YGYNO-975898; No. of pages: 4; 4C: Gynecologic Oncology xxx (2015) xxx–xxx
Contents lists available at ScienceDirect
Gynecologic Oncology journal homepage: www.elsevier.com/locate/ygyno
The significance of paracardiac lymph-node enlargement in patients with newly diagnosed stage IIIC ovarian cancer Oded Raban a,b,1, Yoav Peled a,b,1, Haim Krissi a,b, Natalia Goldberg b,c, Amir Aviram a,b, Gad Sabah a,b, Hanoch Levavi a,b, Ram Eitan a,b,⁎ a b c
Division of Gynecologic Oncology, The Hellen Schneider Hospital for Women, Rabin Medical Center, Beilinson Campus, Petach Tikva, Israel Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel Department of Radiology, Rabin Medical Center, Beilinson Campus, Petach Tikva, Israel
H I G H L I G H T S • Retrospective study aimed to evaluate the significance of PCLN in stage 3C EOC. • PCLN was associated with a lower rate of complete response to initial treatment. • In survival analysis, DFI and overall survival were shorter for patients with PCLN.
a r t i c l e
i n f o
Article history: Received 17 March 2015 Accepted 12 May 2015 Available online xxxx Keywords: Ovarian carcinoma Metastasis Survival
a b s t r a c t Objective. Extra-abdominal metastases in epithelial ovarian cancer (EOC) are relatively rare. Interpreting computed tomography (CT) scans, during initial work-up, little attention is focused on enlargement of paracardiac lymph nodes (PCLN) and their significance is not clear. We aimed to examine whether the presence of PCLN during initial diagnosis of EOC influences prognosis. Methods. A retrospective study comparing patients with stage 3 EOC who were diagnosed with PCLN on CT scan during initial evaluation to stage 3C patients without PCLN. Scans were reviewed by a single radiologist for peritoneal involvement, distal metastases and presence of PCLN. Disease status at diagnosis, results of surgery, chemotherapy and response, disease-free interval (DFI) and overall survival (OS) were recorded. Results. Thirty one patients with stage 3C EOC with PCLN on initial CT scan were included and compared with 41 controls. There was no significant difference between groups in abdominal optimal cytoreduction rate. Lower rates of complete response (CR) to initial treatment were detected in the study group (45.2% vs. 78.0%, p = .004). In survival analysis, the DFI for patients with PCLN was shorter (median 9.0 vs. 24.0 months, p = .0097) and overall survival was shorter (median 31.7 vs. 61.3 months, p = .001). Multivariate analysis showed that PCLN was significantly associated with a lower rate of CR, a shorter DFI and a shorter OS. Conclusion. The presence of enlarged PCLN at presentation appears to be associated with poor prognosis in stage 3C EOC. Further attention should be given to detection and follow-up of such findings when considering treatment. © 2015 Elsevier Inc. All rights reserved.
1. Background Ovarian cancer is the leading cause of gynecologic cancer death in the United States with approximately 25,000 new cases diagnosed annually and 15,000 women dying of the disease each year [1]. Patients suspected to have cancer of ovarian origin most commonly undergo an initial computed tomography (CT) scan to evaluate the extent of ⁎ Corresponding author at: Gynecologic Oncology Division, Rabin Medical Center, Beilinson Campus, Petach Tikva, Israel. Tel.: +972 3 9377550; fax: +972 3 9377518. E-mail addresses: [email protected], [email protected] (R. Eitan). 1 Contributed equally to the writing of the article.
disease, allocate for treatment (cytoreduction or neo-adjuvant chemotherapy) and provide a baseline for assessment of response to treatment [1]. Combined with clinical assessment and measurement of serum tumor markers, CT scanning is presently the imaging modality of choice for this purpose [2,3]. In the interpretation of the scans, attention is focused on the extent of local pelvic disease, the presence of peritoneal metastases, pelvic and para-aortic lymphadenopathy, ascites, pleural effusions and visceral metastases. Distant, extra-abdominal metastases are not common, with parenchymal liver involvement and malignant pleural effusion being the most frequently observed [4,5]. Enlarged paracardiac lymph nodes (PCLN, also known as cardiophrenic angle lymphadenopathy, Fig. 1)
http://dx.doi.org/10.1016/j.ygyno.2015.05.007 0090-8258/© 2015 Elsevier Inc. All rights reserved.
Please cite this article as: Raban O, et al, The significance of paracardiac lymph-node enlargement in patients with newly diagnosed stage IIIC ovarian cancer, Gynecol Oncol (2015), http://dx.doi.org/10.1016/j.ygyno.2015.05.007
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O. Raban et al. / Gynecologic Oncology xxx (2015) xxx–xxx
Fig. 1. Pre-treatment CT image of a patient with FIGO stage IIIC ovarian cancer who presented with an enlarged PCLN (white arrow).
are often identified, but less attention is paid to them as their significance is uncertain. Anatomically, PCLN belong to the group of parietal thoracic lymph nodes, and are divided into 2 major groups: an anterior and a middle (juxtophrenic) group, which further drain into the parasternal lymph nodes and anterior mediastinal chain, respectively [6,7]. The afferent lymphatics of the PCLN drain portions of the diaphragm, liver, pleura, pericardium and anterior abdominal wall. Based on animal studies [8,9], a major portion of lymph from sub-peritoneal plexuses adjacent to the diaphragm drain thru an anterior transdiaphragmatic route, thus they are a principal nodal station for the lymphatic drainage of the entire peritoneal cavity. Given the above distribution of lymph nodes and lymphatic drainage, it is hypothesized that in the presence of advanced ovarian carcinoma, pathological enlargement of PCLN is usually secondary to peritoneal invasion by tumor, however, enlarged PCLN are seldom biopsied to confirm metastatic disease. According to the updated Federation of Obstetrics and Gynecologists (FIGO 2014) staging guidelines for ovarian carcinoma [10], PCLN represent stage IVb disease spread (distant extra-peritoneal metastasis – lymph nodes outside the abdominal cavity) although there is no specific reference to paracardiac nodes. It has yet to be shown whether the finding of PLCN in patients with advanced ovarian cancer should be considered as regional spread and is of no significance reflecting disease spread in other areas in the abdomen or actually represent stage IVb disease. The aim of the present study is to examine whether the presence of enlarged PCLN suggestive of metastatic spread during initial diagnosis of ovarian cancer influences disease-free survival and overall survival for patients with stage IIIC disease. 2. Patients and methods Patients with newly diagnosed epithelial ovarian carcinoma, fallopian tube or primary peritoneal carcinoma, from January 2000 to January 2012, were included in this single tertiary institution retrospective cohort study. CT scan with oral and intravenous contrast was performed in all patients before treatment. All scans re-evaluated by a single expert radiologist for peritoneal involvement, distal metastases and the presence of PCLN. Paracardiac lymph nodes were considered to be enlarged if they were measured to be larger than 10 mm on the short axis. Patients diagnosed with stage 3C ovarian carcinoma (according to FIGO staging system 2000) [11] with a concurrent diagnosis of enlarged paracardiac nodes composed the study group (biopsies were not performed). All patients went on to receive therapy for ovarian cancer. Based on clinical assessment of the extension of their disease and performance status, some of the patients were eligible for primary cytoreductive surgery followed by adjuvant chemotherapy (carboplatin
and paclitaxel X6). Cytoreduction was defined optimal if no residual macroscopic disease was detected. Patients not suitable for primary surgery were treated with neo-adjuvant chemotherapy (carboplatin and paclitaxel X3) followed by interval cytoreduction and adjuvant therapy in eligible cases (carboplatin and paclitaxel X3). Patients with rapidly progressive disease not allowing initiation of treatment were excluded. Consecutive patients matched for age and stage with stage 3C ovarian cancer without PCLN involvement were used as controls. Medical records were reviewed for all clinico-pathologic information. Disease status at diagnosis, results of surgery, chemotherapy and response, disease-free interval (DFI) and overall survival (OS) were extracted. Disease-free interval was calculated from the end of adjuvant chemotherapy to the date of the scan demonstrating disease recurrence, and overall survival was measured from the date of first intervention to the date of death or last follow-up. Response was assessed by RECIST 1.1 and CA125 levels [12]. Data analysis was performed with the SPSS 21.0 software (SPSS Inc., Chicago, IL). The Mann–Whitney U test was used to compare continuous variables between the groups, and chi-square and Fisher exact test were used for categorical variables. Multivariate logistic regression analysis was performed to evaluate confounders. Survival was calculated using the Kaplan–Meier method, and differences in survival were compared using the log-rank test. Multivariate survival was assessed using Cox's proportional hazard model. Differences were considered significant when p b .05. Approval was obtained from institutional Scientific Ethics committee. 3. Results During the study period, 421 patients were newly diagnosed with epithelial ovarian cancer. Of them a total of 44 patients with PCLN on initial CT scan were detected (10.5%), out of which 4 had FIGO stage 2 ovarian cancer, 5 had stage 4 and 35 were diagnosed with stage 3C disease. After four patients were excluded due to rapidly progressive disease, 31 stage 3C ovarian cancer patients were included in the study. The control group consisted of 41 patients with stage 3C disease without PCLN on initial CT scan. The characteristics of patients with enlarged PCLN and the control group are compared in Table 1. Mean age at first intervention was similar between PCLN group and controls (64.5 vs. 59.5, p = 0.1) and no significant difference was detected in the rate of ascites (87.1% vs. 75.6%), omental involvement (100% vs. 90.2%) or levels of CA-125 (1248 vs. 1549). None of the PCLN patients had a tumor with endometroid histology, compared with 8 patients (22.9%) in the control group. No difference was detected in other histologic classifications. Table 1 Patients' clinicopatologic characteristics. PCLN, N (%)
No PCLN N, (%)
P Value
67.8 (17.1) 694.0 (833) 27 (87.1%) 23 (74.2%) 6 (19.4%) 31 (100%)
60.7(16.2) 536.5 (2194) 75.6 (31) 39 (95.1%) 9 (22.0%) 37 (90.2%)
0.063 0.43 0.223 0.011 0.788 0.074
Primary tumor Ovary Fallopian tube cancer Primary peritoneal 2nd primary tumor
14 (87.5%) 2 (12.5%) 0 (0) 1 (6.3%)
30 (85.7%) 1 (2.9 %) 4 (11.4%) 2 (5.7%)
0.863 0.174 0.159 0.940
Histology Papillary-serous Endometroid Mixed (endometroid + pap-ser) Poorly differentiated
10 (62.5%) 0 (0) 5 (31.3%) 4 (25%)
19 (54.3%) 8 (22.9%) 5 (14.3%) 12 (34.3%)
0.583 0.037 0.157 0.507
Median age at 1st intervention⁎ Median CA 125⁎⁎ Ascites Adnexal mass Enlarged LN Omental involvement
⁎ Data are represented in median age in years (interquartile range). ⁎⁎ Data are represented as median CA-125 value (interquartile range).
Please cite this article as: Raban O, et al, The significance of paracardiac lymph-node enlargement in patients with newly diagnosed stage IIIC ovarian cancer, Gynecol Oncol (2015), http://dx.doi.org/10.1016/j.ygyno.2015.05.007
O. Raban et al. / Gynecologic Oncology xxx (2015) xxx–xxx
Compared with controls, patients with PCLN were more likely to be treated with neo-adjuvant chemotherapy as primary intervention (71.0 % vs. 26.8%, p b .001) (Table 2), though there was no significant difference in abdominal optimal cytoreduction rate for the patients that underwent surgery (45.5% vs. 51.4%). Lower rates of complete response to initial treatment were detected in the study group (45.2% vs. 78.0%, p = .004). After adjusting for age at first intervention and type of primary treatment, logistic regression showed that PCLN was associated with a significant lower rate of complete response (OR 0.30, 95% CI 0.097–0.94). Persistent PCLN were detected on a follow-up CT scan during treatment in 7 out of 31 patients of the study group, and in 24 patients (77%), follow-up scan did not demonstrate enlarged PCLN. No significant difference was found in the rate of complete remission, diseasefree survival or overall survival in patients with persistent PCLN compared with patients in whom PCLN was not demonstrated following treatment. In survival analysis, a Kaplan–Meier plot showed a shorter diseasefree interval for patients with PCLN compared to controls (median 9.0 vs. 24.0 months, Fig. 2) with a reduced overall survival (31.7 vs. 61.3 months, Fig. 3). Cox regression model, after adjusting for age at first intervention and type of primary intervention, showed that PCLN was significantly associated with a shorter disease-free interval (HR 2.45, 95% CI 1.12–4.33) and a shorter overall survival (HR 2.20, 95% CI 1.12–5.43). Neo-adjuvant chemotherapy as primary treatment, on the other hand, did not significantly affect disease-free interval or overall survival after adjusting for age and the presence of PCLN. 4. Discussion Our study examined the clinical characteristics and response to treatment of patients with newly diagnosed stage 3C ovarian cancer with enlarged PCLN at initial CT scan. Our main findings were that the presence of PCLN at diagnosis was associated with a lower rate of complete response and both shorter disease-free interval and overall survival, which remained significant after adjusting for confounders. Holloway et al. have studied the significance of PCLN in patients with ovarian cancer and found a strong correlation with peritoneal metastasis and that the presence of PCLN had a negative effect on survival (HR 3.7), but the effect on disease-free progression was not statistically significant, and a more adverse outcome was associated with peritoneal metastasis compared to PCLN enlargement [13]. However, this study had a heterogeneous patient population, composed of both primary and recurrent disease and patients with early stage disease (stage II and recurrent stage IC) and included only 9 patients with PCLN at diagnosis. The effect of peritoneal metastasis on the difference between groups, in our study, was not significant due to a more advanced disease status that resulted in a very high rate of peritoneal involvement among both study and control groups (100% and 90%, respectively). In addition, Holloway et al. used a lower limit of 5 mm to measure and diagnose paracardiac lymph nodes. We chose a higher cutoff value for enlarged PCLN (10 mm), which is expected to have a higher specificity for detection of true PCLN involvement. In a more recent, larger study, Kolev et al. have examined the outcome of 212 patients with stage III/IV ovarian cancer who underwent primary cytoreduction, including 92 patients with PCLN (supradiaphragmatic
Fig. 2. Disease-free interval.\ \\ \\ \\ \, Enlarged PCLN, - - - -, no PCLN.
LN) on pre-treatment CT [14]. Enlarged PCLN were associated with higher rate of ascites, peritoneal implants, pelvic adenopathy and abdominal adenopathy. Although not statistically significant, a trend toward lower survival of patients with PCLN was observed. The lower cutoff for diagnosis of PCLN in this trial may have the same effect mentioned above. Without histologic confirmation of PCLN's neoplastic involvement, one might question if the LN enlargement might be secondary to the disease process and represent a reactive response. A recent study by Hynninen et al. has examined the additive value of preoperative FDG PET/CT in the detection of supradiaphragmatic lymph node metastasis (LNM) and found PCLN involvement in 14 out of 30 patients with stage IIC–IV epithelial ovarian cancer (46.7%) of which only 6 had abnormal LN on standard CT scan [15]. Other sites of supradiaphragmatic LN that were detected were parasternal, posterior/middle mediastinal, axillary and subclavian. Patients with supradiaphragmatic LNM had higher CA-125, more ascites and more frequent carcinomatosis of abdominal surface of diaphragm. During follow-up PET-CT, 24 out of 49 supradiaphragmatic LN remained positive and the reduction maximal in standardized uptake value (SUVmax) correlated with clinical response based on Recist 1.1 criteria [16], however, the authors did not specify the response according to exact LN distribution. We believe
Table 2 Primary treatment and outcome of patients with PCLN compared to controls.
Neoadjuvant primary treatment Optimal cytoreduction Achieved complete response at the end of primary treatment
PCLN, N (%)
No PCLN, N (%)
P Value
22 (71.0%) 11(45.5%) 14 (45.2%)
11 (26.8%) 19 (51.4%) 32 (78%)
b0.001 0.66 .004
3
Fig. 3. Overall Survival.\ \\ \\ \\ \, Enlarged PCLN, - - - -, no PCLN.
Please cite this article as: Raban O, et al, The significance of paracardiac lymph-node enlargement in patients with newly diagnosed stage IIIC ovarian cancer, Gynecol Oncol (2015), http://dx.doi.org/10.1016/j.ygyno.2015.05.007
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that PCLN enlargement detected in our study represent genuine neoplastic involvement: enlarged PCLN were detected on post-treatment CT in only 7 out of 31 patients, implying in most cases they have responded to chemotherapy. The use of PET/CT in the pre-treatment assessment of patients with newly diagnosed ovarian cancer is still under debate [17,18] and if applied, may assist in the diagnosis of these nodes before treatment decisions are made. By using PET/CT for the initial diagnosis of advanced carcinoma, Risum et al. have detected 27 out of 66 patients with radiologic stage IV disease compared with only 2 with FIGO stage IV disease, and 10 out of 24 LNM were mediastinal [19]. Patients with PET/CT stage III disease had a higher rate of optimal cytoreduction on primary surgery and a longer OS compared to patients with PET/CT stage IV, although the only statistically significant prognostic factor on multivariate analysis was optimal cytoreduction, and mediastinal LN influence was not separated from other PET/CT findings such as pleural or liver metastasis. PET/CT has a higher sensitivity for detection of LNM [20], however, due to false positive findings resulting from previous tuberculosis, pneumonitis or other pulmonary conditions, a pathological confirmation can sometimes be considered. Such pathological diagnosis and cytoreduction were described using video-assisted thoracic surgery (VATS) [21] or trans-abdominally via diaphragmatic incision [22] without major complications, though these studies did not address the impact of such procedures on prognosis. Limited by its retrospective design, and lack of PET/CT follow-up on PCLN response to treatment, and the lack of a stage 4 disease comparison group, our study was unable to unequivocally conclude if PCLN involvement should be regarded as stage IV disease. In addition, even though most of the clinical features were similar between the groups, patients with PCLN had a higher rate of neo-adjuvant chemotherapy as their primary treatment compared to controls. Assuming that patients who underwent primary neo-adjuvant treatment had a more progressive disease than those selected for primary surgery, this difference might partially account for their worse prognosis. However, after adjusting for the type of primary intervention, the lower rate of complete response and shorter disease-free interval and overall survival remained significantly different. Furthermore no difference was detected in the rate of optimal cytoreduction surgery between the groups which has been shown to be the strongest independent factor predicting overall survival [23]. 5. Conclusions At present, the detection of paracardiac lymph nodes is not specifically included in the staging criteria of epithelial ovarian cancer. The importance of PCLN has still to be determined, though accumulating data suggest that they are associated with adverse outcome. Our study has shown that PCLN are associated with a worse prognosis in stage 3C ovarian cancer patients, and supports the findings of earlier studies. Our data also support the hypothesis that the finding of PCLN on pretreatment imaging for women with newly diagnosed ovarian cancer is really an indicator of disease that behaves like stage 4 cancer and should be taken into consideration when planning treatment. Future prospective research is needed in order to determine the effect of PCLN on the prognosis of ovarian cancer and choose the most appropriate primary treatment. Conflict of interest statement
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The authors have no conflict of interest to declare.
Please cite this article as: Raban O, et al, The significance of paracardiac lymph-node enlargement in patients with newly diagnosed stage IIIC ovarian cancer, Gynecol Oncol (2015), http://dx.doi.org/10.1016/j.ygyno.2015.05.007
Contents lists available at ScienceDirect
Gynecologic Oncology journal homepage: www.elsevier.com/locate/ygyno
The significance of paracardiac lymph-node enlargement in patients with newly diagnosed stage IIIC ovarian cancer Oded Raban a,b,1, Yoav Peled a,b,1, Haim Krissi a,b, Natalia Goldberg b,c, Amir Aviram a,b, Gad Sabah a,b, Hanoch Levavi a,b, Ram Eitan a,b,⁎ a b c
Division of Gynecologic Oncology, The Hellen Schneider Hospital for Women, Rabin Medical Center, Beilinson Campus, Petach Tikva, Israel Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel Department of Radiology, Rabin Medical Center, Beilinson Campus, Petach Tikva, Israel
H I G H L I G H T S • Retrospective study aimed to evaluate the significance of PCLN in stage 3C EOC. • PCLN was associated with a lower rate of complete response to initial treatment. • In survival analysis, DFI and overall survival were shorter for patients with PCLN.
a r t i c l e
i n f o
Article history: Received 17 March 2015 Accepted 12 May 2015 Available online xxxx Keywords: Ovarian carcinoma Metastasis Survival
a b s t r a c t Objective. Extra-abdominal metastases in epithelial ovarian cancer (EOC) are relatively rare. Interpreting computed tomography (CT) scans, during initial work-up, little attention is focused on enlargement of paracardiac lymph nodes (PCLN) and their significance is not clear. We aimed to examine whether the presence of PCLN during initial diagnosis of EOC influences prognosis. Methods. A retrospective study comparing patients with stage 3 EOC who were diagnosed with PCLN on CT scan during initial evaluation to stage 3C patients without PCLN. Scans were reviewed by a single radiologist for peritoneal involvement, distal metastases and presence of PCLN. Disease status at diagnosis, results of surgery, chemotherapy and response, disease-free interval (DFI) and overall survival (OS) were recorded. Results. Thirty one patients with stage 3C EOC with PCLN on initial CT scan were included and compared with 41 controls. There was no significant difference between groups in abdominal optimal cytoreduction rate. Lower rates of complete response (CR) to initial treatment were detected in the study group (45.2% vs. 78.0%, p = .004). In survival analysis, the DFI for patients with PCLN was shorter (median 9.0 vs. 24.0 months, p = .0097) and overall survival was shorter (median 31.7 vs. 61.3 months, p = .001). Multivariate analysis showed that PCLN was significantly associated with a lower rate of CR, a shorter DFI and a shorter OS. Conclusion. The presence of enlarged PCLN at presentation appears to be associated with poor prognosis in stage 3C EOC. Further attention should be given to detection and follow-up of such findings when considering treatment. © 2015 Elsevier Inc. All rights reserved.
1. Background Ovarian cancer is the leading cause of gynecologic cancer death in the United States with approximately 25,000 new cases diagnosed annually and 15,000 women dying of the disease each year [1]. Patients suspected to have cancer of ovarian origin most commonly undergo an initial computed tomography (CT) scan to evaluate the extent of ⁎ Corresponding author at: Gynecologic Oncology Division, Rabin Medical Center, Beilinson Campus, Petach Tikva, Israel. Tel.: +972 3 9377550; fax: +972 3 9377518. E-mail addresses: [email protected], [email protected] (R. Eitan). 1 Contributed equally to the writing of the article.
disease, allocate for treatment (cytoreduction or neo-adjuvant chemotherapy) and provide a baseline for assessment of response to treatment [1]. Combined with clinical assessment and measurement of serum tumor markers, CT scanning is presently the imaging modality of choice for this purpose [2,3]. In the interpretation of the scans, attention is focused on the extent of local pelvic disease, the presence of peritoneal metastases, pelvic and para-aortic lymphadenopathy, ascites, pleural effusions and visceral metastases. Distant, extra-abdominal metastases are not common, with parenchymal liver involvement and malignant pleural effusion being the most frequently observed [4,5]. Enlarged paracardiac lymph nodes (PCLN, also known as cardiophrenic angle lymphadenopathy, Fig. 1)
http://dx.doi.org/10.1016/j.ygyno.2015.05.007 0090-8258/© 2015 Elsevier Inc. All rights reserved.
Please cite this article as: Raban O, et al, The significance of paracardiac lymph-node enlargement in patients with newly diagnosed stage IIIC ovarian cancer, Gynecol Oncol (2015), http://dx.doi.org/10.1016/j.ygyno.2015.05.007
2
O. Raban et al. / Gynecologic Oncology xxx (2015) xxx–xxx
Fig. 1. Pre-treatment CT image of a patient with FIGO stage IIIC ovarian cancer who presented with an enlarged PCLN (white arrow).
are often identified, but less attention is paid to them as their significance is uncertain. Anatomically, PCLN belong to the group of parietal thoracic lymph nodes, and are divided into 2 major groups: an anterior and a middle (juxtophrenic) group, which further drain into the parasternal lymph nodes and anterior mediastinal chain, respectively [6,7]. The afferent lymphatics of the PCLN drain portions of the diaphragm, liver, pleura, pericardium and anterior abdominal wall. Based on animal studies [8,9], a major portion of lymph from sub-peritoneal plexuses adjacent to the diaphragm drain thru an anterior transdiaphragmatic route, thus they are a principal nodal station for the lymphatic drainage of the entire peritoneal cavity. Given the above distribution of lymph nodes and lymphatic drainage, it is hypothesized that in the presence of advanced ovarian carcinoma, pathological enlargement of PCLN is usually secondary to peritoneal invasion by tumor, however, enlarged PCLN are seldom biopsied to confirm metastatic disease. According to the updated Federation of Obstetrics and Gynecologists (FIGO 2014) staging guidelines for ovarian carcinoma [10], PCLN represent stage IVb disease spread (distant extra-peritoneal metastasis – lymph nodes outside the abdominal cavity) although there is no specific reference to paracardiac nodes. It has yet to be shown whether the finding of PLCN in patients with advanced ovarian cancer should be considered as regional spread and is of no significance reflecting disease spread in other areas in the abdomen or actually represent stage IVb disease. The aim of the present study is to examine whether the presence of enlarged PCLN suggestive of metastatic spread during initial diagnosis of ovarian cancer influences disease-free survival and overall survival for patients with stage IIIC disease. 2. Patients and methods Patients with newly diagnosed epithelial ovarian carcinoma, fallopian tube or primary peritoneal carcinoma, from January 2000 to January 2012, were included in this single tertiary institution retrospective cohort study. CT scan with oral and intravenous contrast was performed in all patients before treatment. All scans re-evaluated by a single expert radiologist for peritoneal involvement, distal metastases and the presence of PCLN. Paracardiac lymph nodes were considered to be enlarged if they were measured to be larger than 10 mm on the short axis. Patients diagnosed with stage 3C ovarian carcinoma (according to FIGO staging system 2000) [11] with a concurrent diagnosis of enlarged paracardiac nodes composed the study group (biopsies were not performed). All patients went on to receive therapy for ovarian cancer. Based on clinical assessment of the extension of their disease and performance status, some of the patients were eligible for primary cytoreductive surgery followed by adjuvant chemotherapy (carboplatin
and paclitaxel X6). Cytoreduction was defined optimal if no residual macroscopic disease was detected. Patients not suitable for primary surgery were treated with neo-adjuvant chemotherapy (carboplatin and paclitaxel X3) followed by interval cytoreduction and adjuvant therapy in eligible cases (carboplatin and paclitaxel X3). Patients with rapidly progressive disease not allowing initiation of treatment were excluded. Consecutive patients matched for age and stage with stage 3C ovarian cancer without PCLN involvement were used as controls. Medical records were reviewed for all clinico-pathologic information. Disease status at diagnosis, results of surgery, chemotherapy and response, disease-free interval (DFI) and overall survival (OS) were extracted. Disease-free interval was calculated from the end of adjuvant chemotherapy to the date of the scan demonstrating disease recurrence, and overall survival was measured from the date of first intervention to the date of death or last follow-up. Response was assessed by RECIST 1.1 and CA125 levels [12]. Data analysis was performed with the SPSS 21.0 software (SPSS Inc., Chicago, IL). The Mann–Whitney U test was used to compare continuous variables between the groups, and chi-square and Fisher exact test were used for categorical variables. Multivariate logistic regression analysis was performed to evaluate confounders. Survival was calculated using the Kaplan–Meier method, and differences in survival were compared using the log-rank test. Multivariate survival was assessed using Cox's proportional hazard model. Differences were considered significant when p b .05. Approval was obtained from institutional Scientific Ethics committee. 3. Results During the study period, 421 patients were newly diagnosed with epithelial ovarian cancer. Of them a total of 44 patients with PCLN on initial CT scan were detected (10.5%), out of which 4 had FIGO stage 2 ovarian cancer, 5 had stage 4 and 35 were diagnosed with stage 3C disease. After four patients were excluded due to rapidly progressive disease, 31 stage 3C ovarian cancer patients were included in the study. The control group consisted of 41 patients with stage 3C disease without PCLN on initial CT scan. The characteristics of patients with enlarged PCLN and the control group are compared in Table 1. Mean age at first intervention was similar between PCLN group and controls (64.5 vs. 59.5, p = 0.1) and no significant difference was detected in the rate of ascites (87.1% vs. 75.6%), omental involvement (100% vs. 90.2%) or levels of CA-125 (1248 vs. 1549). None of the PCLN patients had a tumor with endometroid histology, compared with 8 patients (22.9%) in the control group. No difference was detected in other histologic classifications. Table 1 Patients' clinicopatologic characteristics. PCLN, N (%)
No PCLN N, (%)
P Value
67.8 (17.1) 694.0 (833) 27 (87.1%) 23 (74.2%) 6 (19.4%) 31 (100%)
60.7(16.2) 536.5 (2194) 75.6 (31) 39 (95.1%) 9 (22.0%) 37 (90.2%)
0.063 0.43 0.223 0.011 0.788 0.074
Primary tumor Ovary Fallopian tube cancer Primary peritoneal 2nd primary tumor
14 (87.5%) 2 (12.5%) 0 (0) 1 (6.3%)
30 (85.7%) 1 (2.9 %) 4 (11.4%) 2 (5.7%)
0.863 0.174 0.159 0.940
Histology Papillary-serous Endometroid Mixed (endometroid + pap-ser) Poorly differentiated
10 (62.5%) 0 (0) 5 (31.3%) 4 (25%)
19 (54.3%) 8 (22.9%) 5 (14.3%) 12 (34.3%)
0.583 0.037 0.157 0.507
Median age at 1st intervention⁎ Median CA 125⁎⁎ Ascites Adnexal mass Enlarged LN Omental involvement
⁎ Data are represented in median age in years (interquartile range). ⁎⁎ Data are represented as median CA-125 value (interquartile range).
Please cite this article as: Raban O, et al, The significance of paracardiac lymph-node enlargement in patients with newly diagnosed stage IIIC ovarian cancer, Gynecol Oncol (2015), http://dx.doi.org/10.1016/j.ygyno.2015.05.007
O. Raban et al. / Gynecologic Oncology xxx (2015) xxx–xxx
Compared with controls, patients with PCLN were more likely to be treated with neo-adjuvant chemotherapy as primary intervention (71.0 % vs. 26.8%, p b .001) (Table 2), though there was no significant difference in abdominal optimal cytoreduction rate for the patients that underwent surgery (45.5% vs. 51.4%). Lower rates of complete response to initial treatment were detected in the study group (45.2% vs. 78.0%, p = .004). After adjusting for age at first intervention and type of primary treatment, logistic regression showed that PCLN was associated with a significant lower rate of complete response (OR 0.30, 95% CI 0.097–0.94). Persistent PCLN were detected on a follow-up CT scan during treatment in 7 out of 31 patients of the study group, and in 24 patients (77%), follow-up scan did not demonstrate enlarged PCLN. No significant difference was found in the rate of complete remission, diseasefree survival or overall survival in patients with persistent PCLN compared with patients in whom PCLN was not demonstrated following treatment. In survival analysis, a Kaplan–Meier plot showed a shorter diseasefree interval for patients with PCLN compared to controls (median 9.0 vs. 24.0 months, Fig. 2) with a reduced overall survival (31.7 vs. 61.3 months, Fig. 3). Cox regression model, after adjusting for age at first intervention and type of primary intervention, showed that PCLN was significantly associated with a shorter disease-free interval (HR 2.45, 95% CI 1.12–4.33) and a shorter overall survival (HR 2.20, 95% CI 1.12–5.43). Neo-adjuvant chemotherapy as primary treatment, on the other hand, did not significantly affect disease-free interval or overall survival after adjusting for age and the presence of PCLN. 4. Discussion Our study examined the clinical characteristics and response to treatment of patients with newly diagnosed stage 3C ovarian cancer with enlarged PCLN at initial CT scan. Our main findings were that the presence of PCLN at diagnosis was associated with a lower rate of complete response and both shorter disease-free interval and overall survival, which remained significant after adjusting for confounders. Holloway et al. have studied the significance of PCLN in patients with ovarian cancer and found a strong correlation with peritoneal metastasis and that the presence of PCLN had a negative effect on survival (HR 3.7), but the effect on disease-free progression was not statistically significant, and a more adverse outcome was associated with peritoneal metastasis compared to PCLN enlargement [13]. However, this study had a heterogeneous patient population, composed of both primary and recurrent disease and patients with early stage disease (stage II and recurrent stage IC) and included only 9 patients with PCLN at diagnosis. The effect of peritoneal metastasis on the difference between groups, in our study, was not significant due to a more advanced disease status that resulted in a very high rate of peritoneal involvement among both study and control groups (100% and 90%, respectively). In addition, Holloway et al. used a lower limit of 5 mm to measure and diagnose paracardiac lymph nodes. We chose a higher cutoff value for enlarged PCLN (10 mm), which is expected to have a higher specificity for detection of true PCLN involvement. In a more recent, larger study, Kolev et al. have examined the outcome of 212 patients with stage III/IV ovarian cancer who underwent primary cytoreduction, including 92 patients with PCLN (supradiaphragmatic
Fig. 2. Disease-free interval.\ \\ \\ \\ \, Enlarged PCLN, - - - -, no PCLN.
LN) on pre-treatment CT [14]. Enlarged PCLN were associated with higher rate of ascites, peritoneal implants, pelvic adenopathy and abdominal adenopathy. Although not statistically significant, a trend toward lower survival of patients with PCLN was observed. The lower cutoff for diagnosis of PCLN in this trial may have the same effect mentioned above. Without histologic confirmation of PCLN's neoplastic involvement, one might question if the LN enlargement might be secondary to the disease process and represent a reactive response. A recent study by Hynninen et al. has examined the additive value of preoperative FDG PET/CT in the detection of supradiaphragmatic lymph node metastasis (LNM) and found PCLN involvement in 14 out of 30 patients with stage IIC–IV epithelial ovarian cancer (46.7%) of which only 6 had abnormal LN on standard CT scan [15]. Other sites of supradiaphragmatic LN that were detected were parasternal, posterior/middle mediastinal, axillary and subclavian. Patients with supradiaphragmatic LNM had higher CA-125, more ascites and more frequent carcinomatosis of abdominal surface of diaphragm. During follow-up PET-CT, 24 out of 49 supradiaphragmatic LN remained positive and the reduction maximal in standardized uptake value (SUVmax) correlated with clinical response based on Recist 1.1 criteria [16], however, the authors did not specify the response according to exact LN distribution. We believe
Table 2 Primary treatment and outcome of patients with PCLN compared to controls.
Neoadjuvant primary treatment Optimal cytoreduction Achieved complete response at the end of primary treatment
PCLN, N (%)
No PCLN, N (%)
P Value
22 (71.0%) 11(45.5%) 14 (45.2%)
11 (26.8%) 19 (51.4%) 32 (78%)
b0.001 0.66 .004
3
Fig. 3. Overall Survival.\ \\ \\ \\ \, Enlarged PCLN, - - - -, no PCLN.
Please cite this article as: Raban O, et al, The significance of paracardiac lymph-node enlargement in patients with newly diagnosed stage IIIC ovarian cancer, Gynecol Oncol (2015), http://dx.doi.org/10.1016/j.ygyno.2015.05.007
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that PCLN enlargement detected in our study represent genuine neoplastic involvement: enlarged PCLN were detected on post-treatment CT in only 7 out of 31 patients, implying in most cases they have responded to chemotherapy. The use of PET/CT in the pre-treatment assessment of patients with newly diagnosed ovarian cancer is still under debate [17,18] and if applied, may assist in the diagnosis of these nodes before treatment decisions are made. By using PET/CT for the initial diagnosis of advanced carcinoma, Risum et al. have detected 27 out of 66 patients with radiologic stage IV disease compared with only 2 with FIGO stage IV disease, and 10 out of 24 LNM were mediastinal [19]. Patients with PET/CT stage III disease had a higher rate of optimal cytoreduction on primary surgery and a longer OS compared to patients with PET/CT stage IV, although the only statistically significant prognostic factor on multivariate analysis was optimal cytoreduction, and mediastinal LN influence was not separated from other PET/CT findings such as pleural or liver metastasis. PET/CT has a higher sensitivity for detection of LNM [20], however, due to false positive findings resulting from previous tuberculosis, pneumonitis or other pulmonary conditions, a pathological confirmation can sometimes be considered. Such pathological diagnosis and cytoreduction were described using video-assisted thoracic surgery (VATS) [21] or trans-abdominally via diaphragmatic incision [22] without major complications, though these studies did not address the impact of such procedures on prognosis. Limited by its retrospective design, and lack of PET/CT follow-up on PCLN response to treatment, and the lack of a stage 4 disease comparison group, our study was unable to unequivocally conclude if PCLN involvement should be regarded as stage IV disease. In addition, even though most of the clinical features were similar between the groups, patients with PCLN had a higher rate of neo-adjuvant chemotherapy as their primary treatment compared to controls. Assuming that patients who underwent primary neo-adjuvant treatment had a more progressive disease than those selected for primary surgery, this difference might partially account for their worse prognosis. However, after adjusting for the type of primary intervention, the lower rate of complete response and shorter disease-free interval and overall survival remained significantly different. Furthermore no difference was detected in the rate of optimal cytoreduction surgery between the groups which has been shown to be the strongest independent factor predicting overall survival [23]. 5. Conclusions At present, the detection of paracardiac lymph nodes is not specifically included in the staging criteria of epithelial ovarian cancer. The importance of PCLN has still to be determined, though accumulating data suggest that they are associated with adverse outcome. Our study has shown that PCLN are associated with a worse prognosis in stage 3C ovarian cancer patients, and supports the findings of earlier studies. Our data also support the hypothesis that the finding of PCLN on pretreatment imaging for women with newly diagnosed ovarian cancer is really an indicator of disease that behaves like stage 4 cancer and should be taken into consideration when planning treatment. Future prospective research is needed in order to determine the effect of PCLN on the prognosis of ovarian cancer and choose the most appropriate primary treatment. Conflict of interest statement
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The authors have no conflict of interest to declare.
Please cite this article as: Raban O, et al, The significance of paracardiac lymph-node enlargement in patients with newly diagnosed stage IIIC ovarian cancer, Gynecol Oncol (2015), http://dx.doi.org/10.1016/j.ygyno.2015.05.007
