Pelvic Mass in the Female Patient Differentials and Workup David C Murphy, D.O. IOA Summer Conference French Lick, Indiana August 2017

~ 20% will develop a pelvic mass sometime in their lives 5-10% lifetime risk of surgery Occurs from fetus to elderly Asymptomatic 25 – 40 : 7.8% Asymptomatic postmenopausal: 2.5%

Clinical approach Determine most likely etiology Anatomic location Age Reproductive status Features of urgent conditions are fairly specific Malignancy must be excluded for any mass not clearly benign

Anatomic location Ovarian Fallopian tube Paratubal or paraovarian Tuboovarian abscess Broad ligament leiomyoma Ov: physiologic cysts, benign neoplasms, cancer or metastatic disease Ft: ectopic pr, hydrosalpinx, cancer

Age and reproductive status Children and adolescents:adnexal torsion or ovarian malignancy (10-20%) Premenopausal women: most masses are benign Pregnant: ectopic pregnancy, luteomas, corpus luteum, theca lutein cysts Postmenopausal: excluding malignancy is main priority Germ cell tumors~35% -v- 20% in adults. Prem: incidence of ov cancer increases w age- 1.8-2.2/100,000 age 20-29, v 9.0-15.2/100,000 age 40-49. PM: avg age @ dx is 63 in US

General evaluation Medical history: pelvic pain or pressure Physical exam: size, consistency, mobility, abdominal distention, ascites Imaging studies: pelvic ultrasound, MRI Lab evaluation: pregnancy test, cbc, tumor markers Characteristics: onset, location, duration, constant/intermittent, other associations. Adnexal mass and bleeding ?ectopic, hx of fever and vaginal discharge-TOA, persistent serosanguinous discharge without fever-fallopian tube cancer, Infertility- endometrioma or hydrosalpinx

Evaluation of urgent conditions First trimester bleeding or pain Acute pelvic or abdominal pain Adnexal torsion Ruptured or hemorrhagic ovarian cyst Fever : TOA, periappendicial abscess, diverticular abscess

Evaluation of malignancy Ovarian cancer- most common histiologic type is epithelial ovarian cancer High grade serous EOC, fallopian tube and peritoneal carcinomas are considered a single clinical entity. Metastatic disease from another primary- gastric and breast most common Likelihood of malignancy depends on imaging findings, age/menopausal status, risk factors, lab results No minimally invasive biopsy technique- would upgrade tumor Family history of ovarian, breast, uterine, or colon cancer High grade serous EOC, fallopian tube and peritoneal cancers are considered a single clinical entity

Evaluation- continued Pelvic ultrasound is first line-sensitivity 86-91%, specificity 68-83% MRI Additional studies may be necessary to evaluate for metastasis Serum markers Surgical evaluation allows a definitive histiologic diagnosis Patients with a complex adnexal mass, findings suggestive of metastatic EOC, fallopian tube or peritoneal carcinoma, or laboratory testing suggestive of ovarian cancer should be referred to a gynecologic oncologist.

Differential diagnosis of adnexal mass

A consensus paper from the Society of Radiologists in Ultrasound in 2010 indicated that transvaginal ultrasound, supplemented by transabdominal ultrasound, was the best technique for imaging and characterizing an adnexal cyst.

Pics ov anatomy and origins of ovarian tumors Most common neoplasms are epithelial. Ovarian germ cell tumors are derived from primordial germ cells. Ovarian sex cord-stromal tumors derive from stem cells that would normally give rise to supporting epithelial cells, including ovarian stroma and follicles.

Fetuses, children, and adolescents Pelvic mass in newborn is most likely a physiologic cyst, but can include GU disorders, GI tract disorders, or miscellaneous Neonatal to puberty- physiologic cysts are uncommon because gonadotropin ovarian stimulation decreases in infancy and rises with puberty. Ovarian neoplasms <1% of tumors in this age group Menarche – 18: simple and complex cysts common. <5% of ovarian cancers However: ovarian cancer is the most common gynecologic malignancy in women<25. Germ cell tumors ½ - 2/3 , compared to 20% in adults In girls younger than 9, approximately 80% of ovarian neoplasms are malignant Peak age for germ cell tumors between 10 - 30

Premenopausal women Many adnexal masses stimulated by hormones, including physiologic cysts, endometriomas, and leiomyomas

Prevalence of specific adnexal mass pathologies- IOTA n=4848 International Ovarian Tumor Analysis group

Follicular cysts appear smooth, thin-walled and unilocular Follicular cysts appear smooth, thin-walled and unilocular. Simple cysts < 3 cm are considered physiologic. Generally < 10 cm Corpus luteal can be simple, or complex, containing internal debris, and thick walls. Can be up to 8 cm, and generally resolve spontaneously

Theca lutein cysts are a result of overstimulation from high human chorionic gonadotropin. Gestational trophoblastic disease, multiple gestation, ovarian hyperstimulation, or pregnancy complicated by fetal hydrops. May cause maternal virilization, hyperemesis gravidarum, preeclampsia or thyroid dysfunction.

Polycystic Ovarian Syndrome (PCOS)- enlarged ovaries with multiple small follicular cysts. Classic phenotype is obese, hirsute and anovulatory. Treated to manage abnormal uterine bleeding, infertility, insulin resistance, obesity, and hirsutism.

Ectopic pregnancy is suggested by history of a missed menses, abdominopelvic pain, and vaginal bleeding.

Endometriosis is often associated with pelvic pain, dysmenorrhea and dysparunia. Chocolate cyst- complex mass typically containing homogenous internal echoes. Ground glass

Leiomyoma- benign neoplasm of smooth muscle origin. Clinically apparent in 25% of reproductive age women. Depending on size and location, patients present with c/o pelvic pressure, pain, menorrhagia, and/or dysmenorrhea

Tubo-ovarian abscess- inflammatory mass involving the fallopian tube, ovary, and occasionally adjacent pelvic organs Characteristically presents with abdominopelvic pain, fever, purulent cervical discharge, and cervical motion tenderness.

Hydrosalpinx should be suspected when a dilated, tubular cystic structure is seen adjacent to the ovary Often have incomplete septations

Serous or mucinous cystadenoma- among most common benign ovarian neoplasms. Thin-walled, uni- or multi-locular, and can range from 5 – 20 cm. Mucinous occur less frequently, are more likely to be multilocular, are larger, and tend to be unilateral. Many are assymptomatic and found incidentally on exam. Benign-appearing masses that are persistently symptomatic should be removed.

Mature cystic teratoma(dermoid) is a benign germ cell tumor and is the most common ovarian neoplasm in the 2nd and 3rd decades. Contain elements to all three germ layers: ectodermal, mesodermal and endodermal Ec- skin, hair, follicles and sebaceous glands, Me- muscle, urinary, En- lung, GI. Bilateral in 10 -15% of patients

Malignant neoplasms Incidence in adnexal mass ranges from 6 – 11% Most are partially cystic and derive from epithelial cell Germ cell tumors 2nd most common in women < 30, rare afterwards Krukenberg tumor- metastatic to ovary from another primary site, classically GI tract or breast At least 30% of ovarian masses in women >50 are malignant. Nonmalignant etiologies include many of those seen in reproductive age KT: gastric adenocarcinoma, especially at the pylorus, most common

Risk factors for ovarian cancer

Estimated cancer risks brca1 and brca2

Estimated Cancer Risks (cont)

Lynch syndrome cancer risk

Epithelial neoplasms Accounts for 90% High grade serous carcinoma 70 – 80 % Endometroid carcinoma 10% Clear cell carcinomas 10 % Mucinous carcinoma 3 % Low-grade serous carcinoma < 5% Different subtypes also differ in risk factors and clinical behavior High-grade tubal intraepithelial neoplasia/carcinoma is typically seen either associated with an ovarian or tubal mass or as a pathology result after risk-reducing SO in a patient with a BRCA mutation Average age of diagnosis is ~ 60 Vague GI symptoms

Represent 70% of ovarian neoplasms in 10 – 30 year olds Germ cell tumor Malignant degeneration of a teratoma, is the most common germ cell tumor in postmenopausal women Represent 70% of ovarian neoplasms in 10 – 30 year olds Sex cord-stromal tumors ~ 1.2% of primary ovarian cancers Avg age of diagnosis ~ 50 Often comprised of cells that produce ovarian hormones (estrogens, androgens) Meigs syndrome: adnexal mass, ascites, pleural effusions. The prevelance of a simple unilocular cyst in postmenopausal women ranges from 2.5 – 18 %

Ultrasound differentiation Determine whether the mass is almost certainly benign or whether the mass has some reasonable chance of being malignant. Masses may be physiologic or pathologic Gray-scale gives a 2 dimensional display of anatomy Doppler look for presence or absence of flow in solid areas or septations Combine with pertinent clinical information Expertise of sonologist influences the likelihood of a correct diagnosis Most physiologic masses are cystic.

Steps in characterizing a mass 1:Is it a simple cyst? 2: Is there a physiologic process that can account for potentially confusing findings? 3: Are there characteristics of specific entities? 4: Follow-up ultrasound or additional testing

10 simple rules M1 Irregular solid tumor M2 presence of ascites M3 At least 4 papillary structures M4 Irregular multilocular solid tumor with largest diameter > 100 mm M5 Very strong blood flow (color score 4) B1 Unilocular B2 Presence of solid components where the largest solid component has a largest diameter < 7 mm B3 Presence of acoustic shadows B4 Smooth multilocular tumor with largest diameter < 100 mm B5 No blood flow(color score 1) If one or more M-rules apply in the absence of a B-rule, the mass is classified as malignant. If one or more B-rules apply in the absence of an M-rule, the mass is classified as benign. If both rules, or no rules, the mass cannot be classified International Ovarian Tumor Analysis (IOTA)group

Serum biomarkers CA 125 HE4 OVA1 Risk of Malignancy Algorithm (ROMA) The United States National Institutes of Health defines a biomarker as “a characteristic that is objectively measured and evaluated as an indicator of normal biologic processes, pathogenic processes, or pharmacologic response to therapeutic intervention”. Currently no serum biomarker is both sensitive and specific

Markers secreted by germ cell and sex cord-stromal tumors of the ovary

CA 125 1983 Most widely used biomarker Large transmembrane glycoprotein derived from coelomic and mullerian epithelia CA 125: <35U/ml CA 125 II: <20 U/ml Number on benign processes that can cause elevation C- pericardium, pleura, peritoneum M- fallopian, endometrial, endocervical

Human epididymIs protein 4 (HE4) 2008 Monitoring for recurrent or progressive disease in patients with EOC Antigen that is overexpressed in serous and endometroid ovarian carcinoma Reference range is <150 pM

Carcinoembryonic antigen (cea) Protein normally found in embryonic or fetal tissue In adults- mucinous cancers associated with the GI tract or ovary Also associated with breast, pancreas, thyroid and lung Benign elevations- smoking, mucinous cystadenoma of ov or appendix, cholecystitis, cirrhosis, diverticulitis, inflammatory bowel disease, pancreatitis and pulmonary infections Nonsmokers: <3.8 mcg/L Smokers: <5.5 mcg/L

Cancer antigen 19-9 mucin protein that may be elevated in EOC Used primarily to monitor disease response, or recurrence Gastric, pancreatic, gallbladder, cholangiocarcinoma and adenocarcinoma of the ampulla of Vater Investigational biomarkers Osteopontin, mesothelin, lysophosphatidic acid, haptoglobin, transthyretin, apolipoprotein A1, serum C-reactive protein, and OVX1

Ova 1 2009 includes 5 serum biomarkers- CA 125 II, beta 2 microglobulin, transferrin, transthyretin, apolipoprotein A1 Ovarian malignancy risk index score Premenopausal women Low < 5.0, High >5.0 Postmenopausal women Low <4.4, High >4.4 Affected by elevated triglycerides or rheumatoid factor levels

overa 2016 as a second generation multivariate index assay CA 125 II, HE4, apolipoprotein A1, FSH and transferrin Low risk < 5.0 High risk > 5.0

Risk of malignancy algorithm 2011 Includes CA 125 and HE4 to determine likelihood of malignancy in women undergoing surgery for an adnexal mass Also uses two separate logistic regression algorithms, depending on menopausal status Premenopausal: high risk of malignancy > 13.1% Postmenopausal: high risk of malignancy > 27.7%

Risk of malignancy index Used primarily in UK Combines menopausal status, CA 125 and pelvic ultrasound RMI I = U x M x CA 125 U- multi-locular cyst, solid areas, metastasis, ascites, bilat masses 3= 2-5 points M- 1 for pre and 3 for post

Referral to gyn-onc: acog guidelines Premenopausal (refer if any present) Very elevated CA 125 level Ascites Evidence of abdominal or distant metastasis Postmenopausal (refer if any present) Elevated CA 125 level Ascites Nodular or fixed pelvic mass Evidence of abdominal or distant metastasis Committee Opinion No. 477

references Ultrasound differentiation of benign versus malignant adnexal masses. (n.d.). Retrieved June 02, 2017, from https://www.uptodate.com/contents/approach-to-the-patient-wit-an-adnexal-mass/print? Differential diagnosis of the adnexal mass. (n.d.). Retrieved June 02, 2017, from https://www.uptodate.com/contents/differential-diagnosis-of-the-adnexal-mass/print? Approach to the patient with an adnexal mass. (n.d.). Retrieved June 02, 2017, from https://www.uptodate.com/contents/approach-to-the-patient-with-an-adnexal-mass/print? Serum biomarkers for evaluation of an adnexal mass for epithelial carcinoma of the ovary, fallopian tube, or peritoneum. (n.d.). Retrieved June 02, 2017, from https://www.uptodate.com/contents/serum-biomarkers-for-evaluation-of-an-adnexal-mass-for-epithelial-carcinoma-of-the-ovary-fallopiantube-or-peritoneum/print?

References Diagnosis and Management of the Adnexal Mass. (n.d.). Retrieved June 01, 2017, from www.aafp.org/afp/1998/0515/p2471.html (n.d.). Retrieved June & july, 2017, from https://radiopaedia.org/ Kaunitz, A., M.D. (2016, November 30). How to Apply New Guidelines for Evaluating Adnexal Mass. Retrieved July 20, 2017, from www.medscape.com