Reproductive System; Pathology

Vulva
 Inflammatory dermatologic diseases that affect skin elsewhere  also occur on the vulva,
such as psoriasis, eczema, and allergic dermatitis
 more prone to skin infections,  constantly exposed to secretions and moisture
 Nonspecific vulvitis  due to immunosuppression
 Most skin cysts (epidermal inclusion cysts) and skin tumors also occur.

Bartholin Cyst
 Infection of the Bartholin gland  acute inflammation within the gland (adenitis) /+
leading to abscess  require drainage.
 Bartholin duct cysts  relatively common  result from obstruction of the duct by an
inflammation.
 Cysts lined by flattened epithelium; can be large (i.e., 3 to 5 cm diameter) and painful

Non-Neoplastic Epithelial Disorders

 A heterogeneous group of lesions—clinically designated leukoplakia— manifest as opaque,
white, plaque-like thickenings and are often accompanied by pruritus and scaling.
 Pathologic evaluation is required to distinguish inflammatory etiologies from neoplastic
causes.

Lichen Sclerosus
 Lesions begin as papules or macules that eventually coalesce into smooth, white
parchment-like areas.
 Microscopically, there is:
 epidermal thinning,
 disappearance of rete pegs,
 hydropic degeneration of the basal cells,
 superficial hyperkeratosis, and
 dermal fibrosis with a scant mononuclear perivascular infiltrate.
 When entire vulva is affected, the labia can become atrophic and stiffened, with
constriction of the vaginal orifice.
 occurs in all age groups but is most common in postmenopausal women.
 An autoimmune response is implicated because:
 presence of activated T cells in the subepithelial inflammatory infiltrate, and
  the increased frequency of autoimmune disorders in these women

Squamous Cell Hyperplasia

 Also called lichen simplex chronicus, this is a non-specific response to recurrent rubbing or
scratching to relieve pruritus.
 It is characterized by white plaques that histologically reveal thickened epithelium, surface
hyperkeratosis, expansion of the stratum granulosum, and dermal inflammation.
 Does not exhibit epithelial atypia
 No increased predisposition to malignancy, But often present at the margins of vulvar
carcinoma.

Benign Exophytic Lesions

 As opposed to condyloma acuminatum/Genital warts (due to human papillomavirus [HPV]
infection), or condyloma latum (due to syphilis), vulvar fibroepithelial polyps (skin tags)
and squamous papillomas are not related to any infectious agent.
 Papillomas are benign exophytic proliferations lined by non-keratinizing squamous
epithelium and can be single or numerous (vulvar papillomatosis).

Condyloma Acuminatum
 sexually transmitted,
 benign lesions
 distinct verrucous gross appearance
 more frequently multifocal: they may involve vulvar, perineal, and perianal regions as well
as the vagina and, less commonly, the cervix.
 The lesions are identical to those found on the penis and around the anus in males
 HPV types 6 or 11.
 Histologically, they consist of branching, treelike cores of stroma covered by thickened
squamous epithelium
 Mature superficial cells exhibit nuclear enlargement, hyperchromasia, and a cytoplasmic
perinuclear halo (koilocytotic atypia).
 Not considered pre-cancerous.

Squamous Neoplastic Lesions

Vulvar Intraepithelial Neoplasia and Vulvar Carcinoma******
 Carcinoma of the vulva  uncommon; (approximately one eighth as frequent as cervical
cancer)
 Squamous cell carcinoma  most common type of vulvar cancer
 Vulvar squamous cell carcinomas divided into:
 1. basaloid and warty carcinomas: related to infection with high oncogenic risk HPVs
(30% of cases)
 2. keratinizing squamous cell carcinomas: not related to HPV infection (70% of cases).
 Basaloid and warty carcinomas:
 arise from precancerous in situ lesions called classic vulvular intraepithelial neoplasia
(classic VIN) (previously designated carcinoma in situ or Bowen disease);
 most are positive for HPV 16; less frequently HPV 18 or 31.
 often associated with vaginal and/or cervical HPV-related lesions.
 Cancer risk increases with age and with immunosuppression.
 Morphology
 Classic VIN lesions:
 manifest as discrete, hyperkeratotic, fleshcolored or pigmented, slightly raised
plaques.
 Typically multicentric (10% to 30% of patients with VIN also have vaginal or
cervical HPV-related lesions)
 demonstrate marked nuclear atypia increased mitosis and lack of cellular
maturation.
 analogous to cervical squamous intraepithelial lesions
 Basaloid carcinoma: can be exophytic or indurated, often with ulceration; the
tumors are characterized by nests and cords of small, tightly packed cells resembling
immature basal cells.
 Warty carcinoma exhibits exophytic architecture with prominent koilocytic atypia.

Glandular Neoplastic Lesions

Papillary Hidradenoma
 This benign tumor arises from modified apocrine sweat glands.
 may be confused clinically with carcinoma because of its tendency to ulcerate.
 Gross: presents as a sharply circumscribed nodule, most commonly on the labia majora or
interlabial folds.
 Histology: consists of papillary projections covered with two layers of cells: the top
columnar, secretory cells and an underlying layer of flattened “myoepithelial cells.
 identical in appearance to intraductal papillomas of the breast

Extramammary Paget Disease

 Rare
 as a pruritic, red, crusted, sharply demarcated, maplike area, occurring usually on the labia
majora + may be accompanied by a palpable submucosal thickening or nodule.


Malignant Melanoma
 Melanomas of the vulva are rare
 Representing less than 5% of all vulvar cancers and 2% of all melanomas in women.
 they have a peak incidence between ages 60 and 80 years.
 Histologic characteristics are comparable to melanomas at other sites + capable of
widespread metastatic dissemination.
 5-year survival is less than 32% due to delays in detection and rapid progression to a
vertical growth phase.
 It can usually be differentiated by from Paget disease:
 its uniform reactivity with antibodies to S100 protein,
 absence of reactivity with antibodies to cytokeratin, and
 lack of mucopolysaccharides.

Cervix

Cervicitis
 Inflammatory conditions of the cervix are extremely common
 may be associated with a purulent vaginal discharge
 Cervicitis can be subclassified as infectious or noninfectious.
 differentiation is difficult owing to the presence of normal vaginal flora including
incidental vaginal aerobes and anaerobes, streptococci, staphylococci, enterococci, and
Escherichia coli and Candida spp.
 Much more important are:
 Chlamydia trachomatis,
 Ureaplasma urealyticum,
 T. vaginalis,
 Neisseria gonorrhoeae,
 HSV-2 (the agent of herpes genitalis), and certain types of HPV, all of which are often
sexually transmitted.
 C. trachomatis; most common; 40% of cases.

Neoplasia of Cervix
Pathogenesis
Risk factors: Common risk factors of CIN and carcinoma of cervix include:
(1) human papilloma virus,
(2) environmental factors.

Human Papillomavirus Infection

 tropism for the immature squamous cells of the transformation zone.
 Most infections are transient and are eliminated within months by the host
immune response
 Persists to squamous intraepithelial lesions (SILs), which are precursors from
which most invasive cervical carcinomas develop
 Virions must be shed from the surface of the squamous mucosa, yet under
normal circumstances squamous cell maturation is accompanied by a cessation
of DNA replication, which would prevent virus production
 Risk factors for CIN and carcinoma cervix related to HPV exposure:
 1. Early age at first intercourse
 2. Multiple sexual partners
 3. Male partner with multiple previous sexual partners.
 4. Persistent infection with High-risk HPV (16 and 18).
 5. Inefficient immune system.
 Classification of HPV:
 A. Low oncogenic risk:
 Type 6 and 11
 development of condylomas of the lower genital tract.
 express E6 and E7 variants with different or weaker activities and do not
integrate into the host genome, remaining instead as free episomal viral
DNA
 B. High oncogenic risk:
 Types 16 and 18
 Major risk factor for development of SIL that can progress to carcinoma.
 70% cases
 show a propensity to integrate into the host cell genome.
 Oncogenesis by HPV:
 Actions of E7 protein of HPV: (1) Inactivation of RB and inhibition of cyclin-
dependent kinase inhibitors (e.g. p21 and p27). These two actions increases
progression of cell cycle and impair the ability of cells to repair DNA damage.
 Actions of E6 protein of HPV: (1) Degradation of the tumor suppressor
protein p53 and up-regulates the expression of telomerase leads to cellular
immortalization.
 Integration of viral DNA into the host cell genome: 1) integration always
disrupts an HPV gene that negatively regulates E6 and E7, which leads to
 their increased expression; and 2) sometimes HPV integrates near a host cell
oncogene such as MYC, leading to its overexpression as well
 Extrachromosomal (episomal) form of viral DNA: It is observed in precursor
lesions associated with high-risk HPVs and in condylomata associated with
low-risk HPVs.

Uterus

Endometritis
 Inflammation of the endometrium
 classified as acute or chronic depending on whether a neutrophilic or a lymphoplasmacytic
infiltrate predominates
 Acute endometritis:
 uncommon
 usually caused by bacterial infections occurring after delivery or miscarriage and is
related to retained products of conception. Curettage and antibiotics are usually
sufficient therapy.
 Chronic endometritis:
 diagnosis of chronic endometritis generally requires the presence of plasma cells, as
lymphocytes are present even in the normal endometrium.
 occurs in patients with:
 Chronic PID (Chlamydia; most common, N. gonorrhoeae)
 Retained gestational tissue post-abortion or postpartum
 Intrauterine contraceptive devices
 Disseminated tuberculosis (rare), (granulomatous endometritis, along with
tuberculous salpingitis and peritonitis)
 15% have no obvious cause
 Clinical Presentation:
 fever,
 abdominal pain,
 menstrual abnormalities
 increased risk of infertility
 ectopic pregnancy due to damage and scarring of the fallopian tubes.
Adenomyosis
 Definition: Adenomyosis is defined as the presence of endometrial tissue within the
myometrium (uterine wall).
 Nests of endometrial stroma, glands, or both are found deep in the myometrium
(interposed between the muscle bundles), and continuous with endometrial lining.
 Induces reactive hypertrophy of the myometrium, resulting in an enlarged, globular uterus,
with a thickened uterine wall.
 Clinically: produce menorrhagia, dysmenorrhea, and pelvic pain, particularly just prior to
menstruation, and can coexist with endometriosis

Endometriosis
 Definition: Endometriosis is the presence of endometrial glands and stroma) outside of the
uterus.
 Involves:
 pelvic structures (ovaries, pouch of Douglas, uterine ligaments, tubes, and rectovaginal
septum).
 Less frequently, distant areas of the peritoneal cavity or periumbilical tissues are
involved.
 Uncommonly, distant sites such as lymph nodes, lungs, and even heart, skeletal muscle,
or bone are affected
 Age: 10% of women in their reproductive years and in nearly half of women with infertility
 Four hypotheses:
 The regurgitation theory, which is currently favored, proposes that menstrual backflow
through the fallopian tubes leads to implantation.
 The benign metastases theory holds that endometrial tissue from the uterus can
“spread” to distant sites via blood vessels and lymphatics.
 The metaplastic theory, on the other hand, posits endometrial differentiation of
coelomic epithelium (mesothelium of pelvis and abdomen from which endometrium
originates) as the source.
 The extrauterine stem/progenitor cell theory, proposes that circulating stem/progenitor
cells from the bone marrow differentiate into endometrial tissue
 Molecular changes:
 endometriotic tissue exhibits increased levels of inflammatory mediators, particularly
prostaglandin E2  recruitment and activation of macrophages by factors made by
endometrial stromal cells  inflammation.
 Stromal cells make aromatase  local production of estrogen.
  These factors enhance the survival and persistence of the endometriotic tissue within a
foreign location (a key feature in the pathogenesis of endometriosis)
 help to explain the beneficial effects of COX-2 inhibitors and aromatase inhibitors in the
treatment of endometriosis
 Clinical Presentation:
 Severe dysmenorrhea
 pelvic pain resulting from intra-pelvic bleeding and intra-abdominal adhesion
 discomfort in the lower abdomen and infertility (due to extensive scarring of the
fallopian tubes and ovaries)
 pain on defecation (Rectal wall involvement)
 dyspareunia (painful intercourse) and dysuria (involvement of the uterine or bladder
serosa)

GERM CELL TUMORS

Breast

Disorders of Development
 Milkline remnants:
 These can produce hormone responsive supernumerary nipples or breast tissue from
the axilla to the perineum.
 These mainly come to attention secondary to painful pre-menstrual enlargement.
 Accessory axillary breast tissue:
 Occasionally, normal ductal tissue extends into subcutaneous tissue of the axilla or chest
wall.
 present as a lump in the setting of lactational hyperplasia, or it can give rise to
carcinoma outside the breast proper.
 Congenital nipple inversion:
 Common
 Usually corrects during pregnancy or with traction;
 acquired nipple inversion is concerning for carcinoma or inflammatory conditions

Clinical Presentations of Breast Disease

Most symptomatic breast lesions (>90%) are benign.
Of women with cancer, about 45% have symptoms, whereas the remainder come to attention
through screening tests
1. Pain (mastalgia or mastodynia):
 common
 Diffuse cyclic pain (related to menses)  possibly due to cyclic edema and swelling, No
pathologic correlate  Therapy targets hormonal levels.
 Non-cyclic pain  localized + secondary to infection, trauma, or ruptured cysts.
 95% of painful masses are benign, although 10% of breast cancer presents with pain.
2. Inflammation:
 edematous and erythematous breast.
 Rare
 most often caused by infections, which only occur with any frequency during lactation and
breastfeeding.
 “inflammatory” breast carcinoma.
3. Nipple discharge:
 normal when small in quantity and bilateral
 most common benign lesion  papilloma arising in the large ducts below the nipple
 Discharges that are spontaneous, unilateral, and bloody  greatest concern for
malignancy.
 Note:
 Bloody or serous discharges  most commonly due to cysts or intraductal papillomas,
and benign bloody discharge can also occur during pregnancy.
 Milky discharge (galactorrhea) outside of pregnancy related to:
 prolactin-producing pituitary adenomas,
 hypothyroidism,
 anovulatory cycles, or
 certain medications
4. Lumpiness:
 Or a diffuse nodularity throughout the breast.
 result of normal glandular tissue
 Imaging studies may help to determine.
5. Palpable masses:
 arise from proliferations of stromal cells or epithelial cells
 generally detected when they are 2 to 3 cm in size
 Most (~95%) are benign  tend to be round to oval and to have circumscribed borders.
 Malignant tumors usually invade across tissue planes and have irregular borders.
 However, because some cancers grow deceptively as circumscribed masses, all palpable
masses require evaluation.
 Women< 40 years  10% of palpable masses carcinomas, Women > 50  60% masses
carcinomas.
6. Gynecomastia:
 Common in males only.
 increase in both stroma and epithelial cells
 due to imbalance between estrogens, which stimulate breast tissue, and androgens.
Mammographic screening
 means to detect early, nonpalpable asymptomatic breast carcinomas before metastatic
spread has occurred.
 Can detect about 1 cm size of carcinoma, and only 15% will have metastasized to regional
lymph nodes at the time of diagnosis.
 Principal mammographic signs associated with carcinoma are densities and calcifications.
 Most neoplasms (benign and malignant)  radiologically denser than normal breast
tissue;
 Calcifications form on secretions, necrotic debris, or hyalinized stroma and are
associated with both benign and malignant lesions.
 Likelihood that an abnormal mammographic finding is caused by malignancy increases with
age, from 10% at age 40 to more than 25% in women older than age 50.
 Note:
 The sensitivity and specificity of mammography increases with age, due to the
progressive replacement of radiodense fibrous youthful breast tissue with fatty,
radiolucent stroma.
 At age 40 years, mammographic lesions reflect carcinoma in only 10% of cases; this
increases to 25% in patients older than 50 years.

INFLAMMATORY PROCESSES
 Rare
 caused by infections, autoimmune disease, or foreign body–type reactions
 Symptoms:
 Erythema
 edema,
 pain
 focal tenderness
 possibility that the symptoms are caused by inflammatory carcinoma should always be
considered
 Staphylococcus aureus:
