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Non-Gestational Ovarian Choriocarcinoma: Comparison
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Please note this is a comparison between Version 2 by Yvaine Wei and Version 1 by Sean Cronin.

Non-Gestational Ovarian Choriocarcinoma (NGOC) is an extremely rare ovarian tumor, with an incidence of less than 0.6% of malignant ovarian germ cell tumors. Its close pathologic resemblance to Gestational Ovarian Choriocarcinoma (GOC). On pathologic examination, the tumor is indistinguishable from GOC, and only after review of tissue for paternal genetic components can the diagnosis of NGOC be made. Treatment is vastly different from GOC; NGOC requires treatment with both surgical resection and chemotherapy, with Bleomycin, Etoposide, and Cisplatin (BEP) being the most used regimen. With correct diagnosis and treatment, patients can often receive fertility sparing treatment with long term survival.

  • non-gestational ovarian choriocarcinoma
  • germ cell tumors

1. Introduction

Ovarian choriocarcinoma is an extremely rare form of ovarian cancer. It can be broadly classified into two variants, gestational ovarian choriocarcinoma (GOC) and non-gestational ovarian choriocarcinoma (NGOC). NGOC are further subdivided into mixed, which contain other germ cell components, and pure subtypes, which contain only choriocarcinoma. The incidence of GOC is 1:369,000,000 whereas the incidence of NGOC accounts for just 0.6% of malignant ovarian germ cell tumors [1,2,3,4,5][1][2][3][4][5]. GOC is a form of gestational choriocarcinoma and related to a patient’s previous pregnancy history and may exist concurrently with a well-developed corpus luteum, with cure rates approaching 90% with single agent chemotherapy, typically methotrexate [6].
NGOCs are unrelated to pregnancy, and DNA analysis demonstrates the absence of any paternal genes [7,8,9][7][8][9]. NGOCs often occur in children and young adults, arising from midline structures that form during embryogenesis or primordial germ cells in the gonads after birth and demonstrate trophoblastic differentiation [7,10,11][7][10][11]. It has also been proposed that NGOCs arise from “retrodifferentiation” to an earlier embryonic cell stage of somatic tumors that have already undergone neoplastic transformation [12].
NGOCs are characterized by rapid growth and a relatively poor prognosis; overall survival of International Federation of Gynecology and Obstetrics (FIGO) stage I, II, and III disease is 100% over 3 years, with the survival rate of FIGO IV disease dropping to just 25% at 3 years. When divided into pure and mixed NGOC tumors, the former have a 94% overall survival while the latter have just 50% overall survival at 3 years [13].

2. Background

There are two types of NGOC: the pure type and the mixed type. The pure type, which is extremely rare, only contains choriocarcinoma [14]; the absence of other germ cell elements is demonstrated by the lack of immunohistochemical staining for CD30, PLAP, and AFP [15]. The mixed type contains other germ cell tumors, including immature teratomas, endodermal sinus tumors, embryonal carcinomas, and dysgerminomas [13]. Histologically, both GOC and NGOCs have identical presentation with abnormal trophoblastic hyperplasia and anaplasia, absence of chorionic villi, high proliferative index, and the presence of hemorrhage and necrosis within the tumor tissue [2,16][2][16]. The histologic similarities between GOC and NGOC contribute to the diagnostic conundrum, see Table 1 [2,14,17][2][14][17].
Table 1.
 Features of NGOC, GOC, and ectopic pregnancy.
  NGOC GOC Ectopic Pregnancy
Chorionic villi No No Yes
Abnormal trophoblastic tissue Yes Yes No
Abdominal pain and vaginal bleeding Yes Yes Yes
Positive pregnancy test Yes Yes Yes
Paternal genetic material No Yes Yes
Treatment Surgery/chemotherapy Chemotherapy Surgery and/or methotrexate

3. Presentation and Diagnosis

The symptoms of NGOC are vague and non-specific, and the age at presentation aligns with other beta-HCG producing conditions, including ectopic pregnancy. NGOC usually affects younger reproductive-aged woman and often presents with metastatic disease [18]. In the largest case review done by Lui et al., 39 case reports were reviewed with the peak age of onset ranging 12 to 25 years [13]. The most common signs and symptoms are vaginal bleeding, abdominal pain, adnexal mass on ultrasound, and a positive pregnancy test [6,11,13,14,18][6][11][13][14][18]. In children, initial presentation may also include precocious puberty [19]. 

3.1. Clinical

Patients with non-specific abdominal pain, bleeding, and a positive pregnancy test are often evaluated in the emergency department with a transvaginal ultrasound which yields non-specific findings. Pelvic ultrasound often shows a highly vascular, echogenic non-homogeneous unilateral mass and a normal uterus with a thin endometrial stripe [3,20,21][3][20][21]. Follow up imaging with Computed Tomography (CT) is then usually obtained. CT images can further help to evaluate the extent of the disease and the presence of hemorrhagic lesions in other locations [3,13,22][3][13][22].
Similar to GOC, hemorrhage causes significant morbidity and mortality in patients with NGOC [3]. The vascularity is due to the trophoblastic cells’ innate capacity to invade and erode vascular structures [13]. Bleeding is the most often reported presentation of NGOC [23], including non-gynecologic bleeding such as profound hematochezia in a patient who had metastatic disease involving the intestines [18]. As a result, patients often have severe anemia requiring multiple blood transfusions or massive transfusion protocols [18,24][18][24]. 

3.2. Laboratory

Beta-HCG levels for NGOC patients are often extremely elevated, as is typically seen in GOC. At beta-HCG levels seen in NGOC cases, the Hook Effect becomes relevant [25]. When using point of care urine pregnancy tests, the Hook Effect occurs in sandwich immunoassays when the antigen concentration is high enough to saturate both the migratory phase and fixed detection antibodies independently, rather than binding occurring to subunits of the same molecule [14,15][14][15]. Thus, a falsely negative test could potentially lead to a delay in diagnosis and allow for progression of disease [26]. This can be overcome by diluting the sample, either 1:10 or 1:100, to allow for dilution of the beta-HCG [27]. However, serum-based beta-HCG tests are not subject to the Hook Effect and will reveal the true elevation of beta-HCG, which has been reported to be as high as 1 million [14].

3.3. Genetic Testing

Previously, the primary way to diagnose patients with NGOC was with a detailed patient history, including recent sexual activity and antecedent pregnancy. If there is no history of intercourse and/or an antecedent pregnancy, then a patient would be diagnosed with NGOC [14,16,28,29][14][16][28][29]. In 1963, Saito and colleagues developed a 4-item set of diagnostic criteria for NGOC: (1) absence of disease in the uterine cavity, (2) pathological confirmation of choriocarcinoma with the persistence of elevation in beta-HCG, (3) exclusion of molar pregnancy, and (4) exclusion of coexisting intrauterine pregnancy [6].

3.4. Staging

The aggressive nature of NGOC makes metastatic disease a concern, with hematologic and local spread occurring early in the disease process [30]. Local spread appears to follow the embryological pathway of germ cell migration [31]. In the largest chart review of 39 patients with NGOC, 80% of patients had metastatic disease to the lungs, 30% to the pelvis, 20% to the vagina, and 10% to the liver [13,32][13][32]. Other sites with less common metastatic disease included the gastrointestinal tract, spleen, and kidney [3,4,13,16,18][3][4][13][16][18]. 

4. Treatment

Due to the rarity of pure NGOC, there have not been large-scale studies evaluating the optimal surgical treatments.

4.1. Surgery

The basis for surgical resection is extrapolated from the treatment of germ cell tumors. Shao et al. reported on patients who underwent either cytoreductive surgery (resection of the uterus, bilateral ovaries, bilateral fallopian tubes, omentum, pelvic and para-aortic lymph nodes, appendix, and any other abdominal, pelvic metastases) or fertility-preserving surgery (any combination of removal of tumor and reproductive organ not resulting in sterilization) [6]. Six patients who were initially treated with fertility-preserving surgery subsequently underwent cytoreductive surgery, most commonly due to an unsatisfactory decrease in beta-HCG or relapse. One patient who initially underwent fertility-sparing surgery subsequently underwent total hysterectomy to address profuse vaginal bleeding due to the mistaken diagnosis of primary uterine choriocarcinoma, but evaluation of the uterine and adnexal specimen showed no evidence of disease [33].

4.2. Fertility-Sparing Surgery

Fertility-preservation surgery should be discussed with patients at the time of surgical management, given that the peak incidence of NGOC is during a woman’s early/peak reproductive years. Liu et al. recommend that patients with suspected stage I disease be offered fertility-sparing surgery [13]. However, many patients already have advanced disease at presentation [6,13,34][6][13][34]; as seen in larger case series, more than 50% present with stage II, II, or IV disease [6,13][6][13]. Minimally invasive surgical approaches to ovarian cancer have previously been described [35,36][35][36]. Xin et al. reported a patient with stage IIb NGOC treated with fertility-sparing resection via minimally invasive approach followed by adjuvant chemotherapy and achieved remission at nine months after therapy [37]. Inaba et al. reported a patient with stage III NGOC treated with fertility-sparing subtotal tumor resection followed by high-dose chemotherapy and achieved complete remission after eighteen months [38].

4.3. Chemotherapy

GOCs are often treated with methotrexate-based chemotherapy regimens based on the FIGO score; single agent methotrexate is often used for patients with a FIGO score of less than 7 [39]. However, single agent chemotherapy is ineffective in patients with NGOCs [9]. NGOCs fall within the diagnostic realm of a germ cell tumors and should be addressed as such from both a treatment and prognostic standpoint. However, NGOCs are more difficult to treat [2] and have a worse prognosis compared to GOCs [1,13,40][1][13][40]. Treatment typically consists of both surgery and systemic chemotherapy [6]. However, due to the rare occurrence of the disease and a lack of clinical trials, a preferred chemotherapy regimen has not been established [13]. Both platinum-based and multi-agent methotrexate-based treatments have been utilized for treating NGOCs. Most recent case reports describe treatment with Bleomycin, Etoposide, and Cisplatin (BEP), which had shown excellent activity in other malignant germ cell tumors; however, successful responses have been observed with other regimens [6,13,41,42][6][13][41][42].

4.4. Radiation

Radiation therapy is infrequently used for patients with NGOC. Chemoradiotherapy was recommended in one case series for patients with advanced disease followed by palliative surgical resection of any residual disease [13]. In another case report, a patient received radiation therapy after suspected diagnosis during an exploratory laparotomy. She only received 5 fractions before complications arose and radiation therapy was stopped; treatment was then converted to platinum-based chemotherapy with BEP [18]. 

4.5. Choriocarcinoma Syndrome

Patients with advanced NGOC may also develop choriocarcinoma syndrome, a rare but potentially fatal complication that should be suspected in patients with high tumor burden, significant metastatic disease, and elevated tumor markers [34]. This syndrome has been described as occurring after initiation of chemotherapy, or spontaneously in advanced disease, and is thought to be related to tumor invasion of small blood vessels and subsequent hemorrhage [34,43][34][43]. Clinical manifestations most commonly include pulmonary hemorrhage and acute respiratory distress syndrome, as well as gastrointestinal hemorrhage, intra-hepatic and/or intra-abdominal hemorrhage, hemo- or pneumothorax, and cerebral hemorrhage [7,34,44][7][34][44]. Choriocarcinoma syndrome has a very poor clinical prognosis; initiating milder chemotherapy regimens and ensuring multimodal supportive therapy, timely and sequential intensive chemotherapy has been proposed to prevent and manage choriocarcinoma syndrome [34]. Modified regimens of BEP have been proposed to prevent this fatal syndrome and have shown favorable results [7,45][7][45].

5. Conclusions

NGOC is a distinct and rare disease from the more common GOC and poses diagnostic challenges as its presentation can mimic gestational trophoblastic disease or more common conditions in reproductive-aged women (i.e., ectopic pregnancy) and cannot be differentiated from GOC on histopathology. Therefore, special attention needs to be paid to ensuring the prompt and proper diagnosis by acknowledging a patient’s history that excludes or minimizes the possibility of pregnancy and utilizing tissue genotyping (when appropriate). Patients presenting with a large, unilateral solid tumor should raise the suspicion of a germ cell tumor and negative point-of-care pregnancy tests should be confirmed with a serum beta HCG level. With proper diagnosis, chemotherapy, and surgical resection, patients can experience positive outcomes both from a survival benefit as well as fertility preservation.

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