Fertility-sparing for young patients with gynecologic cancer: How MRI can guide patient selection prior to conservative management

Most ovarian cancers manifest in postmenopausal women as advanced-stage disease. However, a substantial subset occurs in reproductive age women, with the incidence rising with age ( 125 ). Majority of ovarian malignancies in young women are germ cell tumors and epithelial borderline tumors, with invasive epithelial ovarian cancers and sex-cord stromal tumors being less common ( 126 , 127 ). Surgery is the cornerstone of the initial management of ovarian tumors. The goals are to resect the ovarian tumor to attain accurate histologic diagnosis, comprehensively stage apparently early stage disease, or cytoreduce advanced-stage disease ( 128 ). Preoperative imaging can aid the characterization, map the extent of disease, and guide surgical approach (i.e. laparoscopy versus laparotomy) ( 128 ). The review of intraoperative frozen-sections by an expert gynecologic pathologist is invaluable to tailor surgical procedures based on the histologic information. Fertility-sparing surgery, defined as unilateral salpingo-oophorectomy (USO) with preservation of the uterus and contralateral ovary, is possible for most young women who desire future fertility and have any stage malignant germ cell tumors, sex-cord stromal tumors, borderline tumors or have early stage epithelial carcinomas ( 129 – 133 ). Five percent of germ cell tumors are malignant; the rest are benign mature cystic teratomas. Malignant germ cell tumors manifest in very young women (younger than 20 years) and are the most common ovarian malignancy in this age group ( Figure 8 , and Figure 9 ) ( 127 ). Dysgerminomas and immature teratomas are the most frequent, followed by yolk sac and mixed tumors ( 134 ). Most patients present with Stage I (ovary-confined) disease and have >90% 5-year overall survival; even advanced-stage disease has a good prognosis due to high chemosensitivity making fertility preservation possible ( 135 ). Conservative surgery for malignant germ cell tumors is considered appropriate regardless of histologic subtype and FIGO stage ( 129 , 130 ). USO is combined with comprehensive peritoneal staging. Advanced-stage disease is debulked although extensive resections are avoided due to chemo-responsiveness. Lymphadenectomy can be omitted if lymph nodes are macroscopically normal ( 129 ). Adjuvant platinum-based chemotherapy is advised for most malignant germ cell tumors; exceptions are Stage I pure dysgerminoma and well-differentiated Stage I immature teratoma ( 129 , 130 ). Most malignant sex-cord stromal tumors are comprised of granulosa cell tumors (70%) and Sertoli-Leydig tumors ( 132 ). Granulosa cell tumors (GCTs) are subdivided into adult (95%) and juvenile (5%) types. Adult type manifests mostly in perimenopausal women, whereas juvenile type predominates in pre-pubertal girls. Sertoli-Leydig tumors affect women younger than 30 years and are the most common androgen-producing ovarian tumors (with 30% being hormonally active) ( Figure 10 ) ( 136 ). The majority of sex-cord stromal tumors are unilateral and ovary-confined at diagnosis with >90% 5-year overall survival rate for Stage I disease ( 132 ). Fertility-sparing surgery for patients with sex-cord stromal tumors is similar to that of malignant germ cell tumors ( 129 , 130 , 137 ). Endometrial curettage is mandatory in patients with granulosa cell tumors to rule out synchronous endometrial carcinoma (secondary to estrogen excess production by the tumor) ( 129 ). Adjuvant platinum-based chemotherapy is considered for patients with either high-risk Stage I disease or Stage > I disease ( 129 , 132 ). Borderline ovarian tumors commonly manifest in premenopausal women (average age: 38 years) ( 138 ). Serous followed by mucinous borderline tumors are the most common histologic subtypes ( 139 ). While most mucinous borderline tumors are confined to a single ovary at presentation, serous borderline tumors may involve both ovaries (15–40%), develop peritoneal implants (35%), and at times involve lymph nodes ( Figure 11 ) ( 139 ). Young women with borderline tumors are amenable to fertility-sparing surgery regardless of FIGO stage as long as there are no invasive peritoneal implants (i.e., low-grade serous ovarian cancer). Unilateral serous borderline tumors are approached with ovarian cystectomy or USO. Mucinous borderline tumors require USO due to their large size and to exclude intra-epithelial carcinoma ( 140 – 143 ) ( 144 ). Bilateral serous borderline tumors are managed with bilateral cystectomy or combined USO and contralateral cystectomy ( 140 ). These procedures are combined with appendectomy (if mucinous histology) and comprehensive peritoneal staging to exclude low-grade serous ovarian cancer (which is a contraindication to conservative fertility-sparing management). Epithelial ovarian cancers are most common in postmenopausal women; however, around 12% of cases manifest in women younger than 45 years ( 125 ). Most patients present with advanced staged disease making these the most lethal of all gynecologic cancers ( 1 ). Young women with early stage disease and a strong desire for fertility may be offered fertility-sparing management. Patients with unilateral ovarian involvement (Stage IA or IC disease) and favorable histology (serous, mucinous, endometrioid, or mixed histologic subtypes) or Stage IA clear cell carcinoma (less favorable histology) may be candidates for USO plus comprehensive peritoneal staging and lymphadenectomy. Adjuvant platinum-based chemotherapy is required for Stage IA clear cell carcinoma and Stage IC tumors ( 131 , 133 ). Bilateral ovarian involvement (Stage IB) and extra-ovarian spread preclude conservative management ( 131 , 133 ). Patients with concerning symptoms and/or pelvic mass undergo pelvic ultrasonography and assessment of serum tumor markers (serum human chorionic gonadotropin (hCG), α-fetoprotein (AFP), lactate dehydrogenase (LDH), inhibin, and CA–125) ( 128 , 145 – 148 ). Elevation of these markers can aid diagnosis; normal levels don’t rule out ovarian tumor. Elevated AFP or hCG are virtually diagnostic of malignant germ cell tumors ( 134 ). CA-125 can be raised with epithelial tumors (both borderline and invasive types), although non-neoplastic conditions including endometriosis, pelvic inflammatory disease, and uterine leiomyoma may also cause nonspecific elevation. Inhibin may serve as a useful marker of granulosa cell tumor ( 132 ). Pelvic ultrasonography is the best imaging modality for the initial assessment of a suspected adnexal mass. When sonographic findings are suspicious for malignancy, a patient should be referred to a gynecologic oncologist and undergo staging CT, which is the current standard of care. Preoperative CT helps surgical planning by demonstrating the extent of disease including unilateral or bilateral ovarian involvement, presence and distribution of peritoneal implants, lymphadenopathy and distant metastases. Up to 25% of adnexal mass cannot be characterized with US as definitely benign or definitely malignant ( 146 , 147 ). In this setting, MRI is the most accurate and cost-effective imaging modality ( 7 , 149 ). In addition to lesion characterization, MRI shows the presence of preserved ipsilateral ovarian tissue (important if cystectomy is being considered), evaluates contralateral ovary, detects and maps peritoneal implants, and demonstrates enlarged lymph nodes facilitating clinical decision-making with regard to fertility-sparing surgery. The European Society of Uroradiology has recently proposed an updated step-by-step algorithmic approach to assist the interpretation of multi-parametric MRI acquired to characterize sonographically indeterminate adnexal masses ( Figure 12 ) ( 27 ). This approach helps to characterize adnexal masses as probably-definitely benign, probably-definitely malignant, or indeterminate ( 40 ). It relies on the evaluation of lesion origin, morphology and SI on conventional sequences (T1WI, FST1WI, T2WI), SI on high b-value DWI (≥800 sec/mm 2 ), and enhancement characteristics/kinetics on DCE-MR ( 27 ). In the first step, conventional T1WI and T2WI are reviewed to divide adnexal masses into one of three broad categories: T1 “bright” masses, T2 solid masses, and complex cystic or cystic-solid masses ( 27 , 28 ). T1 “bright” masses require further assessment with fat saturated T1WI to differentiate fat from blood. If fat is observed within adnexal mass (high SI on TWI that suppresses after fat saturation), the differential diagnosis is narrowed to frequent mature cystic teratoma or rare malignant immature teratoma. Mature teratoma often presents as a cystic mass filled with fatty sebaceous fluid and may contain coarse tooth-like calcifications (best seen on CT) allowing confident diagnosis of a benign mass ( 134 ). In contrast, immature teratoma is typically a solid-cystic mass with small foci of fat, cysts filled with simple fluid, and scattered fine calcifications (best seen on CT) ( 134 ). If a T1 “bright” mass contains blood products (high SI on T1WI that persists after fat saturation) and demonstrates no solid components, the differential diagnosis can be narrowed to benign entities such as a hemorrhagic cyst or endometrioma. If solid components are detected within a T1”bright” mass further evaluation is performed as for a complex cystic/cystic-solid mass (described below) ( 27 ). If a T2 solid mass is identified, the most likely origin (i.e. ovarian, uterine, or other) should be determined. Findings suggestive of ovarian origin are the ovarian beak sign and absent normal ipsilateral ovary. Features indicative of uterine origin are the uterine claw sign, “bridging vessel” sign (if pedunculated leiomyoma), and normal ipsilateral ovary ( 27 ). T2 solid masses are divided further into homogenous T2 “dark” masses (SI similar to that of skeletal muscle) or heterogeneous T2 “intermediate” masses (SI higher than that of skeletal muscle). If a homogenous T2 dark mass has low SI on high b-value DWI, benign etiology (ovarian fibroma or cystadenofibroma) is likely ( 27 , 42 ). Heterogeneous T2 “intermediate” masses present a diagnostic challenge since differential diagnosis is broad and includes a variety of benign and malignant entities. Although confident diagnosis is not always possible, knowledge of patient age and serum tumor markers in combination with key MR imaging features can be useful. For example, dysgerminoma (most common malignant germ cell tumor) is suggested by young patient age, elevated LDH ± HCG, and heterogeneous T2 “intermediate” mass that contains fibro-vascular septa with low SI on T2WI and avid enhancement ( 134 ). Purely cystic lesions or cystic lesions with few thin septa can be confidently diagnosed as benign ( 40 ). In contrast, complex cystic and cystic-solid masses require comprehensive assessment utilizing conventional sequences, DWI, and contrast-enhanced imaging (preferably DCE-MRI). This group includes adnexal masses caused by infection (pelvic inflammatory disease) and ovarian tumors including borderline tumors and invasive ovarian cancers ( 27 , 28 ). MR imaging features of overtly malignant ovarian masses are well established and include mixed cystic-solid mass, irregular or nodular thick septa and walls, intermediate SI solid components on T2WI, high SI on high b-value DWI, and contrast enhancement ( 40 , 42 , 149 – 151 ). The distinction between borderline and invasive tumors is an important and clinical relevant issue because epithelial ovarian cancer is amenable to conservative management only if confined to a single ovary whereas borderline tumors, particularly serous histology, are amenable to fertility-preservation even in the presence of bilateral ovarian involvement and peritoneal spread ( 130 ). Unfortunately, this differentiation presents an ongoing diagnostic challenge since these tumor types can have overlapping MR features such as a cystic-solid mass with intermediate SI solid component(s) on T2WI and contrast enhancement. The presence of papillary projections (enhancing solid finger-like projections) is one architectural feature that is common to serous borderline tumors and suggests the diagnosis ( 152 ). On T2WI, papillary projections range from small low-to-intermediate SI lesions to larger lesions with characteristic internal branching low SI fibrous stalk and high SI peripheral clumps ( Figure 11 ) ( 152 ). Emerging evidence also indicates that addition of DWI and DCE-MRI may facilitate the differentiation between borderline and invasive tumors. On DWI, solid components of borderline tumor have lower-SI on high b-value images and higher mean ADC values than invasive tumor ( 153 ). On DCE-MRI acquired using perfusion technique (as described in Part III), moderate initial enhancement followed by a plateau (Type 2 curve) may indicate borderline tumors, whereas rapid intense early enhancement with subsequent washout (Type 3 curve) may suggest malignant mass ( 27 , 39 – 42 ). However, the advantage of perfusion imaging over traditional dynamic multiphase approach remains to be proven.

Cancer survivorship has improved over the years and increasingly there are many young survivors including both children and women of reproductive age. It is estimated that in 2016, 10% of cancer survivors in the United States will be younger than 40 years ( 1 ). As such, quality of life issues including fertility preservation have become increasingly valuable to patients, families, and physicians. In the evaluation and treatment of cancer, there has been a paradigm shift leading to the emergence of oncofertility, a new field that recognizes the psychosocial impact of cancer-related infertility, bridges oncology with reproductive research, and assists patients to make informed decisions regarding cancer treatment and future fertility ( 2 , 3 ). Physicians need be familiar with the latest fertility-sparing approaches to effectively counsel women of reproductive age or parents/guardians of pediatric patients ( 4 ). Fertility-preserving options are influenced by the patient’s age, primary cancer, planned treatment, participating male partner or patient preferences regarding the use of donor sperm, and time interval to the initiation of therapy ( 4 , 5 ). For appropriately selected patients with non-gynecologic or gynecologic cancer, fertility-sparing options include assisted reproductive technologies and ovarian transposition ( 5 ). For appropriately selected patients with gynecologic cancer, fertility-sparing surgeries such as conization or trachelectomy for cervical cancer, cystectomy or unilateral salpingo-oophorectomy (USO) for ovarian tumors, and conservative medical endocrine treatment for endometrial cancer are also possible ( 5 ). Selection of the appropriate fertility-preserving option for the optimal benefit and safety of the patient depends on accurate cancer staging. MRI (magnetic resonance imaging) is particularly well suited to play an important role for assessing patient eligibility. MRI has unique utility for evaluation of gynecologic malignancies, particularly local staging of cervical and endometrial cancer ( 6 ) and characterization of sonographically indeterminate adnexal masses ( 7 ). This review gives an overview of fertility-sparing options currently available to young patients with gynecologic cancers, illustrates the essential role of MRI in evaluating these options, and highlights the key imaging findings to include in the imaging report to address selection criteria. General eligibility considerations in identifying suitable candidates for fertility preservation are summarized in Table 1 .

Fertility-sparing approaches are now included in various treatment guidelines (including ESMO and NCCN) and are increasing accepted as safe for appropriately selected reproductive age women with gynecologic cancer. MRI plays an important role in preoperative workup and proper selection of patients who are being considered for conservative fertility-sparing management of cancer. Radiologists should to be familiar with various fertility-sparing options and their eligibility criteria in order to provide comprehensive and clinically relevant imaging reports and to serve as effective consultants for their clinical colleagues.