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PATHOLOGY: Female Genital System and Breast (Breast (Benign Epithelial…

- - - - regurgitation theory: currently favored: menstrual backflow through fallopian tubes leads to implantation
      - Benign metastases theory: source: endometrial tissue from uterus
      - metaplastic theory: endometrial differentiation of coelomic epithelium (mesothelium of pelvis and abdomen from which endometrium originates) as source
      - extrauterine stem/progenitor cell theory: circulating stem/progenitor cells from bone marrow differentiate into endometrial tissue
  - - - endometrioid carcinoma: 80%
        
        patho: arise in a. w/ estrogen excess in setting of endometrial hyperplasia in perimenopausal ; Mutations in mismatch repair genes + tumor suppressor gene PTEN are early events; Women with germline mutations in PTEN (Cowden Syndrome) and germline alterations in DNA mismatch repair genes (Lynch Syndrome) are at high risk for this cancer. TP53 mutations relatively uncommon + late events
      - serous carcinoma: 15%
        
        patho: arise in setting of endometrial atrophy in older postmenopausal; Nearly all have mutations in TP53 tumor suppressor gene, whereas mutations in DNA mismatch repair genes + PTEN rare
      - RFs: (1) obesity, (2) diabetes, (3) hypertension, (4) infertility, and (5) exposure to unopposed estrogen.
    - - categories
        
        hyperplasia w/o atypia
        
        hyperplasia w/ atypia: inactivation of PTEN gene identified at a substantial frequency (50%); precursor lesion for endometrioid endometrial carcinoma
      - common cause of estrogen excess: obesity. Others: failure of ovulation (such as in perimenopause), prolonged administration of estrogenic steroids w/o counterbalancing progestin, and estrogen-producing ovarian lesions (such as polycystic ovary syndrome and granulosa-theca cell tumors of ovary).
      - When hyperplasia w/ atypia: u. warrants a hysterectomy in patients no longer desiring fertility. In younger patients, treatment w/ high-dose progestins may be used in an attempt to preserve uterus
    - - gross: sharply circumscribed, firm gray-white masses w/ a characteristic whorled cut surface; more often occur as multiple tumors scattered within uterus, ranging from small nodules to large tumors that may dwarf uterus. Some within myometrium (intramural), whereas others immediately beneath endometrium (submucosal) or serosa (subserosal: may extend out on attenuated stalks, even become attached to surrounding organs, from which they may develop a blood supply (parasitic leiomyomas))
      - histologic: bundles of smooth muscle cells mimicking appearance of normal myometrium
    - - morpho: diagnostic features: tumor necrosis, cytologic atypia, and mitotic activity.
  - - - chronic: lymphoplasmacytic infiltrate predominates; diagnosis generally requires presence of plasma cells, as lymphocytes present even in normal endometrium
      - acute: neutrophilic infiltrate predominates
- - - - benign fibroadenoma: circumscribed borders and low cellularity
      - malignant phyllodes: stromal cells tend to outgrow epithelial cells--> bulbous nodules of proliferating stromal cells that are covered by epithelium, the characteristic “leaflike” growth pattern
    - - benign soft tissue tumors found elsewhere in the body (hemangiomas and lipomas)
      - only malignant: angiosarcoma
  - - - sclerosing adenosis
      - complex sclerosing lesion
      - epithelial hyperplasia
      - papilloma
    - - fibrosis
      - adenosis
      - most common nonproliferative breast lesions: simple cysts lined by a layer of luminal cells that often undergo apocrine metaplasia (apocrine secretions may calcify + be detected by mammography); cysts rupture--> chronic infl and fibrosis in response to spilled debris may produce palpable nodularity of breast (so-called “fibrocystic changes”)
    - - atypical lobular hyperplasia
      - atypical ductal hyperplasia
  - - - Noninvasive: terms ductal and lobular misleading, as both arise from cells in terminal duct that give rise to lobules. LCIS u. expands involved lobules, whereas DCIS distorts lobules into ductlike spaces
        
        DCIS: Calcifications frequently a. w/ DCIS
        
        LCIS: uniform appearance, cells monomorphic, have bland, round nuclei, and found in loosely cohesive clusters within lobules; virtually always an incidental finding bc, unlike DCIS, it is only rarely a. w/ calcifications.
      - Invasive
        
        Invasive ductal carcinoma (all carcinomas that are not of a special type)—70% to 80%
        
        Invasive lobular carcinoma— ~10% to 15%: infiltrating cells morphologically similar to tumor cells seen in LCIS; cells invade stroma individually and often are aligned in “single-file”
        
        Carcinoma with medullary features— ~5%:
        
        sheets of large anaplastic cells (abundant cytoplasm, pleomorphic nuceli w/ prominent nucleoli) a. w/ pronounced lymphocytic infiltrates composed predominantly of T cells
        
        rounded masses (difficult to distinguish from benign on imaging)
        
        Mucinous carcinoma (colloid carcinoma) — ~5%
        
        Tubular carcinoma— ~5%: tumor cells arranged in well-formed tubules and have low-grade nuclei;
        
        Inflammatory carcinoma: a swollen erythematous breast w/o a palpable mass. underlying invasive carcinoma generally poorly differentiated and diffusely infiltrates and obstructs dermal lymphatic spaces, causing “inflamed” appearance; true inflammation absent
    - - Race/Ethnicity. highest: European descent (higher incidence of ER-positive); Hispanic and African American: a younger age + more likely to develop aggressive tumors. (a combination of differences in genetics, social factors, and access to health care)
      - Reproductive History. Early age of menarche, nulliparity, absence of breastfeeding, and older age at first pregnancy: incr risk, probably bc each incr exposure of “at-risk” breast epithelial cells to estrogenic stimulation
      - Ionizing Radiation. Radiation to chest if exposure occurs while breast is still developing
      - Others. Postmenopausal obesity, postmenopausal hormone replacement, mammographic density, and alcohol consumption The risk a. w/ obesity probably due to exposure of breast to estrogen produced by adipose tissue. In keeping with this, obesity is only a. w/ an increased risk of tumors that express ER.
      - Geographic Factors. risk significantly higher in Americas and Europe than in Asia and Africa. migrants from lowincidence to high-incidence areas tend to acquire the rates of their new home countries (Diet, reproductive patterns, and breastfeeding practices)
      - Family Hx of Breast Cancer. greatest risk: individuals w/ multiple affected first-degree relatives w/ early-onset breast cancer. most families: combinations of low penetrance, “weak” cancer genes responsible for incr risk.
      - Age and Gender: rare in women <25, but incr in incidence rapidly after 30; 75% older than 50; incidence in men is only 1% of that in women
- - - - morpho: produce cystic masses that may be indistinguishable from serous tumors except by mucinous nature of the cyst contents, are more likely to be larger and multicystic , much
        less likely to be bilateral (useful in differentiating mucinous tumors of ovary from metastatic mucinous adenocarcinoma from a GI tract primary (the so-called “Krukenberg tumor”), which more often produces bilateral ovarian masses)
    - - types
        
        high grade
        
        low grade
      - morpho
        
        gross: cut section: small cystic tumors: single cavity, but larger ones: divided by multiple septa. cystic spaces u. filled w/ a clear serous fluid. Protruding into cystic cavities: papillary projections (more prominent in malignant tumors);
        
        histologic
        
        benign: single layer of columnar epithelial cells lining cyst or cysts. cells often ciliated. Psammoma bodies (concentrically laminated calcified concretions) common in tips of papillae.
        
        malignant: cells markedly atypical, papillary formations are usually complex and multilayered, and nests or sheets of cells invade ovarian stroma.
        
        borderline: less cytologic atypia + no stromal invasion. may seed peritoneum, but u. “noninvasive.”
    - - Table 19-4
- - - - 90%: squamous cell carcinomas: two distinct forms
        
        first form:
        
        less common; related to high-risk HPV strains (esp 16); in middle-aged women, partic cigarette smokers;
        
        often preceded by precancerous changes in epithelium: vulvar intraepithelial neoplasia (VIN): progresses in many to greater degrees of atypia and eventually to carcinoma in situ; progression to invasive carcinoma not inevitable; Environmental factors (cigarette smoking and immunodeficiency) appear to incr risk of such progression
        
        second form:
        
        preceded by a subtle lesion, differentiated vulvar intraepithelial neoplasia (dVIN), characterized by cytologic atypia confined to basal layer and abnormal keratinization. If left untreated it may give rise to HPV negative, well-differentiated, keratinizing squamous cell carcinoma.
        
        in older women, sometimes following a long history of reactive epithelial changes, principally lichen sclerosus.
      - other tumors: adenocarcinomas or basal cell carcinomas
      - morpho: commonly manifest as areas of leukoplakia; In 1/4, lesions pigmented (melanin); With time transformed into overt exophytic or ulcerative endophytic tumors. HPV-positive often multifocal and warty and tend to be poorly differentiated SCCs, whereas HPV-negative u. unifocal and typically are well-differentiated keratinizing SCCs
    - - Condylomata lata: not common; flat, minimally elevated lesions that occur in secondary syphilis
      - condyloMATA acuminata:
        
        gross: more common; may be papillary and distinctly elevated OR somewhat flat and rugose
        
        histologic: charac feature: koilocytosis (a cytopathic change characterized by perinuclear cytoplasmic vacuolization and a wrinkled nuclear contour), a hallmark of HPV infection
  - - - Lichen Simplex Chronicus:
        
        histologic: marked by epithelial thickening (particu of stratum granulosum) and hyperkeratosis; Leukocytic infiltration of dermis sometimes pronounced
        
        gross: smooth, white plaques (leukoplakia)
        
        These nonspecific changes are a consequence of chronic irritation, often caused by pruritus related to an underlying inflammatory dermatosis
      - Lichen Sclerosus
        
        histologic: charac by thinning of epidermis, disappearance of rete pegs, a zone of acellular, homogenized, dermal fibrosis, and a bandlike mononuclear inflammatory cell infiltrate
        
        occurs in all age groups but most commonly: postmenopausal + prepubertal
- - - - clinical presentation: young woman, seeing stains
      - gross: small glandular or microcystic inclusions develop in vaginal mucosa. red mass in ant vaginal wall
      - histologic: lesions appear as red, granular foci lined by mucus-secreting or ciliated columnar cells: vaginal adenosis, benign but important bc it is from such precursor lesions that clear cell adenocarcinoma arises; sheets of cells w/ clear cytoplasm
      - a very rare tumor, identified in a cluster of young women whose mothers took di-ethyl-stil-bestrol during pregnancy to prevent threatened abortion
- - - - HPV-related carcinogenesis begins w/ precancerous epithelial change termed SIL; peaks in incidence at about 30 yrs of age: classification
        
        low-grade (LSIL)
        
        histologic: charac by dysplastic changes in lower third of squamous epithelium and koilocytotic change (a cytopathic change charac by perinuclear cytoplasmic vacuolization (halo) and a wrinkled nuclear contour), a hallmark of HPV infection) in superficial layers of epith
        
        (still often referred to as cervical intraepithelial neoplasia I (CIN I))
        
        high-grade (HSIL)
        
        (cervical intraepithelial neoplasia II and III (CIN II and III))
        
        histologic
        
        CIN II: dysplasia extends to middle third of epithelium in form of variation in cell + nuclear size, heterogeneity of nuclear chromatin, and presence of mitoses, some atypical, above basal layer extending into middle third of epithelium. superficial layer of cells in CIN II still shows differentiation and occasional koilocytotic change
        
        CIN III: almost complete loss of differentiation, even greater variation in cell and nuclear size, chromatin heterogeneity, disorderly orientation of the cells, and abnormal mitoses, changes that affect virtually all layers of epithelium. Koilocytotic change u. absent.
    - - High-risk
        
        most important RF for development of SIL that can progress to carcinoma
        
        infections more likely to persist; propensity to integrate into host cell genome, an event that is linked to progression; precancerous, but majority of them fail to progress to cancer and may even regress.
        
        ex 16 and 18: account for 70% of SIL and cervical carcinoma
      - Low-risk
        
        do not integrate into host genome, remaining instead as free episomal viral DNA.
        
        ex 6 and 11
        
        10x more common than HSIL
- - - - morpho: u. appear as hemorrhagic, necrotic uterine masses. Sometimes necrosis so extensive that little viable tumor remain (primary lesion may “self-destruct,” and only metastases). Very early, tumor insinuates itself into myometrium and into vessels. In contrast w/ hydatidiform moles and invasive moles, chorionic villi are not formed; instead, tumor is composed of anaplastic cuboidal cytotrophoblasts and syncytiotrophoblasts
      - Choriocarcinoma, a very aggressive malignant tumor, arises from gestational chorionic epithelium or, less frequently, from totipotential cells within gonads (as a germ cell tumor).
      - most cases presents as a bloody, brownish discharge accompanied by a rising titer of β-hCG(much higher than those a. w/ a mole) in blood and urine, in absence of marked uterine enlargement, such as would be seen with a mole.
      - Clinical features: gestational ones remarkably sensitive to chemotherapy (100% cured, even those w/ metastases at sites such as lungs) By contrast, response to chemotherapy with choriocarcinomas that arise in gonads (ovary or testis) is relatively poor
    - - Complete
        
        not compatible w/ embryogenesis and rarely contain fetal parts. All chorionic villi abnormal, and the chorionic epithelial cells diploid (46,XX or, uncommonly, 46,XY); entire genetic content supplied by two spermatozoa (or a diploid sperm)
        
        morpho: hydropic swelling of poorly vascularized chorionic villi w/ a loose, myxomatous, edematous stroma. chorionic epithelium: prolif of both cytotrophoblasts and syncytiotrophoblasts. Histologic grading to predict clinical outcome of moles supplanted by monitoring of hCG levels
        
        incidence much higher in Asian countries; most common<20 and >40 years, and a history of the condition incr risk for molar disease in subsequent pregnancies
      - Partial
        
        compatible w/ early embryo formation and may contain fetal parts, has some normal chorionic villi, and is almost always triploid (e.g., 69,XXY); a normal egg is fertilized by two spermatozoa (or a diploid sperm)
        
        villous edema involves only a subset of \villi, and the trophoblastic prolif focal and slight.
      - 80-90% of moles do not recur after thorough curettage, but 10% of complete moles invasive. No more than 2% to 3% give rise to choriocarcinoma