Ovarian Clear Cell Carcinoma: Metastatic Pathways

Ovarian carcinoma reflects the biggest challenge among the field of gynecologic oncology. It represents the most common death cause of genital carcinomas throughout years. The major classification consists of epithelial and non-epithelial types. Due to the histologic origin, epithelial types of ovarian carcinoma are endometrioid, serous-mucinous, and clear cell types. Due to intense metastatic infiltration and rapid tumor spread, clear cell ovarian carcinoma constitutes type of lesion with the most poor prognosis, decreased overall survival, decreased free survival, and poor quality of life of the patient. The metastatic infiltration is strongly accompanied with all significant prognostic factors. All biochemical pathways at the time of the infiltration are correlated with tumor size, lymphatic spread, staging of the lesion, histologic type, and grade of differentiation of the lesion.


Introduction
According to current literature, ovarian cancer represents a high mortality neoplasm in gynecologic malignancy. The 2017 incidence estimates 22,400 new cases in the United States [1]. The increased mortality rate is strongly accompanied with staging of the lesion at the time of the diagnosis. Many predisposition factors influence the therapeutic mapping. Age of the patient, parity, staging, cluster of differentiation, surgical margins, and lymphatic infiltration consist the gold standard of therapeutic strategy (Figure 1).
The frequency of the lesion increases in ages between 55 and 65 years old. There are also studies implicating younger or older patients. The lesion is more frequent in developed countries of the Western World and less in Asian countries [2]. Ovarian neoplasms express a wide variety. The most practical and useful classification depends on the histogenetic origin. Histological classification represents an autonomic entity with independent subtypes, disease-free survival, and quality of life of the patient (Figure 2).
All recent conducted studies with classification parameter of the histogenetic origin express in 90% of cases the epithelial type as the most common type of ovarian carcinoma. Many useful tools, such as physical examination, transvaginal ultrasonography, Ca-125 levels, abdominal CT, or MRI, are mandatory in order to establish a more accurate clinical diagnosis [4]. Depending on clinical diagnosis, proper therapeutic mapping can be performed.
Among histologic subtypes of epithelial ovarian carcinoma, the most significant type with chemoresistance and poor prognosis consists clear cell ovarian carcinoma (CCC).
Clear cell carcinoma represents a distinct entity of epithelial ovarian carcinoma with an incidence less than 5% of all ovarian lesions [5]. Gold standard concerning therapeutic strategy of epithelial ovarian cancer and, respectively, of clear cell carcinoma is based on abdominal total hysterectomy, bilateral salpingo-oophorectomy, partial omentectomy with peritoneal sampling, and lymphadenectomy, adding cytoreductive surgery in advanced cases.
In many cases, surgical mapping for clear cell carcinoma remains a controversial issue. Many studies underline the decreased impact of adjuvant chemotherapy in patients with stage I clear cell carcinoma and the relation of the lesion with overall survival [6]. The ultimate scope of cytoreductive surgery in patients with clear cell carcinoma reflects the acknowledgment of high-risk patients correlated with recurrence of the lesion.

Discussion
Despite poor prognosis, overall survival, and quality of life of the patient, all conducted studies are focusing on the pathologic and metastatic pathways of the lesion. This issue remains controversial.   [7]. All the efforts lead to correlate the risk factors of endometriosis and clear cell carcinoma. We must never forget the role of endometriosis as trigger point and prominent risk factor of ovarian cancer. On the other point, many conducted studies depict the opposite statistic conclusion, gaining the impression of controversial issue. Zafrakas et al. correlated all the current data without an informative meta-analysis [8]. More conducted studies were mandatory in order to establish such a hypothesis.
Critical points of clear cell ovarian carcinoma remain the understanding of carcinogenesis, the genetic changes of the lesion, and most of all the mechanisms of target therapy.
Mabuchi et al. described and correlated all the critical genetic changes in clear cell carcinoma [9] ( Table 2). Focusing on gene mutation, pathway bridge, and following tumor implications, we can explain the carcinogenesis of clear cell carcinoma.
Focusing on tumor angiogenesis, many conducted studies described targeted antibodies as therapeutic shield toward the production of tumor vessels [10]. Classical examples of target therapy consist monoclonal antibodies against vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), fibroblast growth factor (PDGF), and angiopoietin/ Tie2 receptor complex [11]. Therapeutic philosophy depends on adjunction of monoclonal antibodies with growth factors, in order to prohibit tumor angiogenesis and infiltration. The emphasis in this procedure reflects the significant chemoresistance and poor prognosis of the lesion. The results of this target therapy remain controversial, justifying the significance of therapeutic strategy (Figure 4).
All therapeutic strategies consisted of overall survival, patient's quality of life and, in young ages with early stage lesion, the fertility-sparing surgery [12]. There are extreme selected indications, performing this surgical dissection.
Nasioudis et al. using the National Cancer Institute's Surveillance Epidemiology and End Results (SEER) database managed to perform the safety of fertility-sparing surgery in stages IA and IC of ovarian clear cell carcinoma [13]. The comparison, in patients with stage I ovarian clear cell carcinoma with preservation of the uterus and ovaries with general survival outcome, did not lead to statistical conclusion. However, further conducted studies are mandatory, in order to establish this type of surgical strategy in young female patients with stage IA or IC ovarian clear cell carcinoma.
Besides understanding the carcinogenesis of the lesion, the biochemical pathways, and the effort of fertility-sparing surgery in young female patients, we must mention the advanced metastatic opportunity of the lesion.
Lymphatic, hematogenic, and endoperitoneal infiltration of the lesion can lead to advanced metastatic possibilities. First of all, the lesion can penetrate the local anatomic organs: the salpinx, round ligament, uterus, peritoneal wall, colon, or even the omentum [14].
The most common, premature, and characteristic route of infiltration consists of the endoperitoneal [15]. All neoplasmatic cells are deafened, entering the peritoneal cavity. Through respiratory movements, endoperitoneal fluid with neoplasmatic cells finally reaches all epithelial areas and especially the hemidiaphragms. Final result, building of metastatic lesions as metastatic plaque or in advanced lesion as neoplasmatic "cake" (Figure 5). Through the right hemidiaphragm, the lesion can be spread in the pleura area, provoking hydrothorax or reaching the subclavian lymph nodes.
Usual distant organs with signs of infiltration are liver, lungs, and lymph nodes beyond the pelvic and para-aortic chains. Lymphatic spread of this lesion is common. The spread route follows the lymphatic vessels of ligamentum teres uteri or the lymphatic vessels of the right hemidiaphragm. The most common areas are pelvic lymph nodes with less frequent inguinal, axillary, or subclavian lymph nodes.
Hematogenic infiltration is strongly connected with advanced stages of the lesion. In these cases, the most common is liver and lung infiltration. In extreme advanced stages of the lesion, there are cases of skin or brain infiltration.
Nam et al. reported skin metastases in ovarian clear cell carcinoma as severe advanced metastatic area of the lesion [16]. Infiltration of these organs reflects severe decrease of disease-free survival, overall survival, and quality of life of the patient.  Postoperative treatment of clear cell ovarian carcinoma deviates, representing a distinct entity from other epithelial ovarian carcinomas. Reflecting a chemoresistant phenotype, the final prognosis of the lesion is poor, decreasing the quality of life of the patient. In cases of clear cell  carcinoma, gold standard combination with paclitaxel and carboplatin consists a not promising therapeutic strategy. Irinotecan hydrochloride, a topoisomerase I inhibitor, reflects an alternative solution regarding the postoperative treatment of clear cell carcinoma [17] (firstline chemotherapy for clear cell carcinoma) ( Table 3).
Many conducted studies managed to express the synergic effects of the combined therapeutic strategy of irinotecan and cisplatin (

Cancer Metastasis
The main objective of the previous study was the presentation and implementation of an epithelial-type ovarian carcinoma with specific metastatic pathways, prohibiting especially episodes of target therapy. New scientific keys, in the near future, will unlock unknown biochemical mechanisms and give answers to many questions, concerning the understanding of carcinogenesis of this lesion.

Conclusion
Ovarian clear cell carcinoma represents a rare histological entity with extreme chemoresistance and poor prognosis in correlation with overall survival and quality of life of the patient. Better understanding of metastatic and biochemical pathways of the lesion could schedule a proper therapeutic mapping. Further conducted studies are needed, in order to establish such strategy.