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Recurrence patterns in patients with abnormal cardiophrenic lymph nodes at ovarian cancer diagnosis
  1. Alyssa Larish,
  2. Ismail Mert,
  3. Michaela McGree,
  4. Amy Weaver,
  5. Shannon Sheedy and
  6. William Cliby
  1. Obstetrics and Gynecology, Mayo Clinic, Rochester, Minnesota, USA
  1. Correspondence to Dr Alyssa Larish, Obstetrics and Gynecology, Mayo Clinic, Rochester, MN 55905, USA; alyssalarish{at}gmail.com

Abstract

Objectives Metastases in cardiophrenic lymph nodes noted at diagnosis of epithelial ovarian cancer confer a poor prognosis. It is unclear if cardiophrenic nodal metastases portend an atypical pattern of recurrence. We report on patients with radiographically involved cardiophrenic lymph nodes who underwent optimal primary debulking surgery to describe patterns of recurrence and response to chemotherapy.

Methods Patients undergoing primary debulking surgery for stage IIIC/IV epithelial ovarian carcinoma with residual disease ≤1.0 cm at our institution from 2003 to 2011 with a pre-operative computed tomography (CT) scan were identified. Scans were reviewed by blinded radiologists, who identified abnormal cardiophrenic lymph nodes via a qualitative assessment scale based on size, heterogeneity, and architecture.

Results Of the 250 patients identified, a recurrence site was documented in 22/27 (81.5%) with abnormal pre-operative cardiophrenic lymph nodes (defined by an elevated Qualitative Assessment Scale (QAS) score of ≥4), and in 128/223 (57.4%) without abnormal pre-operative cardiophrenic lymph nodes. Median short axis and long axis lymph node diameters for these patients was 9 (range 6–15) mm and 15 (range 11–22) mm, respectively. Cardiophrenic lymph nodes were resected in one patient. Patients with abnormal cardiophrenic nodes are more likely to have synchronous recurrence in thorax/pelvis and abdomen (50.0% (11/22) vs 25.0% (32/128), p=0.02) and less likely to have isolated recurrence in pelvis or abdomen (40.9% (9/22) vs 68.0% (87/128)). All patients who had a CT scan after six cycles of chemotherapy had improvement (defined as reduction of QAS score) in cardiophrenic lymphadenopathy.

Conclusions Despite cardiophrenic adenopathy demonstrating a complete radiographic response to chemotherapy, their presence pre-operatively is associated with an increased risk of recurrence in the thorax. Knowledge of this propensity to recur in the thorax is important to ensure all extra-abdominal recurrence sites are diagnosed and managed appropriately.

  • lymph nodes
  • ovarian cancer
  • neoplasm metastasis
  • pleural cavity
  • lymphatic metastasis

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HIGHLIGHTS

  • Patients with abnormal cardiophrenic lymph nodes at diagnosis are more likely to experience thoracic recurrence.

  • Abnormal cardiophrenic lymph nodes demonstrate a robust and near complete response to chemotherapy.

  • Thoracic recurrences are not limited to cardiophrenic nodes, and include pleura, pericardium, and parenchyma.

Introduction

Recurrence sites of epithelial ovarian cancer have long been thought to be influenced by stage, initial disease sites, operative interventions, grade, and individual histologic subtypes.1–3 Cardiophrenic lymph nodes represent a common site of both pre-operative and recurrent metastatic disease, and enlargement may be detected in pre-operative imaging in up to 28% of patients with advanced epithelial ovarian cancer.4 This enlargement has been shown to predict pathologically proven metastatic disease in greater than 95% of patients with radiographically abnormal cardiophrenic lymph nodes undergoing surgical resection.4 5 Defining the specific abnormalities and imaging characteristics of nodes that indicate metastatic disease has proven to be a challenge, with varying measurements and scoring systems in place.

Reporting systems measuring lymph node diameter in the short axis alone to predict the presence of disease are limited in sensitivity (63%–90%) and specificity (83% at >7 mm and 90% at >10 mm).6–8 Alternative scoring systems which take into account not only size, but heterogeneity and architecture, such as the Qualitative Assessment Scale (QAS) have been proposed to be favorable in light of the sensitivity and specificity limitations of nodal diameter-based diagnostic criteria.9 Alternative options include positron emission tomography scans, which have been shown to have high sensitivity and specificity, but can be cost and time prohibitive.10 11

An actively emerging body of evidence has demonstrated that the presence of cardiophrenic adenopathy alone portends a poor prognosis with worse survival outcomes, even in cases with no residual disease at primary debulking surgery.9 Other factors, including the presence of any residual intra-abdominal disease at the time of surgery, have also been shown in large, well-designed studies to have a large impact on the progression-free and overall survival of these patients.8 Surgical resection of these nodes via the transdiaphragmatic approach has become common at some institutions. This has been shown to be both feasible and safe, with a marginal increase in operating time and short-term morbidity.5 7 12–14 Initial long-term data have suggested that surgical resection has little role in extending survival, but has not identified the effect of this practice on sites of recurrence utilizing a comparison group.8

In spite of these recent advances in our scope of surgical practice, no published data exist on the anatomic recurrence site patterns in patients with pre-operatively abnormal cardiophrenic lymph nodes. Knowledge of recurrence sites is important for patient counseling, surveillance, planning of surgical goals, and to better understand the biology of cardiophrenic nodal metastases. Given this gap in knowledge, we performed this pilot study to begin to describe recurrence patterns, radiographic response to chemotherapy, and trends in cancer antigen 125 (CA125) levels of patients with pre-operatively abnormal cardiophrenic lymph nodes on CT imaging.

Methods

This was a single institution, retrospective cohort study approved by the Mayo Clinic Institutional Review Board. Patients were selected from a database of those who had undergone primary debulking surgery for advanced stage IIIC/IV epithelial ovarian carcinoma between January 2003 and December 2011 and who had not denied access to their medical records for research purposes. These patients were further restricted to those with both pre-operative computed tomography (CT) imaging of the chest (34 patients), as well as optimal surgical cytoreduction defined as no gross residual or ≤1.0 cm of gross residual disease (27 patients). Scans were re-reviewed by two radiologists who were blinded to clinical information. The QAS was used to classify the probability that a node represented metastatic disease by scoring size, heterogeneity, and architecture of the node. Using this scale, a score of 1 represents normal, 2 probably normal, 3 indeterminate, 4 probably abnormal, and 5 definitely abnormal. In this study, cardiophrenic lymph nodes were classified as abnormal if they had a pre-operative QAS score of 4 or 5, and normal if they had a score of 1–3. QAS scores were determined at diagnosis, after adjuvant chemotherapy, and at recurrence by the same radiologists, who were blinded to the patient information and timing of the CT scans. Resection of cardiophrenic lymph nodes was rarely performed during this era of our practice (only one patient had resection at primary debulking surgery), and no patients underwent neoadjuvant chemotherapy. Recurrences were ascertained from medical record review and from a standardized questionnaire mailed to patients or their next of kin. The absence of a recurrence was confimed with a questionnaire mailed to the patient or their family a minimum of 5 years after their diagnosis. No patients with enlarged cardiophrenic lymph nodes were lost to follow-up, and one patient without enlarged cardiophrenic lymph nodes was lost to follow-up. Recurrence was defined as the presence of gross disease on subsequent imaging or pathology specimen, including abnormal lymph nodes (QAS score 4–5) or malignant ascites or pleural effusions. Isolated biochemical elevation of CA125 was not classified as recurrent disease for statistical analysis. Recurrence sites were classified as: pelvis/upper abdomen, thorax (including pleura, pleural effusions, lung parenchyma, posterior mediastinal, subcarinal and axillary nodes, and effusions of the pericardium), cardiophrenic lymph nodes, or central nervous system. The study design is summarized in Figure 1.

Figure 1

Study design and patient selection. CPLN, cardiophrenic lymph node; CT, computed tomography; EOC, epithelial ovarian cancer; IQR, interquartile range (25th and 75th percentiles); PDS, primary debulking surgery; QAS, Qualitative Assessment Scale; RD, residual disease.

Comparisons between patients with normal versus abnormal pre-operative cardiophrenic lymph nodes were evaluated using the Wilcoxon rank-sum for CA125, and chi-square or Fisher’s exact test for the categorical variables of recurrence sites. All calculated p values were two-sided and p values <0.05 were considered statistically significant. Statistical analyses were performed using SAS version 9.4 software (SAS Institute, Inc., Cary, NC, USA).

Results

Among 250 patients that met the surgical and staging inclusion criteria during the specified timeframe, 27 (10.8%) had cardiophrenic lymphadenopathy defined by a QAS score of 4–5 based on pre-operative CT, and 223 (89.2%) did not. All 27 patients with abnormal cardiophrenic lymph nodes underwent post-operative adjuvant platinum-based chemotherapy, four via the intraperitoneal route. At the time of diagnosis, 13 of the patients with abnormal cardiophrenic nodes had pleural effusions, and two had lung parenchymal/interstitial metastatic disease. Thoracentesis was performed on seven of the patients with effusions, and cytology was positive in four of seven. The following results are further restricted to the subset in both groups with a documented recurrence. All patients were followed until time of death or a minimum of 5 years if recurrence-free.

The majority (23/27, 85.2%) of the patients with abnormal cardiophrenic lymph nodes had a recurrence, including all six with stage IV thoracic disease at diagnosis. One patient never achieved remission, and was excluded. The mean age of these patients at diagnosis was 58.4 (range 43.5–71.4) years. Of the 23 patients, CT scans were available for 18 of them after chemotherapy and 21 at the time of recurrence. Chest imaging was routinely obtained on all patients with pre-operative cardiophrenic adenopathy at the time of a suspected recurrence. Most (21/23) of the patients were managed at our home institution at the time of recurrence. Recurrence was verified with outside medical records in one patient, and by next-of-kin report in the other. The QAS scores of these patients are summarized in Table 1. Median short axis and long axis lymph node diameters for these 27 patients was 9 (range 6–15) mm and 15 (range 11–22) mm, respectively. The median number of radiographically suspicious nodes per patient was 3 (range 1–8) nodes. Comparing the qualitative assessment scale scores pre- versus post-chemotherapy, all 18 patients had a reduction in their scores to less than suspicious: 17/18 (94.4%) noted improvement to a QAS score of 1 (normal), and 1/18 (5.6%) noted improvement to a QAS score of 3 (indeterminate). Median short and long axis lymph node measurements after chemotherapy were 0 (range 0–14) mm. However, 4/18 the patients with improvement after chemotherapy had a score of 4 (probably abnormal) or 5 (definitely abnormal) again at the time of their recurrence, corresponding to an increase in median lymph node diameter to 2.5 mm on the short axis (0–17 mm) and 4 mm on the long axis (0–22 mm) One additional patient had a score of 4 at the time of the recurrence but did not have an available CT scan after chemotherapy. In general, the majority of patients with abnormal cardiophrenic lymph nodes demonstrated response of the lymph nodes, as measured by a decrease in QAS score (see Table 1).

Table 1

Qualitative Assessment Scale scores at diagnosis, post-chemotherapy, and recurrence for the 23 patients with abnormal cardiophrenic lymph nodes at diagnosis

The specific sites of recurrence are listed in Table 2. Median time to recurrence was 14.25 (range 0–34) months. Among those with documented sites of recurrence, patients with abnormal (vs normal) cardiophrenic lymph nodes were significantly less likely to have an isolated pelvis/upper abdomen recurrence (40.9% (9/22) vs 68.0% (87/128), p=0.01) and more likely to recur concurrently in both the thorax (including cardiophrenic nodes) and pelvis/upper abdomen (50.0% (11/22) vs 25.0% (32/128), p=0.02). However, women with abnormal cardiophrenic lymph nodes were not significantly more likely to recur in the cardiophrenic nodal basin (with or without in the pelvis/upper abdomen) than patients without abnormal cardiophrenic lymph nodes (27.3% (6/22) vs 11.7% (15/128), p=0.09). In the 12 patients with thoracic recurrences, seven had stage IIIC disease at diagnosis and five had stage IV disease at diagnosis. Within the thorax itself, patients with pre-operative abnormal cardiophrenic lymph nodes were found to have recurrent disease at many sites, not restricted to the nodal basin. Among these patients, the predominant disease site was the pleura, including pleural effusions11 and significant overlap was noted with other thoracic sites, including the lung parenchyma or posterior mediastinal, subcarinal, internal mammary or axillary nodes,6 and effusions of the pericardium.3

Table 2

Recurrence sites and site-specific comparisons for abnormal cardiophrenic lymph nodes upon pre-operative computed tomography scan

Median CA125 values at diagnosis and recurrence were not different based on presence of abnormal cardiophrenic lymph nodes. Specifically, for patients with abnormal cardiophrenic lymph nodes, median CA125 at diagnosis and recurrence was 730 (IQR 359–1710) and 61 (IQR 50–133) U/mL, respectively, compared with 809 (IQR 266–2284) and 68 (IQR 32–219) U/mL among those without abnormal cardiophrenic nodes, respectively.

Discussion

We report the first data noting the propensity for combined thoracic and abdominopelvic recurrence among patients with primary ovarian cancer who present with clinically abnormal cardiophrenic nodes. While abnormal cardiophrenic lymph nodes are commonly encountered on pre-operative imaging in patients with advanced epithelial ovarian cancer, there is no consensus on ideal management. First, we observed that all patients’ cardiophrenic lymph nodes improved in response to chemotherapy. This finding is in accordance with Laasik et al, who found that despite normal node dimensions, pre-operative fluorodeoxyglucose (FDG) avid supradiaphragmatic adenopathy is likely to respond to adjuvant chemotherapy, with 50% of patients having recurrence of the FDG avidity at the time of disease recurrence.15 In our limited study, this response does appear to be sustained for many patients, as a large proportion did not have recurrences in the cardiophrenic nodal basin. Given this, our dataset suggests that adjuvant chemotherapy following optimal primary debulking surgery is a reasonable approach to treat suspicious cardiophrenic lymphadenopathy.

Patients with abnormal pre-operative cardiophrenic lymph nodes were more likely to recur regionally in the thorax and not be restricted to the cardiophrenic nodal basin. This is consistent with the tumor stem cell hypothesis, which hypothesizes that quiescent malignant cells not progressing through the cell cycle are less likely to be effectively targeted by chemotherapy, with ultimately their reactivation resulting in a disease site recurrence.16 17 Unfortunately, we also observed that independent of thoracic disease and despite optimal and often complete cytoreductive surgery, abdominopelvic recurrences remain common, though whether this represents seeding from the nodal basin or subclinical disease at original diagnosis is unclear. Knowledge of this patient population’s specific propensity to recur in the thorax may help shape future surveillance strategies to also include full-chest CT in patients with pre-operative cardiophrenic adenopathy, as well as counseling regarding respiratory symptoms of thoracic recurrence.

The question of the ideal initial surgical management of these patients remains in the forefront of our minds. Prader et al recently conducted a matched retrospective cohort study of 52 resected patients with surgical resection of cardiophrenic lymph nodes to those without cardiophrenic node surgical resection (abdominopelvic primary debulking surgery).8 They found that overall survival was not different between the groups, suggesting a lack of benefit of resection. At our institution, Mert et al found no survival benefit to resecting patients with cardiophrenic adenopathy to no gross residual abdominopelvic disease, compared with those with residual disease.9 If patients with abnormal cardiophrenic lymph nodes undergo optimal primary debulking surgery with adjuvant chemotherapy and ultimately have a high incidence of abdominopelvic recurrences, this calls into question the benefit of thoracic cytoreduction. Given this dilemma, we propose following sites of recurrence among patients who have undergone surgical resection to help clarify the role of surgery, and call for multi-institutional collaboration to build datasets with larger numbers of patients.

Strengths of our study include long-term follow-up of patients, QAS scoring, and lymph node measurements performed by two experienced, blinded radiologists at the time of diagnosis, and a single blinded and experienced radiologist after chemotherapy and at recurrence to minimize variability, a large and well-followed internal group of patients without cardiophrenic adenopathy at diagnosis for comparison, standardized use of pre-operative and recurrence chest imaging, and a comprehensive individual chart review by a clinician.

Limitations of our study include the highly restricted number of recurrences (n=23) within our cohort of patients with abnormal cardiophrenic lymph nodes, and incomplete chest CT scans for two patients at the time of recurrence. Consequently, we hope the present study generates interest in multi-institutional collaboration to build numbers and clarify management of these controversial patients. Additionally, we did note a potential high incidence of pre-operative extra-nodal thoracic disease, in that 13 effusions and two interstitial pulmonary metastasis were identified. However, it should be noted that only seven effusions were of sufficient volume for cytologic sampling, with positive cytology noted in four patients. Any trace or small effusion discovered on rereview was documented, some of which were not diagnosed on the initial clinical reading. Six patients were pathologically confirmed stage IV, and all underwent optimal cytoreduction. Including these patients increases the generalizability of the study findings to both stage IIIC and IV patients. Larger studies must be performed on patients with enlarged cardiophrenic nodes and optimal resection to address the specific impact of additional findings such as positive pre-operative pleural cytology on recurrence sites. Next steps for future study would include somatic testing of tumors in patients with cardiophrenic adenopathy to determine if they align with a specific molecular subtype, following patients after resection to evaluate for the effect of this practice on recurrence sites and symptoms, and development of evidence-based protocols for appropriate surgical and non-surgical treatment. Lastly, in light of the use of intraperitoneal chemotherapy, it will be important to assess the effect of this modality on transdiaphragmatic disease and cardiophrenic adenopathy.

References

Footnotes

  • Correction notice Author name 'William A Cilby' has been corrected to 'William A Cliby'.

  • Contributors Each author contributed meaningfully to the final work, including study design (AL, IM, WC), data abstraction (AL), radiology abstraction-review (SS), and data analysis and manuscript preparation or revision (AL, IM, WC, and statisticians AW and MMcG).

  • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

  • Competing interests None declared.

  • Patient consent for publication Not required.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Data availability statement Data are available upon reasonable request. De-identified data may be requested from authors. Approval will be made on a case-by-case basis, compliant with IRB and HIPPA policies.

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