Primary Ovarian Choriocarcinoma : One Case in 20 Years at INCA and Literature Review

Primary ovarian choriocarcinoma treatment doesn’t have a specific protocol and therefore several questions about this disease are still unanswered. This study is interesting because we performed a comprehensive review of the medical literature and report through descriptive analysis the only case registered as Primary ovarian choriocarcinoma in the period of 20 years at the Brazilian National do Cancer. Reading this paper may offer you the opportunity to understand biological behavior, pathological and clinical aspects, imaging indications and usefulness for a rare and deadly disease. Because it is a rare neoplasm and with few studies, there is no consensus for the treatment.


Introduction
Primary ovarian choriocarcinoma is an extremely rare neoplasm and therefore little reported in the medical literature.It comprises 2.1% of all ovarian germ cell neoplasms and accounts for only 0.6% of all neoplasms of ovarian origin [1][2][3][4][5].It can have either gestational or non-gestational origin.The gestational type is defined as the result of the proliferation of an uterine or tubal trophoblastic disease to the ovary or, more rarely, the anomalous development of a gravid ovary.However, the non-gestational form results from the anomalous development of the ovary's own germinative cells without gestation [6][7][8][9][10].However, the distinction between Ovarian choriocarcinoma presentation forms is extremely difficult due to immunohistochemical similarity [8].Some authors establish tumor DNA analysis as the ideal method for this distinction [2][3][4][5][6][7], however, this technique is little used due to its high cost [2][3][4][5][6][7][8][9].
Clinical manifestation of the primary ovarian choriocarcinoma is varied ranging from pelvic pain, bleeding during intercourse, dyspareunia and even acute abdomen or cor pulmonale due to tumor embolism [5].Due to this variable manifestation and to the unfavorable prognosis, primary ovarian choriocarcinoma is characterized as an oncological urgency that requires immediate diagnosis and therapeutic approach [1][2][3][4][5]11].
This single case concerns a 35-year-old white female patient admitted to Onco-gynecology Division of this hospital due to a pelvic mass in January 2016.

Lab and radiological investigations
The patient brought, with herself, the result of a Magnetic Resonance Imaging (MRI) of the pelvis, carried out at our institute dated December 2015.This MRI showed heterogeneous expansive formation with necrotic area located in the right adnexal region measuring 7.5 × 7.8 × 6.4 cm and estimated volume of 187.2 cm³.In addition, serum levels of βHCG were 831,659.0mIU/mL, CA125 was 42.22 U/mL and CEA was 7.21 ng/mL at that time.At the initial examination, the patient presented Performance Status (PS) 2, (Table 1) tachydyspnea, abdomen with a fixed, hard and palpable mass with irregular contours occupying the area from mesogastrium to hypogastrium and projected to both iliac fossae, especially to the right one.
The patient was referred to hospital admission due to respiratory distress associated with elevated βhCG and underwent diagnostic investigation.Computed tomography (CT) scan of the chest, abdomen and pelvis, performed at our institute, revealed the presence of multiple pulmonary implants, as well as massive heterogeneous pelvic expansive formation with cystic and solid components measuring 21.2 × 13 × 16.

Diagnosis
On the second day of the hospitalization, the patient evolved with a significant clinical respiratory worsening.Therefore, the surgical procedure for diagnostic confirmation was suspended and a percutaneous biopsy guided by pelvic CT scan was performed and add to this, an urgent histopathological evaluation was requested due to the strong suspicion of ovarian choriocarcinoma.

Treatment and complications
Still on the second day of hospitalization, chemotherapy was started with cisplatin and etoposide.On the third day of hospitalization, the patient evolved with Acute Respiratory Insufficiency (ARI) requiring oro-tracheal intubation and Mechanical Ventilation (MV) in the Intensive Care Unit (ICU).On the same day, percutaneous biopsy histopathological report was compatible with choriocarcinoma with positive immunohistochemistry for CK7 and βHCG, consequently the patient underwent EMA/ CO chemotherapy (etoposide, methotrexate, actinomycin D at stage 1 and cyclophosphamide and vincristine at stage 2).The patient remained on MV for 11 days and was discharged from the Intensive Care Unit 7 days after oro-tracheal extubation.βHCG serum measured after the second cycle of chemotherapy showed a significant decrease in relation to the value presented at the time of admission (βHCG after chemotherapy: 230,995 mUI/ mL).In abdominal CT scan performed in March 2016, still during hospitalization referred, a massive subcapsular expansive formation with heterogeneous appearance was observed at the right hepatic lobe, associated with the appearance of other small nodules scattered over the hepatic parenchyma.In MRI of the skull performed in March 2016, still during hospitalization referred, staging examination, was observed the presence of multiple nodules lesions, distributed diffusely over the cerebral and cerebellar parenchyma, two of which were located in the occipital lobes, the largest on the left, measuring 1.1 cm, with signs suggestive of late subacute bleeding.The patient was discharged after 48 days of hospitalization with PS 1.

Response to treatment or progress of disease
EMA/CO protocol was followed for 4 cycles up to April 2016, and because of the hepatotoxicity, evidenced by laboratory tests in April 2016, a second line of TE/ TP chemotherapy regimen (paclitaxel-etoposide and paclitaxel-cisplatin) was started and maintained for 4 cycles up to August 2016, when, during the outpatient follow-up, the tests showed elevated serum levels of βHCG and raised the hypothesis of disease progression to the Central Nervous System.Skull CT scan of September 2016 revealed the appearance of two hyperdense, nodular lesions with dural basis of implantation in the right occipital lobe, the smaller one measuring 0.4 cm and the larger one measuring 0.9 cm, the latter with adjacent vasogenic edema compatible with secondary implants.Although throughout this period the patient was PS 2, in the presence of uncontrolled hepatic and pulmonary metastatic disease and in the absence of neurological symptoms, the patient was not referred to radiotherapy evaluation of the cerebral lesion, and due to the elevation of βHCG and CT scan findings, the third line of chemotherapy with FA was started in August 2016 (5-fluoracil and actinomycin D).

Outcomes
However, on October 17, 2016, the patient was admitted to the emergency room with a left unilateral headache associated with left inferior quadrantanopsia in the left eye.Skull CT scan revealed increased expansive lesions in the Central Nervous System with a midline deviation of 0.6 cm to the left (Figures 4 and 5) evolving to death on October 18, 2016.
Skull CT scan on 10/17/16 evidencing progression of the disease to the Central Nervous System (figure 4, 5).

Epidemiology of the cancer
Primary ovarian choriocarcinoma is an extremely rare neoplasm and occurs more frequently in women with childbearing potential [1][2][3][4][5][6][7][8].In women with active sex life, due to the high level of βHCG, the differential diagnosis between ectopic pregnancy and abortion should be considered.Due to the rarity of reported cases of ovarian choriocarcinoma, the ethnic prevalence for the occurrence of this pathology cannot yet be stated [1][2][3][4][5][6].

Cell of origin, pathological features and tumor biology
The real mechanism for the development of this neoplasm is not clear, but it is known that it can originates from gestational tissue (gestational type) or ovarian origin germ cells (non-gestational type) [1].Many researchers state that in virgin women diagnosed with choriocarcinoma it is possible to declare the nongestational form without confirmation by DNA analysis [8].

Most common clinical resentation
However, although the gestational form is more frequent (1 case for 369,000,000 pregnancies), the nongestational form also occurs in women with childbearing potential, and even after menopause [12,13].Usually, previous history of molar gestation, tubal gestation and abortion is associated with gestational presentation of this type of neoplasm.However, some studies argue that the distinction between the two manifestations is surely proven through tumor DNA analysis, but the high cost of this method limits its routine application [8].

Recommended/proposed treatment options
Because it is a rare condition with only 65 cases of primary ovarian choriocarcinoma reported in the medical literature (Tables 2 and 3), many questions about the staging and treatment of Primary ovarian choriocarcinoma remain unanswered [5].Aucouturier et al. [14], defend surgical staging and recommend total hysterectomy with bilateral salpingooophorectomy, omentectomy, peritoneal biopsies, and lymphadenectomy.Santos et al. [5], recommend total hysterectomy with bilateral salpingo-oophorectomy.Heo et al. [4], also recommend surgical staging, and defend performing total abdominal hysterectomy with bilateral salpingo-oophorectomy, omentectomy, peritoneal biopsies of diaphragmatic domes and parietocolic gutters with peritoneal lavage collection, and suggest that lymphadenectomy should be performed only when lymph node metastasis is suspected.Exman et al. [1], Xin et al. [8] and Wang et al. [12], recommend imaging staging, and the treatment for cases with distant metastasis should begin with neoadjuvant chemotherapy followed by total hysterectomy with bilateral salpingooophorectomy, omentectomy, peritoneal biopsies and lymphadenectomy.In young patients with tumor limited

Follow-up and survillance
However, all medical-scientific literature advocates for combined treatment with surgery and adjuvant and/ or neoadjuvant chemotherapy and the response to the treatment is assessed by quarterly serial serum βhCG analysis for at least five years [1][2][3][4][5].
In a survey conducted at our institution (Table 4), the data show that from January 1991 to March 2016 the INCA recorded 33 cases of choriocarcinoma.Of these, only the object of this report is a primary ovarian choriocarcinoma.
The data from our institution reinforce the evidence of global medical literature about the rarity of Primary ovarian choriocarcinoma and also reinforce that early detection, assertive diagnosis and treatment as oncological urgency are key factors for the patient prognosis.
In our report, the initial approach to a young, tachypneic patient with high serum level of βHCG, abdominal scan showing ovarian tumor and thoracic scan revealing multiple pulmonary nodules with no association of pleural effusion, incited the assistant team to conduct the case as recommended by medical literature [1,8,12], with chemotherapy.
The rarity of Primary ovarian choriocarcinoma is an incentive to research.Although there are studies, reports and case series, as well as bibliographic reviews, the medical literature still presents questions about the natural history of the disease and treatment regimens.
Therefore, future research is fundamental for a more accurate understanding of the pathophysiology of this tumor type and for the emergence of new therapeutic perspectives with impact on survival.
5 cm, extending to umbilical region and pushing intestinal loops laterally, densification of mesenteric fat and absence of free liquid (Figures 1, 2 and 3).Abdomen/pelvis CT scan showing heterogeneous expansive formation on topography of right attachment on 02/01/2016 (figure 1, 2).

Table 4 :
Supplementary Material.Patients Admitted with Diagnosis of Choriocarcinoma at the Brazilian National do Câncer from Jan/1991 to Mar/2016