Benign and Malignant Tumors of the Female Reproductive System Flashcards
Role of HPV E6 and E7
Gestational trophoblastic disease
- Group of benign disorders of abnormal trophoblastic proliferation
- Lesions arise from fetal tisue (trophoblast!) rather than maternal tissue
- Includes hydatidiform moles/molar pregnancies and placental site nodules
Molar pregnancy
- Form of gestational trophoblastic disease caused by polyspermy
- Benign, but has a risk for transformaton into malignant lesion (gestational trophoblastic neoplasia)
- Looks like a bubbly mass that may occupy the entire uterus (complete) or only part with a present fetus (partial)
- Often causes hyperthyroidism due to the excessive amount of beta hCG, which can act at TSH receptors to stimulate T4 production
Gestational trophoblastic neoplasia
- Group of malignant trophoblastic proliferation disorders
- Includes invasive moles, choriocarcinoma, placental site trophoblastic tumor, epithelioid trophoblastic tumor
ZP3 receptor
ZP for zona pellucida
Expressed on the surface of the zona pellucida of an egg and binds to the head of a sperm cell, triggering the release of acrosin from the sperm and initiating the acrosome reaction
Partial molar pregnancy
- Dispermy -> 69 xxy, xxx, or xyy -> partial molar pregnancy
- Ultrasound shows hydropic placenta and a fetus, however the fetus is nonviable
- Histology shows a mixture of normal villi and hydropic villi, as well as exaggerated implantation site trophoblasts. There will also be trophoblastic proliferation between the villi.
- 1-5% risk of malignant trophoblastic lesion progression
Mechanisms of preventing polyspermia
- Depolarization of the membrane during the acrosome reaction due to opening of sodium channels (short term effect)
- Cortical reaction: calcium let in by the hole made by the sperm causes release of granule contents at the rim of the oocyte. Carbohydrates from these granules are attached to the outer rim of the zona pellucida, forming a physical barrier to sperm.
Complete molar pregnancy
- Egg contains no genetic material -> sperm duplicates its own DNA after meiosis (called androgenesis) -> usually 46, XX -> complete molar pregnancy
- Both sets of chromosomes are paternal
- Described as “clear vesicles” or “cluster of grapes”
- “Snowstorm” pattern is typical, often with large “Lutein” cysts present on ovaries due to prolonged, high-level hCG stimulation
- Histologically, enlarged hydropic villi with central cisterns
- 15-20% risk of maligiant trophoblastic lesion progression
Placentas in molar pregnancy are often described as. . .
. . . “hydropic” due to the cystic lesions
Treatment for complete molar pregnancy
Suction dilation and curettage both confirms the diagnosis and is optimal therapy.
Follow procedure with serial beta hCG levels weekly. Once normalized, continue monitoring with monthly beta hCG levels.
GTN is usually diagnosed by. . .
. . . elevated beta hCG levels and a consistent clinical picture with supportive imaging findings
Histology is NOT taken as part of diagnosis, but will be pathologically analyzed as part of therapeutic excision to retroactively confirm the diagnosis
Evaluation for metastatic gestational trophoblastic neoplasia
- Pelvic ultrasound and chest x-ray are first steps
- If seen on the above, CT abdomen/pelvis and brain MRI are performed
Why should GTN never be biopsied?
Because it is SO HIGHLY VASCULAR
The patient will bleed out.
Treatment of GTN
- Disease confined to uterus: Hysterectomy
- Otherwise: Chemotherapy
- Brain involvement: Radiation therapy
HPV strains that cause genital warts
HPV6, HPV11
HPV strains that cause cervical epithelial neoplasia
- HPV 16, 18
- HPV 31, 33, 35, 39 (all 3x odd but 37)
- HPV 51, 52
Koilocytes
Cervical epithelial cells with nuclear enlargement and a “halo”
Sign of low-grade HPV infection
CIN grading system
In other words, if p16 is positive, it is considered a high grade lesion
CIN grading diagram
Note that the principle factor is thickness of the neoplastic cell region relative to the height of the epithelium, with “high-grade” being >2/3 of the epithelium replaced with neoplastic cells
HPV-derived squamous cell carcinoma histology
LFIL or CIN1 will likely. . .
. . . resolve on its own. So, we just need to check again in 1 year to ensure that it has.
The mechanism here is that, in CIN1, HPV has usually not integrated into the genome, so it is unlikely to persist.
What is going on in this cervical histology?
Adenocarcinoma in situ
Also usually driven by HPV 16 and 18
___ is a risk factor for more severe CIN
Smoking is a risk factor for more severe CIN
This is somewhat counterintiutive, since it is a virally driven process, but data shows that smokers are more likely to have severe CIN independent of other risk factors.
The HPV vaccine contains . . .
. . . L1 capsid proteins from various HPV strains
Layers of the endometrium
Proliferative and secretory endometrium cycling
Endometrial biopsy is recommended for women over the age of __ with abnormal uterine bleeding.
Endometrial biopsy is recommended for women over the age of 45 with abnormal uterine bleeding.
It is also recommended in women younger than 45 if there are risk factors for endometrial cancer (obesity, chronic anovulation)
What causes benign endometrial hyperplasia?
Estrogen signaling unopposed by progestins
What is going on in this endometrial biopsy?
What are the major risk factors for endometrial hyperplasia?
It’s all about unopposed estrogen signaling
PCOS: Chronic anovulation due to low FSH -> no corpus luteum -> no progesterome -> unopposed estrogen signaling
Obesity: Increased number of adipocytes -> adipocytes express aromatase -> converts androstenedione to estrone -> estrone converted to estradiol -> increased estrogen:progesterone ratio
Also tamoxifen therapy, nulliparity, early menarche, late menopause
How do you treat benign endometrial hyperplasia?
Lower the estrogen, raise the progesterone!
Progestin contraceptives highly effective.
What is going on in this endometrial biopsy?
Endometrial intraepithelial neoplasia
Note that in this biopsy there is one normal gland in the top left corner for comparison. Its epithelia are much smaller than all of the others.
Treatment recommendation for endometrial intrepithelial neoplasia
Total hysterectomy is recommended
However, for those who wish to preserve fertility or are unable to undergo surgery, progestin therapy with close follow-up and repeat sampling
Types of cell that give rise to ovarian cancers
Most common ovarian cancer
High-grade serous carcinoma
A form of epithelial ovarian cancer
Many have a mutation in TP53, BRCA1, or BRCA2
Endometroid carcinoma
- Type of epithelial ovarian cancer
- 15-20% occur with concurrent uterine cancer
- Associated with Lynch syndrome
Ovarian clear cell carcinoma
- Type of epithelial ovarian cancer
- May arise from endometriosis
- There is risk reduction in women with tubal ligation
Ovarian mucinous carcinoma
- Type of ovarian epithelial cancer
- Usually presents in stage 1 in premenopausal women
- Tumors usually unilateral and may be quite large, as large as 20 centimeters
Ovarian low-grade serous carcinoma
- Type of epithelial ovarian cancer
- Slow-growing and as such resistant to platinum-based chemotherapy
- Characterized by hyalinized stroma with numerous psammoma bodies
Growth factors that promote the growth of ovarian epithelial tumors
- FGF (promotes cancer cell growth and proliferation directly)
- PDGF (stabilizes new blood vessels, promotes angiogenesis)
- VEGF (causes endothelial proliferation, promotes angiogenesis)
Dermoid / Mature teratomas
- Accounts for 95% of germ cell tumors
- Benign
- Contains ectoderm, endoderm, AND mesoderm, and often forms strange structures like hair or teeth
- Associated with a paraneoplastic syndrome of anti-NDMA receptor encephalitis (any teratoma can be!)
Immature teratoma
- Most common malignant germ cell ovarian tumor
- Usually arises from the ectodermal tissue in a teratoma
- Associated with a paraneoplastic syndrome of anti-NDMA receptor encephalitis (any teratoma can be!)
Rokatansky pertuberance at the junction of ovarian tissue and tumor
Indicates that the tumor is a teratoma
This region also has the highest likelihood of harboring malignant tissue within the teratoma, and must be excised and carefully evaluated.
Dysgerminoma
- Rare form of ovarian germ cell tumor
- Equivalent to the male seminomas
- Rapidly growing tumor that occurs in young women
Yolk sac tumor
- Rare type of ovarian germ cell tumor
- Accounts for 1/3 of tumors in pre-menarchal girls
- Histologically characterized by Schiller-Duval bodies
Tumor markers for germ cell tumors
Note that this is just for germ cell tumors
They may be helpful when trying to identify if an ovarian cyst is benign or malignant
Granulosa cell tumors
- Type of ovarian sex cord stromal tumor
- Most likely to have malignant potential of all sex cord tumors
- Tend to be very large and unilateral
-
Secrete estrogen, inhibin A, and inhibin B
- As such, endometrial hyperplasia is common, so all these patients should have endometrial sampling
- Inhibin A and B can be used as biomarkers
- Histologically characterized by the presence of Call-Exner bodies
Sertoli-Leydig tumors
- Type of ovarian sex cord stromal tumor
- Less than 20% are malignant
- Secrete androgens and androgen precursors
Thecoma
- Type of ovarian sex cord stromal tumor
- Solid, generally benign, but can be very large
- 15-25% stimulate uterine and endometrial pathology, requiring broad assessment
Fibroma
- Most common ovarian sex cord stromal tumor by far
- Universally benign
- Solid tumors, usually occur in post-menopausal women
- Assocaited with Meig’s triad:
- Ascites
- Pleural effusion
- Fibroma
Pathophysiology of Meig’s syndrome
Thought to be associated with highly elevated levels of VEGF with fibromas, which increase vascular permeability.
The effusion tends to be R sided
How to think about biomarkers for adnexal masses
None of them are sensitive or specific! They are used, but take them with a grain of salt, and remember that their NPV is poor. A negative biomarker panel does NOT mean that an adnexal mass is benign.
CA125
- Ovarian epithelial cancer marker
- A large transmembrane glycoprotein
- Elevated in 50% of women with early epithelial ovarian cancers, and in 80% of women with late epithelial ovarian cancers
- Unfortunately, it is also elevated in peritoneal inflammation, which limits its specificity
- Uterine fibroids, endometriosis, cirrhosis, PID, etc
HE4
- Marker for serous and endometrioid type epithelial ovarian cancers
- “Human epididymis protein 4”
- Used as part of malignancy risk assessment
AROMA algorithm
- Risk algorithm for ovarian cancer
- Used to assess risk for ovarian cancer for women with an ovarian mass of unknown origin
- Takes into account CA125, HE4, and menopausal status
OVA Panel
- An ovarian cancer risk algorithm
- Includes five markers:
- CA125
- Beta 2 microglobulin
- Transferrin
- Transthyretin
- Apolipoprotein A1
- Menopausal status also taken into account
___ is risk-reducing for patients who may be at risk for ovarian cancer
OCP use is risk-reducing for patients who may be at risk for ovarian cancer
Five year culumative use of OCPs decreases the incidence of ovarian cancer by half
Functional cysts are the result of. . .
. . . normal ovulation
Unlike for most other GYN cancers, the most common route of metastasis for ovarian cancer is ___.
Unlike for most other GYN cancers, the most common route of metastasis for ovarian cancer is transcoelomic (across peritoneal surfaces)
Consequently, omentectomy is a common procedure for staging ovarian cancer.
“Krukenberg” tumor
Tumor that metastasized to the ovary from a distant site, such as the colon.
Young women very rarely get ___ ovarian cancer
Young women very rarely get epithelial ovarian cancer
Sonographic characteristics that make an adnexal mass more suspicious for ovarian cancer
- Complexity w/ solid components
- Size > 10 cm
- Mural nodules
- Bilaterality
- Presence of ascites
Ovarian cyst in a postmenopausal woman
- Less likely to be functional, since they are not ovulating
- However, still quite likely benign if small and no concerning features
- These are managed with follow-up sonography in 6 months to ensure that they are stable.
“Microinvasive” cervical cancer
< 3mm invasion beyond the basement membrane
Leuprelide for uterine fibroids
- Second-line after OCP and hormonal therapies
- Maximal response achieved by ~3 months
- Hot flashes experienced by ~75% of patients (start at 3-4 wks of treatment, diminished by 1-2 months after end of treatment)
- After cessation, menses return in ~10 weeks
- Myoma and uterine size will return to pre-leuprelide size within 3-4 months – it is a temporizing measure
Management for young patients with fibroids distorting the uterus as a probably cause of intertility
Myomectomy is a good option for these patients in order to restore fertility
There is a substantially higher incidence of molar pregnancy among women of ___-descent.
There is a substantially higher incidence of molar pregnancy among women of Asian-descent.
Once you confirm a molar pregnancy, pending therapy via dilation and curretage, you should obtain. . .
. . . a chest X-ray
Since malignant GTN likes to spread to the lungs
Liver enzymes and thyroid tests are also often ordered
Adjuvant therapy for complete molar pregnancy
- Only done in high risk complete molar pregnancies (Lutein cysts, snowstorm uterus, sky high beta hCG)
- Methotrexate is administered in addition to surgery to prevent any GTN from developing
Managing abnormal Pap results in a pregnant patient
- Only invasive cancer would truly alter management of the pregnancy
- ASCUS: Re-Pap postpartum. Reflexive HPV not recommended.
- HSIL: Colposcopy
Atypical glandular cells on Pap may indicate. . .
. . . cervical OR endometrial process
The most common ovarian tumors of women under 30
Benign cystic teratomas
However, they may contain thyroid tissue and cause hyperthyroidism. This is called “struma ovarii”
Diagnosing dermoid cysts
Ultrasound is highly reliable for this purpose
Echogenic mass within the cyst made up of hair, teeth or fat
Telling apart mucinous and serous epithelial ovarian tumors
Serous: Most common. Usually bilateral.
Mucinous: Less common. Unilateral. Can be VERY large – if the prompt states that the tumor is unilateral and >15 cm, think mucinous
The combination of vaginal itching and anal itching is highly specific for. . .
. . . lichen sclerosis
Other etiologies may cause one or the other, but not both
Smoking and endometrial cancer
Smoking induces a hypo-estrogeneic state, and as such it is actually protective against endometrial cancer
Smoking protects against endometrial cancer and ulcerative colitis
When endometrial cancer occurs in a patient without estrogen-related risk factors, its prognosis is. . .
. . . poor
Usually these cancers are the non-hormonally driven endometrial cancers, which are much more aggressive
Sometimes called “type II” endometrial cancer
Endocervical curretage
Used if there is an abnormal Pap, but colposcopy does not show any abnormal areas or if the transformation zone (the area at risk for HPV infection and pre-cancer) cannot be seen with the colposcope
DES exposure is associated with development of ___
DES exposure is associated with development of clear cell adenocarcinoma
Lymphangiosarcoma
Rare, secondary malignancy that originates in vascular endothelial cells and occurs secondary to chronic lymphedema, classically in women who have undergone axillary lymphadenectomy after mastectomy.
If DHEAS and testosterone are both elevated in someone with sudden onset virilization and hirsuitism, ___ is the likely cause
If DHEAS and testosterone are both elevated in someone with sudden onset virilization and hirsuitism, adrenal tumor is the likely cause
If it were just testosterone, a sertoli-leydig ovarian tumor would be most likely
