequency of p53 mutations-many of these tumors appear to arise from the fimbriated end of the fallopian tube

28. Morphology *Gross:-typically large cystic masses filled with serous fluid; intracystic loculations can occur-Benign cystadenomas have a smooth and glistening inner lining-the cystadeno-carcinomas can have small mural nodularities or papillary projections. Bilaterally is common

*Micro:-Benign lesions are lined by a single layer of tall, columnar, ciliated epithelial cells, occasionally forming microscopicpapillae-Frankly malignant cystadenocarcinomas - have multilayered epithelium with MANY PAPILLARY AREAS and large,solid epithelial masses focally invading stroma-borderline tumors demonstrate mild atypia with complex micropapillary epithelial architecture without invasion

29. Mucinoustumors

-account for 30% of all ovarian neoplasms-80% are benign or borderline-primary mucinous carcinomas amount to less than 5% of all ovarian malignancies

-SMOKING is a risk factor-KRAS mutations are a common feature

-these tumors can seed the peritoneum with numerous implants that produce extensive mucinous ascites, calledPSEUDOMYXOMA PERITONEI-5 year for stage 1 are more than 90%

30. Morphology *Gross:-tumors tend to produce large multiloculated cystic masses filled with sticky, gelatinous fluid, less than 10% are bilateral

*Micro:-benign lesions are lined by tall, columnar non-ciliated epithelium with apical mucin akin to benign cervical orintestinal epithelium; Mullerian mucinous tumors are associated with endometriosis and have cells resembling cervicalor endometrial epithelium-Cystadenocarcinomas usually exhibit intestinal-type epithelium and display solid tumor growth, necrosis, and stromalinvasion-Borderline mucinous tumors exhibit complex growth analagous to serous tumors but lack solid growth or stromalinfiltration

31. Endometrioid Tumors -account for 20% of all ovarian cancers-they exhibit epithelium resembling benign or malignant endometrium-about 15-20% of cases occur in the setting of concurrent endometriosis, although direct origin from theovarian surface is possible-in 15-30% of cases, independent endometrial carcinomas also occur-PTEN, KRAS, and B-catenin mutations occur frequently, as well as microsatellite instability-p53 mutations are common in poorly differentiated tumors-5 year, stage 1 is 75%

*Morphology-Gross: lesions are a combination of solid and cystic masses; 40% are bilateral-Micro: the glandular pattern bear a strong resemblance to endometrial adenocarcinoma

32. Clear celladenocarcinoma

-uncommon-considered a variant of endometrial adenocarcinoma-tumors can be cystic or solid; the large epithelial cells contain abundant clear cytoplasms-patients with cancer confined to the ovary have a 5 year survivals of 65%-with extra ovarian spread, 5 year is unusual

33. Brenner tumor (B's)

(end)

-variably sized (1-30 cm)-solid tumor (adenofibroma) characterized by dense fibrous stroma and nests of epithelium resemblingurinary transitional or rarely columnar epithelium (looks like Bladder)-pale yellow-tan color and appears encapsulated-they are usually unilateral; the vast majority of these tumors are Benign

34. Clinical Course,Detection, andPrevention of SurfaceEpithelial Tumors

*these tumors tend to have similar mainfestations:-lower ab pain and enlargement, with symptoms secondary to bowel or bladder compression-Benign lesions are readily resected-malignant lesions are associated with progressive cachexia, and dissemination beyond the capsule cancause massive ascites and/or diffuse peritoneal studding-most patients are diagnosed only after the tumor has become large or disseminated -->overall poor suvival

*CA-125 (a high molecular weight glycoprotein marker of ovarian cancer) is present in the serum of morethan 80% of patients with serous or endometrial carcinomas. However, it is more useful as a tool inmonitoring disease progression than in primary diagnosis since non-specific peritoneal inflammation alsoincreases the serum levels-elevated OSTEOPONTIN levels may allow earlier ovarian cancer detection

*Fallopian tubal ligation and oral contraceptive use reduce the risk of dev. ovarian malignancy

35. Germ cell tumors(start)

-rep. 15-20% of all ovarian tumors-most tumors are BENIGN CYSTIC TERATOMAS-they are similar to male germ cell tumors and arise from neoplastic transformation of totipotential germ cellscapable of differentiating into the three germ cell layers

36. Teratomas *Mature (benign) teratomas typically arise in YOUNG WOMEN during their active rep. years-the karyotype of virtually all benign teratomas is 46XX, and they likely ARISE FROM AN OVUM after the firstmeiotic division-mature teratomas are characteristically CYSTIC MASSES lined by squamous epithelium with adnexal structuresincluding hair shafts and sebaceous glands; tooth structures and tissues from other germ layers can often also beidentified-tumors are BILATERAL in 10-15% of cases-the vast majority of such tumors are cured by excision-1% undergo malignant transformation, most commonly as squamous cell carcinoma

*Monodermal or specialized teratomas-differentiate along the line of a single abnormal tissue-the most common is STRUMA OVARII, composed entirely of mature thyroid tissue; ovarian carcinoid is anothervariant

*Immature (malignant) teratomas-rare tumors composed of embryonic (rather than adult) elements resembling immature fetal tissues-these occur chiefly in adolescents and young women-although they grow rapidly and frequently penetrate the capsule, low-grade tumors have an excellent prognosis,and even high-grade malignancies can respond well to chemotherapy

37. Dysgerminoma -ovarian counterpart of testicular seminoma-account for 2% of all ovarian cancers but about half of the malignant germ cell tumors-most occur b/w ages 20 and 40 years, and most have no endocrine function*Oct3, Oct4, and Nanog transcription factor expression dygerminomas maintain pluripotency-the tumors also express the c-KIT receptor tyrosine kinase-All dysgerminomas are MALIGNANT, but only about one third are highly aggressive; **b/c they are CHEMOSENSITIVE, overall survival exceeds 80%-associated with Turner Syndrome

*Markers:-hCG-LDH

38. Morphology *Gross:-tumors are solid, yellow-white to gray-pink, and fleshy; 80% to 90% are unilateral

*Micro:-lesions consist of sheets ad cords of large vesicular cells separated by scant fibrous stroma

39. EndodermalSinus (Yolk sac)tumor

-rare malignancy resulting from differentiation of germ cells TOWARD YOLK SAC STRUCTURES-HISTO: there are GLOMERULUS-LIKE structures with a central vessel enveloped by germ cells within a cysticspace lined by additional germ cells (Schiller-Duvall body)-Intracellular and extracellular hyaline droplets are conspicuous and can contain a-fetoprotein (AFP)-the tumors occur in children and young women and grow aggressively, although they are CHEMORESPONSIVE

40. Choriocarcinoma -another example of extra-embryonic differentiation of malignant germ cells; -most such tumors exist in combination with other germ cell tumors*HISTO: they are identical to placental malignancies and elaborate chorionic gonadotropins -early hematogenous spread to lungs-can dev. during preg. in mother or baby-malignancy of trophoblastic tissue*Chorionic villi ARE NOT PRESENT-hCG is marker-Ovarian choriocarcinomas are HIGHLY MALIGNANT, metastasize widely, and are much more resistant tochemotherapy than their placental counterparts

41. Sex Cord-StromalTumors (start)

-originate from OVARIAN STROMA, which, in turn, derives from the sex cords of the embryonic gonad-the tumors frequently produce estrogen or androgens

42. Granulosa-Thecacell tumors

-constitute 5% of all ovarian tumors-composed of various combinations of theca and granulosa cells-2/3 occur in postmenopausal women

*INHIBIN produced by granulosa cells can be a useful biomarker to diagnose and monitor tumors-these tumors can elaborate large amounts of ESTROGEN and thus produce PRECOCIOUS SEXUAL DEV. andENDOMETRIAL HYPERPLASIA (predispose to endometrial carcinoma)-occasionally, granulosa cell tumors produce masculinizing androgens

*while 5-25% of granulosa cell tumors are malignant, most have an indolent course, with 10 year survival rates of85%. Pure thecomas are virtually always benign

43. Morphology *Gross:-tumors are usually unilateral, solid, and white-yellow

*Micro:-granulosa cell component consists of small cuboidal-to-polygonal cells growing in cords, sheets, or strands-there can be occasional gland-like structures with acidophilic material (Call-Exner body = small follicle filledwith eosinophilic secretions). The thecal cell components are composed of sheets of plump spindle cells oftencontaining lipid droplets

44. Fibromas,Thecomas, andFibrothecomas

-account for 4% of all ovarian neoplasms-vast majority of these are benign-they are usually UNILATERAL, solid, hard, gray-white masses-the fibrous component is composed of well-differentiated fibroblasts and scant collagenous CT-the thecoma portion contains plump spindle cells with lipid droplets

*Curiously: 40% of all tumors are associated with ascites and occasionally right -sided hydrothorax (Meigssyndrome)-they can also be associated with basal cell nevus syndrome

45. Sertoli-Leydig CellTumors

*androblastomas-recapitulate the cells of the testis and commonly produce masculinization or defeminization-they are usually unilateral and consist of tubules composed of Sertoli cells and/or leydig cells interspresed withstroma

46. Metastatic tumors -most commonly derive from tumors of mullerian origin (e.g. uterus, fallopian tube, contralateral ovary, or pelvicperitoneum)-the sources of the most common extra-mullerian metastases are carcinomas of the breast and GI tract*KRUKENBERG TUMORS -ovarian cancers (often bilateral) caused by metastatic mucin-producing signet cells,usually originating from the stomach

47. Spontaneousabortion

"miscarriage"-preg. loss before 20 weeks gestation; -10-15% of clinically recognized pregnancies (and a sig. number of unrecognized pregnancies) terminatespontaneously

*Causes:-Maternal (e.g. diabetes, luteal-phase defects, and other endocrine disorders)-Fetal, with 50% having chromosomal abnormalities, and additional numbers having with more subtle geneticdefects-Uterine defects (e.g. leiomyomas, polyps, or malformations-systemic disorders affecting the maternal vasculature-Infections-Idiopathic

48. EctopicPregnancy

-denotes embryo implantation at a site other than the uterus, often in the fallopian tubes (90%) but also in the ovaryor abdominal cavity-occurs in 1 of 150 pregnancies

*Predisposing factors:-PID with scarring-intrauterine devices (2.5-fold increased risk)-peritubal adhesions related to endometriosis or prior surgery-50% occur is apparently normal tubes

49. Clinical features(4 outcomes)

1) Intratubal hemorrhage with the formation of HEMATOSALPINX

2) Tubal rupture with intraperitoneal hemorrhage*MEDICAL EMERGENCY characterized by acute abdomen and shock;

3) spontaneous regression with resorption of the products of conception

4) Extrusion into the abdominal cavity (tubal abortion)

$$ DIAGNOSIS is suggested by HIGH hCG levels, ultrasonographic findings, and an endometrial biopsy showingdecidual (the thick layer of modified mucous membrane that lines the uterus during pregnancy and is shed with theafterbirth.) changes and absent chorionic villi

50. Twin Placentas -arise from fertilizations of TWO OVA or division of one fertilized ovum (i.e. monozygotic)-->the resulting placentas can be mono- or dichorionic-a single chorion indicates monozygotic twins, and depending on the time of splitting these can be mono- ordiamniotic-Dichorionic placentas are always diamniotic and can occur with either mono- or dizygotic twins

*In MONOCHORIONIC TWINS PREGNANCIES - vascular anastomoses can allow sharing of the fetal circulations-TWIN-TWIN TRANSFUSION SYNDROME occurs if imbalanced flow occurs through an arteriovenous shunt;subsequent disparities in blood volume can lead to death of one or both fetuses

51. Abnormalitiesof PlacentalImplantation

*Placenta Previa-denotes placental implantation in the LOWER UTERINE SEGMENT OR CERVIX and is associated with severe 3rdtrimester bleeding-complete coverage of the cervical os requires a cesarean delivery to avert the placental rupture and maternalexsanguination of a vaginal delivery

*Placenta accreta-occurs when there is absence of decidua and the PLACENTA ADHERES DIRECTLY TO THE MYOMETRIUM; atdelivery, the placenta fails to separate, and there is potentially life-threatening hemorrhage

52. PlacentalInfections

*Ascending (usually bacterial) infections via the birth canal are most common-these can cause infection of the chorionic membranes (acute chorioamnionitis) that then produces prematuremembrane rupture and preterm delivery-inflammation involves the chorion-amnion and fetal umbilical and chorionic plate vessels

*Hematogenous infections-can result from a MATERNAL SEPTICEMIA, including listerial, streptococcal, and TORCH (i.e. toxoplasma,rubella, syphillis, CMV, herpes) organisms. These are characterized by villous chorionic inflammation (villitis)

53. Preeclampsia **Syndrome characterized by (3):-hypertension-proteinuria-edema

-occurs in 3-5% of pregnancies, usually in the 3rd trimester

*ECLAMPSIA-more severe form associated with SEIZURES and COMApatients also present with hypercoagulability, renal failure, and pulmonary edema-10% develop HELLP (Hemolysis, Elevated Liver enzymes, Low Platelet count)

54. Pathogenesis 1) Abnormal placental vasculature - an underlying precursor lesion-in normal preg., fetal trophoblast cells convert the maternal high-resistance decidual spiral arteries into highcapacitance uteroplacental vessels lacking a smooth muscle coat$$ In preeclampsia - THIS DOES NOT OCCUR and the placenta cannot meet perfusion demands of late preg.

2) Ischemic placenta releases anti-angiogenic factors (i.e. sFlt-1 and ENDOGLIN) that reduce placentalvascular dev.

3) these placental factors also enter maternal circulation and disrupt her endothelial function --> SYMPTOMS

55. Morphology -placenta exhibits numerous small, peripheral infarcts (with accelerated villous maturation indicative ofchronic ischemia), and retroplacental hematomas)

56. Clinical Features -usually occurs after 34 weeks gestation-onset is typically INSIDIOUS*DELIVERY is the only definitive treatment, but mild pre-term disease can be managed conservatively withmonitoring and bedrest-in severe disease, anti-hypertensive therapy does not affect the course or outcome

57. GestationalTrophoblasticDisease

-start

58. Hydatiform Mole -cystic swelling of chorionic villi, accompanied by variable trophoblastic proliferation-these can be precursors of choriocarcinoma*RISK of mole is highest at either extreme of the reproductive years-U.S. incidence = 1 per every 1,000 to 2,000 pregnancies

*BENIGN NONINVASIVE MOLES are classified as COMPLETE or PARTIAL, based by histologic, cytogenic,and flow cytometric studies

1) Complete Mole-occurs when an egg that has lost its chromosomes is fertilized by 1 or 2 sperm-all genetic material is therefore paternally derived -about 90% of complete moles derive from the duplicated genetic material of one sperm and are 46, XX; theremainder derive from 2 sperm and are 46, XX or 46, XY*there is a 2.5% risk of choriocarcinoma

2) Partial Mole-occurs when an egg with normal chromosomal content is fertilized by two sperms to get a triploid complementof genetic material-the karyotype is 69, XXX or 69, XXY, or 69XYY-there is NO increased risk of choriocarcinoma

59. Morphology *Gross:-moles consist of masses of thin-walled, translucent, cystic, grapelike structures. -Fetal parts are rarely seen in complete moles and are more common in partial moles

*Micro:-complete moles show hydropic swelling of villi, inadequate vascularization of villi, and significanttrophoblastic proliferation-partial moles show only focal edema and focal and slight trophoblastic proliferation

60. Clinical features -moles can be diagnosed by ULTRASOUND EXAM and by serum hCG, revealing levels exceedingthose produced by a normal pregnancy of similar age-thorough CURETTAGE is adequate therapy for most moles, although 10% develop into invasivemoles; 2.5% develop into CHORIOCARCINOMA-follow up hcG determinations canID those at risk

61. Invasive moles -penetrates and may even perforate the uterine wall-associated with proliferating cytotrophoblasts and synctiotrophoblasts-villi can embolize to distant sites but do not grow*invasive moles are associated with persistently elevated hCG-the tumor RESPONDS WELL to chemotherapy but can result in uterine rupture

62. Choriocarcinoma -a MALIGNANT TUMOR arising in 1:20,000 to 1:30,000 pregnancies in the United States-half arise in hydatiform moles-25% in previous abortions-22% in normal pregnancies-the rest in ectopic pregnancies

*Morphology:-Gross: tumors are large, soft, yellow-white, fleshy masses with areas of necrosis and hemorrhage-Micro: lesions consist of mixed cytotrophoblastic proliferations-tumor invades the underlying endometrium, penetrates blood vessels and lymphatics, and canmetastasize widely

*Clinical features-vaginal bleeding and discharge that can appear in the course of an apparently normal pregnancy,after a miscarriage, or after curettage-hCG titers are elevated to levels ABOVE THOSE SEEN IN HYDATIFORM MOLE-commonly widespread metastases are already present at time of initial discovery-Gestational choriocarcinomas are highly sensitive to chemotherapy, with 100% remission rates andhigh cure rates

63. Placental-site trophoblastictumors (PSTT)

-comprises less than 2% of gestational trophoblastic tumors -rep. neoplastic proliferations of extravillous (intermediate) trophoblasts-the lesion differs from choriocarcinoma because synctio- and cytotrophoblastic elements are absentand the tumors make lower levels of hCG-most are only locally invasive, but 10% to 15% result in metastases and death