Pathology of

Female Genital System And Breast

2008

Contents:

Pathology of

Vulva Vagina Cervix Body of Uterus Fallopian Tubes Ovaries Diseases of Pregnancy Breast

VULVA
Diseases of vulva: Vulvitis (more common but not serious). Non-Neoplastic epithelial disorders. Carcinomas (uncommon but life threatening). Painful bartholin cysts (caused by obstruction of the excretory ducts of the glands). Imperforate hymen in children. Impeding secretions and menstrual flow later in life.

Vulvitis
Most important forms of vulvitis related to sexually transmitted disease: HPV: produce condylomata acuminata and vulvar intraepithelial neoplasia. Herpes genitalis (HSV1 or 2): causing vesicular eruption. Gonococcal suppurative infection Syphilis: produce primary chancre at site of inoculation. Candidal vulvitis.

Vulvitis
Contact dermatitis: the most dommon causes of vulvar pruritus is a reactive inflammation to an exogenous stimulus, whether an irritant or an allergen. Contact irritant dermatitis: presents as welldefined erythematous weeping and crusting papules and plaques. May be a reaction to urine, sops, detergents, antiseptics, or alcohol. Contact allergic dermatitis: has similar gross appearance and may result from allergy to perfumes and other additives in creams, lotions, and soaps, chemical treatments on clothing and other antigens.

Non-Neoplasic epithelial disorders

The epithelium of vulvar mucosa may undergo atrophic thinning or hyperplastic thickening There are two forms of non-neoplastic epithelial disorders: lichen sclerosus and lichen simplex chronicus. Both may coexist in different areas in the same person, and both may appear macroscopically as depigmented white lesions, referred to as leukoplakia.

Non-Neoplastic epithelial disorders

Lichen Sclerosus: Characterized by atrophic epithelium, usually with dermal fibrosis. Pathogenesis is uncertain, autoimmune reaction may involved Carries an increased risk of developing squamous cell carcinoma. Lichen Simplex Chronicus End reaction of many inflammatory dermatoses, marked by epithelial thickening, expansion of stratum granulosum and surface hyperkeratosis. Generally, there is no inrecased predisposition to cancer, but suspiciously, lichen simplex chronicus is often present at margins of established cancer of the vulva.

Non-Neoplastic epithelial disorders

Lichen Sclerosus Lichen simplex chronicus

Lichen Planus Its benign dermatoses

Tumors
Condylomas and low-grade vulvar intraepithelial Neoplasian (VIN) Condylomas fall into two distinctive biologic forms: - Condylomata lata: (not commonly seen today), are flat, moist, minimally elevated lesions that occur in secondary syphilis - Condylomata accuminata: (more common) may be papillary and distinctly elevated. They occur anywhere on the anogenital surface. Significant characteristic cellular morphology is: perinuclear cytoplasim vacuolization. Vulvar cndylomas are not pre-cancerous but coexist with foci of intraepithelial neoplasia in vulva (VIN grade 1) and cervix.

Condylomas

Giant condyloma accuminata

A vulva chancre and condylomata

Tumors

(continued )

High-grade vulvar intraepithelial neoplasia and carcinoma of the vuvla - Carinoma of vulva represent about 3% of all genital tract cancers in women. - 90% of vulvar carcinomas are squamous cell carcinomas; and 90% of them are HPV related, and most common seen in relatively younger patients. - Non-HPV-related vulvar squamous cell carcinoma occorus in older women; It is well differentiated and unifocal, and is associated with lichen sclerosus or other inflammatory conditions.

Extramammary Paget Disease

Like that of breast, is essentially a form of intraepithelial carcinoma. Unlike breast, vulvar Paget disease have no demonstrable underlying carcinoma. Microscopically, red, scaly plaque; characterized by spread of malignant cells within the epithelium, occasionally with invasion of underlying dermis

Review Questions
1. A 62 year old woman presented with stenosis (narrowing) of her introitus and symmetrical atrophic changes of the labia. A biopsy showed thinning of the epidermis with replacement of the underlying dermis by dense connective tissue. These findings are most consistent with: Moderate dysplasia (VIN II) Squamous hyperplasia Condyloma acuminatum Verrucous carcinoma Lichen sclerosis 2. A 75-year old woman presents with a pruritic vulvar lesion. Physical examination reveals an irregular white, rough area involving her vulva. If this leukoplakia is due to lichen sclerosis, then biopsies will most likely reveal Atrophy of epidermis with dermal fibrosis Epidermal atypia with dysplasia Epithelial hyperplasia and hyperkeratosis Individual malignant cells invading the epidermis Loss of epidermis pigment

A. B. C. D. E.

A. B. C. D. E.

VAGINA
The vagina is seldom the site of primary disease; more often it is secondarily involved in the spread of cancer or infection arising in cervix, vulva, bladder, or rectum. The only primary disorders discussed here are a few congenital anomalies, vaginitis, and primary tumors. Congenital anomalies are uncommon and include entities such as total absence of vagina, a separate or double vagina, and congenital small lateral Gartner duct cysts arising from persistent embryonic remnants.

Vaginitis
Relatively common clinical problem that is usually transient and not serious. A large variety of organisms are implicated; in adults, primary gonorrheal infection of the vagina is uncommon; However, it may occur in newborn born to infected mothers. The frequent organisms are Candida Albicans and Trichomonas vaginalis. Candidal vaginitis produces a curdy white discharge, it is present in about 5% of normal adults, and so the appearance of symptomatic infection always involves predisposing influences or sexual transmission of new aggressive strains.

Vaginitis

(continued)

T. vaginalis produces a watery, copious green discharge, in which parasite can be identified microscopically. However, T. vaginalis can also be identified in 10% of asymptomatic women, and so symptomatic infection usually represent a sexually transmitted new strain. Nonspecific atrophic vaginitis may be encountered in postmenopausal women with preexisting atrophy and thinning of the squamous vaginal mucosa.

Vaginal intraepithelial neoplaisa and squamous cell carcinoma

Extremely uncommon, usually occur in women older than age 60 years. Risk factors are similar to those for carcinoma of the cervix (discussed later). Associated with HPV infection in most cases. Vaginal clear cell adenocarcinoma, usually encountered in young women in their late teens whose mothers took diethylstilbestrol during pregnancy; overall risk is 1 per 1000 of those exposed in utero. Vaginal adenosis, are small glandular or microcystic inclusions appear in vaginal mucosa, appear as red glandular foci lined by mucus-secreting cell; from such inclusions rare clear cell adenocarciona arises.

Review Questions
3. The most frequent malignancy of the vagina is: A. Embryonal rhabdomyosarcoma B. Clear cell adenocarcinoma C. Vaginal adenosis D. Sarcoma botryoides E. Squamous cell carcinoma 4. Vaginal adenosis is most likely to precede the development of A. Condyloma acuminatum B. Cervical carcinoma C. Clear cell carcinoma D. Carcinoma of the endometrium E. Squamous carcinoma of the vagian

CERVIX
Cervix is often the seat of disease. Fortunately, most cervical lesions are relatively banal inflammation But cervix is also the site of the most common cancers in women; squamous cell carcinoma.

Cervicitis
At birth, the columnar mucus-secreting epithelium of the endocervix meets the sqamous epithelial covering of the exocervix at the external os; not visible by naked eye. In young women, squmocolumnar junction comes to lie visibly on the exocervix (condition called extropion). In adult, regeneration of both squamous and columnar epithelium in region known as the transformation zone. Frequently, overgrowth of these epithelium blocks the orifices of endocervical glands in the transformation zone to produce small nabothian cysts.

Cervicitis

(contiued )

Inflammation of the cervix are extremely common, and are associated with purulent vaginal discharge. These inflammation can be infectious or noninfectious cervicitis. Microorganisms often present are indigenous, incidental vaginal aerobes and anaerobes, streptococci, staphylococci, enterococci, Escherichia coli, Chlamydia trachomatis, Ureplasma urelyticum, T. vaginlais, Candida spp., Neisseria gonorrheae, herpes simplex genitalis, and HPV. Many of these organisms are transmitted sexually, so cervicitis may represent sexually transmitted disease. Among these organisms, C. trachomatis represent 40% of cases of cervicitis encountered in sexually transmitted disease clinics.

Tumors of the cervix

Cervical carcinoma is one of the major causes of cancer-related deaths in women, despite improvements in early diagnosis and treatment. Since introduction of the Papanicolaou (Pap) smear 50 years ago, the incidence of cervical cancer has plummeted. The pap smear remains the most successful cancer screening test ever developed. Over the same period, the incidence precursor cervical intraepithelial neoplasia (CIN) has increased to more than 50,000 cases annually. It is important to know that nearly all invasive cervical squamous cell carcinoma arise from epithelial changes CIN.

Cervical intraepithelial Neoplasia

Cytologic examination can detect epithelial changes (CIN) before the development of an overt cancer by many years. However, only a fraction of cases of CIN progress to invasive carcinoma. The peak incidence of CIN is about 30 years, whereas that of invasive carcinoma is about 45 years. Risk factors for the development of CIN and invasive carcinoma are: -Early age at first intercourse -Multiple sexual partners -Male partner with multiple previous sexual partners -persistent infection by High-risk HPV They point to the likelihood of sexual transmission of a causative agent, in this case HPV.

Cervical intraepithelial Neoplasia

Normal squamous epithelium of the cervix. There is weak positive cytoplasmic staining

Left, normal epithelium. Right, CIN2/3 Strongly positive staining nuclie

HPV

(additional information)

High-risk HPV types: 16, 18, 45, and 31, account for the majority of carcinomas, smaller contributions by HPV33, 35, 39, 45, 52, 56, 58, and 59. The viral DNA integrates into the host genome and express E6 and E7 proteins which inactivate tumor suppressor genes p53 and RB, respectively. Low-risk HPV types: 6, 11, 42, 44 which produce condylomas; the viral DNA does not integrate into the host genome. The recently introduced HPV vaccine is very effective in preventing HPV infections and cervical cancers. Many women harbor these viruses, only few develop cancer, suggesting other influences like cigarette smoking and exogenous or endogenous immunodeficiency.

Invasive carcinoma of the cervix

The most common cervical carcinoma are sqamous cell carcinoma 75%, adenocarcinoma and adenosquamous carcinoma 20%, and small cell neuro-ednocrine carcinoma 5%. In some individual with aggressive intraepithelial changes, the time interval may be considerably shorter, whereas in other women CIN precursors may persist for life. The only reliable way to monitor the course of the disease is with careful follow-up and repeat biopsies. The relative proportion of adenocarcinoma has been increasing in recent decades; glandular lesions are not detected well by Pap smear.

Invasive carcinoma of the cervix

(continued)
advanced cases of cervical cancer are invariably seen in women who either have never had a Pap smear or have waited many years since the prior smear. Such tomors may be symptomatic, called to attention by unexpected vaginal bleeding, leukorrhea, painful coitus, and dysuria. Detection of precursors by cytologic examination and their eradication by laser vaporization or cone biopsy is the most effective method of cancer prevention. Invasive carcinomas range from microscopic foci of early stromal invasion to grossly conspicuous tumors encircling the os. Tumors encircling the cervix and penetrate into the stroma produce a barrel cervix, which can be identified by direct palpation.

Review Questions
5. Risk factors for cervical cancer include all of the following except: A. Multiple sexual partners B. A male partner with multiple previous sexual partners C. Endocervical polyps D. Early age at first intercourse E. Cigarette smoking 6. All of the following are significant causes of acute or chronic cervicitis EXCEPT: A. Gonococci B. Lactobacilli C. Chlamydia D. Mycoplasma E. Herpes

Review Questions
7. A. B. Which of the following statements concerning carcinoma of the cervix is true? Stage II disease is confined to the cervix Distant metastases accounts for most deaths Peak incidence is 20 to 25 years 85% associated with human papillomavirus Definitive diagnosis is made by Pap smear 8. A 31 year old woman was found to have abnormal cells on pap smear a separate sample of which were sent for HPV (human papillomavirus) typing. Which of the following HPV types would put her at highest risk for subsequent development of squamous cell carcinoma of the cervix? (From additional information) 6 11 16 42 44

C.
D. E.

A. B. C. D. E.

Review Questions
9. Multiple small mucinous cysts of the endocervix that result from blockage of endocervical glands by overlying sqmaous metaplastic epithelium are called: A) Bartholines cysts B) Chocolate cyst C) Follicular cyst D) Gartners duct cyst E) Nabothian cyst

BODY OF UTERUD
Many disorders of this organ are common, often chronic and recurrent, and sometimes disastrous. Only the more frequent and significant ones are considered here. Endometritis Adenomyosis Endometriosis Dysfunctional uterine bleeding and endometrial hyperplasia Tumors

Endometritis
Can be seen with pelvic inflammatory disease. It may be associated with foreign bodies or retained tissue subsequent to miscarriage or delivery. They act as a nidus for infection. Removal of the foreign body and offending tissue typically results in resolution. Endometritis is classified as acute or chronic based on whether there is a predominant neutrophilic or lymphoplasmacytic response, Generally the diagnosis of chronic endometritis requires the presence of plasma cells. Acute endometritis is frequently due to N. gonorrhoeae or C. trachomatis.

Endometritis

(continued )

Endometritis may present with fever, abdominal pain, menstrual abnormalities, infertility and ectopic pregnancy due to damage to the fallopian tubes. Granulomatous endometritis: seen in immunocompromised individuals in U.S, and in other countries where tuberculosis is endemic.

Adenomyosis
It is the growth of basal layer of the endometrium down into the myometrium. Endometrial stroma, glands are found well in the myometrium between the muscle bundles. The uterine wall often becomes thickened and the uterus is enlarged. Because they are drived from the stratum basalis of the endometrium, they do not undergo cyclical bleeding. Nevertheless, adenomyosis may produce menorrhagia, dysmenorrhea, and pelvic pain before the onset of menstruation.

Endometriosis
It is characterized by endometrial glands and stroma in a location outside the endomyometrium. It may present as a pelvic mass filled with degenerating blood. Regurgitation theory: (currently most accepted theory) proposes menstrual backflow through the fallopian tubes with subsequent implantation. Indeed, menstural endometrium is viable and survives when injected into the anterior abdominal wall.

Endometriosis

(continued )

Manifestations depend on the distribution of the lesions. Extensive scaring of the oviducts and ovaries produces discomfort in the lower abdominal quadrants, and eventually causes sterility. Pain on defecation reflects rectal wall involvement, and dyspareunia (painful intercourse) and dysuria reflect involvement of the uterine and bladder serosa, respectively. Almost in all cases, there is severe dysmenorrhea and pelvic pain as a result of intrapelvic bleeding and periuterine adhesions.

Common locations of endometriosis within the pelvis and abdomen

Dysfunctional uterine bleeding

Abnormal bleeding in the absence of a well-defined organic lesion in the uterus is called dysfunctional uterine bleeding. It depends somewhat on the age of the women. Various causes can be segregated into four groups: - Failure of ovulation. Leads to an excess of estrogen relative to progesterone. - Inadequate luteal phase. Corpus luteum fail to mature normally, leading to relative lack of progesterone. - Contraceptive-induced bleeding. Induce a variety of endometrial responses, e.g. decidua-like stroma and inactive, non-secretory glands. - Endomyometrial disorders. Including chronic endometritis, endometrial polyps, and leiomyomas.

Endometrial hyperplasia
An excess of estrogen relative to progestin, induce hyperplasia, which can be preneoplastic. They can be classified into simple hyperplasia, complex hyperplasia and atypical hyperplasia. The risk of developing carcinoma is dependent of the severity of the hyperplastic changes. Potential contributors include failure of ovulation, prolonged administration of estrogenic steroids, polycystic ovaries (estrogen-producing ovarian lesion) cortical stromal hyperplasia, and granulosatheca cell tumors of the ovary. Common risk factor is obesity, because adipose tissue processes steroid precursors into estrogens.

Tumors
They tend to produce bleeding as the earliest manifestation. Endometrial polyps: sessile, usually hemispheric. Histologically, composed of endometrium resembling the basalis, frequently with small muscular arteries. More often they have cystic dilated glands, but some have normal endometrial architecture. They may occur at any age, but more commonly, they develop at time of menopause. clinical significance: - production of abnormal uterine bleeding. - risk of giving rise to a cancer (rare).

Tumors

(continued)

Leiomyoma: - The most common benign tumor in females and are found in 30% to 50% of women during reproductive life. More frequent in blacks than in whites. - They are often referred to as fibroids because they are firm. - Estrogens and oral contraceptives stimulate their growth; conversely, they shrink postmenopausally. - They may be entirely asymptomatic, discovered on routine pelvic examination. The most frequent manifestation, when present, is menorrrhagia, with or without metrorrhagia. They may become palpable to the woman or may produce a dragging sensation. - They rarely transform into sarcomas.

Tumors

(continued)

Liomyosarcomas: - Typically arise de novo from mesenchymal cells of the myometrium. - Almost always solitary tumors. - They are frequently soft, hemorrhagic and necrotic. - Diagnostic features include tumor necrosis, cytologic atypia, and mitotic activity. - They present a wide range of differentiation - Recurrence after removal is common with these cancers. - Many metastasize, typically to the lungs. Yielding a 5-years survival rate of about 40%.

Tumors

(continued)

Endometrial carcinoma: The most frequent cancer occurring in the female genital tract in the U.S and other Western countries. - Appears most frequently between the ages of 55 and 65 years. - There are two clinical stettings in which endometrial carcinomas arise: in perimenopausal women with estrogen excess and in older women with endometrial atrophy. (endometroid and serous carcinoma of the endometrium, respectively). - Well-defined risk factors for endometroid carcinoma: obesity-diabetes-hypertension-infertility - These risk factors poin to increased estrogen stimulation, and it is well recognized that prolonged estrogen replacement therapy and estrogen-secreting tumors increase the risk of this cancer.

Tumors
Endometrial carcinoma: (continued)
Many of these risk factors are the same as those for endometrial hyperplasia, and endometrial carcinoma frequently arises on a background of endometrial hyperplasia. - These tumors are termed endometrioid because of their similarity to normal endometrial gland. - Breast cancer occurs more frequently in women with endometrial cancer than by chance alone. - Two familial cancer syndromes that have an increased risk of the endometrioid type of endometrial carcinoma: 1. hereditary nonpolyposis colon cancer syndrome. 2. Cowdens syndrome (carries an increased risk of carcinoma of the breast, thyroid, and endometrium, have mutations in PTEN, a tumor suppressor gene).

Tumors
Endometrial carcinoma: (continued)
Serous carcinoma of the endometrium typically arises in a background of atrophy, sometimes in the setting of an endometrial polyps. Mutations in DNA mismatch repair genes and PTEN are rare in serous carcinoma; however, nearly all cases have mutations in the p53 tumor suppressor gene. Marked leukorrhea and irregular bleeding are the fist clinical indication of all endometrial carcinoma. With progression, uterus may be palpably enlarged, and in time it becomes fixed to surrounding structures by extension of the cancer beyond the uterus. Fortunately, these are usually latemetastasizing neoplasms, but dissemination eventually occurs.

Review Questions
10. _______Causes enlargement of the uterine wall A. Endometriosis B. Adenomyosis C. Both D. Neither 11. _____ May result in pelvic adhesions A. Endometriosis B. Adenomyosis C. Both D. Neither

Review Questions
12.Endometrial carcinoma risk factors include all except: A Obesity B Hypertension C Diabetes mellitus D HPV infection E Infertility

FALLOPIAN TUBES
Salpingitis is the most common disease of the fallopian tubes, almost always as a component of pelvic inflammatory disease. It is almost always microbial in origin. Non-gonococcal infections are more invasive, penetrate the wall of the tubes, and give rise to blood-borne infections and seeding of the meninges, joint spaces, and sometimes the heart valves. Salpingitis increase risk of tubal ectopic pregnancy. All forms of salpingitis may produce fever, lower abdominal or pelvic pain, and pelvic masses. They may result in tubo-ovarian abscess, or tubo-ovarian complex. And damage or obstruction of the tubal lumina may produce permanent sterility.

FALLOPIAN TUBES

(continued)

Primary adenocarcinomas: may be of papillary serous or endometrioid histology. They seem to be increased in women with BRCA mutations. Because the lumen and fimbria of the fallopian tube have access to the peritoneal cavity, fallopian tube carcinomas frequently involve the omentum and peritoneal cavity at presentation.

OVARIES

(contents):

Follicle and luteal cysts Polycystic ovaries Tumors of the ovary - Surface epithelial-stromal tumors - Serous tumors - Mucinous tumors - Endometrioid tumors - Brenner tumor - Other tumors - Teratomas *Benign (mature) cystic teratomas *Immature malignant teratomas *Specilized teratomas

OVARIES
Follicle and luteal cysts: - Common place of physiologic variants. - Originate in unruptured graafian follicles or in follicles that have ruptured and immediately sealed. - They may become palpable masses and produce pelvic pain, when they achieve diameters of 4-5cm. - When small thy are lined by granulosa lining cells or luteal cells, but as the fluid accumulates, pressure may cause atrophy of these cells. - Sometimes these cysts rupture, producing intraperitoneal bleeding and acute abdominal symptoms.

OVARIES

(continued)

Polycystic ovaries: - Oligomenorrhea, hirsutism, infertility, and sometimes obesity may appear in girls after menarche secondary to excessive production of estrogens and androgens by multiple cystic follicles in the ovaries. - They are also called Stein-Leventhal syndrome. - Ovaries usually twice normal in size, gray-white cortex, studded with subcortical cysts. - Histologically, thickened outer tunica, with hypertrophic and hyperplastic luteinized theca interna. And corpora lutea is absence. - The principal biochemical abnormalities are excessive production of androgens, high concentration of LH, low concentration of FSH.

Tumors of the ovary

Ovarian cancer is the fifth most common cancer in US women. It is also the fifth leading cause of cancer death in women. Three cell types make up the normal ovary: the multipotential surface (coelomic) covering epithelium, the totipotential germ cells, and the multipotntial sex cord/stromal cells. Each of these cell types gives rise to a variety of tumors. Neoplasms of the surface epithelial origin account for almost 90% of ovarian cancers.

Tumors of the ovary

(continued)

Pathogenesis: several risk factors for epithelial ovarian cancers have been recognized. - Two of the most important are nulliparity and family history. - Prolonged use of oral contraceptives reduce the risk somewhat. - A majority of hereditary ovarian cancers seem to be caused by mutations in the BRCA1 and BRCA2 genes. - HER2/NEU protein is overexpressed in 35% of ovarian cancers, with poor prognosis. - K-RAS protein is overexpressed in up to 30% of tumors, mostly mucinous cystadenocarcinomas. - P53 is mutated in about 50% of all ovarian cancers.

Surface epithelial-stromal tumors

They are derived from the coelomic mesothelium that covers the surface of the ovary. With repeated ovulation and scarring the surface epithelium is pulled into the cortex of the ovary, forming small epithelial cysts. Benign lesions are usually cystic (cystadenoma) or have a stromal component (cystadenofibroma). Malignant tumors may also be cystic (cystadenocarcinoma) or solid (carcinoma). There are also intermediate, borderline category, tumors of low malignant potential. They are lowgrade cancers with limited invasive potential.

Serous Tumors
These are the most frequent of the ovarian tumors. Benign lesions are usually encountered between ages 30 and 40 years, and malignant serous tumors are more commonly seen between 45 and 65 years of age. Serous tumors are the most common malignant ovarian tumors, account for 60% of all ovarian cancers. Grossly, may be small, but most are large, spherical to ovoid, cystic structures. The prognosis for the individual with clearly invasive serous cystadenocarcinoma after treatment is poor and depends on the stage of the disease at the time of diagnosis.

Mucinous tumors
The differ essentially from serous tumors in that the epithelium consists of mucin-secreting cells simlar to tthose of the endocervical mucosa. Their incidence is much lower and they are less likely to be malignant than serous tumors, accounting for about 10% of all ovarian cancers. 10% of them are malignant, 10% are of low malignant potential, 80% are benign. The prognosis is of mucinous tumors is better than for the serous counterpart, but the stage is the major determinant of treatment success.

Endometrioid tumors
They may be solid or cystic, but sometimes they develop as a mass projecting from the wall of a cyst filled with chocolate-colored fluid. Microscopically, formation of tubular glands, similar to those of the endometrium. They are usually malignant tumors, although benign and borderline forms also exist. 15-30% of women with these ovarian tumors have a concomitant endometrial carcinoma. Similar to endometrial cancer, endometrioid carcnoma have mutations in PTEN suppressor gene.

Brenner tumor
They are uncommon, most are benign, solid, usually unilateral tumors, consisting of an abundant stroma containing nest of transitionl-like epithelium resembling that of the urinary tract. Occasionally, the nests are cystic and are lined by columnar mucus-secreting cell. They are generally somoothly encapsulated. They may arise from the surface epithelium or from urogenital epithelium trapped within the germinal ridge. Rarely, they are formed as nodules within the wall of a mucinous cystadenoma.

Teratomas
Neoplasms of germ-cell origin constitute 15% to 20% of ovarian tumors. They arise in the first two decades of life. Thy younger the person, the greater is the likelihood of malignancy However, more than 90% of these germcell are benign mature cystic teratomas. The immature malignant variant is rare.

Benign (mature) cystic teratomas

They are marked by differentiation of totipotential germ cells into mature tissues representing all three germ cell layers. Usually there is cysts lined by recognizable epidermis replete. On transection, they are often filled with sebaceous secretion and matted hair, when removed, reveal a hairbearing epidermal lining. Sometimes teeth protrude from nodular projection. Occasionally, foci of bone and cartilage, nests of bronchial or GIT epithelium, and other recognizable lines of development are also present. Sometimes, they produce infertility for unknown reasons. In about 1% of cases there is malignant transformation, usually taking form of a squamous cell carcinoma. For unknown reasons, these tumors are prone to undergo torsion, producing an acute surgical emergency.

Immature malignant teratomas

They are found early in life, the mean age is 18 years. Differ from benign teratomas insofar as they are often bulky, and predominantly solid or near-solid on transection, and are punctuated by areas of necrosis. Uncommonly, one of the cystic foci may contain sebaceous secretion, hair, and other feature similar to those in the mature teratoma. Microscopically, the distinguishing feature is an immature areas of differentiation toward cartilage, bone, muscle, nerve, and other structure. Particularly ominous are foci of neuropithelial differentiation, because they are aggressive and metastasize widely.

Specialized teratomas
Struma ovarii is composed entirely of mature thyroid tissue that may hyperfunction and produce hyperthyroidism. They appear as small, solid, unilateral brown ovarian masses. Struma ovarii and carcinoid may combined in the same ovary. One of these elements may become malignant. Specialized teratoma

Tomors of the ovary

Serous tumor

Mucinous ovarian tumor

Brenner tumor

Endometrioid tumor

Mature (benign) teratoma

Immature (malignant) teratoma

Review Questions
13. A 27 year old nulliparous woman presents with hirsutism and oligomenorrhea. Ultrasound shows bilateral 8 cm ovaries with multiple small cortical cysts. The most likely diagnosis: A Granulosa cell tumor B Polycystic ovary disease C Thecal luteal cysts D Bilateral cysts of Morgagni E Bilateral Brenner tumors

DISEASES OF PREGNANCY
Diseases of pregnancy and pathologic conditions of the placenta are important causes of intrauterine or perinatal death, premature birth, congenital malformations and growth retardation, maternal death, and morbidity for both mother and child. Some disorders: - Placental inflammations and infections - Ectopic pregnancy - Gestational trophoblastic disease * hydatidifrom mole: complete and partial * invasive mole * choriocarcinoma * placental site trophoblastic tumor - Preeclampsia/eclampsia (toxemia of pregnancy)

Placental inflammations and infections

Infections reach placenta by two pathways: Ascending infections through the birth canal. The most common, they are bacterial and are associated with premature birth. Choriomnion shows polymorph leukocytic infiltration with edema and congestion of the vessels. When it extends beyond the membranes, it may cause acute vasculitis of the cord. They are caused by mycoplasms, Candida, and bacteria of the vaginal flora.

Placental inflammations and infections (continued)

Hematogenous spread. - Histologically, the villi are most often affected (villitis). - Syphilis, tuberculosis, listeriosis, toxoplasmosis, rubella and cytomeglaovrius and herpes simplex viruses can all cause placental villitis. - Transplacental infections can affect the fetus and give rise to the so-called TORCH complex.

Ectopic pregnancy
It is implantation of the fertilized ovum in any site other than the normal uterine location. Occurs as many as 1% of pregnancies. In 90% of these cases, implantation is in the oviducts (tubal pregnancy) other sites include the ovaries, the abdominal cavity, and the intrauterine portion of the oviduct. Any factor that retard the passage of an ovum from oviduct to uterus predispose to ectopic pregnancy. In adult half of the cases, such obstruction is based on chronic inflammatory changes in the oviduct, although tumors and endometriosis may also retard passage of the ovum. In half of tubal pregnancy no anatomic cause can be demonstrated.

Ectopic pregnancy

(continued)

Ovarian pregnancies result when ovum is fertilized within its follicle just at time of rupture. Gestation within the abdominal cavity occurs when the fertilized eggs drops out of the oviduct and implants on the peritoneum. Until rupture occurs, an ectopic pregnancy may be indistinguishable from a normal one. Under the influence of the placental hormones, the endometrium (in 50% of cases) undergoes the characteristic changes. (although there is absence of elevated gonadotropin levels). Rupture of an ectopic pregnancy may be with sudden onset of intense abdominal pain, often followed by shock. Prompt surgical intervention is necessary.

Gestational trophoblastic disease

They are divided into three overlapping morphologic categories: - Hydatidiform mole - Invasive mole - Choriocarcinoma They range in aggressiveness from the dydatidiform moles, most of which are benign, to the highly malignant choriocarcinomas. All elaborate human chorionic gonadotropin (hCG), which can detected considerably higher than those found during normal pregnancy. The titers progressively rising from hydatidiform mole to invasive mole to choriocarcinoma. The fall or rise in the level of the hormone can be used to monitor the effectiveness of treatment.

Hydatidiform mole
It is a voluminous mass of swollen, sometimes cystically dilated, chorionic villi, appears as grapelike structures. The swollen villi are covered by varying amounts of normal to highly atypical chorionic epithelium. Two distinctive subtypes of moles have been charaterized: - Complete hydatidiform: does not permit embryogenesis therefore never contain fetal parts. All of the chorionic villi are abnormal, and the chorionic epithelial cells are diploid (46,XX or, uncommonly, 46,XY). - Partial hydatidiform: compatible with early embro formation, has some normal chorionic villi, and is almost always triploid (69,XXY), rarely give rise to choriocarcinoma Moles are most common before age 20 years and after age 40 years, and a history of the condition increases the risk in subsequent pregnancies. Elevation of hCG in the maternal bllod and absence of fetal parts or fetal heart sound are typical.

Invasive mole
They are complete moles that are more aggressive locally but do not have the aggressive metastatic potential of a choriocarcinoma. An invasive mole retains hydropic villi, which penetrate the uterine wall deeply, causing rupture and sometime life-threatenining hemorrhage. Local spread to the broad ligament and vagina may also occur. Hydropic villi may embolize to distant organs, such as lungs or brain, but they do not constitute true metastases and may actually regress spontaneously. Because of the greater depth of invasion into the myometrium, an invasive mole is difficult to remove completely by curettage, and therefore serum hCG may remain elevated.

Choriocarcinoma
It is very aggressive malignant tumor. Arises from gestational chorionic epithelium or, less frequently, from totipotential cells within the gonads or elsewhere. Rare in western countries, and much more common in Asian and African countries. The risk is greater before age 20 years and after age 40. 50% of choriocarcinoma arise in complete hydatidiform moles, 25% after abortion, and the remainder occur during a normal pregnancy. The more abnormal the conception the greater is the risk of developing gestational choriocarcinoma. In most cases there is a bloody, brownish discharge, accompanied by a rising titer of hCG.

Choriocarcinoma

(continued)

By the time most choriocarcinomas are discovered, there is usually widespread dissemination via the blood most often to lungs, vagina. Lymphatic invasion is uncommon. despite extreme aggressiveness of these neoplasms, which made them nearly fatal in the past, present-day chemotherapy has achieved remarkable results. Nearly 100% of cases can be cured By contrast, there is relatively poor response to chemotherapy in chocriocarcinoma that arise in the gonads (ovary or testis). This striking difference may related to the presence of paternal antigens on placental choriocarcinoma but not gonal lesion, maternal immune response against paternal antigens helps by acting as an adjunct to chemotherapy.

Placental site trophoblastic tumor

These uncommon tumors are diploid, are often XX in karyopte, derived from the placental site or intermediate trophoblast. Typically arise a few months after pregnancy. Intermediate trophoblasts do no produce large amount of hCG, so hCG concentration is only slightly elevated. They produce human placental lactogen. They are indolent and have favorable outcome if confined to endometrium. However, they are not sensitive to chemotherapy, and the prognosis is poor if they spread beyond the uterus.

Preeclampsia/eclampsia (toxemia of pregnancy)

Preeclampsia is the development of hypertension, accompanied by proteinuria and edema in third trimester of pregnancy. Occurs in 5% to 10% of pregnancies, particularly with first pregnancies in women older than age 35 years. In those severely affected, renal function is impaired, the blood pressure mounts, convulsive seizures may appear, the symptom complex is then termed eclampsia. Preeclampsia and eclampsia are referred to as toxemia of pregnancy.

Preeclampsia/eclampsia (toxemia of pregnancy) (continued)

Full-blown eclampsia may lead to disseminated intravascular coagulation, with widespread ischemic organ injuries, and so eclampsia is potentially fatal. However, early recognition and treatment of preeclampsia has now made eclampsia rare. The basic feature underlying all cases is inadequate maternal blood flow to the placental secondary to inadequate development of spiral arteries of the uteroplacental bed. Recent studies suggest imbalance between proangiogenic and antiangiogenic factors. Increase in the antiangiogenic factor sFlt1 and reduction in the level of the proangiogenic factor VEGF have been noted.

Review Questions
14.Triploid Karyotype A. Complete mole B. Partial mole C. Both A and B D. Neither 15.Fetal parts may be present A. Complete mole B. Partial mole C. Both A and B D. Neither

Review Questions
16.Edematous changes of all the villi A. Partial hydatiform mole B. Complete hydatiform mole C. Invasive mole D. Choriocarcinoma E. Placental site trophoblastic tumor 17. _____ Admixture of edematous and normal villi A. Complete mole B. Partial mole C. Both D. Neither

Review Questions
18.Elevated HCG in serum A. Complete mole B. Partial mole C. Both A and B D. Neither

BREAST
Fibrocystic changes: Different changes range from those that are innocuous to patterns associated with an increased risk of breast carcinoma. Some of them produce palpable lumps. This range of changes is the consequence of an exaggeration and distortion of the cyclic breast changes that occur normally in the menstrual cycle. Estrogenic therapy and oral contraceptives do not seem to increase the incidence of these alterations. They may cause nodularity; only a small minority represent forms of epithelial hyperplasia that are clinically important. Lumps that are produced by the various patterns of fibrocystic change must be distinguished from cancer.

Fibrocystic changes

(continued)

They can be subdivided into nonporliferative and proliferative patterns. - The nonproliferative lesions include cysts and/or fibrosis without epithelial cell hyperplasia (simple fibrocystic change). - The proliferative lesions include a range of innocuous to atypical duct or ductular epithelial cell hyperplasias and sclerosing adenosis. They tend to arise during reproductive period of life but may persist after menopause. Nonproliferative changes are so common, being found at autopsy in 60% to 80% of women, that they almost constitute physiologic variants.

Nonproliferative change
Cysts and fibrosis: Characterized by an increase in fibrous stroma associated with dilation of ducts and formation of cysts of various size. The stroma is usually compressed fibrous tissue, having lost in their normal delicate, myxomatous appearance. A stromal lymphocytic infiltration is common in this and other variants of firbrocystic change.

Proliferative change
Epithelial hyperplasia: It is proliferative lesion within the ductules, the terminal ducts, and sometimes the lobules of the breast. Some of the epithelial hyperplasia are mild and orderly, and carry little risk of carcinoma. But there is more florid atypical hyperplasia that carry significantly greater risk. The epithelial hyperplasia are often accompanied by other histologic variants of fibrocystic change. Occasionally it produces microcalcifications on mammography, rising fears about cancer.

Proliferative change

(continued)

Sclerosing adenosis: This variant is less common than cysts and hyperplasia, but it is significant because its clinical features are smilar to those of carcinoma. They contain marked intralobular fibrosis and proliferation of small ductules and acini. Although it is difficult to differentiate from carcinoma, it is associated with only a minimally increased risk of pregression to carcinoma.

Inflammations
They are uncommon, and during acute stages usually cause pain and tenderness in the involved areas. In this category there are several forms of mastitis and traumatic fat necrosis. They are not associated with increased risk of cancer. Mammary duct ectasia (periductal or plasma cell mastitis) is nonbacterial chronic inflammation of the beast associated with inspiration of breast secretions in the main excretory ducts. It is uncommon, and encountered in women in their 40s and 50s who have borne children. Mammary duct ectasia is significant because it leads to induration of the breast substance mimicking the changes caused by some carcinomas.

Tumors of the breast

They may arise from either connective tissue or epithelial structures. That latter give rise to common breast neoplasms.

Fibroadenoma
It is the most common benign neoplasms of the female breast. They almost never become malignant. Usually appear in young women; the peak incidence is in the third decade of llife. An increase in estrogen activity is thought to contribute to its development. Smiliar lesions may appear with fibrocystic changes. They usually present as solitary, discrete, movable mass. They may enlarge late in the menstrual cycle and during pregnancy.

Phyllodes tumor
They are much less common than fibroadenomas. Arise from the periductal stroma and from preexisting fibroadenomas. They may be small or grow to large massive size, distending the breast. Some become lobulated and cystic; on gross section they exhibit leaflike clefts and sliits, that is why they called phylodes tumors. In the past they had the name cystosarcoma phyllodes, an unfortunate name because they are benign. The most ominous change is the appearance of increased stromal cellularity with anaplasia and high mitotic activity, accompanied by rapid increase in size, and invasion of adjacent breast tissue by malignant stroma. they remain localized and are cured by excision;even malignant tumors also tend to remain localized. Only the most malignant (15% of cases) metastasize to distant sites.

Intraductal papilloma
It is a neoplastic papillary growth within a duct. Most are solitary, found within the principal lactiferous ducts or sinuses. Present clinically as a result of - Appearance of serous or blody nipple discharge - Precence of small subareolar tumor - Nipple retraction (rare). In some cases there are multiple papillomas in several ducts (intraductal papillomatosis). These lesion sometimes become malginant, wherease the solitary papilloma almost always remain benign.

Carcinoma
Despite advances in diagnosis and treatment, almost one-fourth of women who develop these neoplasms will die of the disease. 75% of women with breast cancer are older than age 50. only 5% are younger than the age 40. Epidemiology and risk factors: Geographic distribution: there are differences among countries in the incidence and mortality rates of breast cancer. The risk is significantly higher in North America and northern Europe than in Asia and Africa. These difference seems to be environmental rather than genetic in origin. Age: uncommon in women younger than 30 ys, the risk steadily increase throughout life, but after the menopause the slope of the curve is almost plateous.

Carcinoma

(continued)

Getetics and family history: - 5% to 10% of breast cancer are related to inherited mutations. - Women are more likely to carry a breast cancer susceptibility gene if they develop breast cancer before menopause, have bilateral cancer, have other associated cancer like ovarian cancer, or have a family history. - Half of women with hereditary breast cancer have mutations in gene BRCA1 and one-third have mutations in BRCA2. These genes function in DNA repair. - Less common genetic diseases associated with breast cancer are the Li-Fraumeni syndrome (mutations in p53), Cowden disease (mutations in PTEN), and carriers of ataxia-telangiectasia gene.

Carcinoma

(continued)

prolonged exposure to exogenous estrogens postmenopausally: know as a hormone replacement therapy, prevents or delays the onset of osteoporosis. However, use of combined estrogen plus progestin hormone therapy is associated with an increased risk of breast cancer, diagnosis at more advanced stage, and more abnormal mammograms. Oral contraceptives: they have been suspected of increasing the risk of breast cancer. Ionizing radiation to the chest increases the risk of breast cancer. Only women irradiated before age 30, seem to be affected. 20% to 30% of women irradiated for Hodgkin lymphoma in their teens and 20s develop breast cancer, but the risk for women treated later in life is not elevated. Other less well-established risk factors: obesity, alchohol consumption, and a diet high in fat.

Carcinoma

(continued)

Pathogenesis: as with all cancers, the cause of breast cancer remain unknown. however, three set of influences seem to be important: Genetic change: - Mutations affecting proto-oncogenes and tumor supressor genes in breast epithelium contribute to the oncogenic transformation process. - Overexpression of the HER2/NEU proto-oncogene, found to be amplified in up to 30% of invasive breast cancers. - Amplification of RAS and MYC genes has also been reported in some breast cancer. - Mutation of the tumor suppressor genes RB and p53 may also be present.

Carcinoma
-

(continued)

A large number of genes including the estrogen receptor may be inactivated by promoter hypermethylation. - Most likely, multiple acquired genetic alterations are involved in the sequential transormation of a normal epithelial cell into a cacerous cell. - Gene expression profiling can stratify breast cancer into five subtypes: luminal A, luminal B, HER2/NEU overexpression, basal-like, and normal breast like. These subtypes are reproducible and are associated with difference outcomes. Hormonal influences: - Endogenous estrogen excess or hormonal imbalance has a significant role. Many risk factors (mentioned before) imply increased exposure to estrogen peaks during the menstrual cycle.

Carcinoma
-

(continued)

Functioning ovarian tumors that elaborate estrogens are associated with breast cancer in postmenopausal women. - Estrogens stimulate the production of growth factors by normal breast epithelial cells and by cancer cells. Estrogen and progesterone receptors are present in breast epithelium and in breast cancer cells, may interact with growth promoters to create an autocrine mechanism of tumor development. Enviornmental variables: - They are suggested by the variable incidence of breast cancer in genetically homogeneous groups and the geographic differences in prevalence. Important environmental variables include irradiation and exogenous estrogens.

Carcinoma

(continued)

Spread of breast cancer:

Occurs through lymphatic and hematogenous channels. Lymph node metastasis are present in about 40% of cancers presenting as a palpable masses. Outer quadrant and centrally located lesions typically spread to the axillary nodes. Those in the inner quadrants often involve the lymph node along the internal mammary arteries. The supraclavicular nodes are sometimes the primary site of spread, but they become involved only after the axillary and internal mammary nodes are affected. Metastatic involvement maybe to any organ, such as lungs, skeleton, liver, adrenals brain, spleen, and pituitary. Matastases may appear many years after apparent therapeutic control of the primary lesion, sometimes 15 years later.

Carcinoma

(continued)

Clinical course: Breast cancer is often discovered by the woman or physician as a discrete, solitary, painless, and movable mass. At this time, involvement of regional lymph nodes is already present in about half of patients. With mammographic screening, carcinomas are frequently detected before they become palpable, and only 15% of these have nodal metastases. Magnetic resonance imaging is being studied in highrisk young patients with dense breasts that are difficult to image by mammography.

Carcinoma
1. 2.

(continued)

3. 4.

Prognosis is influenced by the following variables: The size of the primary carcinoma. Invasive carcinoma smaller than 1cm have an excellent prognosis in the absence of lymph node metastases. Lymph node involvement and the number of lymph nodes involved by metastases. 5-year survival rate is 90% with no axillary node involvement. The survival rate is decreases with each involved lymph node and is less than 50% with 16 involved nodes. Distant metastases. Patient who develop hematogenous spread are rarely curable. The grade of the carcinoma. The most common grading system for breast cancer evaluates tubule formation, nuclear grade, and mitotic rate to divide carcinomas in to three groups. Well-differentiated or poor differentiated or moderately differentiated.

Carcinoma
5. 6.

(continued)

7. 8.

9.

The histologic type of carcinoma. All specialized types of breast carcinoma (tubular, medullary, cribriform, adenoid cystic, and mucinous) have a better prognosis than carcinomas of no special type (ductal carcinoma). The presence or absence of estrogen or progesterone receptors. The presence of receptors confers a slightly better prognosis. The reason for determining their presence is to predict the response to anti-estrogen therapy. The proliferation rate of the cancer. High proliferative rates are associated with a poorer prognosis. Aneuploidy. Carcinoma with an abnormal DNA content have a slightly worse prognosis. Overexpression of HER2/NEU. Ovexpression is associated with poorer prognosis. However, the importance of evaluating HER2/NEU is to predict resposne to monoclonal antibody Herceptin to the gene product.

Carcinoma

(continued)

The major prognostic factors are used by the American Joint Committee on Cancer to devide breast cancer into clinical stages as follows: - Stage 0. DCIS or LCIS (5-year survival rate: 92%) - Stage 1. invasive carcinoma 2cm, without nodal involvement (5-year survival rate: 87%) - Stage 2. invasive carcinoma 5cm, with up to 3 involved axillary nodes (5-year survival rate: 75%) - Stage 3. invasive carcinoma 5cm with four or more involved axillary nodes. (5-year survival rate: 43%) - Stage 4. breast cancer with distant metastases (5year survival rate: 13%)

Male breast
Only two disorders occur in male breast with sufficient frequency. Gynecomastia: male breast are also subject to hormonal influences, but they are less sensitive than are female breasts. Gynecomastica may occur in response to estrogen excess. The most important cause is cirrhosis of the liver, with consequent inability of the liver to metabolize estrogens. Other causes include Klinefelter syndrome, estrogen-secreting tumors, estrogen therapy, digitalis therapy. Physiologic gynecomastia occurs in puberty and in old age. Morphologic features are simlar to intraductal hyperplasia. Carcinoma: frequency ratio to breast cancer in the female of 1:125. It occurs in advanced age. Because of scant amount of breast substance in males, the tumor rapidly infiltrates the skin and underlying thoracic wall. Almost half have spread to regional nodes and more distant sites by the time they are discovered. They resemble invasive carcinoma in females both morphologically and biologically.

Review Questions
19. The most likely cause of 1 cm mass in the upper outer quadrant of the breast of 65 year old woman. A) Fibrocystic change B) Acute mastitis C) Fibroadenoma D) Carcinoma E) Pagets disease of the breast 20.All of the following are associated with carinoma of the breast, except: A) High-fat diet B) Positive family history C) Obesity D) Early menarche E) multiparity

Additional informations
Infectious disorders: Candidiasis: most common form of vagnitis Trichomoniasis: second most common type of vaginitis. Garnerella vaginitis: clue cell are characteristic cells Toxic shock syndrome: associated with use of tampons. Gonorrhea: frequent cause of pelvic inflammatory disease. Chlamydial infection: clymedial cervicitis lymphogranuloma venereum. Herpes simplex virus infection: produce small viscels and shallow ulcers. Shyphilis: 1st stage: chancre, 2nd stage: condyloma lata. Chancroid: soft and painful ulcerated lesion. Caused by haemophilus dureyi Granduloma inguinale: characterized by donovan bodies. Cased by calmmatobacterium granulomatis.

Review Test
21. All of the following condition correctly matched with the appropriate association, except: A) Endometriosis: severe menstrual pain B) Endometrial hyperplasia: excess estrogen stimulation C) Leiomyoma: postmenopausal decrease in size D) Endometrial carcinoma: multiparity E) Ectopic pregnancy: hematosalpinx

22.HPV infection is not associated with: A Vulvar intra epithelial neoplasia (VIN) B Vaginal intra epithelial neoplasia (VAIN) C Cervical intra epithelial neoplasia (CIN) D Endocervical glandular dysplasia E Paget's disease of the vulva

Review Test
23. Fishy odor, "clue cells, caused by (from additional information) A. Trichomonas B. Gardnerella C. Candida D. Herpes E. Gonorrhea 24. Which of the following neoplasms of the vagina has been associated with in utero exposure to diethylstilbestrol? A. Vaginal intraepithelial neoplasia (VAIN) B. Squamous cell carcinoma C. Embryonal rhabdomyosarcoma D. Clear cell adenocarcinoma E. Leiomyoma

Review Test
25.The most common site of an ectopic pregnancy: A. ovary B. peritoneal cavity C. endocervical canal D. endometrial cavity E. fallopian tube
26. A 21 year old woman is at week 25 of her first pregnancy. Her gynecologist tells you she has pre_eclampsia. You would expect to find which constellation of findings on your evaluation: A Hypertension; otherwise normal B Hypertension and proteinuria; otherwise normal C Glucose intolerance; otherwise normal D Glucose intolerance, and hypertension; otherwise normal E Hypertension, proteinuria and peripheral edema

Review Test
27. A 32-year-old woman with a history of hyperthyroidism was found to have a left adnexal tumor composed entirely of the tissue as depicted microscopically. The best diagnosis is: A. Krukenberg tumor B. Struma ovarii C. Immature teratoma D. Ovarian carcinoid E. Strumal carcinoid 28. A 27 year old woman had a palpable right ovary which an x-ray was found to contain a well developed molar tooth. The most likely diagnosis would be: A. Dysgeminoma B. Yolk sac tumor C. Sertoli-Leydig cell tumor D. Mature cystic teratoma E. Denturoma

Review Test
29.Elevated beta - HCG A. Choriocarcinoma B. Fibroma C. Granulosa cell tumor D. Endodermal sinus tumor E. Immature teratoma 30.A 21 year old woman was diagnosed as having pre-eclampsia. Which of the following would not be consistent with that diagnosis? A. Hypertension B. Convulsions C. Proteinuria D. Edema

Review Test
31. The most common primary sites for the oringin of Pagets disease are the nipple and the A. Anal canal B. Liver C. Nasopharynx D. Penis E. Vulva
32. A 26-year old female in the third trimester of her first pregnancy develops persistent headaches and swelling of her legs and face. Her blood pressure is 170/105 mmHg and urnialysis reveals slight proteinuria. What is the diagnosis A. Eclampsia B. Gestational trophoblastic disease C. Nehritic syndrom D. Nehprotic syndrom E. preeclampsia

Review Test
33.The most important factor related to the prognosis of breast cancer is A. the presence of activated oncogenes B. The histologic type and grade C. The size of the tumor D. The status of axillary lymph nodes E. The presence of estrogen receptors.

Answers
1-E. 2-A. 3-E. 4-C. 5-C. 6-B. 7-D. 8-C. 9-E. 10-B. 11-A. 12-D. 13-B. 14-B. 15-B. 16-B. 17-B. 18-C. 19-D. 20-E. 21-D. 22-E. 23-B. 24-D. 25-E. 26-E. 27-B. 28-D. 29-A. 30-B. 31-E. 32-A. 33-E.

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