Although refractory chylous effusions complicate lymphoma treatment in only 2% of cases, this accounts for over 10% of chylous effusions overall [10]. These effusions usually occur spontaneously without direct lymph vessel injury. Chylous effusions may be evident at the time of lymphoma diagnosis, but can also develop later during treatment [10].

As the cause of lymphatic leakage cannot be inferred from previous trauma or surgery, an exact work-up of lymphoma involvement and lymphatic imaging is of particular importance in non-traumatic effusions to elucidate the underlying lymphatic abnormality and plan targeted treatment [5]. Importantly, the course of a chylous effusion does not necessarily align with the success of treating the underlying lymphoma, and it can persist as a chronic issue despite successful oncologic treatment.

As reported previously [1, 11, 12], the majority of patients in our cohort suffered from follicular lymphoma or DLBCL. However, a wide range of different lymphoma types may lead to chylo-lymphatic effusions and it is currently not possible to predict the occurrence, location or course of effusions based on clinical parameters alone [11, 13]. The question remains which mechanism may lead to lymphatic effusions in lymphoma patients. In this respect three basic principles specifically in lymphoma-patients have been suggested [14,15,16,17]:

1.

Lymph vessel (i.e. thoracic duct) rupture due to direct lymphoma infiltration leading to frank lymphatic leakage,

2.

Obstruction of lymphatic run-off by compression of the thoracic duct by lymphoma-mass with subsequent backflow into pleural/peritoneal lymphatics,

3.

High viscosity of the lymphatic fluid due to elevated numbers of cells/protein content leading to a pressure increase and therefore backflow.

Furthermore, interactions between the lymphatic system, the tumor characteristics as well as the body's reaction to the disease and treatment may also be additional factors in the development of chylous effusions not yet understood [15,16,17].

In both scenarios 2 and 3 distension of lymphatic vessels is thought to lead to an increased fragility of lymph-vessels with micro-ruptures already after minor trauma. However, the imaging findings in our cohort suggest that alterations in lymph-flow (possible due to lymph-node involvement and/or altered viscosity of lymph) with subsequent reflux into pleural/peritoneal lymphatics and seepage of lymph into the respective cavity represent the more prevalent mechanism of effusion formation in these patients (11/17 patients presented with reflux). This is corroborated by the fact that patients in the present cohort all had non-malignant effusions making direct infiltration of larger lymph-vessels unlikely. This is in line with a previously reported low rate of only 20% of lymphoma cells in chylous effusions [12, 18,19,20,21,22].

All patients in our cohort had mediastinal and/or retroperitoneal lymph node involvement on cross-sectional imaging. However, although all 3 patients with combined abdomino-thoracic effusions showed lymph-node enlargement both of mediastinal and retroperitoneal nodes, 8/11 patients showed mediastinal and retroperitoneal involvement, but presented with only a chylothorax. Additionally one patient only had enlarged lymph nodes in the mediastinum, but presented with chylous ascites. This underlined the importance of dedicated lymphatic imaging as chylo-lymphatic reflux and/or obstruction of lymphatic run-off rather than active localized leakage in the location of involved lymph-nodes could be identified as the cause of effusions in the majority of cases.

It has been proposed from single case studies that due to the anatomy of the thoracic duct, lymphoma-associated chylothorax generally occurs in the left hemithorax and that bilateral chylothorax is a rare condition [23,24,25]. Our data do not support this suggestion as left-sided chylothorax was seen only in 1/14 patients while 8/14 presented with bilateral and 5/14 with right-sided chylothorax. This is again most likely due to the fact that we observed chylo-lymphatic reflux rather than frank leakage from the thoracic duct to be the cause of the effusion in the majority of patients.

Owing to the rarity of the clinical problem, there is so far no standardized treatment strategy. Non-traumatic chylous effusions in general are more difficult to treat than the more common traumatic leakages [25,26,27,28]. Paradigmatic for DLBCL is the intricate interplay of factors such as lymphatic infiltration, angiogenesis, cell adhesion-mediated drug resistance (CAM-DR), tumor microenvironment and tumor progression that may contribute to the development of chylous effusions [12, 27, 29, 30].

Treatment usually involves drainage of the excess fluid and an initial conservative treatment attempt (dietary measures, octreotide/somatostatin), which aims at reducing lymphatic flow [4, 5, 9]. As chylo-lymphatic effusions may decrease in patients with lymphoma remission [11, 12], targeted treatment of the underlying disease is also important. However, especially in high-output effusions, chemotherapy alone may not be sufficient [3, 13]. In our cohort, all patients presented with effusions refractory to conservative and oncologic therapy. Interestingly, there is no definitive correlation between remaining lymphoma mass under successful treatment and resolution of effusions.

When conservative therapy fails, more invasive treatment options have to be considered. Traditionally surgical treatment was attempted by performing thoracic duct ligation or pleurodesis. However, identifying the thoracic duct, often occurring anatomical variations or alternate pathways during surgery can be problematic. Therefore “blind” ligation without knowledge of the exact cause and location of the underlying lymphatic pathology can be potentially dangerous and should be avoided. Pleurodesis can be effective in treating chylothorax [31], but is limited by several potentially long-lasting adverse events (e.g. pain, respiratory impairment) and often incomplete success especially in high-volume effusions [32]. Therefore, pleurodesis should nowadays be a bail-out procedure in patients not responding to less invasive alternatives.

In recent years, minimally-invasive procedures such as XRL or LVE have been shown to be safe and effective in treating chylous effusions [5]. However, only very few dedicated reports on interventional treatment of lymphoma-associated spontaneous chylous effusions are available with the largest group published so far including only 5 patients [1, 11].

XRL is can visualize the anatomy of and the flow within the central lymphatic system as well as associated pathologies [5]. This is particularly helpful for further treatment planning in non-traumatic chylous effusions as, in contrast to traumatic lymph vessel injuries, the underlying lymphatic abnormality is typically unknown prior to imaging. In addition, iodized-oil used for XRL can also have a therapeutic effect by sealing of leakage sites with considerably less morbidity compared to surgical approaches [1, 8, 11, 18, 33]. It is currently assumed that leaking iodized-oil directly blocks the leakage and that secondary sterile inflammation leads to formation of scar tissue [11, 34, 35]. In general, the therapeutic effect of XRL alone for thoracic lymphatic leakages varies considerably with success rates reported between 7 and 100% [4]. Higher success rates have been reported for traumatic lymphatic leakages (around 75%) while especially for non-traumatic chylous effusions clinical success rates seem to be considerably lower (around 20%) [36]. This is in line with a reported clinical success rate of only 20% for XRL also in patients with lymphoma-associated chylous effusions (n = 10) [37]. However, several factors such as the underlying disease, drainage volume as well as the amount of applied iodized-oil may also influence treatment success. In contrast to earlier reports we observed resolution of chylous effusions in > 80% of patients after XRL (with continued conservative treatment and chemotherapy). This higher rate of clinical success may be due to a higher dose of iodized-oil applied in our cohort. While Fukumoto and colleagues for example used only small amounts of contrast agent (6-12ml) in repeated interventions (up to 5 interventions per patient) [1], our patients all received XRL with 20 ml of iodized-oil in a single treatment session. This is in line with a recent report by Jardinet et al. [34] demonstrating a high success rate (83%) of high-volume iodized-oil XRL in traumatic chylothorax (mean dose per procedure, 75 ml). Of note, the amount applied by Jardinet et al. is several times higher than the manufacturer's recommended dose. At our institution we tend to limit the amount of applied iodized-oil to 20 ml in the average adult patient. Interestingly, we observed not only a higher clinical success rate of XRL, but resolution of the effusions also occurred earlier than reported previously. In addition to the effect of a higher dose of iodized-oil, the inclusion of patients with different lymphoma types or the volume of lymphatic output might also play a role in this respect [11, 13, 38].

It is so far impossible to predict when a therapeutic effect of XRL will set in with reported time intervals of days to several weeks [5]. The effect of additional direct LVE, in contrast, is more predictable and has a generally higher success rate [1]. If the thoracic duct can be intubated successfully, LVE is successful in well over 90% in patients with traumatic chylothorax. In contrast to XRL alone, LVE has recently be demonstrated to be effective in non-traumatic causes with a success rates of up to 85% [3, 37, 39,40,41]. This is in line with our results in patients with lymphoma-associated lymphatic leakage with clinical success in all patients undergoing LVE. Compared to XRL alone, LVE lead to a significantly faster resolution of the effusions (within only one days after embolization compared to a mean for 9 days after XRL). However, as obstruction of lymphatic out-flow seems to play a role in several of the patients with lymphoma-associated chylous effusions, we advocate to employ LVE sparingly and as selectively as possible in cases with identifiable active leakage or after failure of XRL alone. Further obstruction of lymphatic run-off by embolization (or ligation) may otherwise even worsen lymphatic leakage.

After successful treatment of the effusions, the positive effect of interventional treatment seems to be long lasting as we observed no recurrence of effusions within a mean clinical follow-up interval of over one year (up to 4 years). As reported before, interventional treatment is quite safe as post-interventional complications are rare and were not observed in our cohort. Considering high clinical success and low morbidity rates, interventional procedures should therefore be considered a primary treatment options in patients with refractory lymphoma-associated chylous effusions.

Our study has several limitations. First, data were analyzed retrospectively with inherent methodological limitations. Second, although—to our knowledge—being the largest patient cohort receiving interventional-radiological treatment of refractory lymphoma-associated chylous effusions, the sample size is still rather small due to the relatively rarity of this clinical problem. Third, the patient cohort was overall rather heterogeneous due to different underlying lymphoproliferative disorders. We therefore refrained from more in-depth statistical analysis. Since many patients were referred to us from outside hospitals for interventional treatment, data regarding the previous oncological therapies with regard to different chemotherapeutic agents are heterogeneous and only partially documented. In addition, the study was performed at a single center with all lymphangiographies being performed by the same interventionalist which may impair generalizability of the results. The source of the lymphatic effusions in patients with normal findings on imaging remains unclear to a certain extent. Lymphatic imaging was focused on the central lymphatic system at the time of treatment of the included patient cohort. Since then other imaging options such as mesenteric or hepatic lymphangiography have become available and might have shown abnormalities in the respective lymphatic systems as a source of the effusions [5]. Further research into long-term effects in larger, multi-center studies certainly is warranted.

In conclusion, interventional-radiological treatment of refractory, non-traumatic lymphoma-induced chylous effusions is safe and effective with a clinical success rate of 88%. Lymphangiography is helpful in identifying lymphatic abnormalities in the majority of patients and, at the same time, can already be therapeutic in > 80% of patients. Active lymphatic leakage is found in only a third of patients and can be managed by additional targeted lymph vessel embolization.