Detection of metabolically active sdLNs have been reported in a number of studies using PET/CT imaging [5, 6, 9, 10, 14, 15]. These findings often lack histologic confirmation, since anatomical sites such as the parasternal and mediastinal lymph chain are unreachable for biopsy. Radiologic follow-up is an indirect method to confirm their malignant nature. To the best of our knowledge, the current study is the first one designed for prospective and systematic monitoring of the behavior of FDG-avid sdLNs with repeated PET/CT scans during treatment and relapse.
Our data suggest that the FDG-avid sdLNs do represent metastatic infiltration and are not artefactual or reactive changes. In line with previous studies [5, 10, 14], our follow up including 127 meticulously analyzed PET/CT scans showed that the vast majority of sdLNs accumulating FDG are normal in size. The metastatic nature of FDG avid sdLNs is suggested by two findings. Firstly, similar to the patients’ other lesions (including retroperitoneal LNM), FDG-avid sdLNs respond to first line chemotherapy both in a per-lesion and in a per-patient assessment. The metabolic response was similar in FDG-avid sdLNs and retroperitoneal LNM already after NACT prior any debulking surgery was performed.
Secondly, in half of the patients, the same sdLNs reactivated and enlarged during the recurrence. The number of histopathologically confirmed sdLNM was small (N = 5). However, FDG-PET/CT finding led to histological sampling of the hot spot and upstaging the disease from FIGO stage IIIC to IVB in all of these patients. The confirmed sdLNM also showed complete metabolic response to first line chemotherapy and often reactivated at the time of recurrence. In addition to decrease in SUVmax values, sdLNs that were detectable after first line treatment decrease in size after treatment and thickened when relapse was detected. However, the change was only a few millimeters and sdLNs were all along normal in size.
The prognostic significance of the PET positive sdLNs in pretreatment scan may be limited. Neither the size nor the SUVmax of sdLNs in the pretreatment scan predicted the patients’ primary therapy outcome. Compared to patients with complete metabolic resolution in sdLNs post treatment, partial metabolic response to the initial therapy was not associated with earlier disease relapse. In addition, in the majority of sdLNs in non-responders group showed some metabolic response, albeit progression of the disease in the abdominal cavity. This weakens the prognostic value of sdLNs as their metabolic response to the treatment does not seem to reflect the disease status in the abdomen nor instructs the possible further treatment.
In agreement with previous reports [10, 16, 17], we found that among patients with suspected extra-abdominal disease the recurrence to the thorax alone is rare and the most common site of the first relapse is the abdomen. The multidirectional migration of malignant cells and the reseeding of the primary tumor by metastasis has been demonstrated in human prostate cancer [18]. Post treatment residual metastatic infiltration in sdLNs may theoretically also represent a reservoir of malignant cells in OC. In present study, some patients had large volume residual disease in abdominal cavity after surgery and therefore any conclusions on role of sdLNs as cancer reservoir cannot be concluded.
Resection of enlarged cardiophrenic LNs has been reported to be a safe and feasible procedure for patients with advanced EOC [19,20,21,22]. However, there is controversial data about the survival benefit of extending PDS outside the abdominal cavity [10, 22, 23] and no consensus over the cutoff for pathologic cardiophrenic LNs. Values ranging between 5 and 10 mm have been suggested [19, 24, 25]. In our cohort, the majority of FDG-avid sdLNs were normal in size (when cutoff ≥10 mm for enlarged was used) and they were most commonly localized in the cardiophrenic and parasternal areas. However, only a small proportion of patients had all of the metabolically suspicious sdLNs in surgically approachable area.
The role of routine retroperitoneal lymphadenectomy of normal size nodes has been questioned in advanced EOC, since it is reported not to improve patients’ outcome [26, 27]. It can be anticipated that this is also liable to be the case with sdLNs. Garbi et al. [21] recently reported no recurrences in the cardiophrenic angle when debulked during PDS. Since they did not use PET/CT preoperatively or in the follow up, the status of other sdLNs was not known. In a recent study of Lee et al [10], primary debulking of sdLNM did not improve survival. In our study, only a minority of advanced EOC patients with intrathoracic disease had FDG-avid sdLNs in a single surgically approachable anatomical site. That may raise questions about the benefit of removing only the suspicious cardiophrenic LNs. We suggest that the centers committing cardiophrenic LNs resection should consider performing FDG-PET/CT covering also thorax area prior to surgery and during the follow-up in order to clarify the clinical significance of detected FDG-avid sdLNs and the survival benefit of cardiophrenic surgery in EOC.
This study has certain limitations including the absence of histological verification of sdLNMs in the majority of patients (36/41), restriction in the assessment of prognostic significance due to the small number and heterogenous characteristics of patients. The strengths of our study are the prospectively designed, systematic and detailed evaluation of the FDG-avid sdLNs behavior with PET/CT throughout the disease, and the long follow-up time of the patients.