Reproductive Pathology Fact
Stack
Mike Ori
Disclaimer
• Faculty has not reviewed or vetted the
information contained herein.
• If you think this material is any way accurate,
you are mistaken.
• Celebrity voices are impersonated
• Which hormone is responsible for endometrial
proliferation and which for increased gland
development?
• Estrogen is proliferative
• Progesterone is responsible for gland
maturation
• Define dysfunctional uterine bleeding
• Bleeding between menstrual cycles caused by
abnormalities in the cycle or by systemic
disease and not by organic abnormalities.
• I.E. Hormone imbalances caused by PCOS,
liver disease, etc
• Define abnormal uterine bleeding
• The occurrence of bleeding at times other
than the expected menses.
Describe the structure of the endometrium
• An epithelium composed of stroma and glands
with a relatively constant stratum basalis and
a variable stratum functionalis. The latter
undergoes cyclic growth, maturation, and
degeneration in response to estrogen and
progesterone.
• Define endometriosis
• The presence of endometrial glands or stroma
outside the uterine cavity.
• Define adenomyosis
• Endometrial tissue within the myometrium at
a depth of 2+mm from the stratum basalis.
• What are the common sx of endometriosis
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•
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Dysmenorrhea
Menstral irregularities
Recurrent pelvic pain
Infertility (30-40%)
• What are the three theories of regarding the
genesis of endometriosis
• Menstrual regurgitation
• Blood/lymphatic dissemination
• Metaplasia
• What is the most common organism for
suppurative salpingitis
• Neisseria Gonorrhea
• Distinguish primary fallopian tube
adenocarcinoma from secondary (ovarian
origin).
• Must have a dominant tubal mass involving
the lumen of the tube that originates from
tubal epithelium.
• Define gestational trophoblastic disease
• A variety of tumors and tumor-like conditions
characterized by proliferation of pregnancyassociated trophoblastic tissue of increasing
malignant potential.
• Describe hydatidiform moles
• Pathologic cystic swelling of the chorionic villi
with variable degrees of associated
trophoblastic proliferation. Resulting in high
levels of HCG, large for gestational age uterus,
and passage of small grape-like structures.
The distribution is bimodal with peaks in teens
and then forties.
• Describe the three benign subclasses of moles
• Complete – swelling of all or almost all villi with diffuse
trophoblastic hyperplasia. These result from the
fertilization of an empty ovum by two sperm (2x1n) or by a
single 2n sperm. All genetic material is of paternal origin.
There is absent or limited vascularization of the villi.
• Partial – The fusion of a 1n ovum and 1x2n or 2x1n sperm
resulting in a 3n fertilization. The fetus may be viable for
weeks and thus fetal parts and an amniotic sac may be
present. Both normal appearing and hydropic villi will be
seen. HCG level are high but are less than with complete
mole.
• Invasive – invasion of the myometrium by hydropic villi.
Responds well to chemotherapy.
• Describe choriocarcinoma
• A malignant neoplasm of the chorionic
epithelium characterized by a large, bulky,
soft, fleshy, yellow-white mass with areas of
hemorrhage and necrosis that does not
develop chorionic villi.
– 50% arise from previous GTD
– 25% from normal pregnancy
– 25% follow abortion
• List the benign ovarian cysts
• Follicular cysts – serous > 2cm
• Luteal cysts – Lined by layers of granulosa cells
conveying bright golden yellow color. Usually
regress spontaneously
• Cystic follicles – serous < 2cm
• List the sx associated with ovarian cancer
•
•
•
•
•
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Pelvic or abdominal pain
Pelvic and abdominal swelling
Vague but persistent GI issues
Unexplained changes in bowel habits
Urinary urge and increased frequency
Ongoing unusual fatigue
• Rank the incidence and prognosis for ovarian,
endometrial, and cervical cancer from most
common to least common and from most
serious to least
• Incidence (most common -> least common)
– Endometrial > ovarian > cervical
• Prognosis (worst -> best)
– Ovarian > cervical > endometrial
• Which blood test can you use to confirm
ovarian cancer
• There is no confirmatory blood test. CA-125 is
used as a tracking test to monitor progression
of the disease.
• What are the risk factors for ovarian cancer?
• Family hx (Ovarian, colon, prostate (?), breast)
• Increasing age
• Undesired infertility
• What explains the prognostic difference
between endometrial and ovarian cancer?
• Endometrial cancer presents in post
menopausal women with vaginal bleeding –
an obvious sign. In contrast, ovarian cancer
presents with vague signs that require clinical
experience and judgment to recognize as part
of a larger syndrome. Hence, ovarian cancer
presents at a more advanced stage.
• Which cancers is the pap smear diagnostic
for?
• The pap smear is not diagnostic for any
cancer. It is a screening test. Any positive
indicator must be followed by culposcopy and
biopsy.
• What is the average age of a patient
diagnosed with breast cancer. What is the
male:female ratio
• 64 years
• 1:100 M:F
• Describe the structure of the lactating human
breast and the importance of this structure for
the development of cancer
• Secretory lobules filled with alveoli lined with
epithelial and surmounted by myoepithelium.
Components are separated by connective
tissue stroma and adipose tissue. Lobules
connect to the nipple via ducts. Cancers
typically arise in the ductal > lobular
epithelium
• Describe the clinical presentation of breast
disease in broad terms
•
•
•
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Pain
Palpable mass
Nipple discharge
Mammographic screenin abnormality
• Describe acute mastitis
• Painful erythematous breast with fever in
lactating women. If not lactating suspect
inflammatory carcinoma.
• Describe periductal mastitis
• Painful often recurrent sub-areolar mass in
both women and men that is associated with
smoking (90%)
• Describe fibroadenomas
• Well circumscribed, rubbery, freely movable
mass that waxes and wanes in response to the
menstrual cycle and that typically occurs in
women < 30 years of age.
• Stromal tumor
• Describe phyllodes tumor
• Small to large bulbous protrusions with Leaf
life slits in an overgrown stroma that typiclly
presents in the 50’s. Must be excised with
wide margins.
• Stromal tumor
• Describe fibrocystic changes to the breast
• Increased nodularity (lumpy bumpy) of the
breast in women in their 30’s and 40’s. It
presents without a dominant mass but it often
becomes tender premenstrually.
• Cysts, fibrosis, adenosis
• Up to 60% of cadavers have histologic
evidence
• Differentiate proliferative breast disease with
and without atypia from atypical lobular
hyperplasia and estimate the cancer risk of
each
• Proliferative
– Without atypia
• Moderate to florid epithelial hyperplasia, adenosis,
papilloma, fibroadenoma with complex features
• Cancer risk 1.2-2x
– Atypia
• 4-5x cancer risk for both
• Ductal
– Resembles DCIS but is quantitatively or qualitatively insufficient
• Lobular
– Similar to LCIS but affects fewer than 50% of the acini in a lobule.
– Always incidental finding
• Which breast cancers are found in males?
• Pretty much ductal as men should lack
lobules.
• What is the ratio of ductal to lobular
carcinoma in situ.
• 80:20 ductal:lobular
• Describe the cardinal feature of carcinoma in
situ
• Lack of invasion past the epithelium’s
basement membrane. 45555555 (cat)
• What is the risk for invasive carcinoma with
DCIS and LCIS and is the risk bilateral?
• Both DCIS and LCIS carry a 25-35% risk of
invasive carcinoma over 20 years
• LCIS indicates bilateral and multicentric risk of
20-40%
• What is the lifetime risk of breast cancer for a
90 year-old and what are the general risk
factors
• 1 in 8 risk (12%)
• Risk factors
– Age
– Increased reproductive life span (menarche –
menopause)
– Age at primiparity. Older conveys increased risk
– Race (caucasian > black > asian > hispanic)
– First degree relative with breast cancer
– Prior hx of atypical hyperplasia in the breast
• List the invasive carcinomas, their frequency
as a percentage of all breast cancer, and their
clinical appearance
Type
Frequency
Clinical
Infiltrating ductal – no
specific type
80%
Palpable mass with
irregular borders and gritty
feel. mammographic
density. Tubules, nests,
cords, sheets of cells
Lobular
10%
Mass or mammographic
density. Cells in single file
diffusely infiltrating
Medullary
2%
See notes. BRCA1
association
Mucinous
1-6%
Mucin. BRCA1 association
Tubular
10%
See notes
Invasive papillary
1%
See notes
Inflammatory
Clinical morphology.
• What are the major and minor prognostic
factors for breast cancer.
• Major
– Invasive v in situ
– Metastasis
• Lymph node
– Inflammatory carcinoma
• Distant
– Tumor size
– Locally advanced
• Minor
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Histologic subtype
Tumor grade
ER/PR status
Her2/Neu status
Lymphovasular invasion (nodal mets = major)
Proliferation rate
DNA content
• What are the zones of the prostate and how
do they relate to BPH and cancer?
• Peripheral – adenocarinoma
• Transitional - BPH
• Central
• Describe the age correlation with prostate
disease
• Both BPH and prostatic adenocarcinoma
increase with age. The incidence of
adenocarcinoma is as high as 70% at age 70
but most are indolent. BPH incidence is as
high as 90% at age 70.
• Describe the clinical, gross, and microscopic
findings for BPH.
• Clinical
– Dysuria, nocturia, urinary obstruction,
hydronephrosis, cystitis, pyelonephritis.
• Gross
– Enlarged prostate with nodular appearance
• Microscopic
– Increase glandular and stromal components with a
nodular appearance.
• Describe the gross, microscopic, and clinical
manifestations of prostate adenocarcinoma.
• Gross
– Yellow-white, gritty, firm growths in the peripheral
zone.
• Microscopic
– Proliferation of small glands that lack the branching
and papillary infolding of normal glands.
• Clinical
– Frequently silent until bone pain presents from mets
to spine. May present as masses on digital rectal
exam.
• What stains differentiate adenocarcinoma
from BPH.
• Adenocarcinoma glands typically lacks the
basal cells whereas BPH glands will stain
positive for basal cells.
• Describe prostatic intra-epithelial neoplasia.
• High grade PIN is considered a precursor for
prostate cancer. The overall structure is
preserved and the glands stain positive for
basal cells but the epithelial cells are
neoplastic.
• Describe the staging system for prostate
adenocarcinoma
• Modified TMN
• T
– 1 – Confined to prostate but found incidentally
– 2 – Confined to prostate but found as a result of
clinical suspicion
– 3 – invading the capsule
– 4 – direct invasion of nearby organs
• M and N as normal
• Describe the gleason system
• Adds together the two most common
morphologies seen on prostate biopsy to yield
a score of 2 – 10. Scores above 7 predicts a
worse prognosis.
• Describe the utility of PSA
• Prostate specific antigen (serine protease) can
be used as a marker for prostate
adenocarcinoma. It may be falsely elevated
for a number of conditions such as trauma,
recent ejaculation, prostatitis, and BPH.
Levels above 10 ng/mL warrant further
investigation. Serial PSA tests are useful to
detect changes that may be indicative of
cancer. Not all prostate cancers elaborate
PSA.
• List the fibrotic structural diseases of the penis
• Peyronies – chronic fibrosis of the subtunical
sheath
• Phimosis – Narrowed prepuce that prevents
retraction of the foreskin
• Paraphimosis – results when phimotic foreskin
is forcibly retracted and then cannot return.
• What disease is the character of Bert from
Mary Poppins at higher risk for?
• Scrotal cancer independent of HPV infection.
Describe Bowen disease, erythroplasia of
Queyrat, and bowenoid papulosis and the
relative cancer risk of each.
• Bowen and Queyrat histologically appear as
carcinoma in situ of the skin of the penis. Lead to
invasive squamous cell carcinoma in 10% of
cases. Association with HPV 16.
– White plaque = Bowen
– Red = Queyrat
• Bowenoid papulosis present as multiple
pigmented papules that histologically resemble
bowen but that are not associated with invasive
cancer.
• To which lymph nodes do cancers of the
penis/scrotum, testes, and prostate spread
• Prostate
– Obturator early then para-aortic later
• Penis/scrotum
– Inguinal then iliac
• Testis
– Retroperitoneal (below diaphragm)
• What is the clinical significance of
cryptorchidism
• Left untreated it will result in testicular
atrophy leading to infertility if bilateral.
• Increases cancer risk 5-10 times if untreated
• What are the causes of testicular atrophy
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Klinefelters
Cryptorchidism
Radiation
Drugs
Malnutrition
Prolonged exposure to female hormones
• What is the likely etiology of Hank and Dean
Venture’s testicular torsion? See the PSA on
youtube.
• http://www.youtube.com/watch?v=BHKMCrD
aHRY
• Failure of the terminal portion of the
gubernaculum to anchor the tunica albuginea
to the scrotum. The so-called bell clapper
malformation
• What is the most common type of testicular
tumor and which chromosomal abnormality is
it associated with?
• 95% are germ cell
• 90% of germ cell tumors are associated with
isochromosome of short arm of chromosome
12
• Categorize germ cell tumors of the testis.
Describe their incidence, spread, and usual
treatment.
• Seminatous
– Peaks in 30’s (seminoma) and 60’s (spermocytic)
– Spread via lymphatics
– Radiosensitive
• Non-seminatous
– Peaks in teens to twenties
– Spread via both hematagenous and lymphatic
routes.
– Surgery and chemo
• Describe the staging system for testicular
cancer
• Stage I
– Confined to testis, epididymis, spermatic cord
• Stage II
– Mets to retroperitoneal (sub diaphragm) lymph
nodes
• Stage III
– Distant mets
• Describe the seminatous germ cell tumors
• Seminoma
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Peak age in 30’s
Placental alkaline phosphatase positive.
C-kit (CD-117) positive
Uniform population of cells with clear to eosinophilic cytoplasm
Lymphocytic invasion in fibrous stroma
Similar to ovarian dysgermioma
• Spermatocytic seminoma
– Peaks in 60’s
– Composed of three cell types
• Morphology variation in tumor
– Non-cohesive cells in scant or edematous stroma
– Immunohistochemical stains negative
– Rarely mets
• Differentiate the non-seminatous germ cell
tumors
•
Embryonal
– Large cells with abundant clear to basophilic cytoplasms.
– Peak incidence at 30
– CD30 positive
•
Yolk sac (endodermal)
– Schiller-duvall bodies
•
capillary surrounded by tumor cells
– Alpha fetoprotein positive
– Median age 16-17 months
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Choriocarcinoma
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Invading trophoblast cells
Beta HCG positive
Median age 25-30
Poor prognosis – in contrast to placental forms
Teratoma
– Mature are benign in 1-2 year olds
– All are malignant in post-pubertal
• Differentiate testicular stromal tumors
•
Leydig
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Elaborate testosterone
Most common in adults from 20’s-50’s
Painless enlargement of testis
10% have malignant potential
May cause precocious puberty
Usually benign
Sertoli
– Vimentin and inhibin (variably) positive
– Usually benign
•
Gonadoblastoma
– Mixed gonadal dysgenesis (45,X/46, XY mosaicism)
– Undergoes malignant transformation to seminoma
•
Testicular Lymphoma
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Difficult to determine if primary or secondary
Stains positive for B cell markers CD 19,20
Most common testicular neoplasm over age 60
12% 5-year survival
• List the categories of ovarian tumors, their
frequency, their age range, and their
malignant potential
Type
Proportion
Age
Malignancy
Epithelial
70%
Adult->elder
85-90%
Germ Cell
15%
Young women
3-5%
Stromal
10%
Any
2-5%
Metastatic
5%
Any
100%
• List the types of epithelial ovarian tumors
•
•
•
•
Serous
Mucinous
Endometriod
Clear Cell
• Describe in broad terms serous tumors of the
ovary. What is their incidence and malignant
potential.
• Cystic neoplasm of the ovary filled with serous fluid
and lined by tall columnar ciliated epithelium
• Often bilateral
• 30% of ovarian tumors
• 75% benign -> borderline
• 25% malignant
• Note there appear to be conflicts in the notes about
percentages as 40% of all malignant ovarian tumors are
serous cystadenocarcinomas but only 8% would be by
the numbers above.
• List and describe the types of serous tumors
• Serous Cystadenoma
– Benign
– From one to a few smooth walled cysts with no epithelial stratification
• Borderline (low malignant potential)
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Increasing complexity and papillary projections into the cyst cavity.
Up to 4-5 epithelial cell layers
No stromal invasion
Psammoma bodies common
• Serous cystadenocarcinoma
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Most common malignancy of the ovary (40%)
Increasingly solid, papillary, and irregular.
Invasion of stroma
Psammoma bodies
• Describe in broad terms mucinous tumors of
the ovary
• Multiple cysts lined by mucinous columnar
epithelium
• 25% of all ovarian tumors
• Occur in middle adult life
• Typically unilateral
• List and describe the mucinous tumors of the
ovary
•
Pseudomyxoma Peritonei
– Clinical finding
– Implant on peritoneal surface leading to mucinous ascites
– Arise from tumors of the ovary or more commonly (?) appendix or other GI tract organs.
•
Mucinous Cystadenoma
– Benign
– Tall columnar epithelium with apical mucin
– Large cysts filled with sticky fluid
•
Borderline/low malignant potential
– Increased papillary structures and gland complexity.
– Up to several layers of epithelium
– No invasion of stroma
•
Mucinous cystadenocarcinoma
– 5% of all ovarian cancers
– 20% bilateral
•
remember most other mucinous tumors are unilateral
– May be metastatic implant from remote source
– Increased stratification and atypia
• Describe endometriod carcinoma of the ovary
• 40% bilateral
• 40% 5 year survival
• Grossly resembles endometrial
adenocarcinoma
• Associated with
– Uterine endometriod carcinoma
– Endometriosis
– Clear cell adenocarcinoma of the ovary
• Describe clear cell adenocarcinoma of the
ovary
• Not associated with DES
• Very aggressive
• Clear cells
• List and differentiate the germ cell tumors of
the ovary
• Dysgermioma
– Similar to testicular seminoma
– Good prognosis
– Occurs in young adults
• Teratoma
– Mature are benign in females
– Immature are malignant (??)
– Mature AKA dermoid cysts
• Endodermal sinus tumor (yolk sac tumor)
– Elaborates alpha fetoprotein
– Schiller duval bodies
• Choriocarcinomas (Non-placental origin type)
– Less responsive to therapy than placental variety
– Usually occur in mixed germ cell tumors
• Differentiate the stromal tumors of the ovary
• Granulosa-theca cell tumor
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Older women (2/3 post menopausal)
Call-exner bodies
Coffee bean nuclei
Usually benign
Recurrent
Elaborates estrogens
• Precocious puberty
• Endometrial hyperplasia
• Theca-fibroma
– 90% unilateral
– Meigs syndrome
• Tumor, ascites, pleural effusion
• Sertoli-leydig
– Elaborates androgens
– Occurs in teens and twenties
• Describe CIN, VAIN, VIN
• These refer to intra-epithelial neoplasia of the
cervix, vagina, and vulva
• Very strong associated with HPV 16 and 18
• Leads to squamous cell carcinomas of the
affected organ
• Cervix is most commonly affected
• Describe the staging of cervical
adenocarcinoma
• Stage 0
– CIN III
• Stage I
– Confined to cervix
• Stage II
– Extension beyond cervix
• Stage III
– Extension to pelvic wall or lower 1/3 of vagina
• Stage IV
– Extension to nearby organs or distant mets
• Differentiate leukoplakia, lichen sclerosis, and
lichen simplex chronicus, and malignant
melanoma of the vulva
•
Leukoplakia
– Clinical term
– Caused by a variety of benign, premalignant, and malignant lesions
•
May signal premalignancy
– Plaque like mucosal thickening
•
Lichen sclerosis
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•
Parchment like pale gray skin
Atrophy of the dermis
Band like lymphocytic invasion of the dermis
Possibly autoimmune
Not premalignant but oddly associated with vulvar carcinoma
Lichen simplex chronicus
– Acanthosis of the squamous epithelium
– Hyperkeratosis
– Not premalignant
•
Melanoma
– Rare
– Peak age 50’s and 60’s
• Differentiate pagets disease of the breast and
vulva
• Histologically similar
• Breast has 40% association with underlying
invasive ductal carcinoma
• Vulvar pagets is rarely associated with
underlying carcinoma
• Differentiate adenocarcinoma of the vagina
from embryonal rhabdomyosarcoma of the
vagina
• Clear cell adenocarcinoma
– Associated with DES use
– Most tumors in upper 1/3 of vagina
– Women in teens
• Embryonal rhabdomyosarcoma
– AKA sarcoma botryoides
– Presents in infancy and early childhood
– Grape like structures composed of malignant
rhabdomyocytes.
– Often protrudes into the vagina or out the intraoitus
• Describe the etiology and appearance of
endometrial hyperplasia
• Arises from excess estrogen stimulation as a
result of
– estrogen elaborating tumors
– unopposed exogenous estrogens
– HPG axis issues
– PCOS
• Excess growth of endometrial tissue
• List the classifications of endometrial
hyperplasia and their likely progression to
cancer.
• What is the new terminology replacing the
older classification scheme
Without atypia
Atypia
Simple
1%
3%
Complex
< 8%
29%
•Old scheme
•Four types as above
•New scheme
•Endometrial intra-epithelial neoplasia
• List the types and etiology of endometrial
cancer, their age of onset, and the prognosis
• Type I – Endometriod
– Endometrial hyperplasia
– PTEN and MSI gene changes
– 50-60’s, less aggressive, good if early
• Type II
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Serous
Clear cell
Carcinosarcoma
P53 gene changes
Resting endometrium
60’s-70’s, more aggressive, poor
• Describe the grading system for edometrial
carcinoma
• FIGO (Histologic)
– Grade 1 < 5% solid
– Grade 2 6-50% solid
– Grade 3 >50% solid
• Nuclear grading
– Grade 1 – not too messed up (minimal atypia)
– Grade 2 – somewhat messed up (intermediate)
– Grade 3 – really messed up (marked atypia)
• Describe carcinosarcoma and list its rapper
name
• Endometrial adenocarcinoma accompanied by
malignant stroma often resulting in a grossly
large mass that extends beyond the uterus.
• Rapper name: trip-M
– Mixed mullerian malignancy
• Differentiate leiomyoma from leiomyosarcoma
• Leimyoma
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Benign smooth muscle tumor
Well circumscribed
Up to 25% of women
Multiple lesions common
Estrogen responsive
• Regresses post menopause
• Leiomyosarcoma
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–
–
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Malignant smooth muscle tumor
Peak incidence 40’s-60’s
Bulky mass commonly with hemorrhage and necrosis
40% 5 year survival