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Reproductive System Pathology - Complete Guide

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PART 1: FEMALE GENITAL SYSTEM

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1. VULVA

Vulvitis

Nonneoplastic Epithelial Disorders

• Thinning of the epidermis, loss of rete ridges, and dense fibrous tissue in dermis
• White, parchment-like plaques on vulva
• Seen in postmenopausal women and young girls
• Associated with slightly increased risk of squamous cell carcinoma (SCC)

• Hyperkeratosis and acanthosis (thickening) of the epithelium
• Caused by chronic rubbing/scratching
• White, thickened skin patches

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Tumors of the Vulva

• Caused by HPV (low-risk types 6 and 11)
• Two types:
  • Condyloma acuminatum - raised, verrucous (cauliflower-like) lesion; benign
  • Condyloma latum - flat lesion of secondary syphilis; NOT HPV related
• Histology: koilocytes (vacuolated cells with wrinkled nuclei = pathognomonic for HPV)

• ~3% of female genital cancers
• Two pathways:
  1. HPV-related (younger women): High-risk HPV (16, 18) → VIN (Vulvar Intraepithelial Neoplasia) → basaloid/warty SCC
  2. Non-HPV-related (older women): Background of lichen sclerosus → keratinizing SCC
• Spreads to inguinal, then pelvic lymph nodes

• Paget cells (large cells with pale cytoplasm) in the vulvar epithelium
• Presents as red, crusted, eczematous lesion
• Unlike breast Paget, vulvar Paget usually has NO underlying carcinoma (only ~25% do)

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2. VAGINA

Vaginitis

• Most common cause: Gardnerella vaginalis (bacterial vaginosis) - "fishy" odor, clue cells on smear
• Trichomonas vaginalis - strawberry cervix, flagellated protozoan
• Candida albicans - cottage cheese discharge, pseudohyphae on KOH prep
• Mucosal atrophy in postmenopausal women → atrophic vaginitis

Malignant Neoplasms

• Rare; mainly in older women
• Most are extensions from cervical carcinoma

• Most common vaginal tumor in infants and children under 5
• Gross: grape-like polypoid masses protruding from vagina
• Micro: "cambium layer" - dense zone of malignant rhabdomyoblasts beneath the epithelium
• Highly aggressive but responds to combination therapy

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3. CERVIX

Cervicitis

• Extremely common; often asymptomatic
• Acute cervicitis: Chlamydia trachomatis (#1 STI cause), Neisseria gonorrhoeae, HSV
• Chronic cervicitis: Most common; caused by normal vaginal flora

• Benign, soft, pedunculated, mucus-secreting mass in cervical canal
• Presents with abnormal vaginal bleeding
• Treated by simple excision

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Neoplasia of the Cervix - VERY HIGH YIELD

• Nearly ALL cervical cancers caused by high-risk HPV (types 16 and 18)
• HPV proteins E6 (degrades p53) and E7 (inactivates Rb) = drive malignant transformation
• The transformation zone (squamocolumnar junction) is the critical target area

• Pap smear is the gold-standard screening tool
• Koilocytes = pathognomonic of HPV infection on Pap smear

• Squamous cell carcinoma = 80% (from exocervix, SIL)
• Adenocarcinoma = 20% (from endocervical glands, also HPV-related)
• Clinical: abnormal vaginal bleeding (especially postcoital), watery discharge
• Spreads locally → bladder, rectum, then lymphatics
• FIGO staging determines treatment:
  • Stage I: Confined to cervix
  • Stage II: Beyond cervix, not to pelvic wall
  • Stage III: To pelvic wall or lower 1/3 vagina
  • Stage IV: Bladder/rectum or distant

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4. UTERUS

Endometritis

• Acute: Postpartum, post-abortion; caused by Group B Streptococcus, Staphylococcus; retained products of conception predispose
• Chronic: Chlamydia, gonorrhea, TB (in endemic areas); plasma cells in endometrium = diagnostic hallmark (plasma cells are NOT normally present in endometrium)

Adenomyosis

• Endometrial glands and stroma present deep within the myometrium
• Causes: uterine enlargement, dysmenorrhea, menorrhagia
• Differs from endometriosis (adenomyosis is INSIDE the uterine wall, not outside)

Endometriosis

• Endometrial glands/stroma outside the uterus
• Common sites: ovaries (#1), uterine ligaments, rectovaginal septum, pelvic peritoneum
• Classic triad: dysmenorrhea, dyspareunia, infertility
• Ovaries → "chocolate cysts" (endometriomas filled with old blood)
• Theories of origin: retrograde menstruation (Sampson), coelomic metaplasia
• Responds to hormonal therapy (estrogen-suppressive) or surgical excision

Abnormal Uterine Bleeding

• Most common cause varies by age:
  • Reproductive age: anovulation → unopposed estrogen → endometrial hyperplasia
  • Postmenopausal: endometrial carcinoma until proven otherwise
• Also: fibroids (leiomyomas), polyps, coagulation defects

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Proliferative Lesions of the Endometrium and Myometrium

• Caused by unopposed estrogen (anovulation, obesity, HRT without progesterone, estrogen-secreting ovarian tumors)
• Classification:
  • Simple hyperplasia (without atypia): Low risk of cancer (~1%)
  • Complex hyperplasia (without atypia): ~3% risk
  • Simple/Complex with atypia (EIN - Endometrial Intraepithelial Neoplasia): ~30% risk of carcinoma; precursor lesion
• Treated with progestins or hysterectomy if atypia present

• Most common gynecologic malignancy in the US (NOT the most common cause of cancer death - ovarian is more deadly)
• Two types:

• Presents as postmenopausal bleeding (#1 symptom)
• Diagnosis: endometrial biopsy
• Treatment: hysterectomy + bilateral salpingo-oophorectomy ± radiation

• Benign, protruding masses of endometrial glands and stroma
• Cause abnormal uterine bleeding
• Small malignant potential

• Most common tumor in women; found in ~25% of reproductive-age women
• Benign smooth muscle tumors of the myometrium
• Estrogen-dependent → grow during reproductive years, shrink after menopause
• Gross: well-circumscribed, firm, whorled white masses
• Multiple types: intramural, submucosal (bleed most), subserosal
• Symptoms: menorrhagia, pelvic pressure, urinary symptoms
• Most are asymptomatic; treatment if symptomatic (myomectomy, hysterectomy, GnRH agonists)

• Malignant smooth muscle tumor; usually arises de novo (NOT from pre-existing leiomyoma)
• More common in older/postmenopausal women
• Criteria: >10 mitoses per 10 HPF, coagulative tumor cell necrosis, cytologic atypia
• Poor prognosis

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5. FALLOPIAN TUBES

Salpingitis (Pelvic Inflammatory Disease - PID)

• Most common cause of fallopian tube pathology
• Agents: Chlamydia trachomatis (#1), N. gonorrhoeae; often polymicrobial
• Leads to: hydrosalpinx (tube distended with fluid), pyosalpinx (pus), adhesions
• Major complication: ectopic (tubal) pregnancy (risk increases 6-10x with prior salpingitis)
• Also causes infertility via tubal scarring

Ectopic Pregnancy

• 95% in fallopian tube (ampulla most common site)
• Risk factors: prior PID, previous ectopic, endometriosis, IUD
• Presents with: missed period, pelvic pain, rupture → surgical emergency
• Rupture → hemoperitoneum, shock

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6. OVARIES

Follicle and Luteal Cysts

• Common, usually asymptomatic
• Follicular cysts: unruptured Graafian follicle lined by granulosa cells; may cause pain or abnormal bleeding
• Corpus luteum cysts: may cause delayed menstruation, rupture → hemoperitoneum

Polycystic Ovarian Syndrome (PCOS)

• Most common endocrine disorder in women of reproductive age
• Features: oligomenorrhea/amenorrhea, hirsutism, obesity, infertility
• Labs: elevated LH:FSH ratio (>2:1), elevated androgens, insulin resistance
• Grossly: enlarged ovaries with multiple small follicular cysts (≤1 cm), thickened cortex
• Long-term risk: endometrial hyperplasia/carcinoma (from unopposed estrogen), type 2 diabetes, metabolic syndrome

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Tumors of the Ovary - HIGH YIELD

• 80% arise from surface epithelium (covering of ovary = modified peritoneum)
• Risk factors: family history (BRCA1/2), nulliparity, early menarche, late menopause
• Protective: OCPs, multiparity, breastfeeding, tubal ligation

• Most common ovarian tumors
• Lined by Fallopian tube-type epithelium (tall, ciliated columnar cells)
• Types: Benign (serous cystadenoma), Borderline, Malignant (serous cystadenocarcinoma)
• Serous cystadenocarcinoma = most common ovarian malignancy
• Psammoma bodies (laminated calcified concentric spheres) = characteristic finding in serous carcinoma
• Bilateral in ~30% of malignant cases
• Genetic: low-grade → KRAS/BRAF mutations; high-grade → TP53 mutations

• Lined by mucin-secreting columnar cells (resembling endocervical or intestinal epithelium)
• Tend to be large, multilocular
• Rupture → pseudomyxoma peritonei (jelly-like mucin filling peritoneal cavity)
• Bilateral in only ~5% of benign cases
• Less common than serous

• Glands resembling endometrium
• Usually malignant
• 15-20% coexist with endometrial carcinoma (synchronous tumors)
• Mutations: PTEN, PI3K-AKT pathway

• Large cells with clear cytoplasm
• Associated with endometriosis
• Same mutations as endometrioid (PIK3CA, ARID1A, KRAS, PTEN, TP53)

• 15-20% of ovarian tumors; >90% are benign
• Mature (Dermoid Cyst):
  • Contains fully differentiated tissues from all 3 germ layers (skin, hair, teeth, thyroid, bronchial epithelium)
  • Most common ovarian tumor in young women and children
  • Usually unilateral (right side more common)
  • Usually <10 cm
  • Risk: torsion; rarely malignant transformation (SCC most common)
• Immature Teratoma:
  • Contains immature (fetal) tissue, especially immature neural elements
  • Malignant; occurs in first 2 decades
  • Graded 1-3 based on amount of immature neural tissue
• Monodermal Teratoma:
  • Struma ovarii (thyroid tissue) → can cause hyperthyroidism
  • Carcinoid tumors

• Counterpart of testicular seminoma
• Most common malignant germ cell tumor of ovary
• Occurs in young women
• Radiosensitive; excellent prognosis
• Cells: large, pale, glycogen-rich; lymphocytic infiltrate + fibrous septa

• Occurs in children/young adults
• Produces AFP (alpha-fetoprotein) = tumor marker
• Schiller-Duval bodies (perivascular structures resembling fetal glomeruli)

• Most common malignant stromal tumor
• Produces estrogen → precocious puberty (in children) or postmenopausal bleeding
• Call-Exner bodies (small follicle-like structures with eosinophilic fluid) = pathognomonic
• Tumor marker: Inhibin
• Low-grade malignancy; late recurrence possible

• Fibroma: benign, fibrous stromal cells; associated with Meigs syndrome (ovarian fibroma + ascites + hydrothorax)
• Thecoma: produces estrogen

• Produces androgens → virilization
• Low malignant potential

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7. GESTATIONAL TROPHOBLASTIC DISEASE (GTD)

• Complete mole karyotype: 46,XX (both chromosomes paternal - "androgenetic diploid")
• All GTD monitored by serial serum beta-hCG levels
• Choriocarcinoma is HIGHLY chemosensitive (methotrexate, actinomycin-D); excellent cure rates even with metastases

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PART 2: MALE GENITAL SYSTEM

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8. PENIS

Congenital Anomalies

• Hypospadias: Urethral opening on ventral (under) surface of penis - more common (~1/300 births)
• Epispadias: Urethral opening on dorsal (upper) surface - less common
• Both can cause: urinary obstruction, ascending infections, infertility (if at base of penis)

Phimosis

• Prepuce (foreskin) orifice too small to retract over glans
• Causes: congenital or acquired (from recurrent infections and scarring)
• Complications: accumulation of smegma → secondary infections → increased risk of penile carcinoma

Inflammation

• Balanoposthitis: Infection of glans + prepuce; organisms include Candida, anaerobes, Gardnerella
• More common in uncircumcised males

Tumors of the Penis

• Benign wart from HPV types 6 and 11
• Histology: koilocytes; papillary lesion

• Three histologic subtypes; all caused by high-risk HPV 16, 18:
  • Bowen Disease: Leukoplakia-like plaque on shaft
  • Erythroplasia of Queyrat: Red, velvety, moist plaque on glans (higher risk of invasive carcinoma)
  • Bowenoid Papulosis: Multiple small papules; occurs in younger men; rarely progresses

• ~1% of male cancers in the US
• Risk factors: phimosis, HPV 16/18, poor hygiene, no circumcision (circumcision is protective)
• Slow-growing, spreads to inguinal → iliac lymph nodes
• Prognosis depends on lymph node involvement

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9. TESTIS

Cryptorchidism (Undescended Testis)

• ~1% of males at 1 year of age
• Most common anomaly of male genitalia
• Risk: germ cell tumors (3-5x increased risk, even in contralateral testis); infertility
• Histology: tubular atrophy, Leydig cell hyperplasia, basement membrane thickening
• Treatment: orchiopexy before age 2 (improves fertility; does NOT eliminate cancer risk)

Orchitis

• Granulomatous orchitis: Idiopathic; presents as painless testicular mass
• Mumps orchitis: In post-pubertal males (prepubertal = usually asymptomatic); 20-30% bilateral → infertility

Testicular Torsion

• Twisting of spermatic cord → venous obstruction → arterial ischemia → infarction
• Classic "bell-clapper deformity" (improperly attached tunica vaginalis)
• Surgical emergency; must be corrected within 4-6 hours

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Testicular Tumors - HIGH YIELD

• Most common cancer in males aged 15-35
• 95% are germ cell tumors
• Risk factors: cryptorchidism, Klinefelter syndrome, family history
• Presents as painless testicular mass (pain = late or torsion)
• Tumor markers: AFP, beta-hCG, LDH

• Seminoma: radiosensitive, spreads to para-aortic nodes first, excellent cure
• Non-seminoma: chemotherapy (BEP - bleomycin, etoposide, cisplatin)

• Older men (>50)
• No known association with cryptorchidism
• Benign behavior; does NOT metastasize

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10. EPIDIDYMIS AND SPERMATIC CORD

Epididymitis

• Most common cause:
  • Young sexually active men: Chlamydia trachomatis or N. gonorrhoeae
  • Older men or children: E. coli, Pseudomonas (from UTI)
• Clinical: painful testicular swelling, fever; Prehn sign (elevation of testis relieves pain in epididymitis - helps distinguish from torsion)

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11. PROSTATE

Benign Prostatic Hyperplasia (BPH)

• Extremely common in men >50 (50% by age 60, 90% by age 80)
• Hyperplasia (not hypertrophy) of both glandular epithelium AND stromal smooth muscle
• Occurs in the central/transitional zone (periurethral zone)
• Obstructive symptoms (LUTS): hesitancy, poor stream, dribbling, nocturia, urinary retention
• PSA may be mildly elevated
• Histology: nodular glandular and stromal proliferation with corpora amylacea (prostatic concretions)
• Treatment: alpha-blockers (tamsulosin), 5-alpha-reductase inhibitors (finasteride), surgery (TURP)

Prostatitis

• Acute bacterial: Fever, dysuria, perineal pain; E. coli most common; PSA elevated
• Chronic bacterial: Recurrent UTIs, perineal discomfort; E. coli most common
• Chronic pelvic pain syndrome (non-bacterial): Most common form; no organism identified
• Granulomatous prostatitis: After BCG therapy for bladder cancer

Prostatic Adenocarcinoma - VERY HIGH YIELD

• Most common cancer in men in the US
• Second most common cause of cancer death in men (after lung)
• Risk factors: age (>50), African-American race, family history, high-fat diet
• Arises in the peripheral zone (posterior aspect, palpable on DRE)
• Often initially asymptomatic (contrast with BPH which is symptomatic)
• Symptoms when advanced: obstructive symptoms, bone pain (osteoblastic metastases - lumbar spine most common)

• Based on glandular architecture (not cytology)
• Grade 1 = well-formed glands; Grade 5 = no glandular differentiation
• Gleason score = primary pattern + secondary pattern (most common + second most common)
• Range: 2-10; higher score = worse prognosis
• Grade Groups 1-5 (modern system):
  • Grade Group 1 = Gleason ≤6 (low risk)
  • Grade Group 5 = Gleason 9-10 (very high risk)

• Most common driver: TMPRSS2-ERG gene fusion (androgen-regulated TMPRSS2 promoter fused to ETS transcription factor ERG) → androgen-dependent overexpression of ERG
• Other: PTEN loss, TP53 mutations in advanced disease

• Organ-specific (not cancer-specific) serine protease
• Elevated in: cancer, BPH, prostatitis, trauma
• PSA density, PSA velocity, free:total PSA ratio improve specificity
• Screening: controversial; benefits vs. overdiagnosis

• Localized: radical prostatectomy or radiotherapy (external beam or brachytherapy)
• Metastatic: androgen deprivation therapy (ADT) via orchiectomy OR LHRH agonists (leuprolide, goserelin) - desensitize pituitary → suppress LH → reduce testosterone
• Castration-resistant prostate cancer (CRPC): enzalutamide, abiraterone

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SUMMARY TABLE: KEY Tumor Markers

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SUMMARY TABLE: Key Histologic Findings

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SUMMARY TABLE: HPV Types to Know

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• Robbins & Kumar Basic Pathology, Chapter 17: Female Genital System and Breast
• Robbins, Cotran & Kumar Pathologic Basis of Disease, Chapter on Male Genital Tract

• Surface Epithelial Tumors (80%) - serous, mucinous, endometrioid, clear cell
• Germ Cell Tumors (15%) - teratoma, dysgerminoma, yolk sac, choriocarcinoma
• Sex Cord-Stromal Tumors (5%) - granulosa cell, thecoma-fibroma, Sertoli-Leydig

• Seminoma vs. Non-seminomatous GCT breakdown
• Embryonal, yolk sac, choriocarcinoma, teratoma, mixed GCT
• Non-germ cell: Leydig, Sertoli, Spermatocytic tumor