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Non-Epithelial Ovarian Cancer ANTICANCER RESEARCH 36 : 5031-5042 (2016) doi:10.21873/anticanres.11072 Review Non-epithelial Ovarian Cancer: Elucidating Uncommon Gynaecological Malignancies STERGIOS BOUSSIOS 1, GEORGE ZARKAVELIS 1, ESMERALDA SERAJ 1, IOANNIS ZERDES 1, KONSTANTINA TATSI 2 and GEORGE PENTHEROUDAKIS 1 1Department of Medical Oncology, Medical School, University of Ioannina, Ioannina, Greece; 2Gynaecology Unit, G. Hatzikosta General Hospital, Ioannina, Greece Abstract. Non-epithelial ovarian cancers (NEOC) are a GCTs are diagnosed principally in the first three decades group of fascinating but uncommon malignancies which can of life (2). In contrast, SCSTs occur in women of all ages be extremely challenging to treat. Collectively, these but increase in frequency during the fourth and fifth tumours only represent 10-15% of all ovarian cancers and decades of age and patients have a median age at diagnosis occur in all age groups from childhood to old age. This of 52 years (3, 4). The incidence rates of these two most broad term includes diverse tumours of germ cell origin, sex common subtypes of NEOC also differ by race. GCTs of cord-stromal cell origin, as well as extremely rare types of are more frequent in Asian and African women (5), whereas ovarian cancer, such as small-cell carcinomas and SCSTs occur more commonly in women of Caucasian sarcomas, each of which require specialist management. It background (3). The yearly adjusted incidence rate is is imperative that these rare tumours are managed with approximately 4 per 1,000,000 and 2 per 1,000,000 women accurate diagnosis, staging and treatment in order to for GCTs and SCSTs, respectively (6). The aetiology of optimize patient outcomes. The aetiology and molecular these tumours remains largely unresolved. Ovarian small origins of each sub-group of NEOC remain poorly cell cancers of hypercalcaemic type affect young women, understood and international cooperation to facilitate high with a median age of diagnosis of 24 years (7). Small cell quality translational research is needed. This review ovarian carcinomas of pulmonary type affects older women summarizes the published literature on the incidence, (median age 59 years) (8); with a clinical course and clinical presentation, pathology, therapeutic interventions, prognosis most similar to that of small cell lung cancer. survival and prognostic factors of each sub-type of NEOC. Sarcomas of the ovary are extremely rare and heterogenous tumours including primary ovarian fibrosarcoma, Non-epithelial ovarian cancer (NEOC) are a group of angiosarcoma and rhabdomyo-sarcoma. The International uncommon, histologically and clinically distinct tumours. The Federation of Gynecology and Obstetrics (FIGO) staging two most frequently diagnosed NEOC are germ cell tumours system for epithelial ovarian cancer is also adopted for (GCTs) and sex cord-stromal cell tumours (SCSTs), each of NEOC, however, due to high chemotherapy sensitivity and which have several histological sub-types (Table I) (1). good prognosis of GCTs, the recommended surgical staging Ovarian small cell cancers (hypercalcaemic and non- is much less aggressive. hypercalcaemic types) and sarcomas are extremely rare and Treatment of NEOC, as a group, should be on the basis of aggressive cancers, with an aggressive clinical course and a sound oncological principles. Due to the rarity of NEOC, generally dismal prognosis. randomised trials for assessing the relative benefits of different treatment modalities are extremely challenging. Cooperation is also required to further our knowledge of the molecular events which lead to NEOC and aid identification This article is freely accessible online. of novel drug targets. The main purpose of this review was to show how an Correspondence to: Dr Stergios Boussios, MD, Ph.D., Department of Medical Oncology, Ioannina University Hospital, Ioannina, interdisciplinary model of case management, involving Greece. E-mail: [email protected] representatives from pathology, radiation, medical and gynecology−oncology can be invaluable in optimizing Key Words: Germ cell tumours, sex cord-stromal tumours, review. patient outcomes. 0250-7005/2016 $2.00+.40 5031 ANTICANCER RESEARCH 36 : 5031-5042 (2016) GCTs Table I. Classification of non-epithelial ovarian cancer (modified from the World Health Organization Histological Classification of Tumours of the Ovary) (1). These tumours occur principally in children and young women aged 10-30 years, with a mean age in the teenage Primitive GCT years. GCTs are the most common ovarian neoplasm in 1. Dysgerminoma women aged <30 years (9). 2. YST 3. Embryonal carcinoma 4. Polyembryoma Clinical presentation. Presenting signs and symptoms can 5. Choriocarcinoma include abdominal pain with a palpable pelvic-abdominal mass Biphasic or triphasic teratoma in the majority of patients (85%), abdominal distension (35%), 1. Immature teratoma fever (10%), and vaginal bleeding (10%). A small proportion 2. Mature teratoma of patients exhibit symptoms of pregnancy or precocious Mixed type (two or more of the above types) SCST puberty, related to β- human chorionic gonadotropin ( β- hCG) 1. GrCT production by the tumour (10). The disease is unilateral in most a. Adult-type GrCT patients with early disease and the presence of bilateral ovarian b. Juvenile-type GrCT involvement suggests dysgerminoma or mixed histology with 2. Theca-fibroma group a predominant dysgerminoma element, of which 10-15% will a. Thecoma b. Fibroma involve both ovaries at presentation (11). c. Fibrosarcoma Due to the age of patients affected by ovarian GCT, this d. Sclerosing stromal tumor disease can manifest during pregnancy. The results of a e. Signet-ring stromal tumor recent study indicated that advanced-stage GCT-complicated 3. Sertoli-stromal cell tumor pregnancies were an independent prognosticator of decreased a. Well-differentiated b. Of intermediate differentiation, variant with heterologous elements maternal survival (12). The timing of oncological c. Poorly differentiated (sarcomatatoid), variant with heterologous intervention and delivery both significantly impacted on the elements outcomes both of foetal and maternal survival. d. Retiform, variant with heterologous elements 4. SCST of mixed or unclassified cell type Diagnosis. Diagnosis can usually be made on morphological a. Gynandroblastoma (specify components) b. SCST, unclassified features, and immunohistochemical markers and chromosome Metastatic tumours, e.g . Krukenberg 12p fluorescence in situ hybridisation can be used to confirm the diagnosis in difficult cases. Sal-like protein 4 (SALL4) is GCT: Germ cell tumours, YST: endodermal sinus tumours, SCST: sex- a sensitive and specific marker for GCT and is positive in cord stromal tumours, GrCT: granulosa cell tumours. dysgerminomas, yolk sac tumours (YSTs), the germ cell component of gonadoblastoma, embryonal carcinoma, some immature teratomas (13), however, it is also positive in rare teratoma and somatic-type tumours associated with dermoid alpha-fetal protein (AFP)-producing fetal-type gastric cysts (Table I) (1). This latter group will follow the clinical carcinomas (14). OCT3/4, a nuclear transcription factor, also course of the somatic-type tumour, therefore their treatment known as POU5F1, is also widely used. In addition, should be tailored to the somatic-tumour type rather than the expression of sex determining region Y-box 2 (SOX2) in benign germ-cell element. embryonal carcinoma and primitive neuroectoderm of Like GCT in males, in clinical practice, ovarian GCTs are teratoma has been recently recognised (4). commonly divided into dysgerminomas (analogously to male Many, but not all, GCTs produce serum tumor markers that seminomas) and non-dysgerminomatous tumours. The latter can aid in the establishment of diagnosis, monitoring during include the more common YSTs and immature teratomas, as therapy, and have a useful role in post-treatment surveillance. well as the rarer embryonal carcinoma, non-gestational YSTs and choriocarcinoma are characterized by production choriocarcinoma, and polyembryoma sub-types. Current of AFP and β- hCG, respectively. Around one-third of approaches to the treatment are summarised in Table II. immature teratomas will produce AFP, and raised lactate dehydrogenase can be a useful marker in dysgerminomas. Dysgerminomas Correspondingly, mixed GCT may produce either AFP, β- hCG, both, or no markers, depending on their composition. Dysgerminomas account for 30-40% of ovarian GCT cases, and 20-30% of ovarian malignancies associated with pregnancy Classification. According to the 2003 WHO classification (15). These tumours uncommonly secrete low levels of β- hCG system, GCT are divided into three categories: primitive (from multinucleated syncytiotrophoblastic giant cells), but AFP GCT, biphasic or triphasic teratoma, and monodermal secretion is not expected with pure dysgerminomas. 5032 Boussios et al : Non-epithelial Ovarian Cancers (Review) Table II. Management options for of germ cell tumours (GCT). GCT Dysgerminomas Immature teratomas Other GCT Stage I USO with preservation of the contralateral ovary and uterus for fertility purposes with a full staging procedure. If patient has completed child bearing, TAH-BSO is acceptable. Stage IA Observation without adjuvant treatment. G1: Observation without adjuvant treatment G2: Adjuvant treatment may be considered Adjuvant chemotherapy G3: Adjuvant chemotherapy Stage IB/C Adjuvant chemotherapy Adjuvant chemotherapy Adjuvant chemotherapy Stage II USO with preservation
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