BRCA for the OB/GYN

Here’s the RoshReview Question of the Week:

A 37-year-old woman presents to your office for health care maintenance. She reports that her maternal cousin was diagnosed with advanced-stage breast cancer at the age of 35. Genetic testing was performed, and her relative tested positive for breast cancer susceptibility gene 1. Which of the following is associated with this condition?

• Microsatellite instability

• Mutation of tumor suppressor gene

• Oncogene

• PTEN mutation

Check your answer at the links above!

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Follow along with ACOG PB 182

What are we talking about, exactly?

• Certain germline mutations predispose patients to heritably higher risk of breast and ovarian cancer

• In particular, you have probably heard of BRCA1 and BRCA2

  • Others you may or may not have heard of include: 

    • Lynch syndrome genes (MSH2, MLH1, MSH6, PMS2), 

    • PTEN, 

    • TP53 (Li-Fraumeni syndrome), and 

    • STK11 (Peutz-Jehger Syndrome), just to name a few!

• However, we’ll spend today’s podcast focusing on BRCA specifically.

What exactly are the BRCA risks?

• Estimates of carrier frequency range from 1/300 to 1/800 for either genes.

• BRCA1 is found on Chr 17

• BRCA2 is found on Chr 13

• Both are tumor suppressor genes that function in DNA repair process.

  • The inherited mutation is non-functional or defective allele in some way, but patients usually have a second, functional copy.

  • If the second allele becomes nonfunctional due to somatic mutation, cancer can develop – 

    • Two-hit hypothesis of tumor suppressor genes.

• Risk of breast cancer in person without BRCA by age 70: ~12% (1/8)

  • Risk in patient by age 70 with BRCA1/2: 45-85%

    • Also more likely to be “triple negative” breast cancer for hormone and HER2 receptor

• Risk of ovarian / fallopian tube / primary peritoneal cancer:

  • BRCA1: 39-46% by age 70

  • BRCA2: 10-27% by age 70

  • Both associated with high grade, serous or endometrioid phenotype

• BRCA1/2 also associated with prostate, pancreatic, uterine cancers as well as melanoma

Who should I send for genetic counseling?

• If your patient has a new cancer, genetics recommended:

  • New ovarian epithelial cancers (including fallopian tube or primary peritoneal)

  • Breast cancer at age 45 or less;

  • Breast cancer, and have a close relative with breast cancer at age 50 or less, or a relative with ovarian cancers at any age; or with limited/unknown family history

  • Breast cancer with two or more relatives affected by breast cancer at any age

  • Breast cancer and two or more close relatives with pancreatic cancer or aggressive prostate cancer

  • Two breast cancer primaries, with the first diagnosed under age 50

  • Triple negative breast cancer at under age 60

  • Breast cancer and Ashkenazi Jewish ancestry at any age

  • Pnacreatic cancer and have 2+ close relatives with breast, ovarian, pancreatic, or aggressive prostate cancer

• If your patient does not have a new cancer, genetics recommended based on the history of:

  • A first-degree or several close relatives that meet the above criteria

  • A close relative carrying a known BRCA1 or BRCA2 mutation

  • A close relative with male breast cancer

• If you’re not sure but the history seems high risk, a referral to cancer genetics to discuss is always worthwhile – the histories above should definitely prompt your referral though! 

• And as you’re taking family history - it bears special mention that both maternal and paternal histories are important!

  • Especially given association with male breast CA, prostate CA, melanoma – be sure to get both sides!

• Genetics may recommend performing BRCA mutation testing, which can have a variety of possible outcomes:

  • True positive: pathogenic BRCA variant identified

  • True negative: no pathogenic variant identified in someone who has known BRCA variant in family

  • Uninformative negative: no pathogenic variant identified, but uninformative because of:

    • a) other family members not tested

    • b) family carries a variant, but it was not detected because of test limitations

    • c) family carries a high risk mutation in another gene

    • d) there is no high risk mutation

  • Variant of uncertain significance (VUS): abnormality detected in BRCA gene, but unknown whether the variant is associated with increased cancer risk

• Patients should be informed about the possible outcomes before undergoing genetic testing so they are aware of potential limitations and importance of family testing.

  • Unintended consequences of testing can include anxiety/stress and family dynamic issues regarding need for disclosure.

• Multigene panel testing also exists to look for mutations beyond BRCA and can be suggested by genetic counselors if indicated. 

How do I counsel and care for the patient with BRCA1 or BRCA2 mutation?

Screening

• Breast:  broken out by age:

  • Age 25-29: clinical breast exam every 6-12 months and annual screen (preferably by MRI with contrast)

    • Avoid ionizing radiation at this younger age as this may increase risk of cancer

  • Age 30+: Annual breast mammography and MRI, generally alternating every 6 months, as well as continuing CBE q6-12 months

• Ovarian:

  • TVUS and CA-125 monitoring routinely is not recommended

    • However, could be considered for short term surveillance around age 30-35 until patient undergoes risk-reducing BSO.

Medical

• Breast:

  • Tamoxifen and raloxifene can be considered (SERMs)

    • Can be considered in patients age 35 or older and not planning on pregnancy, or on prophylactic mastectomy

    • Tamoxifen is used in pre-menopausal and post-menopausal women, and may reduce breast cancer risk by 62% in BRCA2 carriers, but has not been found to reduce risk of cancer in BRCA1 carriers (likely due to higher triple-negative rates in this pop)

    • Raloxifene has been found to be effective in reducing invasive breast cancer in postmenopausal women at increased risk, though not evaluated specifically in BRCA mutation carriers

      • Tamoxifen may have a more significant risk reduction based on one head-to-head trial

    • Recall side effects of SERMs: vasomotor symptoms, vaginal symptoms (dryness, itching, dyspareunia), and increased risk of VTE!

    • Tamoxifen: also associated with concern for endometrial hyperplasia. While generally preferred in pre-menopausal patients, consider this in patietns with risk factors for endometrial hyperplasia!

    • Raloxifene: other significant side effect is leg cramps! Does not act on endometrium so may be considered in patients with significant risk factors. 

  • Aromatase inhibitors

    • Two trials have shown reduction in breast cancer risk in at-risk postmenopausal individuals; could be considered as alternative if contraindication to SERM

    • Not used in premenopausal women because it would end up actually stimulating ovarian function (i.e., ovulation induction)

• Ovarian:

  • OCPs are reasonable to use for cancer prophylaxis until BSO:

    • Reduction of ovarian cancer risk estimated at 33-80% for BRCA1, 58-63% for BRCA2

    • No increased risk of breast cancer in those with BRCA mutations using OCPs

Surgical

• Breast: bilateral mastectomy

  • Can be offered to any patient with BRCA mutation; reduces risk by 85-100%, depending on procedure type

  • However, this is big surgery - should be referred to breast surgeon to discuss risks of surgery in short term (surgical issues like hematomas, flap issues, infection) and long-term (pain, numbness, swelling, breast hardnes)

    • 70+% of patients report satisfaction with choice to undergo mastectomy at a follow up of 14.5 years

• Ovarian: bilateral salpingoophorectomy

  • Most effective option for risk reduction; should be considered by age 35-40 for BRCA1 patients, 40-45 for BRCA2 patients

    • This can be individualized based on patient’s family history and plans for childbearing

    • Also worth discussion of fertility-preservation with oocyte or embryo cryoperservation

  • Salpingectomy alone is not recommended at this time; however, the PB notes that salpingectomy followed by future oophorectomy could be reasonable to consider for some patients desiring this.

  • How to perform a risk-reducing BSO:

    • Perform a survey on entry - visualize peritoneal surfaces for any obvious disease and perform pelvic washings

      • Inspect diaphragm, liver, omentum, bowel, paracolic gutters, appendix, ovaries, falliopian tubes, uterus, bladder serosa, and cul-de-sac; biopsy any abnormal areas

    • All tissue from ovaries and fallopian tubes need to be removed!

      • Ligate IP 2cm proximal to the end of identifiable ovarian tissue

        • Beware of your ureter!

      • If hysterectomy not performed, tubes should be divided at insertion to cornua, and ovary removed from utero-ovarian ligament as close to uterus as possible.

    • Frozen pathology not necessary, as most malignancies identified from this procedure are occult

      • Your pathologist needs to know that the patient is BRCA-carrier though! This will prompt them to perform complete, serial sectioning of the tissue with microscopic screening (rather than representative sections typically performed with other benign BSO)

  • Hysterectomy can be considered simultaneously:

    • Advantages: simplifies hormone therapy (estrogen alone, vs E-P if retained); removal of cornual aspect of fallopian tube; reduce endometrial cancer risk if genetically-predisposed or taking tamoxifen

    • Disadvantages: bigger surgery, longer recovery, higher risk of complications from surgery

  • After BSO:

    • Patients who are premenopausal will need HRT to mitigate effects of early menopause and help with cardiovascular health and bone protection

      • Recall that HRT in the WHI increased risk of breast cancer in the estrogen-progesterone arm, but not in the estrogen-alone arm.

      • Given the higher rates of triple-negative breast cancer in BRCA population – HRT would not alter that course. Data suggests that HRT does not seem to reduce the protective effects of risk-reducing surgery overall.

    • In post-menopausal patients, this is controversial – other options are generally preferred to HRT for VMS management.

    • Local estrogen therapy for vaginal symptoms (genitourinary syndrome of menopause) is safe and effective in BRCA population – please use it! 

    • Ongoing surveillance after BSO is not necessary - so no need to collect CA125 or perform surveillance imaging. Patients should report any concerning symptoms.

Vulvar Intraepithelial Neoplasia (VIN)

Here’s the RoshReview Question of the Week!

A 41-year-old woman, G2P2, presents to your office for postcoital bleeding. She has a history of laparoscopic hysterectomy for persistent cervical intraepithelial neoplasia 3. A vaginoscopy is performed and shows multiple lesions in the upper third of the vagina. One lesion located within a suture recess near the vaginal cuff is not able to be visualized in its entirety. Biopsy reveals a high-grade squamous epithelial lesion. Her social history is significant for smoking. Which of the following is the best therapy?

• CO2 laser ablation

• Human papillomavirus vaccination

• Imiquimod

• Surgical excision

Check your answer at the links above and check out RoshReview’s CREOG question bank!

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Follow along with ACOG CO 675!

What is Vulvar Squamous Intraepithelial Lesions (SIL) and why do we care? - previously called VIN 

• VIN is increasingly common - esp in women in their 40s 

  • VIN has increased more than 4x from 1973 to 2000! 

  • VIN should be considered a premalignant condition

• How do we classify?

  • Has changed a lot over time, but most recently we have used:

    • LSIL of the vulva - used for low grade changes that come from HPV infections (usually present as genital warts) 

    • HSIL of the vulva - used for high grade changes that comes from HPV infections (precancerous lesions) - used to be called “usual type” 

      • VIN, warty type 

      • VIN, basaloid type 

      • VIN, mixed (warty or basaloid) type 

    • Differentiated type - from things like lichen sclerosus 

  • The International Society for the Study of Vulvovaginal Disease ISSVD recommends these terms to unify the nomenclature of HPV-associated squamous lesions of the lower genital tract - all of these are based on histopathologic findings:

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ACOG CO 675

How do we diagnose VIN? 

• Unfortunately, no good screening strategies

  • Detection usually limited to visual inspection 

  • What does it look like?

    • Can vary. Most will be raised, but some can be flat 

    • Discoloration of the skin - white, gray, red, brown, or even black 

  •  Should biopsy to make definitive diagnosis if not sure of diagnosis of something else (ie. LS) 

    • Biopsy should be performed in postmenopausal women with apparent genital warts and in women of all ages with genital warts where topical therapies have failed 

    • Colpo can also be useful - just remember that you need to soak the vulva in acetic acid with a gauze pad for several minutes 

What do we do to treat? 

• Treat all vulvar HSIL (VIN usual type) 

  • Surgery 

    • Wide local excision should be done if there is suspected to be cancer 

    • Can be occult invasion even if initial biopsy is vulvar HSIL 

    • Should include gross margin of 0.5-1 cm around tissue with visible disease 

    • May be altered to avoid injury to critical structures like clitoris, urethra, anus, or other structures 

    • However, if lesions in critical areas, should be referred to specialist to avoid impaired psychosexual function (ie. if extensive around the perineum, reaching back to anus or around the clitoris 

    • If clear margins in excised tissue, much lower risk of recurrence 

  • Laser Ablation Therapy 

    • Should be done if occult invasion is not a concern

    • Can be used for single, multifocal, or confluent lesions, although risk of recurrence may be higher than with excision 

    • Colpo can help delineate lesions of margins 

    • As with excision, 0.5-1cm margin to be treated 

    • Remember than unlike genital warts, the entire thickness of the epithelium must be treated

  • Medical Therapy 

    • Topical imiquimod 5% 

    • Regimens that have been published include 3x/week to affected area for 12-20 weeks 

    • Colpo assessment at 4-6 weeks 

    • Residual lesions require surgical treatment 

• Surveillance

  • Recurrence rate is as high as 9-50% with all treatment regimens

    • Higher with positive margins

    • Lower in surgically treated patients 

  •  Follow up has been limited in most studies 

  • However, women with Vulvar HSIL are at high risk of recurrence during their life time 

  • If complete response to therapy and no new lesions at follow-up visits, scheduled 6 and 12 months after initial treatment should be monitored by visual inspection 

Cervical Cancer

Today we welcome Erin Lips, MD to the podcast. She’s a current 2nd year GYN Oncology fellow at Brown University / Women and Infants of RI!

Cervical cancer is almost a completely preventable disease, yet it represents the 4th most common female malignancy worldwide. The burden of cancer and cancer-related deaths is disproportionately weighted toward populations without access to adequate screening or adequate treatments: 

• 90% of cancer deaths occur in low and middle income countries:

  • Mortality in these countries is 18x higher than in developed countries.

  • In 2012, in high income countries, cervical CA was 11th most common female cancer and 9th most common cause of cancer mortality 

  • In LMICs by comparison, it was the 2nd most common cancer and the 3rd most common cause of cancer death.

  • In Africa and Latin America, cervical cancer is the leading cause of cancer specific mortality in women. 

• SEER estimates 13,800 new cases in the US for the year 2020 and 4290 deaths. 

  • In the US, median age of diagnosis is 47-50 years, and half are diagnosed under 35. 

  • Within the US, racial, socioeconomic, and geographic disparities exist in cervical cancer.

    • Black and Hispanic patients have the highest rates.

    • There is also geographic differences in incidence between states.

    • Multifactorial, but overall due to poor access and barriers to routine care.  

• In high income countries, incidence and mortality have decreased by more than half over last 30 years due to formalized screening programs, involving Pap and HPV testing.

Cervical Cancer Risk Factors:

• Chronic high risk HPV infection causes almost all cases of cervical cancer!

• Early age of sexual debut

• Higher number of sexual partners or high risk sexual partner

• Immunosuppression (organ transplant or HIV)

• h/o STIs

• h/o HPV-related vulvar or vaginal dysplasia

• Non-attendance for screening

• Tobacco is a major risk factor, doubling risk of dysplasia and cancer even after adjusting for HPV status. 

  • Smoking cessation associated with 2-fold risk reduction!

Primary Prevention: the HPV vaccine

• 90% efficacy in preventing HPV 16 and 18 (the 2 types most highly associated with high grade dysplasia). In 2018. a nine-valent vaccine was introduced that covered additional high-risk serotypes.

• Australia was the first country to establish an HPV vaccine program in 2007

  • >70% vaccine coverage in boys and girls aged 12-13 yrs. 

  • 38% reduction in high grade dysplasia in young women within 3 years!

• In countries where at least 50% of females are vaccinated, HPV 16 and 18 infections decreased by almost 70%.

  • In the USA, HPV coverage by 2014 was <50% in girls under age 17

Secondary Prevention: Papanicolau smear 

• Primary HPV testing will likely take over, but we are still holding on to our cotesting strategy and most institutions can’t let go of cytology yet!

• Check out the Pap smear episode for more: Episode 1; Episode 2

Clinical presentation:

• Early stages: 

  • Often asymptomatic 

  • Post-coital or abnormal vaginal bleeding, malodorous discharge

  • Diagnosed after routine screening or pelvic exam

• Advanced disease: limb edema, flank pain, sciatica

• Fistula: passage of urine or stool through the vagina suggests invasion into bladder or rectum c/w vesicovaginal or rectovaginal fistula 

Diagnosis:

• Based on histopathological assessment of a cervical biopsy

  • 80% Squamous, 20% Adenocarcinoma

• Usually when cervical cancer is diagnosed in the US, next step is to stage:

  • A cold-knife cone excisional procedure will often be performed first - with smaller tumors, this is to ensure disease is not more advanced. This may be the point of first diagnosis after identifying dysplasia on Pap/colposcopy.

  • If cancer is diagnosed, in the US:

    • PET/CT scan

    • proceed to the OR for an exam under anesthesia (EUA), cystoscopy, and proctoscopy. 

    • Assess for parametrial invasion on EUA. 

    • Depending on the stage and plan, patient may or may not warrant lymph node dissection. Radiation oncology could be consulted to examine as well for radiation planning.

Staging:

This is a popular topic to be tested on CREOGs and board exams! However, it’s important to know that there is a new FIGO staging system we are now using.

• Traditionally, staged clinically based on exam and use of limited imaging because this cancer is so prevalent in LMICs, and PET scan or surgical staging is not always accessible in these areas. 

  • For instance: in the old staging system, you would choose the stage based on exam. If the patient then ended up having pathologically proven lymph nodes, you might still say “this is a stage IB with positive para-aortic lymph nodes” instead of upstaging to at stage III (like you do in endometrial cancer).

• In 2018, FIGO introduced a new staging system which does incorporate radiologic and lymph node positivity into the staging system, and now resembles endometrial cancer staging that way. You can see them side-by-side below:

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FIGO 2018 Staging

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FIGO 2009 Staging

First Line therapies 

• Rule of thumb is that the ideal approach to these patients is to have the intention of doing either curative surgery or curative radiation, but not both. 

• Surgery and radiation are equally effective but morbidity of doing both is significant and increases risk for lifelong complications. SInce these patients are often young and many have young children, this is a very important piece to consider.

SURGERY:

• Cutoff for surgical candidacy is early. 

• Candidates are patients with a small tumor confined to the cervix (<4cm in size), with no spread to parametria, lymph nodes, or anything else. 

  • IA1 and no lymphovascular space invasion (LVSI): simple hysterectomy, 

  • IA1 with LVSI and IA2: Radical hysterectomy, pelvic lymph nodes

  • IB1, IB2, IIA1 (i.e., tumor <4cm or confined to upper vagina with no parametrial involvement): Radical hysterectomy, pelvic lymph nodes

  • IB3 (AKA tumor >4cm) and beyond: Chemosensitizing radiation. 

  • Distant metastases: Just chemotherapy (no radiation).

• During surgery, if any lymph nodes are enlarged, those should be removed and sent immediately to path → if positive, abort the hysterectomy, sample PALN, and plan for chemoradiation instead.

• After hysterectomy, assess for SEDLIS or PETERS criteria to determine whether patient needs post-op radiation

  • SEDLIS: HIR criteria (tumor size, depth of invasion, and LVSI)

  • PETERS: High risk criteria (positive margins, parametria, or lymph nodes)

What to do about ovaries?

• Usually leave in situ unless patient is post-menopausal

  • Risk of mets to ovaries is very low, and you’re usually only doing surgery if you think it’s very early stage anyway. 

LACC trial 2018: 

• Widely disseminated change of “standard of care” to abdominal rad hyst (not MIS)

• Large Phase III randomized clinical trial comparing outcomes of MIS vs open radical hysterectomy.

• Trial terminated early due to higher recurrence rates and more deaths in the MIS group

  • At 4.5 years, 96.5% of pts who had open surgery had no recurrences, but only 86.0% who had MIS had no recurrences 

  • At 3 years: 99.0% of pts who had open surgery were still alive, while only 93.8% who had MIS were still alive (HR 6.0)

Fertility Sparing Surgical Options:

• IA1 no LVSI: Cone with neg margins

• IA1 with LVSI, IA2: Cone and LND OR Radical trachelectomy and LND

• IB1, select IB2: Radical trachelectomy and LND (traditional cutoff is <2cm tumor size for trachelectomy)

RADIATION:

• If pre-operatively it is known the patient is not a candidate for surgery, want to keep the uterus and cervix in situ to allow for the optimal radiation treatment to be administered.

• PET/CT will usually help delineate spread to lymph nodes. However, if no PALNs lit up, can go to OR to sample. This helps with mapping of RT fields.

• Standard RT is co-administered with chemotherapy, which we call “chemoradiation” or “chemosensitizing radiation.” 

  • Weekly small doses of Cisplatin during course of RT, 5-6 cycles

  • RT is combination of EBRT (whole pelvic) and internal brachytherapy

    • EBRT is 45Gy, divided into 25 fractions. 

      • This means daily, 5 days a week, for 5 weeks

    • Brachytherapy is another 40 Gy, divided up into fractions. 

      • administered via one of several methods: tandem and ovoids, tandem and ring, tandem and sleeve, etc. 

      • LDR (Low dose rate) vs HDR (high dose rate)

      • Interstitial - for cases of obliterated anatomy- radiation source loaded into needles, which are placed into the tumor and remain in place for prescribed period of time for treatment.

  • Very important to stay on schedule, as timing of RT is crucial for optimal cell kill and efficacy. 

CHEMO for METASTATIC DISEASE:

• Typically Cisplatin/Paclitaxel/Bevacizumab

Cervical cancer in pregnancy: 

• Though breast cancer is most common cancer diagnosed in pregnancy, cervix is the most common GYN malignancy in pregnancy - might actually diagnose earlier because of increased care, so usually stage I.

• If gestation is still pre-viable and the patient desires termination, then usually a gravid hysterectomy or radical hysterectomy and lymph node dissection is performed.

• If >24 weeks or if the patient desires continuation of pregnancy, then patient has the option for neoadjuvant chemotherapy until delivery. Deliver via C-section and then can perform a cesarean radical hysterectomy if appropriate mode of treatment OR postpartum RT if non-operative management is indicated.

  • Vaginal delivery is contraindicated in known diagnosis of cervical cancer!

Adnexal Masses Part IV: Sex Cord Stromal Tumors

Thanks for sticking with us until the end of this adnexal mass journey! Today we’re going to cover some rare tumors that always find themselves on CREOGs — the sex cord stromal tumors. These only comprise about 1.2% of primary ovarian cancers. Most people are fortunately diagnosed at an early stage due to the fact that symptoms tend to be much more overt with these types of tumors.

Granulosa Cell Tumors

There are two subtypes of granulosa cell tumors: adult and juvenile. Adult type comprises 95% of these neoplasms, and generally occur in women aged 50-54 years. Juvenile type typically develops before puberty. It has a higher proliferative rate, but lower risk for late recurrences. Regardless of type, these typically present as a large, unilateral mass clinically, with a mean diameter of 12cm. They can produce estrogen and/or progesterone, so symptoms can be related to hyperestrogenism particularly in juveniles (i.e., precocious puberty). The production of estrogen in adult types is also associated with concomitant endometrial hyperplasia or cancer; with EIN present in 25-50%, and endometrial carcinoma present in 5-10% of patients. Thus, it is important to perform endometrial sampling when one of these tumors is suspected or diagnosed.

The histopathology is classic: “Call-Exner bodies", where the pale, round, coffee-bean shaped nuclei characteristic of granulosa cells arrange themselves into rosettes around a central cavity.

Thecomas

Thecomas are solid, fibromatous, generally benign neoplasms. They are generally unilateral, and are comprised of theca cells. The theca cells appear in normal ovulation as follicles develop into secondary follicles, and under the influence of LH produce androgens. After ovulation, theca cells also help to form the corpus luteum with granulosa cells.

Because of this high production of androgen that will be converted, endometrial hyperplasia or cancer can also be found in these patients, and it is wise to perform endometrial sampling for that reason. Up to 20% of patients may have synchronous endometrial cancer.

Fibromas

These are the most common type of sex cord stromal tumor. They are benign, solid, unilateral neoplasms, generally occurring in postmenopausal women, and are not hormonally active. However these can be implicated in Meigs’ syndrome, where the tumor is associated with extensive ascites or a pleural effusion.

Sertoli / Leydig Cell Tumors

These two are the rarest of the sex cord stromal tumors, accounting for less than 0.5% of these. The histopathology of the hollow tubules (Sertoli) surrounded by fibrous stroma (Leydig) is classic. These will often produce androgens and be associated with virilizing symptoms. They also are unilateral and are often associated with large masses, with a mean size of 16cm at presentation. AFP is often another marker.

Adnexal Masses Part II: Epithelial Neoplasms

On today’s episode, we start into epithelial neoplasms of the ovary, which comprise about 90% of cancers of the ovary, fallopian tube, and peritoneum. Here are the show notes in outline format!

Benign epithelial  neoplasms 

1. Serous cystadenoma 

   1. Among the most common benign ovarian neoplasms (20-25%); sized 5-20 cm

   2. Benign, but if persistently symptomatic, can have surgical removal 

   3. There is no good data regarding the decision to observe or remove if they are asymptomatic, but decision to operate may be guided by age, size of mass, ultrasound appearance, family history or other risk factors for ovarian cancer + medical comorbidities 

2. Mucinous cystadenoma, lining similar to viscera or gastric lining  

   1. <5% of ovarian neoplasms 

   2. Contains mucin 

   3. Treatment same as above 

1. Borderline ovarian epithelial neoplasms 

   1. Serous borderline neoplasms - most common histologic subtype of borderline tumors and accounts for 65% of all borderline ovarian neoplasms 

      1. Usually confined to the ovary and is slow growing

      2. 10 year survival rate is 95-100%, though late recurrences are not uncommon 

      3. Prognosis is still excellent even if there is presence of peritoneal implants and regional lymph node involvement 

      4. Histology: serous epithelial proliferation; more complex architectural patterns than a serous cystadenoma, and can have areas of microinvasion (area of cells <5 mm that are invading into the stromal core of the papillae or cyst wall); if it’s >5 mm, then it should be classified as a low-grade serous carcinoma 

      5. In fact, serous borderline neoplasms have similar immunophenotype and molecular biology to LGSC and may suggest that LGSC can arise from borderline neoplasms 

      6. Treatment: surgery 

   2. Mucinous borderline neoplasm - nearly always confined to ovary, unlike serous 

      1. Usually appears large, unilateral, multilocular cyst with smooth, white capsule 

      2. Epithelial lining with two general types: GI type and endocervical (or seromucinous) type 

      3. Approximately 10-20% exhibit microinvasion 

      4. Treatment: surgery 

   3. Endometrioid borderline neoplasm - biologic potential between cystadenomas/adneofibromas and invasive endometrioid adenocarcinoma of the ovary 

      1. Uncommon - 2-10% of borderline neoplasms 

      2. General appearance: firm, with smooth surface and multiple small cysts with clear or hemorrhagic fluid  

      3. Histologically, have adenofibromatous pattern with nodular architecture, but more proliferative with appearance similar to complex atypical hyperplasia of the endometrium 

      4. Actually same criteria exist to differentiate it from invasive carcinoma as there is between complex atypical hyperplasia and well-differentiated endometrioid adenocarcinoma of the endometrium 

      5. Microinvasion can be seen 

2. Carcinomas 

   1. We will talk about staging and treatment in another episode! 

   2. High-grade serous carcinoma (70-80% epithelial carcinomas) 

      1. Most common type of ovarian cancer, and accounts for 70-80% of  all malignant ovarian neoplasms 

      2. Peak age range is 45-65 years; usually diagnosed at advanced stage 

      3. Histologically, HGSC will infiltrate and destroy 

      4. BRCA1 or BRCA2 germline mutations are found in up to 10% of women with HGSC 

      5. Women with these mutations have a 30-50% risk of developing ovarian carcinoma by age 70 

   3. Low-grade serous carcinoma (<5%)

      1. Uncommon 

      2. Typically diagnosed at advanced stage; therefore, long-term prognosis is poor 

      3. Slow-growing, indolent tumors with relative insensitivity to platinum-based chemo 

      4. Can be found alongside noninvasive serous borderline tumors

      5. LGSC differentiated from HGSC by cytologic features; usually have more uniform nuclei, lower mitotic activity; also has numerous psammoma bodies 

   4. Endometrioid carcinoma (10%) 

      1. Unlike serous carcinomas, it is usually identified at an early stage, and therefore, patients have a better prognosis 

      2. Tend to be relatively chemosensitive 

      3. Thought to arise from endometriosis and is associated with carcinoma of the endometrium in 15-20% of cases 

      4. Histologically, this type of carcinoma resembles the uterine counterparts 

   5. Clear cell carcinoma (10%) 

      1. Present most commonly in perimenopausal women in 40s or 50s 

      2. Often presents at an early stage, relatively good prognosis due to absence of distant metastases 

      3. However, if it is present at advanced stage, it has worse prognosis than serous or endometrioid carcinoma, because it is not as sensitive to platinum-based chemo 

      4. Possibly arises from endometriosis 

   6. Mucinous carcinoma (3%)  

      1. Nearly all present in early stages, usually stage I; often seen with borderline neoplasm 

      2. Reason it’s found early is because it is usually large upon discovery: 8-20 cm, but can be even larger

      3. Tends to be cystic or solid, unilateral, and confined to the ovary

      4. There are two patterns of “invasion” - infiltrative invasion and expansile growth pattern

      5. Infiltrative: obvious destructive stromal invasion -  worse prognosis 

      6. Expansile growth pattern: does not demonstrate obvious stromal invasion, but has complex architecture; better prognosis