The uterine choriocarcinoma in postmenopausal women: specificities of diagnosis and treatment

Choriocarcinoma is a gestational trophoblastic tumor that mainly affects women of childbearing age. Cases of choriocarcinoma in postmenopausal women are exceptional. Through an observation and literature review, we propose to study the specific diagnosis and treatment features of this tumor in menopausal women. We report the observation of a pure uterine choriocarcinoma, which occurred in post-menopause. The diagnosis was made on the analysis of surgical specimens confirmed by measurement of hCG. Chemotherapy was started after a total hysterectomy and bilateral salpingo-oophorectomy first. The improvement was dramatic after 3 courses of chemotherapy and the patient is in complete remission after five years of monitoring. The primitive forms of pure choriocarcinoma in postmenopausal women are exceptional. Their etiology is poorly understood and their treatment based on chemotherapy.


Introduction
Gestational Trophoblastic Tumors (GTT) are a rare complication of pregnancy and represent a wide spectrum of diseases containing the hydatiform mole (partial or total), the invasive mole, the choriocarcinoma and the tumor of the placental insertion site [1].
The choriocarcinoma is the most common malignant GTT. It is the most primitive, the less differentiated and the more chemo sensitive GTT [2]. Vascular invasion is standing [3]. It can complicate a previous mole or a normal pregnancy. This gestational tumor reaches preferentially women of childbearing age. Some morphs to post-menopausal revelation have been reported since 1970.

Discussion
The incidence of choriocarcinoma and GTT varies geographically.
The prevalence of GTT was estimated at 1 in 400 live births in the Arab countries and Asia by Rangwala et al. [4] and 1 per 1000 live births in developed countries [5]. The incidence was 12.1 per 1000 deliveries in Turkey between 1998 and 2003 with 6.9% of choriocarcinoma [6]. This tumor can develop in all women of childbearing age and especially beyond 40 years. In a Tunisian retrospective series, the average age was 32 years (range 20 to 49 years) [5]. The median time to onset of choriocarcinoma is 1 year after the last pregnancy [6]. Cases of choriocarcinoma were reported after menopause [7][8][9]. Amenorrhea ranged from 0 to 22 years with a median of 12 months and an average of 33 months [10].
These choriocarcinoma diagnosed in postmenopausal women with gestational degeneration may be a molar pregnancy in its complete form (75%) or after a normal pregnancy carried to term, or after miscarriage, ectopic pregnancy [11,12]. They may be primitive, not gestational, exceptional, sporadic, limited to the uterine level, almost always associated with ovarian damage [12,13]. Their origin is explained by the degeneration of germ cells or somatic cells with malignant metaplasia of the epithelium under the influence of preexisting oncogenes [3,11,12]. These primitive forms usually occur in older patients. They seem to be more aggressive with a poorer prognosis related to later diagnosis, explaining the frequent metastases. The study of DNA polymorphism can help to distinguish between gestational choriocarcinoma (presence of both paternal and maternal alleles in equal amounts in tumor cells) [11] and not gestational (maternal allele only) [11]. This method is expensive, time consuming and requires unfixed fresh tissue collected especially for this purpose [10].In 20% of cases, previous pregnancy is not that at issue [14]. Note that generally, the more the period between the last pregnancy and diagnosis of the tumor is long, the more the prognosis is poor [14]. But in postmenopausal women, the prognostic value of this delay is uncertain.
Page number not for citation purposes 3 The clinic of choriocarcinoma in postmenopausal women is not specific. Most patients consult for postmenopausal bleeding but some cases have arisen in a context of acute surgical abdomen [14]. Sometimes, the clinic may be dominated by secondary metastatic locations (especially lung but also brain, liver, digestive or urinary ones) [14]. The pelvic ultrasound images are not specific either: The tumor masses are relatively hypo-echogenic to the myometrium device with occasional millimeteric fluid beaches related to an identified richly vascularized glandulocystic aspect with a high diastolic flow and a low resistance index [15]. In case of uterine mass in postmenopausal women, it is relevant to retrace the obstetric history of the patient, especially the history of GTT or bleeding after a normal pregnancy or post-abortion. In this case, the dosage of hCG helped the diagnosis and during the follow up, yet it is not prescribed routinely in menopausal patients. The histological diagnosis of choriocarcinoma is quite reliable because when the first pathologist diagnosed achoriocarcinoma, the referent pathologist confirmed it in 86% of cases [14]. In cases of atypical morphology such as the predominance of cytotrophoblast and intermediate trophoblast which can form cohesive monomorphic cell ranges [9], there is a problem of differential diagnosis. It is where immunohistochemistry is the most helpful. If the hCG by immunolabeling is intense and diffuse, the diagnosis is highly possible [10]. The OCT-3/4, CD30 and AFP are not specific markers of germ cell tumors [15]. The OCT-3/4 is a transcription factor expressed in undifferentiated multipotent cells as germ cells. The CD30 is part of the TNF cytokines family and is used as a marker of embryonal carcinoma. The combined use of OCT-3/4 and CD30 helps establish the germ origin of metastatic tumors. If the marking is negative for both, the original germ may be excluded [15].
For uterine described forms, choriocarcinoma is never isolated, unlike our case report. It is found most often associated with adenocarcinomas but also with carcino-sarcomas or mixed mesodermal tumors [10]. Desai  Choriocarcinoma is considered the most curable gynecologic cancer, even if metastatic and its overall survival rates are between 82-100% [10]. Chemotherapy has completely revolutionized the prognosis of these tumors with survival rates going from 19% to 90% (DR). Multidrug therapy is the gold standard first-line in metastatic forms of high-risk gestational tumors such as choriocarcinoma [13]. This typically includes: Etoposide, Methotrexate, Actinomycin D, Cyclophosphamide, and Vincristine [10]. The peculiarity of this poly chemotherapy, administered to older patients often with other chronic and severe illnesses, is the higher incidence of toxicity in the short, medium and long term. This is the case for our patient who keeps a lower extremity neuropathy.
Other reported cases of postmenopausal choriocarcinoma with a significant morbidity and mortality of the chemotherapy: fatal outcome in a context of acute toxicity of chemotherapy (acute toxic epidermal lyses/ Leyell syndrome [16]); toxicity related to etoposide (malignant hypertension) requiring a switch of EMA-CO protocol to methotrexate with folic acid with negativity of hCG after 4 cycles and incident-free survival of 20 months [16]. The toxic death rate of 28% with EPA protocol is unacceptable in the context of a curable disease in more than 80% of cases. The AE protocol, less toxic, was still responsible for a frequent gastrointestinal toxicity (87%) and dermatological side effects in 25% of cases in a retrospective study of Tunisia [8].
The surgery is performed, generally, in a second phase, due to the association with other histologic carcinoma. If the diagnosis is based on the hysterectomy specimen, chemotherapy will depend on the evolution of hCG and staging. This raises the possibility of first nonconservative surgery in these menopausal patients by total hysterectomy associated with bilateral salpingo-oophorectomy.
Surgery is usually indicated as first-line in case of a persistent trophoblastic disease in women at high risk with no desire of pregnancy, or for hemostatic goal [15]. The main advantage of the first hysterectomy followed by chemotherapy versus chemotherapy alone is to lower total doses of drugs [6]. This applies mainly to etoposide, known for its acute toxicity and for its long-term risks of chemotherapy-induced neoplasms, both of which are correlated with cumulative doses received by patients. Surgery of residual masses is unnecessary as the hCG is negative [16].

Conclusion
This case and literature review illustrate that the diagnosis of choriocarcinoma is possible and must be mentioned even in postmenopausal endometrial before any image and heterogeneous, thus, think of the hCG assay, simple and inexpensive examination.
This tumor chemo-sensitive or even curable metastatic has a