Ovarian cancer initially presenting with isolated ipsilateral superficial inguinal lymph node metastasis: a case study and review of the literature

Lymph node metastases can be well recognized in ovarian cancer with sampling of retroperitoneal lymph nodes as an integral part of the staging operation [8]. FIGO introduced inguinal lymph node involvement into the definition of stage IVB in ovarian carcinoma since 2013 [7], while patients exhibited metastatic retroperitoneal lymph nodes are classified as stage IIIC even when the primary tumor is limited to the pelvis [9]. The most common way of spreading in ovarian carcinoma is lymphatic metastasis and transcoelomic spread to adjacent viscera, with distant metastasis often concurring with extensive intra-abdominal dissemination [10]. Nevertheless, isolated SILN involvement in patients without any extended intraabdominal spread is a rare event [6, 11, 12].

The incidence of inguinal lymph node metastasis in ovarian carcinoma was approximately 3-5% as reported in literatures [6, 11, 13, 14], while these studies can't provide enough clinical informations and pathological features. A little bit more detailed descriptions include following cases. A patient presenting with an enlarged inguinal lymph node, was finally diagnosed to be endometrioid carcinoma of the ovary [15]; a patient presented with metastatic inguinal lymphadenopathy was confirmed with poorly differentiated ovarian malignancy until 33 months later [16]; an eighteen-year old female patient complained with enlarged inguinal lymph nodes and secondary lymphedema of both legs, showed ovarian tumors (approximately 6 cm diameter) detected by computed tomography, and was finally proved to be stromal infiltration of signet-ring cell carcinoma in both ovaries [17]; a 48-year-old patient presented with 6-month history of inguinal swelling, was confirmed with a serous papillary ovarian carcinoma, thus indicated that inguinal lymphadenopathy can be initial symptom epithelial ovarian carcinoma [18]. Nevertheless, these studies were also inconclusive, since they neglected to give any further detailed information on pathological examination of the pelvic and paraaortic lymph nodes, and whether inguinal lymph node metastasis occurred in isolation or concurred with other sites of neoplasm metastasis.

To the best of our knowledge, the following three records provided full clinicopathological features in this regards. Scholz et al. [19] firstly reported a patient with undifferentiated serous adenocarcinoma of both ovaries (10 × 5.5 cm), and involvement of fimbria of the right fallopian tube, and positive peritoneal washing, initially displayed an isolated left inguinal node metastasis, without other nodal groups involvement. Then Manci et al. [20] reported that, a patient complained with bilateral inguinal lymphadenopathy, showed an increased uptake of fluorodeoxyglucose in the inguinal and both adnexal areas as detected by [(18)F] fluorodeoxyglucose (FDG) positron emission tomography (PET), then post-operational pathological diagnosis confirmed low-grade differentiation serous papilliferous adenocarcinoma of both ovaries (size not known), and metastatic bilateral inguinal lymph nodes, without any intraperitoneal or lymphatic spread. Afterwards, Ang et al. [21] reported a patient with left ovarian adenocarcinoma (9.0 × 6.4 cm) presented with isolated metastasis to the right inguinal lymph node, there were no other sites of involvement. Thus, the case we reported was one of the few cases which have complete clinicopathological informations in existing literatures. However, different from Scholz’s and Ang's case, in which large (10 × 5.5 cm) and (9.0 × 6.4 cm) tumor burden were found, our case demonstrated relatively small tumor burden (5 cm in largest diameter), disease was localized only within the right ovary, initially presented with right SILN metastasis, without any evidence of extensive intra-abdominal dissemination, and retroperitoneal pelvic or paraaortic lymph nodes metastasis. Therefore, this is the fourth case of ovarian carcinoma which presented with isolated SILN metastasis reported in existing literatures.

Ovarian carcinoma usually presents with advanced stage at their initial visit (FIGO Stage III and IV), with signs and symptoms related to the diffused intraperitoneal disease [2]. However, the presence of asymptomatic isolated SILN at the time of first visit frequently creates a diagnostic dilemma. This situation is unique not only in the manner of disease presentation, but also in the time lag from first seeking advice to evidence of intra-abdominal malignancy [16].

In general, the common condition which might presented with palpable SILN enlargement include metastatic disease or secondary inflammation [22]. Pathology of tumors commonly metastasising to the inguinal lymph nodes include breast cancer [23]; tumours arising from the vulva and lower third of the vagina [24]; pelvic malignancies [25]; malignant tumours of the skin, most commonly primary malignant melanoma or squamous cell carcinoma arising on the legs and trunk [14, 24]; squamous cell carcinoma of the anal canal is also a common gastrointestinal tumour to metastasise to the inguinal lymph nodes [24]. Systematic infectious disease such as syphilis, HIV, HSV, and local infection such as ulcers in the lower genital tract, Neisseria gonorrhoeae, can also cause enlarged inguinal lymph node. Therefore, preoperative diagnosis of inguinal lymph node enlargement always cause diagnostic dilemma and might involve general practitioners, oncologists, dermatologists, and specialist nurses. However, antibiotics treatment for 4 to 6 week is usually prescribed, followed by re-evaluation of the lymphadenopathy [24]. Previous literatures showed that, for patients with isolated inguinal metastasis of unknown origin, laparoscopic surgery provided a minimally invasive diagnostic approach of the abdominal and pelvic cavity, although there controversy that a small tumor within the ovary might be missed [22]. Imaging examination such as TVUSG maybe helpful in detecting the earlier malignancy in ovary. PET might has an appropriate role in the diagnosis of occult ovarian neoplasm, even in the absence of a CA125 elevation [20]. The combination of FDG-PET/CT was successfully used to identify ovarian cancer recurrence in an inguinal hernia sac [26]. Moreover, serum levels of tumor markers such as CA125 can also assist to determine the primary disease when the clinical presentation is atypical or confusing. However, in our case, we proposed that, the management of a patient presenting with inguinal enlargement of unknown origin should include at least a detailed case history collection, complete gynecological examination and some useful auxiliary diagnostic measures for any ovarian neoplasms. Sometimes, even if no evident clinical signs and symptoms of a tumor in the lower genital tract, isolated enlarged SILN should also be paid enough attention for possible existence of an occult malignant ovarian tumor. In other words, ovarian cancer should be part of the differential diagnosis in women with inguinal lymphadenopathy even without any clinical evidence of intra-abdominal disease. Furthermore, surgical excision or lymph node biopsy can be a indication for inguinal lymphadenectomy, can provide better diagnostic and prognostic information.

The role of lymph node metastasis on survival in ovarian cancer has been a matter of debate over the years [27]. Generally, lymph node metastasis is recognized as a parameter of unfavorable prognosis. The prognosis of distant metastasis in ovarian carcinoma is poor and the median survival was only about 12 months [28]. While the opposite view suggested that, patients with ovarian carcinoma which upstaged to stage III based solely on systematic lymphadenectomy, have similar survival to stage I/II patients and superior survival to other stage III patients [29]. In fact, survival difference between node-positive-only stage IIIC and intra-abdominal stage IIIC simply reflect the prognostic impact of small versus large tumor size [30]. “Node-positive-only” stage IIIC have a more favorable outcome than intra-abdominal stage IIIC and IIIA/B in patients with epithelial ovarian cancer [31, 32].

The impact of SILN metastasis on the prognosis in ovarian cancer is also in controversy. Some authors suggested that patients with inguinal lymph node metastasis as their first symptoms were associated with poor prognosis, and can only survive for about three years [16, 18]. While others argued that, in patients with recurrent epithelial carcinoma, who presented as isolated lymph node metastases (including inguinal nodal involvement), complete optimal secondary cytoreductive surgery was achievable in the majority of cases and were associated with relatively favorable long-term survival outcome [33, 34]. Similar study also indicated that, for those suffered with serous carcinoma of the ovary, fallopian tube, or peritoneum, distant lymph node metastasis was an uncommon event (including inguinal nodal involvement), however, this rare presentation does not adversely affect survival, patients with minimal intra-peritoneal disease and extra-abdominal lymph node metastases survive longer than those with bulky peritoneal disease [35]. According to the new stage system, inguinal lymph node metastasis was classified into FIGO Stage IVB ovarian cancer [7]. While in the previous edition of stage system, it was confusion about this, and inguinal lymph node metastasis was usually put into Stage IIIc [9]. Therefore, we supposed that, such stage difference might cause inconsistency in data analysis on prognosis regarding inguinal lymph node metastasis.

The case reported here, was confirmed to be Stage IVB ovarian cancer, and survive for five years after six rounds of carboplatin plus paclitaxel systematic chemotherapy, with no evidence of recurrence. We consider it that such patients presented only with distant lymphatic metastasis, were in relatively better conditions and specific immune status, thus have better prognosis after comprehensive treatment, as compared with bulky peritoneal disease. However, with the issue of new stage system in the year of 2013 [7], large-scale and multicenter analysis should be done to investigate clinical outcome in patients with ovarian cancer confined to the ovary but upstaged to stage IVB due to metastatic SILN, and provide more insight about potential differences in biological and clinical behavior of inguinal lymph node versus intra-peritoneal metastasis. Furthermore, there is no existing guideline on definitive management of patients with ovarian cancers metastasizing to isolated SILN [22], efforts should be made to improve early diagnosis and finally prolong the survival of such patients. We suggested that, such patients should be entered into clinical trials of different treatment modalities in order to develop optimal clinical guideline.

Generally, ovarian cancer has three routes for lymphatic metastasis [36, 37]. Firstly, lymphatic vessels mainly accompany the ovarian vessels within the infundibulopelvic ligament towards the paraaortic and paracaval lymph nodes. Thus, nodes running parallel to lymphatic vessels are at highest risk of involvement. Once the pelvic and paraaortic lymph nodes have been involved, lymphatic channels within the diaphragm and retroperitoneum will facilitate dissemination above the diaphragm. Less commonly, the second route follows the subovarian plexus in the bilateral broad ligament towards the obturator and pelvic iliac lymph nodes. The third potential route follows the bilateral round ligament of the uterus to the external iliac and deep inguinal lymph nodes. We suggested that, in the absence of paraaortic or pelvic lymphadenopathy which mainly depend on the first and the second route as above mentioned, the isolated SILN metastasis might attribute to the third potential channel. Our case just provided support to lymphatic dissemination via this potential channel, through which ovarian cancer metastasize from the round ligament to deep inguinal lymph node and finally drained towards the SILN. However, the existence of such a potential pathway has not been confirmed yet. Moreover, hematogenous dissemination is also another possible pathway for this special metastatic pattern, and was reported to occur in approximately 2% to 3% of patients with primary ovarian carcinoma [10]. Theoretically, hematogenous route may account for dissemination to any distant sites in ovarian cancer. Such as, early extra-abdominal metastases [38], central nervous system metastases [39], axillary lymph nodes [40], and breast metastases [41, 42], all support the model of spreading through hematogenous route. Therefore, in summary, we proposed that the event of isolated SILN metastasis in ovarian cancer potentially involved two channels: via deep inguinal lymphatic routes through round ligament and/or hematogenous route.

In addition to study the routes of isolated SILN metastasis in ovarian cancer, we should also explore its underlying mechanisms. Current study revealed that advanced tumor stage, low-grade cell differentiation were risk factors for the development of distant metastasis [28]. For instance, in our case with G3, low-grade cell differentiation might contribute to one of important risk factors for isolated SILN metastasis. In addition, mutation of p53 tumor suppressor gene was more likely to be associated with distant lymph node metastases in ovarian cancer, indicated that gene mutation and vascularization might also contribute to distant metastasis in ovarian cancer [43]. Moreover, we speculated that, this special metastatic pattern is probably the result of tumor biology and host-tumor immunostatus. The special host immune state within a specific time window perhaps plays a key role, might kill some primary cancer cells but neglect distant isolated lymph node metastasis. Nevertheless, there may be a number of other unknown factors beyond our present knowledge, such as unexplained hormones contributions. Existing literatures have put more emphasis on pelvic and paraaortic lymph nodes metastasis in ovarian cancer [36]. However, few studies had focused on the isolated SILN metastasis, the exact molecular mechanisms and/or risk factors of this special clinic metastatic pattern in ovarian cancer still deserve further investigation.