Research ArticleClinical Studies

Impact of Chemotherapy on Retroperitoneal Lymph Nodes in Ovarian Cancer

MIGNON-DENISE KEYVER-PAIK, JANNE MYRIAM ARDEN, CHRISTINE LÜDERS, THORE THIESLER, ALINA ABRAMIAN, TOBIAS HOELLER, THOMAS HECKING, TIYASHA HOSNE AYUB, ANNA DOESER, CHRISTINA KAISER and WALTHER KUHN
Anticancer Research April 2016, 36 (4) 1815-1824;

Abstract

Background: Complete cytoreduction is the most important prognostic factor in ovarian cancer. However, there exist conflicting data on whether the removal of microscopic tumor metastasis in macroscopically unsuspicious retroperitoneal lymph nodes is beneficial. Patients and Methods: Ovarian cancer tissues and tissues from lymph node metastasis of 30 patients with FIGO IIIC or IV disease undergoing neoadjuvant chemotherapy (NACT) were obtained and assessed using a validated regression score. Histopathological markers, size of largest tumor focus, and overall score were evaluated in lymph node and ovarian tissue. Regression and known prognostic factors were analyzed for influence on survival. Results: No difference in the overall score between lymph nodes and ovarian tissue was shown, however, single parameters such as fibrosis and pattern of tumor infiltration, were significantly different. Conclusion: The pattern of tumor regression in lymph nodes and ovarian tissue are of prognostic value. Lymph node dissection even of unsuspicious nodes should, therefore, be performed.

Ovarian cancer is the 6th most common cancer in women and 75% of women with ovarian cancer die within the first 5 years after diagnosis (1). Women present in late stages since ovarian cancer symptoms are unspecific and set on late in the course of the disease, mostly when carcinosis of the peritoneum has reached the colonic gutters, the diaphragm and lymphatic metastasis is present in the retroperitoneal lymph nodes along the large vessels of the abdomen and pelvis (FIGO stage IIIC or IVA). Hematological metastases occur rarely and late in ovarian cancer (2).

Therapy consists of two major pillars, chemotherapy and surgery. Although, the sequence of these two principal steps of therapy has been a point of discussion within international experts for decades, recent published data show that both approaches are equally effective depending on stage and triage of patients (3-7).

Complete tumor resection (cytoreduction) during laparotomy is the most important prognostic factor for survival, independent of sequence of surgery and chemotherapy. Other known prognostic factors are FIGO stage, age, performance status, grading, histological type, and pN1 status (8-11).

Lymph node dissection in ovarian cancer is a standard procedure and is performed as a systematic dissection of nodes between the V. renalis sinister in the left paraaortic, right paracaval and interaorto-caval region down to the pelvic vessels and obturator fossa. Para-aortic lymph node metastasis occurs independent of pelvic metastasis and bilateral-positive lymph nodes are common even in unilateral ovarian cancer, since lymphatic fluid will drain along the pelvic vessels, the ovarian vessels and the ligaments of the uterus directly (12).

Positive lymph nodes lead to upstaging of the patient, omitting lymph node dissection in earlier stages might, therefore, lead to an underestimation of the disease (12-14). The therapeutic role of lymph node dissection remains unclear. Lymph node dissection in ovarian cancer patients causes prolonged operation time and increases postoperative lymphoceles up to 20%, 25% of which are symptomatic (15). In 2005, Panici et al. published data showing no survival benefit for systematic lymph node dissection (16). On the other hand studies by others have shown that lymph node dissection leads to better survival of patients (17, 18). In 2008, the LION trial (Lymphadenectomy in ovarian neoplasms, NCT00712218) was started, intra-operatively randomizing 640 patients with FIGO stage IIB-IV and macroscopic complete cytoreduction and clinically unsuspicious lymph nodes to systematic lymph node dissection or omitting this procedure. First results are expected in 2017.

In breast cancer, axillary dissection was regularly performed, if frozen sections of the sentinel were found positive and would also lead to secondary axillary dissection, if the sentinel was found positive after initially negative frozen section. Based on the publication of Guiliano et al., it has become common to remove the sentinel nodes only and omit axillary dissection even in cases of up to three positive sentinels if post-breast-conserving radiation therapy with tangential radiation of the axillary region is planned (19). Following the onslaught of tailored therapies for breast cancer, local aggressiveness of surgical therapy has been reduced in favor of a diagnostic procedure (20). Similar approaches have been established in surgery and therapy of malignant melanoma or prostate cancer (21, 22).

In ovarian cancer tailored therapy is still not available. Ovarian cancer is known to have excellent chemo-sensitivity, however, the majority of patients eventually relapse, and no breakthrough agents have been seen established in systemic therapy of ovarian cancer besides standardized therapy with carboplatin and paclitaxel (23).

In the 1980's, data from different groups showed that chemotherapy might not reach ovarian cancer metastasis in lymph nodes as effectively as the intraperitoneal spread. Second-look operations were common procedure at the time and it was noticed that retroperitoneal lymph nodes carried ovarian cancer metastasis even if intraabdominal response was good (24). The hypothesis of the lymph node as a “safe haven” for ovarian cancer tumor cells was then generated (25, 26). Following this hypothesis, patients would benefit from aggressive lymph node dissection to avoid relapse from tumor cells sheltering from chemotherapy in metastatic lymph nodes. On the contrary, Morice et al. published data, where significantly fewer patients were found to have positive lymph nodes after preoperative chemotherapy compared to patients with upfront surgery (27). This may lead to the conclusion that chemotherapy does induce tumor regression in lymph nodes and at the primary site alike.

Although there is little information on histopathologic tumor regression in ovarian cancer, Sassen et al. in 2007 published a regression score for ovarian cancer, taking into consideration fibrosis, necrosis, inflammatory cell infiltration, foamy macrophages, isolated psammoma bodies, hemosiderin, foreign-body giant cells, giant tumor cells and pattern of tumor infiltration. These markers are signs of direct cytotoxic (giant tumor cells, psammoma bodies, necrosis) or indirect cytotoxic (post-hemorrhage hemosiderin) effects and elucidate on the immune response of the host (inflammatory cell infiltration, foamy macrophages, foreign-body giant cells) to the tumor. The pattern of tumor infiltration shows the extent of infiltration of the tumor into the original tissue that will probably become discontinuous and scattered through response to therapy. Fibrosis of tumor tissue is considered the residual state of response to chemotherapy (28). After 3 courses of carboplatin-based chemotherapy, points between one and three were given for each histopathological response marker and added-up to a score between 9 and 27. Patients with a score above the statistical median were considered responders, and the outcome of these patients correlated with a good response to the treatment (29).

View this table:
Table I.

Patients' characteristics of the included 30 patients in this study with FIGO IIIC or IV epithelial ovarian cancer treated with neoadjuvant chemotherapy.

In this trial, we investigated a series of 30 patients with FIGO IIIC or IVA ovarian cancer and positive lymph nodes who received preoperative chemotherapy. Tissue obtained from the ovarian site and the lymph node metastasis was analyzed for regression after chemotherapy and the histopathological responses in tissue of the ovarian site were compared to the histopathological response of the tumor in the lymph node metastasis.

View this table:
Table II.

Regression markers, frequency and histologic treatment response (HTR).

The hypothesis of a “safe haven” for tumor cells of ovarian cancer in lymph nodes could be rejected, if tumor regression in the primary site and lymph node metastasis were found to be similar. This may contribute to the question whether systematic lymph node dissection in patients with advanced ovarian cancer increases morbidity without further benefit or whether it might lead to a longer survival.

Patients and Methods

Thirty patients with pN1 status and ovarian cancer treated with 2 to 3 courses of neoadjuvant chemotherapy (NACT) followed by cytoreductive surgery between 2002 and 2010 were included in this trial. Clinical parameters and patients' outcome were taken from medical files of the patients and cross-referenced with electronic patient file and follow up data.

Patients' characteristics are shown in Table I. All patients were designated for neoadjuvant chemotherapy after histological confirmation of ovarian cancer. Two patients had explorative laparotomy before referral to our cancer center, all others were confirmed by laparoscopy. Out of the 30 patients, 19 (63.3%) were administered with 2 courses of preoperative chemotherapy while the rest 11 (36.7%) were administered with 3 courses. All patients had preoperative carboplatin AUC5, in combination with standard taxane. One patient was postoperatively changed to carboplatin and gemcitabine because of grade 3 neurotoxicity, one patient was switched to topotecan monotherapy because of primary platinum resistance. One patient died of an accident at home postoperatively, this patient was censored for survival analysis. All others continued the chemotherapy after cytoreductive surgery to a completion of six courses. There was no loss to follow-up. Median follow up was 25 months.

Figure 1.
Figure 1.

Progression-free survival. The median PFS was 15.1 months (12.7-17.4 months) in 30 patients with lymph node-positive ovarian cancer.

Figure 2.
Figure 2.

Overall survival. The median OS was 25 months (19.7-30.3 months) in 30 patients with lymph node-positive ovarian cancer.

Standard histological paraffin slides died with hematoxylin-eosin (HE) and periodic acid-Schiff reaction (PAS) were used for the evaluation of histopathological regression markers. The score was assessed by two pathologists in double reading. Material from lymph nodes and ovarian tissue were used, in one case, ovarian tissue was not available and tissue from omentum majus was used instead.

Regression markers fibrosis, necrosis, inflammatory cell infiltration, foamy macrophages, isolated psammoma bodies, hemosiderin, foreign-body giant cells, giant tumor cells and pattern of tumor infiltration were evaluated in a semi-quantitative form, using a modified score system after Sassen et al. One point was given for the marker being not or only minimally present, 2 points for focal occurrence and 3 points for widespread occurrence within the surgical specimen. For the regression marker “pattern of tumor infiltration” 1 point was given for macroscopic large confluent tumor mass(es), 2 points for multiple small tumor foci and 3 points for scattered solitary tumor cells or complete absence of residual tumor. The size of largest tumor focus in millimeters was also noted. Each regression marker in ovarian tissue was compared to the lymph node tissue to evaluate differences using cross-tab analysis.

Figure 3.
Figure 3.

Pattern of tumor infiltration: Ovarian tissue (A) with two small foci of an ovarian carcinoma after neoadjuvant chemotherapy corresponding to a regression pattern of 2 points (HE, magnification 200×; inset HE, magnification 1×) and lymph node (B) with two small foci of an ovarian carcinoma after neoadjuvant chemotherapy corresponding to a regression pattern of 2 points (HE, magnification 200×; inset HE, magnification 7×).

The overall regression score of each patient in her ovarian tissue and in the corresponding lymph node was constructed: Histopathological treatment response (HTR) was evaluated for each single marker. Focal or widespread regressive changes (2 or 3 points) for a marker were classified as HTR+ and compared to minimal presence of the marker (1 point), classified as HTR−, for progression-free and overall survival.

We then analyzed for differences in response to chemotherapy using the statistical median of the overall score as a threshold for responders and non-responders. Responders and non-responders were tested for a difference in progression free and overall survival. Analysis of other known prognostic factors for survival such as resection status postoperatively, FIGO stage, age, ASA (as substitute for performance status), grading and histological subtype was done and multivariate analysis was performed.

Figure 4.
Figure 4.

Fibrosis: Ovary (A) after neoadjuvant chemotherapy with ovarian carcinoma adjacent to hyalinized fibrous tissue. (HE, magnification 50×) and lymph node (B) after neoadjuvant chemotherapy with small tumor infiltrates and an intra- and peritumoral fibrotic reaction. (HE, magnification 100×).

Figure 5.
Figure 5.

Necrosis: Ovarian serous carcinoma (A) after neoadjuvant chemotherapy with a larger necrosis (indicated by asterisk) and a few psammoma bodies (indicated by black arrow) (HE, 100×) and lymph node (B) after neoadjuvant chemotherapy with a focal necrotic metastasis (indicated by asterisk) corresponding to a regression pattern of 1 point (HE, 150×).

Figure 6.
Figure 6.

Inflammatory cell infiltration: Inflammatory cell infiltration after neoadjuvant chemotherapy in ovarian tissue (A) (HE, 200×) and lymph node (B) after neoadjuvant chemotherapy with residual lymphatic parenchyma (indicated by asterisk) and scattered intra- and peritumoral inflammatory cell infiltrates (indicated by black arrows) (HE, 75×).

View this table:
Table III.

Influence of histopathological regression markers on progression-free survival and overall survival.

Statistical analysis was performed using the IBM program SPSS 22, IBM (Ehningen, Germany).

Results

Histopathological tumor regression (HTR) of each of the nine regression markers was evaluated and summed up to the overall score. Statistical median was used to define responders and non-responders. The statistical median was a score of 11 points in the ovarian tissue (range=9-14) and 10 (range=9-14) in the lymph node tissue, and response to chemotherapy was defined as a score ≥10.

Table II shows the HTR in ovarian tissue and lymph node and the difference in response using the McNemar test. Ovary and lymph node tissue showed statistically different HTR for the histological markers pattern of tumor infiltration (p<0.0001) and fibrosis (p=0.007). No test was performed for hemosiderin and foreign-body giant cells because no HTR+ probes were seen in case of foreign-body giant cells and HTR+ probes in lymph node tissue for hemosiderin. All other markers were not statistically different in the two tumor sites.

View this table:
Table IV.

Influence of known prognostic factors on progression-free survival and overall survival.

Progression-free survival (PFS) in the group of patients with unfavorable positive lymph node status was 15.1 months (12.7-17.4 months) (Figure 1), overall survival (OS) was 25 months (19.7-30.3 months), respectively (Figure 2). There was no statistical difference in survival between responders and non-responders defined by the median of the overall score (ovarian tissue PFS p=0.994; OS p=0.520/lymph node PFS p=0.824; OS p=0.728). Univariate analysis of the histopathological response markers (Table III) and known prognostic factors (Table IV) were performed for PFS and OS and showed significant differences for patients' age (p=0.001) for PFS and for the response markers of necrosis (p=0.047) and inflammation (p=0.044) for PFS in the ovary only. PFS was significantly higher in patients showing more inflammation as a sign of histopathological response to chemotherapy in the ovarian tissue, whereas patients showing greater necrosis had a statistically worse outcome. Size of largest tumor focus had no influence on OS (ovary: p=0.390/lymph node 0.976) or PFS (ovary p=0.671/ lymph node p=0.721).

Multivariate analysis (Table V) showed no significant difference between the scores in ovaries and lymph nodes for PFS or OS. For PFS multivariate analysis was significant for age (p=0.001), necrosis (p=0.004) and inflammation (p=0.024) in the ovary, for OS significance was shown for age (p=0.048) and necrosis (p=0.043).

Images of statistically different histopathological markers in place for all markers of the score are shown in Figures 3, 4, 5 and 6.

Discussion

Ovarian cancer is most often diagnosed at a late stage of the disease where lymph node metastases are present in up to 60% of these cases (12). It has been hypothesized that retroperitoneal lymph nodes may function as a “safe haven” for metastatic cells because chemotherapy targets them less effectively than the intraperitoneal spread. Other data suggest there may be no therapeutic value in removing retroperitoneal nodes and the procedure itself is associated with a significant morbidity (15, 16). The LION trial has been designed to answer the question whether patients macroscopically cytoreduced to no residual tumor with unsuspicious nodes would benefit from the removal of microscopic metastatic disease in their nodes, initial results are not expected before 2017.

View this table:
Table V.

Cox regression analysis of overall regression score, regression of single markers necrosis and inflammation in the ovary and lymph node tissue and age of the patient at diagnosis.

In this study, we analyzed 30 pairs of lymph node and ovarian tissue of patients with advanced ovarian cancer after 2-3 courses of platinum based chemotherapy, using very detailed and established regression scores to evaluate the effect of chemotherapy in retroperitoneal lymph nodes in comparison to intraperitoneal tumor sites (29).

We found a significantly different pattern of tumor infiltration between the ovary and the nodal tissue with smaller clusters or single cells more often found in lymph nodes than in the ovary. Fibrosis was significantly more often present in the ovary. In rectal cancer and gastric cancer, regression of local lymph node metastasis has been evaluated for prognosis and other scores exist to semi-quantitatively diagnose grade of regression. Fibrosis, necrosis and foamy macrophages are regularly seen in these nodes, but to our knowledge, no direct comparison of histological regression markers in the metastatic lymph node to the original gastrointestinal site has been performed. Tissue-dependent differences in patterns of regression may, therefore, have gone unnoticed (30).

The regression markers of necrosis, inflammation, psammoma bodies, foamy macrophages and giant tumor cells were not different between the tissues. For hemosiderin and foreign-body giant cells no cross-tab analysis could be performed since regression was very uniform and indeed identical in 93.3% and 100% respectively. The similarity of grade of regression in both sites is also reflected in the median score of regression in lymph nodes with 10 points compared to the ovary (11 points). The statistical median for defining response status in the analysis in the original publication of the regression score was with 13 point higher than with 10 points in this analysis (29). Out of the 30 patients analyzed here, only one specimen from lymph node tissue and 4 specimens from ovarian tissue were given ≥13 points, no specimen was given more than 14 points. In difference to literature, the overall score in this analysis did not correlate with survival (29). In 2009 Ferron et al. published similar findings on tumor regression after NACT concluding, tumor cell viability not being a reliable prognostic marker for survival (31).

In this analysis, influence of known prognostic markers like FIGO stage, resection status or grade could not be shown. This may be due to the limited number of cases and to the homogeneity of the sample with the negative selection of patients with positive lymph nodes. This is also reflected by the low PFS and OS in this group and seems to outweigh even the good overall tumor resection status (40% complete cytoreduction, 37% ≤1 cm) in these patients.

Necrosis and inflammation in the ovary, but not in the lymph nodes, and age were strong independent prognostic markers. Tumor site-depending differences on the prognostic value of tumor regression have already been described for ovarian cancer. In 2015, Böhm et al. published a chemotherapy response score in high-grade serous ovarian cancer, showing tumor response in adnexal mass was not closely linked to response at the omental site and showed the omental site to be more closely related to outcome (32).

Inflammation is a sign of antitumor immune response of the host. In 2003 Zhang et al. showed the presence of tumor infiltrating lymphocytes in 55% of all ovarian cancers examined and found a better prognosis in patients with tumor infiltrating T-cells (33). Milne et al. showed a better progression-free survival in patients with intratumoral CD8+ T-cells as a measure for cytotoxic antitumor activity in these patients (34). Especially serous ovarian cancers show a significant presence of CD8+ T-cells in 80% of cases (34, 35). In 2010, Pölcher et al. published data of ovarian cancer tissues before and after NACT and correlated the post-chemotherapy infiltration of tumor with pro-immunogenic granzyme B-positive cells and low counts of immunosuppressive Foxp3+ cells with survival (36). In our analysis, inflammation as a marker of tumor regression was positively related to survival, underlining the importance of immune response to ovarian cancer for survival.

Presence of larger foci of necrosis in ovarian tissue correlated negatively with survival. Necrosis under chemotherapy is considered a response marker and necrosis yields pro-inflammatory effects. Le et al. published their analysis on tumor regression in ovarian cancer, building a composite score of points for “not/minimally present”, “moderately present” or “extensively present” for histological markers of necrosis, fibrosis, macrophage infiltration and tumor inflammation in 101 patient probes of ovarian tissue after NACT (37). They found their score to be positively related to survival. Interestingly, differently than the other markers, necrosis was minimally present in 51.6% and extensively present in 43.5% of cases, whereas all other markers were distributed not so evenly between the two extremes. The authors did not elucidate on influence of the single markers on prognosis. This analysis also contained 21% sub-types outside the serous type, which is described as more significantly immunogenic than other ovarian cancer sub-types (34). Other authors have described pro-mitogenic effects of tumor cell necrosis through release of multiple growths factors in the microenvironment of a dying cell (38, 39). It is also possible to look at necrosis not as the starting point of a pro-inflammatory host response but also the result of a pre-existing hostile microenvironment as it may be created by fast-growing tumor lesion through hypo-oxygenation and other local factors (39).

Very few data are available on the validity of tumor regression scores and prognostic value of histopathological regression in ovarian cancer. The modified score used in this analysis evaluates multiple changes caused by chemotherapy in tumors of ovarian origin, yet no single score still exists with a widespread use in clinical practice (29, 32).

Using multiple markers of histological tumor regression, no difference between lymph node and primary site was shown in the overall score and for most analyzed markers. However, we did find a difference in favor of regression in the ovary for the most final histopathological change of tumor regression, which is fibrosis (28). Necrosis and inflammation were present in a similar way in the primary-site tissue and in the retroperitoneal lymph nodes samples, but were prognosticly relevant only when present in the ovary, similar to other published data showing different prognostic meanings for tumor regression at different sites (32, 40). We hypothesize that the difference in prognostic relevance of tumor regression under chemotherapy by site in this analysis may be a result of a different immunologic host response to the presence of tumor cells in ovarian tissue compared to their presence in retroperitoneal lymph nodes. Therefore, even a similar tumor regression, when analyzed using a regression score, in two different sites might result in a different significance for the survival of the patient, but the role of regression and prognostic relevance depending on the tumor site has yet to be elucidated.

In conclusion, the hypothesis of a “safe haven” for metastatic ovarian cancer tumor cells in retroperitoneal lymph nodes cannot be completely rejected yet, and a negative prognostic value of vital retroperitoneal tumor cells cannot be ruled-out. Therefore, in our opinion, and until more prospective data are collected, systematic lymph node dissection should continue for ovarian cancer patients after complete cytoreduction.

  • Received February 4, 2016.
  • Revision received March 9, 2016.
  • Accepted March 11, 2016.

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Impact of Chemotherapy on Retroperitoneal Lymph Nodes in Ovarian Cancer
MIGNON-DENISE KEYVER-PAIK, JANNE MYRIAM ARDEN, CHRISTINE LÜDERS, THORE THIESLER, ALINA ABRAMIAN, TOBIAS HOELLER, THOMAS HECKING, TIYASHA HOSNE AYUB, ANNA DOESER, CHRISTINA KAISER, WALTHER KUHN
Anticancer Research Apr 2016, 36 (4) 1815-1824;
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