In this report, we have presented a case of metastatic pure ovarian nongestational choriocarcinoma that was differentiated from gestational choriocarcinoma by DNA STR analysis. This case showed resistance to chemotherapy regimens commonly administered for malignant germ cell tumor (nongestational choriocarcinoma) and for gestational choriocarcinoma.
When histological examination reveals pure ovarian choriocarcinoma lacking uterine lesions, as in this case, the nongestational is often presumed without careful attention, because gestational choriocarcinoma commonly originates from the uterus. Indeed, gestational choriocarcinoma without uterine lesions on initial presentation is very rare(11). However, one paper reported a case of gestational choriocarcinoma (confirmed by DNA analysis) with renal and pulmonary metastases without any uterine lesions(12). This may be due to spontaneous regression of the uterine tumor, possibly because gestational choriocarcinoma is a tissue allograft for the patient that induces strong immune reactions from the patient. In addition, not a few case reports have described primary ovarian gestational choriocarcinoma following ovarian pregnancy including hydatidiform mole(1–3). In those clinical settings, uterine lesions are not necessarily present. Accordingly, precise differentiation of gestational and pure nongestational choriocarcinoma based on histological examination or lesion spread is impractical. A history of past pregnancies is thus crucial. However, even with such information, determining whether the choriocarcinoma is gestational or nongestational is difficult based on the pregnancy history alone, except in cases of patients who are sexually immature, have never had sexual intercourse, or are unable to conceive, because not a few spontaneous abortions pass unrecognized. In the present case, the patient had a fixed partner, had engaged in regular sexual intercourse, and had irregular menstruation cycles before the development of the disease, meaning that the possibility of gestational choriocarcinoma due to unrecognized abortions could not be ruled out.
A STR is a microsatellite consisting of a unit of 2–10 nucleotides repeated several to hundreds of times, and STR analysis allows evaluation of the highly polymorphic STR loci where each individual shows differing numbers of repeated sequences of nucleotides. DNA STR analysis is frequently used in forensic genetics (13) and population genetics(14) to match DNA profiles to an individual. Recently, STR analysis has been utilized to clarify the origin of choriocarcinoma and to differentiate gestational and pure nongestational choriocarcinoma when definitive evidence has not been forthcoming from pathological or other clinical findings (7, 15–20). Because the genome in nongestational choriocarcinoma comprises only a maternal (patient) allele, whereas gestational choriocarcinoma contains a paternal allele, DNA STR analysis can precisely distinguish these two types of choriocarcinoma. In the present case, the tumor genotype entirely matched that of the patient, confirming the nongestational type.
Nongestational pure choriocarcinoma of ovary is an extremely rare, especially with metastatic disease (Table 1) (21–27), .The prognosis of pure nongestational choriocarcinoma is widely considered to be worse than that of gestational choriocarcinoma despite these two types of choriocarcinoma being pathologically identical. If this is indeed the case, such differences may be because the genome of gestational choriocarcinoma is totally or partially different from that of the patient, whereas nongestational choriocarcinoma is genetically identical to the patient, leading to differences in host immunoreactions. However, given with rarity of these pathological entities, no reports have analyzed large numbers of choriocarcinoma cases and compared prognoses between types as diagnosed based on DNA analyses. Combination chemotherapy regimens employing methotrexate, etoposide, and actinomycin-D such as EMA/CO or MEA are administered as first-line therapies against gestational choriocarcinoma, and the complete response rate for these chemotherapy regimens against this disease exceeds 70%(28). Regimens including cisplatin such as TP and BEP therapies are applied for resistant or relapsed disease, with an overall survival rate with or without adjuvant radiotherapy or surgery of around 90%(29). Nongestational choriocarcinoma usually develops as a component of mixed-type germ cell tumor, and seems to show favorable prognosis following surgery and BEP regimen(30, 31). When nongestational choriocarcinoma emerges as a pure type, however, the tumor behavior seems more aggressive. Cisplatin regimens are usually used for resistant or relapsed disease, as well as for gestational choriocarcinoma. In the present case, the tumor was confirmed as pure nongestational choriocarcinoma by DNA STR analysis, but showed multiple chemo-resistances against chemotherapy regimens typically administered against both nongestational or gestational choriocarcinoma.
We have presented a case of metastatic pure nongestational choriocarcinoma that showed poor sensitivity to chemotherapy and the death of the patient. Precise differentiation of gestational and nongestational choriocarcinoma based on STR analysis independent of common clinical information such as the medical history and/or imaging findings is essential for determining appropriate chemotherapy regimens and evaluating the prognosis. With distant metastasis, pure ovarian nongestational choriocarcinoma is highly malignancy and the prognosis is poor.