Pathology of Female Genital Tract and Breast MB.pptx

Pathology of Female Genital Tract and Breast Dr. Wangari Wambugu Outline: Pathology of: Vulva Vagina Cervix Body of Uterus Fallopian Tubes Ovaries Diseases of Pregnancy Breast Anatomy of female genital system  VULVA Diseases of vul...

Pathology of Female Genital Tract and Breast Dr. Wangari Wambugu Outline: Pathology of: Vulva Vagina Cervix Body of Uterus Fallopian Tubes Ovaries Diseases of Pregnancy Breast Anatomy of female genital system  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 common causes of vulvar pruritus is a reactive inflammation to an exogenous stimulus, whether an irritant or an allergen. Contact irritant dermatitis: presents as well-defined erythematous weeping and crusting papules and plaques. May be a reaction to urine, soaps, 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 be 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 increased 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 Planus Lichen simplex It’s benign dermatoses chronicus  Tumors Condylomas and low-grade vulvar intraepithelial Neoplasia (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 acuminata: (more common)  may be papillary and distinctly elevated.  Occur anywhere on the anogenital surface.  Vulvar condylomas are not pre-cancerous but coexist with foci of intraepithelial neoplasia in vulva (VIN grade 1) and cervix.  Condylomas Giant condyloma A vulva chancre and condylomata accuminata  Tumors (continued …) High-grade vulvar intraepithelial neoplasia and carcinoma of the vulva  Carcinoma 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 commonly seen in relatively younger patients.  Non-HPV-related vulvar squamous cell carcinoma occurs in older women; It is well differentiated and unifocal, and is associated with lichen sclerosus or other inflammatory conditions. 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. 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, 1% of malignant neoplasms in the FGT Usually occur in women older than age 60 years. 95% are squamous cell carcinoma Associated with HPV infection in most cases Greatest risk factor is a previous carcinoma of cervix or vulva CERVIX Cervix is often the seat of disease. Fortunately, most cervical lesions are relatively benign inflammation But cervix is also the site of the most common cancers in women; squamous cell carcinoma. Cervicitis 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, Ureaplasma urealyticum, T. vaginalis, Candida spp., Neisseria gonorrheae, herpes simplex genitalis, and HPV. Cervicitis (contiued …) 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. The pap smear remains the most successful cancer screening test ever developed. 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 point to the likelihood of sexual transmission of a causative agent, in this case HPV Cervical intraepithelial Neoplasia Normal squamous Left, normal epithelium. Right, epithelium of the cervix. CIN2/3 There is weak positive Strongly positive staining cytoplasmic staining nuclear Risk factors of cervical cancer 1. Modifiable risk factors: Persistent infection by ‘‘High-risk’’ HPV Sexual history: Early age of sexual debut(esp b4 18yrs) Multiple sexual partners High risk partner: With HPV infection With multiple sexual partners Multiple full-term pregnancies Young age at first full-term pregnancy Immunosuppression Smoking Long-term use of combined oral contraceptives Risk factors Other concurrent STI e.g Chlamydia, Herpes simplex Low socio-economic status Diet low in fruits and vegetables 2. Non-modifiable risk factors Diethylstilbestrol (DES) A hormonal drug that was give to women btw 1938 & 1971 to prevent miscarriage Women whose mothers took DES while pregnant had a higher risk of developing clear-cell adenocarcinoma of vaginal or cervix Family history of cervical cancer HPV 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. HPV 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 tumors 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. Cervical cancer prevention  Three strategies to prevent cervical cancer: Primary prevention Reduction of exposure to risk factors: promote use of cond om and fewer sexual partners—limited effects Vaccination when the causal agent is infectious Secondary prevention Early detection of disease via screening Treatment of precursor lesions Tertiary prevention Reduce long term impact of disease Focus on treatment and follow-up options Natural history of HPV infection Prophylactic HPV vaccines BODY OF UTERUS 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 and 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 granulosa-theca cell tumors of the ovary. Common risk factor is obesity, because adipose tissue processes steroid precursors into estrogens. Inactivation of PTEN tumor suppressor gene is associated with the development of hyperplasia and related cancers Simple endometrial hyperplasia Complex endometrial hypareplasia 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. Leiomyoma Tumors (continued…) Leiomyosarcomas:  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%. Leiomyosarcoma 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 settings 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). Tumors (continued…)  Well-defined risk factors for endometroid carcinoma: obesity-diabetes-hypertension-infertility  These risk factors point 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. Cowden’s 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.  Marked leukorrhea and irregular bleeding are the first 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 late-metastasizing neoplasms, but dissemination eventually occurs. Tumors Endometrial carcinoma: (continued…)  Grading:  Grade 1 well-differentiated  Grade 2 moderately differentiated  Grade 3 poorly differentiated  Classification:  Usual endometrial ca- endometriod endometrial ca  Other variants: - With squamous diff - Papillary serous ca - Clear cell ca - Mucinous ca 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): Non-neoplastic &  Sex-cord stromal tumors functional cysts  Germ cell tumours Follicle and luteal cysts Polycystic ovaries - Teratomas Tumors of the ovary *Benign (mature) cystic  Surface epithelial-stromal teratomas tumors *Immature malignant - Serous tumors teratomas - Mucinous tumors *Specialized teratomas - Endometrioid tumors - dysgerminoma - Brenner tumor - yolk sac tumours - embryonal ca - mixed GCT 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 they 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.  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 multipotential 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 80% 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. Pathogenesis of ovarian cancer 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 low-grade 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. Benign serous adenoma Papilary serous carcinoma 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. Benign mucinous tumour 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 transitional-like epithelium resembling that of the urinary tract. Occasionally, the nests are cystic and are lined by columnar mucus-secreting cell. They are generally smoothly 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. The younger the person, the greater is the likelihood of malignancy However, more than 90% of these germ-cell 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 hair-bearing 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  Tumors of the ovary Serous tumor Mucinous ovarian tumor Brenner tumor Endometrioid tumor Mature (benign) teratoma Immature (malignant) teratoma 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 complications. 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  Also includes PSTT They range in aggressiveness from the hydatidiform 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 embyro 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 blood 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 be related to the presence of paternal antigens on placental choriocarcinoma but not gonadal lesion, maternal immune response against paternal antigens helps by acting as an adjunct to chemotherapy. Microscopically, the tumor is composed of two types of cells: Syncytiotrophoblasts, large multinucleate cells with abundant vacuolated cytoplasm containing hCG and Cytotrophoblasts, polygonal cells with distinct cell borders and single nuclei, which grow in clusters and are surrounded by the syncytiotrophoblasts Placental site trophoblastic tumor (PSTT) These uncommon tumors are diploid, are often XX in karyotype, 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 after 20wks 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. BREAST Inflammations Benign epithelial lesions Breast carcinoma Breast-normal structure Branching system of ducts ending in nipple 15-25 large ducts (lactiferous ducts emerge at nipple) Functional unit is terminal ductal lobular unit (TDLU) 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. Benign epithelial lesions non-proliferative breast changes 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. Benign epithelial lesions non-proliferative breast changes 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 Cyst formation Variably sized cysts lined by flattened or cuboidal epithelial cells Stromal fibrosis Dense periductal and perilobular fibrosis Apocrine metaplasia Cysts lined by large, polygonal cells with abundant granular, eosinophilic cytoplasm and small,hyperchromatic nuclei Proliferative breast disease without atypia Proliferation of ductal epithelium &/ stroma without cellular changes suggestive of malignancy Include: Epithelial hyperplasia Sclerosing adenosis Complex sclerosing lesion (radial scar) Papillomas Proliferative breast disease with atypia Atypical ductal hyperplasia Atypical lobular hyperplasia Tumors of the breast They may arise from either connective tissue or epithelial structures. The 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 phyllodes tumors. 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 bloody nipple discharge  Presence of small subareolar tumor  Nipple retraction (rare). In some cases there are multiple papillomas in several ducts (intraductal papillomatosis). These lesion sometimes become malignant, 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…) Genetics 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: known 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, alcohol consumption, and a diet high in fat. Classification of breast carcinoma Carcinoma in situ Ductal carcinoma in situ Lobular carcinoma in situ Invasive carcinoma No special type(ductal) Lobular Tubular/cribriform Mucinous (colloid) Medullary Papillary Metaplastic Carcinoma in situ  preinvasive - does not form a palpable tumor  not detected clinically (only on imaging)  May show suspicious calcification on mammogram  multicentricity and bilaterality (namely LCIS)  continuum: bland hyperplasia - increasing atypism - carcinoma in situ  basement membrane not breached  risk of invasion depending on grade DCIS Invasive ductal carcinoma Majority 60-70% Gross: Hard fibrotic mass with stellate or infiltrative borders Necrosis may be present Histopathology: Infiltrating tumour composed of malignant ductal cells, with tubule formation or not Invasive ductal carcinoma Grading- based on: Tubule formation Mitotic activity Nuclear pleomorphism Invasive lobular carcinoma 5-15% Poorly defined mass High incidence of multifocal or bilateral disease (up to 20%) Gross: variable size Typicall hard mass with irregular infiltrative borders Invasive lobular carcinoma Histopathology Classic growth pattern consists of tumour cells in a linear or single file(Indian filing) pattern in a sclerotic background Tumour cells may be mucin-filled resulting in signet ring formation Tumour cells are small, uniform and bland Special stain & IHC Estrogen and progesterone receptors HER2/neu (C-erb-B2) Cytokeratins Mb-1 (Ki-67)- mitotic index 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. Metastases 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 high-risk young patients with dense breasts that are difficult to image by mammography. Carcinoma (continued…) Prognosis is influenced by the following variables: 1. The size of the primary carcinoma. Invasive carcinoma smaller than 1cm have an excellent prognosis in the absence of lymph node metastases. 2. 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. 3. Distant metastases. Patient who develop hematogenous spread are rarely curable. 4. 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 (continued…) 5. 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). 6. 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. 7. The proliferation rate of the cancer. High proliferative rates are associated with a poorer prognosis. 8. Aneuploidy. Carcinoma with an abnormal DNA content have a slightly worse prognosis. 9. Overexpression of HER2/NEU. Ovexpression is associated with poorer prognosis. However, the importance of evaluating HER2/NEU is to predict response to monoclonal antibody “Herceptin” to the gene product. 10. Stage of disease 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 (5-year survival rate: 13%)