Reproductive Pathology Flashcards
ddx for testicular lesions
*tender: torsion, orchitis, epididymitis
*non-tender:
1. hydrocele (transillumination +)
2. varicocele (“bag of worms”)
3. malignancy (testicular cancer, lymphoma)
testicular neoplasms - epidemiology
*Caucasian males between 15-45 years
*risk factors:
-associated with cryptorchidism
-intersex syndromes (androgen insensitivity syndrome; gonadal dysgenesis)
-family history (fathers & sons; 8-10x increased risk)
-increased risk in contralateral testis
testicular neoplasms - pathogenesis
*poorly understood
*precursor lesion = germ cell neoplasia in situ
testicular neoplasms - clinical examples
*painless, solid testicular masses
- seminomas:
-may reach considerable size before diagnosis
-metastases occur first in abdominal lymph nodes
-hematogenous metastases occur late - non-seminomatous tumors (NSGCT):
-may have widespread metastases (liver/lungs)
-absent palpable testicular mass
testicular neoplasms - serum markers
*useful in diagnosis and following therapeutic response
1. alpha fetoprotein (AFP)
2. hCG
testicular neoplasms - treatment
*radical orchiectomy (diagnosis & treatment - presumption of malignancy)
seminoma - overview
*most common germ cell tumor in males
*present with bulky mass:
-soft, well-demarcated, gray-white tumor
-confined to tunica albuginea
seminoma - pathology
*large, uniform cells with distinct borders, abundant clear cytoplasm (fried egg appearance)
*lymphocytic infiltrate present
*few syncytiotrophoblasts release hCG (minimally elevated serum levels)
embryonal carcinoma (testicular neoplasm)
*type of non-seminomatous germ cell tumors
*peak incidence 3rd decade of life
*classic presentation: PAINFUl mass, elevated hCG
*more aggressive than seminoma: vascular-lymphatic invasion is common
*ill-defined, invasive mass; extends through albuginea, epididymis, spermatic cord
*undifferentiated cells forming sheets; frequent component of mixed tumors
yolk sac tumor (testicular neoplasm)
*type of non-seminomatous germ cell tumors
*prepubertal, usually < 3 years of age
*histology:
1. Schiller-Duval bodies = perivascular growth (resemble glomeruli)
2. hyaline globules with elevated alpha-fetoprotein (AFP)
choriocarcinoma (testicular neoplasm)
*type of non-seminomatous germ cell tumors
*highly malignant; widespread metastases (liver, lungs); often associated with hemorrhage
*hCG MARKEDLY ELEVATED
*differentiate into placental trophoblasts:
-cytotrophoblasts = small cuboidal cells
-syncytiotrophoblasts = multinucleated cells
teratoma (testicular neoplasm)
*type of non-seminomatous germ cell tumors
*present any time from infancy to adulthood
*germ cells differentiate along MULTIPLE cell lineages:
-heterogenous collection of differentiated organoid structures
-neural brain tissue, cartilage, skin, thyroid, bronchi, intestine
where is BPH most commonly found in the prostate gland?
TRANSITION ZONE of prostate
benign prostatic hyperplasia (BPH) - overview
*common cause of prostatic enlargement
*increased frequency progressively with age, reaching 90% by 8th decade of life
benign prostatic hyperplasia (BPH) - pathogenesis
*excessive androgen-dependent growth of stromal and glandular elements:
-dihydrotestosterone (DHT) synthesized by 5-alpha reductase mediates prostatic growth
benign prostatic hyperplasia (BPH) - clinical presentation
*lower urinary tract obstruction sx:
-difficulty in starting urine stream, intermittent interruption of stream while voiding
-urgency, frequency, nocturia
*increased risk of UTI due to incomplete voiding
*may completely obstruct urinary tract
benign prostatic hyperplasia (BPH) - pathology
*well-circumscribed nodules:
-inner periurethral/transition zone
-urethra compressed to slit
-bulge from cut surface
*variable proportion of glands and fibromuscular stroma:
-small to large to cystic glands
-infolding glands produce a papillary architecture
benign prostatic hyperplasia (BPH) - treatment
- 5-alpha reductase inhibitors (finasteride, dutasteride - inhibit DHT formation)
- alpha-1 adrenergic receptor antagonists (tamsulosin, terzosin - relax prostatic smooth muscle)
- surgical techniques for unresponsive cases
prostatic adenocarcinoma - overview
*most common cancer in men
*20% of all male cancers (2nd cause of cancer-related death in men)
*disease of aging; increased incidence after 50 years
prostatic adenocarcinoma - pathogenesis
*androgens: induce expression of pro-growth and pro-survival genes
*inherited genetic factors: increased risk if first-degree relative with prostate cancer
*acquired genetic aberrations
prostatic adenocarcinoma - clinical findings
*most are asymptomatic lesions
*subset detected on digital rectal exam or needle biopsy to investigate increased PSA
prostatic serum antigen (PSA)
*product of normal and neoplastic prostatic epithelium
*increases with age
*serum assay widely used in diagnosis/management of prostate cancer
*limitations: NOT cancer-specific
prostatic adenocarcinoma - treatment
*localized: radical prostatectomy and radiotherapy
*“watchful waiting” approach for older men
*metastatic carcinoma: treated by androgen deprivation
prostatic adenocarcinoma - pathology
*usually located in peripheral zone; does not produce urinary symptoms
*malignant glands may be admixed with benign:
-nucleoli
-perineural invasion
-absent basal cells
-racemase positive
prostatic adenocarcinoma - grading (Gleason Score)
*architecture of glands from multiple (at least 2) zones
*smaller glands = higher score from 1-5
*higher score = worse prognosis
how does HPV transform cells?
*high-risk HPV types express oncoproteins which immortalize epithelial cells:
1. E6: prevents apoptosis (degrades p53); activates telomerase
2. E7: allows progression in cell cycle; binds RB and displaces E2F; blocks p21 and p27
*co-transfection with a mutated RAS gene results in full malignant transformation
HPV oncogenesis
*implicated in the genesis of several cancers:
-benign squamous papillomas (warts)
-squamous cell carcinomas (cervical, anogenitial, oropharynx)
*low risk types = 6 and 11
*high risk types = 16, 18, 31, 33, 35
cervical dysplasia - pathogenesis
*HPV; tropic for immature squamous cells in transformation zone
*squamous intraepithelial lesions (SIL):
-precancerous epithelial changes
-PAP smear = screening (cells scraped from transformation zone)
-determines low-grade vs. high-grade SIL
cervical carcinoma - overview
*arises from cervical epithelium
*usually from ectocervical squamous epithelium = squamous cell carcinoma (SCC)
*some arise from endocervical glands = adenocarcinoma
*4th most common cancer in women
*9valent vaccine very effective in preventing HPV infection
cervical carcinoma - clinical presentation
*most commonly middle-aged women (40-50 years)
1. vaginal bleeding, esp post-coital
2. cervical discharge
*risk factors:
-high risk HPV (16, 18)
-smoking
-immunodeficiency
cervical carcinoma - pathology
*fungating (exophytic) or infiltrative masses
1. squamous cell carcinoma:
-nests/tongues of malignant squamous epithelium, either keratinizing or nonkeratinizing, invading cervical stroma
2. adenocarcinoma:
-proliferation of malignant endocervical glands
endometriosis - overview
*benign endometrial glands and stroma outside the uterus
*occurs in up to 10% of women in reproductive years and nearly half of women with infertility
endometriosis - pathology
*functional endometrial stroma and glands
*undergo cyclic bleeding and appear as red-brown nodules or implants
*may form large, blood filled chocolate cysts
endometriosis - clinical findings
*frequently multifocal
*pelvic structures, eg. ovaries, uterine ligaments
*dysmenorrhea and pelvic pain
*scarring of fallopian tubes/ovaries → sterility
uterine glandular proliferations: hyperplasia - overview
*benign hyperplasia of endometrial epithelial glands
*prolonged/marked excess estrogen relative to progestin
*clinically: post-menopausal bleeding
uterine glandular proliferations: hyperplasia - etiology
*estrogen excess, due to:
1. obesity: adipose tissue converts steroids into estrogens
2. failure of ovulation (perimenopause)
3. estrogen therapy
4. estrogen-producing ovarian lesions
uterine glandular proliferations: hyperplasia - pathology
*crowded glands with increased gland:stroma ratio:
1. simple hyperplasia:
-without cellular atypia
-rarely progress
2. complex hyperplasia with atypia:
-“back-to-back” glands; little to no stroma
-progresses to carcinoma in 20-50% of cases
uterine glandular proliferations: CARCINOMA
*malignant neoplasm of endometrial epithelial glands
*most frequent cancer occurring in the female genital tract
*manifests between the ages of 55 and 65 years
*classically presents with post-menopausal bleeding
endometrioid endometrial adenocarcinoma
*mutations in PTEN tumor suppressor gene
*background of endometrial hyperplasia
serous endometrial adenocarcinoma
*mutations in TP53 tumor suppressor gene
*background of endometrial atrophy in older women (>70)
leiomyoma - overview
*benign tumor of myometrial smooth muscle cells (“fibroid”)
*affect up to 50% of women of reproductive age
*estrogens stimulate growth; tumors shrink post-menopause
leiomyoma - morphology
*sharply circumscribed, firm gray-white masses
*whorled cut surface
*often multiple
*bundles of smooth muscle cells mimic normal myometrium
leiomyoma - clinical features
*often asymptomatic and discovered incidentally
*present with menorrhagia +/- metrorrhagia
leiomyosarcoma - overview
*malignant tumor of myometrial smooth muscle cells
*arise de novo, NOT from leiomyoma (fibroids do not cause this)
*complex, highly variable karyotypes, frequent chromosomal deletions
leiomyosarcoma - morphology
*usually solitary hemorrhagic masses
*marked necrosis
*cytologic atypia
*increased mitotic activity
leiomyosarcoma - clinical features
*most often occur in post-menopausal women
*recurrence after surgical resection is common
*many tumors metastasize to lung, bone, brain
*prognosis: overall 5-year survival rate ~40%
ovarian surface epithelial neoplasms - overview
*benign or malignant neoplasms derived from ovarian surface epithelium
*most common type of ovarian neoplasm
*TP53 mutations > 95% of cases
*familial germline mutations in BRCA1 or BRCA2
ovarian surface epithelial neoplasms - classification based on epithelium
- serous = cuboidal epithelium with thin, watery fluid
- mucinous = columnar epithelium with mucus
- endometrioid = endometrial epithelium
ovarian surface epithelial neoplasms - pathology
*cystic, large to huge
1. benign tumors:
-serous cystadenoma; mucinous cystadenoma
-smooth cysts lined by simple epithelium layer
2. borderline tumors:
-majority behave in a benign manner
-can recur; some progress to carcinoma
3. malignant tumors:
-serous cystadenocarcinoma; mucinous cystadenocarcinoma
-markedly atypical stratified epithelium layer
-exuberant papillary projections
-epithelial invasion
-spread by peritoneal implants and through lymphatics to regional lymph nodes
ovarian germ cell neoplasm: teratoma - overview
*usually present in first 2 decades of life
*more than 90% are benign (typically malignant in very young pts)
ovarian germ cell neoplasm: MATURE teratoma
*aka dermoid cyst
*benign
*ovarian mass or incidental imaging studies; infertility or ovarian torsion may be presenting sign
*mature tissues derived from ALL THREE germ layers:
-ectoderm, endoderm, and mesoderm
-cysts lined by epidermis with skin adnexa
-produce hair, teeth, bone, cartilage, and other tissues
ovarian germ cell neoplasm: IMMATURE teratoma
*malignant
*arise early in life (<18 years)
*typically are bulky & solid, with areas of necrosis
*immature elements or minimally differentiated tissues
risk factors for the development of breast carcinoma
*first-degree relatives with breast carcinoma
*early menarche
*late menopause
*nulliparity
*obesity
*proliferative fibrocystic disease
*inheritance of mutant copy tumor suppressor genes (TP53, BRCA1, BRCA2); individuals who inherit a mutation develop carcinomas at a younger age
significance of estrogen receptor expression in the pathogenesis of breast cancer
*estrogen may bind to the receptors on the tumor cells and promote their growth
-estrogen is not mutagenic, so it is a tumor promoter, not a tumor initiator
*therapeutic strategies for estrogen receptor + breast cancer:
1. tamoxifen
2. aromatase inhibitors
3. oophorectomy
significance of HER2 expression in the pathogenesis of breast cancer
*HER2 is a growth factor receptor:
-gene amplification → increased overexpression of HER2 receptor and constitutive tyrosine kinase activity → promotion of growth and survival of tumor cells
*respond to treatment with drugs that block HER2 activity
benign breast epithelial lesions - overview
*derived from proliferation of epithelial cells
*majority incidental findings detected by mammography
*major clinical significance is subsequent risk of malignant transformation
benign breast epithelial lesion: papilloma
- large duct papillomas:
-lactiferous sinuses of the nipple
-usually solitary
-more than 80% with nipple discharge (may be bloody) - small duct papillomas:
-multiple and located deeper in ductal system
-clinically small palpable masses, or densities on imaging - multiple branching fibrovascular cores:
-epithelial hyperplasia and apocrine metaplasia are frequently present
benign breast epithelial lesion: fibrocystic changes
*most common change in pre-menopausal breast
*vague, irregular breast tissue; “lumpy breast”
*spectrum of morphology:
1. cysts: flattened atrophic epithelium or by metaplastic apocrine cells
2. fibrosis: cyst rupture → fibrosis; may calcify, leading to image detection
3. adenosis: increase in the number of acini per lobule
benign breast epithelial lesion: usual duct hyperplasia (UDH)
*proliferative disease
*1.5-2x increased risk of malignancy
*usually incidental finding
*increased NORMAL epithelial and myoepithelial cells:
-fill and distend ducts and lobules
-cells maintain normal appearance
-irregular peripheral lumers
benign breast epithelial lesion: atypical ductal hyperplasia (ADH)
*proliferative disease
*4-5x increased risk of malignancy
*both breasts are at increased risk
*increased ATYPICAL epithelial and myoepithelial cells:
-epithelial cell proliferation expands ductal/lobular spaces
-resembles in situ carcinoma
breast carcinoma: in situ - overview
*malignant neoplastic breast epithelial proliferation limited by basement membrane
*may not produce palpable mass
*detected as calcifications on mammography
breast carcinoma: ductal carcinoma in situ (DCIS)
*distorts lobules and ducts
*necrotic debris or secretory material produces Ca2+ (comedo necrosis)
breast carcinoma: lobular carcinoma in situ
*expands involved lobules
*may be MULTIFOCAL
*rarely produces Ca2+; usually incidental
breast carcinoma: invasive - overview
*malignant neoplastic breast epithelial proliferation that penetrates basement membrane
breast carcinoma: invasive ductal carcinoma
*haphazard infiltrating tubules:
-no organized growth
-lack myoepithelial cell layer
*induces a desmoplastic response:
-results in a mammographic density
-eventually produces hard, palpable, irregular mass
breast carcinoma: invasive lobular carcinoma
*makes up 10-15% of invasive carcinomas
*typically infiltrate as discohesive SINGLE CELLS (single file), NOT tubules/ducts; E-cadherin negative
*may FAIL to produce a desmoplastic response; difficult to detect by palpation and imaging
breast carcinoma: invasive medullary carcinoma
*subtype of triple-negative cancer
*well-circumscribed mass
*pushing borders of large anaplastic cells
*lymphocytic T-cell infiltrates
breast carcinoma: invasive inflammatory carcinoma
*“inflamed” reddening, thickening, and fine pitting edema of the skin (peau d’orange)
*lymphatic carcinomatosis
breast stromal proliferations - overview
*neoplasms derived from proliferation of intralobular fibroblasts with entrapped non-neoplastic epithelial cells
breast stromal proliferation: fibroadenoma
*most common benign tumor in breast
*typically presents in women < 30yrs
*frequently multiple and bilateral
*HORMONALLY RESPONSIVE (grow with menses and pregnancy)
*well-circumscribed, mobile, rubbery
*fibroblasts distort/elongated slit-like ducts
breast stromal proliferation: Phyllodes tumor
*typically post-menopausal
*vary in size from small to huge
*fibroadenoma-like but more stromal overgrowth:
-characteristic “phyllodes” (leaflike) growth pattern
