Updates Surg DOI 10.1007/s13304-014-0265-0
REVIEW ARTICLE
Lymphatic drainage of the liver and its implications in the management of colorectal cancer liver metastases Renato Micelli Lupinacci • Franc¸ois Paye • Fabricio Ferreira Coelho • Jaime Arthur Pirolla Kruger Paulo Herman
•
Received: 11 July 2014 / Accepted: 22 August 2014 Ó Springer-Verlag Italia 2014
Abstract The liver is the most common site of distant metastases in patients with colorectal cancer. Surgery represents the mainstream for curative treatment of colorectal cancer liver metastases (CRCLM) with long-term survival up to 58 and 36 % at 5 and 10 years, respectively. Despite advances on diagnosis, staging and surgical strategies, 60–70 % of patients will develop recurrence of the disease even after R0 resection of CRCLM. Tumor staging, prognosis, and therapeutic approaches for cancer are most often based on the extent of involvement of regional lymph nodes (LNs) and, to a lesser extent, on the invasion of regional lymphatic vessels draining the primary tumor. For CRCLM, the presence of intra hepatic lymphatic and blood vascular dissemination has been associated with an increased risk of intra hepatic recurrence, poorer diseasefree and overall survival after liver resection. Also, several studies have reviewed the role of surgery in the patient with concomitant CRCLM and liver pedicle LN metastasis. Although pedicle LN involvement is related to worst survival rates, it does not differentiate patients that will
R. M. Lupinacci (&) Service de chirurgie Digestive, visce´rale et endocrinienne, Groupe Hospitalier Diaconesses Croix-Saint-Simon, 125, rue d’Avron, 75020 Paris, France e-mail: [email protected] R. M. Lupinacci F. F. Coelho J. A. P. Kruger P. Herman Department of Gastroenterology, University of Sa˜o Paulo Medical School, Sa˜o Paulo, Brazil F. Paye University Pierre et Marie Curie, Paris, France F. Paye Department of Digestive Surgery, Hoˆpital Saint Antoine, Paris, France
relapse from those that will not. This review aims to briefly describe the anatomy of the liver’s lymphatic drainage, the incidence of intrahepatic lymphatic invasion and hilar lymph node involvement, as well as their clinical impact in CRCLM. A better understanding of the role of liver lymphatic metastasis might, in the near future, impact the strategy of systemic therapies after liver resection as for primary colorectal tumors. Keywords Colorectal cancer Lymphatic metastasis Hepatectomy Lymphadenectomy
Introduction In patients with colorectal cancer, the liver is the most common site of distant metastases. Surgery represents the basis for curative treatment of colorectal cancer liver metastases (CRCLM) with long-term survival ranging from 36 to 58 % and from 23 to 36 % at 5 and 10 years, respectively [1–7]. Technical improvements and preoperative chemotherapy have improved resectability rates and allowed an expansion of indications to include patients with large, multiple, or bilobar lesions [8–13] with low postoperative morbidity and mortality rates [10, 11]. Several clinical and pathological predictive factors for survival after hepatic resection have been identified. These factors include features of the primary tumor such as pT or pN stage, preoperative level of carcino-embryonic antigen (CEA), and the interval between the diagnosis of the primary and the metastatic lesions. Characteristics of liver metastases such as number of lesions, size, and location have also been identified as prognostic factors [14–16]. However, despite advances on diagnosis, staging and surgical strategies, 60–70 % of patients will develop
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recurrence of the disease even after R0 resection of CRCLM [17, 18]. Tumor staging, prognosis, and therapeutic approaches for cancer are most often based on the extent of involvement of regional lymph nodes (LNs) and, to a lesser extent, on the invasion of regional lymphatic vessels draining the primary tumor [19–21]. Indeed, oncological surgery of most carcinomas includes therefore a concomitant performance of lymphadenectomy [22]. Recent studies support the hypothesis that blood and lymph vessels invasion are not only two different routes of metastatic cancer cells spread, but also present different biological behavior, with lymphatic metastasis playing the role of major pathway to progression into the systemic circulation and to distant organ sites [19–21]. Hereupon, this review aims to briefly describe the anatomy of the liver’s lymphatic drainage, the incidence of intrahepatic lymphatic invasion and hilar lymph node involvement, as well as their clinical impact in CRCLM.
Anatomical considerations Intrahepatic lymphatic vessels The liver produces a large amount of lymph, representing 25–50 % of all lymph flowing through the thoracic duct [23, 24]. As in other organs, lymphatic vessels in the liver work both as a tissue drainage system and an immunological control system [23]. The hepatic lymphatic vessels can be classified into three categories depending on their location: portal, sublobar, and superficial lymphatic vessels [24]. The hepatic lymph comes primarily from the hepatic sinusoids, filters out of the sinusoids into the perisinusoidal space (Disse’s space), reaching the perilobular space (Mall’s space) and at last entering the interstitial space of the portal tract. Lymph coming from the Disse’s space may also travel through channels between hepatocytes to reach sublobular and superficial lymphatic vessels and then the sublobar veins, hepatic capsule, or into lymphatic vessels running along the inferior vena cava [23, 24]. It is suggested that 80 % or more of hepatic lymph drains into portal lymphatic vessels, while the remainder drains through sublobar and capsular lymphatic vessels [24] reaching the caval venous system, or traveling directly toward the posterior mediastinal chains through the ligaments attaching the liver to the diaphragm. Extrahepatic (hilar) lymphatic drainage Liver metastases originate from dissemination of primary colorectal cells to the liver, grow in the liver, and then re-
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Fig. 1 Lymphatic hepatobiliary drainage runs through three main routes within the gastrohepatic omentum
metastasize to the (LNs) [25]. As mentioned above, much of the lymph produced in the liver drains toward the portal pedicle, the coeliac region and then to nodes located between the aorta and inferior vena cava under the renal vein, before reaching the thoracic duct [23]. According to the classification proposed by Ito and colleagues, the lymphatic hepatobiliary drainage runs through three main routes within the gastrohepatic omentum, all reaching para-aortic LNs [23, 26] (Fig. 1). First, the main and constant hepato-cholecystic-retropancreatic route courses from the right lymphatic group of the gastrohepatic omentum to the posterior surface of the head of the pancreas. It includes the LNs of the porta hepatis, cystic node, node of the omental foramen, superior retroduodenal-pancreatic node, retroportal nodes and the posterior pancreatic-duodenal and celiac retropancreatic LNs. Second, the accessory hepato-cholecystic-celiac route runs to the left of the gastrohepatic omentum reaching the common hepatic artery and celiac trunk. It is composed of the retroligamentous node, supra-and retropyloric LNs, anterior and posterior common hepatic LNs, and celiac LNs. Third, the accessory hepato-cholecystic-mesenteric route courses from the anterior and left aspect of the portal trunk to the origin of the superior mesenteric artery [23].
Intrahepatic lymphatic dissemination In primary colorectal cancer, the presence of lymph-vascular invasion has been shown as an independent adverse prognostic factor for early recurrence, disease-free survival, and overall survival after resection [27, 28]. Also, in
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stage II patients it can be used to determine if adjuvant therapy should be employed [29]. For CRCLM, the presence of intra hepatic lymphatic and blood vascular dissemination of CRCLM has been associated with an increased risk of intra hepatic recurrence, poorer disease-free and overall survival after liver resection [30–34]. Sasaki et al. [30] were the first to investigate the role of intrahepatic lymphatic invasion (IHLI) as a mechanism of metastatic spread of CRCLMs. IHLI was observed in 15.4 % of patients and was independently associated with recurrence and death after hepatectomy. Based on immunohistochemical detection of intrahepatic lymphatic vessels, Korita et al. [32] found IHLI in 12.3 % of patients, independently impairing overall and disease-free survival. We have recently confirmed these results and also demonstrated that the presence of tumoral emboli within other intra hepatic structures (blood vessels, sinusoids or biliary ducts) although frequently observed are not related to recurrence or survival [35]. Experimentally, using a murine cancer model, Hadj et al. [36] have demonstrated a concurrent development of lymphatics within CRCLM and normal liver during tumor growth, suggesting that lymphatic development is likely to play a significant role in the intrahepatic and periportal dissemination of CRCLM.
Extrahepatic lymph node involvement In a recent systematic review, the overall prevalence of positive nodes in patients with CRCLM was 16 % [37]. However, there is a wide variation of reported prevalences of lymph node involvement, from 5.4 to 50 %, probably due to differences in patient selection, adequacy of preoperative staging, exclusion of macroscopic nodal disease, number of examined nodes, number of sections per node, and use of dedicated techniques to identify microscopic involvement [22, 37–48]. Noteworthy, studies with systematic dissection of suspicious and non-suspicious hilar LNs report higher rates of nodal involvement, showing that assessment only based on palpation and macroscopic inspection is inaccurate. Regarding the extent of lymphadenectomy, some surgeons harvest only nodes along the hepatoduodenal ligament whilst others also remove nodes along the common hepatic artery, celiac artery, and retropancreatic area. In the study of Jaeck et al. [49] with an extensive lymphadenectomy, the prevalence of involved nodes along the hepatoduodenal ligament and retropancreatic area was only 5 % and an additional 5.6 % of patients had involvement of the nodes along the common hepatic artery and celiac artery.
Some authors tried to describe the main routes of dissemination in accordance to the location of liver lesions. Kokudo et al. [46] have shown a tendency toward pericholedochal nodal involvement in patients with metastases of the right hemi liver and toward the common hepatic artery for lesions of the left hemi liver. Other authors, however, did not find any relationship between involved nodes and the topography of liver metastases [40, 44, 45, 49]. Noteworthy, Elias et al. [45] found microscopic lymph node involvement in several lymphatic chains studied without a continuous progression from one chain to another (lymph node skipping metastasis). Thus, one may conclude that there is no specific lymph node group able to reflect the true overall nodal status in patients with metastatic hepatic lesions. Pre- and peroperative lymph node staging A very important issue is the accuracy of pre- and peroperative assessment of lymph node involvement. This important topic has been poorly investigated and literature shows contradictory results. Grobmeyer et al. studied 100 patients undergoing resection for primary and metastatic hepatic malignancies associated with pedicle lymph node sampling. Clinical intraoperative assessment by inspection and palpation had a high negative predictive value (NPV) = 99 % but a low positive predictive value (PPV) = 39 %. CT scan had a high NPV = 95 % and a low PPV = 30 %, whereas PET scan had a NPV of 88 % and a PPV of 100 %. When preoperative CT and PET scans were both negatives, only 1 out of 48 patients (2.1 %) had metastatic nodal disease [50]. Rau et al. [51] reported different results in a prospective study of 76 patients who underwent liver resection for CRCLM associated with systematic pedicular lymphadenectomy. NPV and PPV of preoperative CT scan were 85 and 56 %, respectively, whereas intraoperative clinical evaluation had high NPV (91 %) and low PPV (43 %). In their series, 27 % of the patients with histologically proven positive LN could not be identified by peroperative evaluation (CT and intraoperative examination). Indeed, the authors concluded that only systematic lymphadenectomy during liver resection can provide an accurate oncological nodal staging. Most authors agree that pedicular lymphadenectomy, with a minimum of 3–4 harvested LNs could be considered as the best way to reliably state lymph node status [44, 45, 52], but to date there is no consensus regarding the extent of lymphadenectomy. Moszkowickz et al. have recently described the technique of a standardized lymphadenectomy with en-bloc resection of supra- and retropyloric anterior and posterior common hepatic duct, pericholedochal, retroligamentous,
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cystic, retroportal, superior retroduodeno-pancreatic, and retropancreatic LNs [23]. At last, although some authors have shown pedicular lymph node involvement to be related to the number of liver metastases, the degree of liver involvement and to high CEA levels [49, 53–55], several studies failed to determine subgroups with high risk of pedicular lymph node involvement [44, 46, 52, 56]. Though surgeons who are reluctant for systematic lymphadenectomy argue that LN dissection increases operative time and carries potential complications, including postoperative bleeding, postoperative lymphatic leakage with ascites, and ischemic bile duct stricture [45, 49], complications of lymphadenectomy are actually uncommon and usually harmless. A lymphatic leak attributable to lymphadenectomy was noted in only 7 % of patients in the series of Elias et al. [45]. In the study from Ercolani et al. [22] only one patient over 120 exhibited a surgical complication (intra-abdominal bleeding) directly related to lymph node dissection, and in the study of Rau et al. systematic LN dissection only slightly increased the operative time by a mean of 20 ± 12.5 min, without any specific morbidity nor mortality attributed to the lymphadenectomy [51]. Sentinel lymph node evaluation The role of sentinel lymph node detection in liver tumors is poorly studied [57, 58]. Kane JM 3rd et al. [57] examined the technique of intraoperative hepatic lymphatic mapping with isosulfan blue dye in CRCLM. A blue-stained lymphatic was visualized in 11 of 13 injections and a blue lymph node was visualized in 7 of 13 injections (54 %) with no complications associated with the intrahepatic dye injections. All biopsied LNs were negative for metastatic tumor. Noteworthy, authors did not perform a systematic hilar lymphadenectomy but only a picking of suspected nodes. Although there is a potential benefit in identifying patients with nodal involvement prior to undertaking a major hepatic resection, no definite conclusion can be drawn thus far from this study.
Role of liver resection for CRCLM in the presence of hilar metastatic lymph nodes Whether hepatic resection is indicated in patients with metastatic hilar LNs remains questionable. Various studies have reviewed the role of surgery in the patient with concomitant CRCLM and extra-hepatic disease (EHD) including liver pedicle LNs. In the largest series on CRCLM resection in the presence of EHD, Carpizo et al. found that patients with a solitary site of EHD (n = 117)
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had an almost twofold difference in median survival compared with patients with multiple EHD sites. Noteworthy, patients with portal lymph node metastases had a worse survival when compared to patients with lung or ovarian metastases [59]. A recent systematic review found an overall 3- and 5-year survival rates in node-positive patients of 11.3 and 1.5 % compared to 3- and 5-year survival rates of 53.9 and 32.1 % in node-negative patients [37]. Other studies that have examined the impact of lymph node involvement on survival have also found a negative effect [44, 48, 49]. Some authors, however, have reported significant survival rates in liver metastasis and hilar lymph node disease in patients who undergo combined liver resection and lymphadenectomy [40, 46, 60, 61]. In two separate series of patients undergoing simultaneous hepatectomy and resection of EHD, Elias et al. have reported 3- and 5-year survival of 20 and 28 %, respectively [10, 62], reinforcing the statement that the presence of EHD should no longer contraindicate resection. Wakai et al. [63] showed a 29 % 5-year long-term survival rate after hilar lymphadenectomy, exactly the same survival rate found for EHD in the largest series from Carpizo et al. [59]. Recently, Adam et al. [64] reported a 18 % global 5-year survival rate in a selected group of patients with hepatic metastases and compromised hepatic hilar LNs that underwent hepatic resection and lymphadenectomy. Two other studies have found 3-year survival rates between 38 and 45 % in patients with positive liver pedicle LNs that underwent liver resection and lymphadenectomy [49, 65]. In a context where the presence of metastatic hilar lymph node should no longer preclude resection, the location of the compromised LNs seems, however, to be a major issue. Jaeck et al. [49] have shown that resection of positive LNs located in the hepatoduodenal ligament/retropancreatic area may offer long-term survival benefits; on the contrary, when positive LNs are located along the common hepatic artery/celiac axis or para-aortic, long-term survival is significantly worse and liver resection should not be recommended. Isolated micrometastatic involvement The study of micrometastases has been routinely used in several solid cancers [66, 67]. Immunohistochemistry (IHC) is particularly helpful for the detection of micrometastases because it associates a specific immunological reaction with the morphological control of immunoreactive cells. Several studies have confirmed that the association of IHC with serial sections expands the diagnostic sensibility and seems to be the best technique for evaluation of H&E negative nodes [52, 67–71]. In a prospective study on systematic hilar lymphadenectomy for non suspected LNs during hepatectomy for
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CRCLM, Viana et al. used multiple serial sections and IHC staining and detected a further 10.8 % of the patients with micrometastatic involvement of pedicle LNs [52]. The clinical impact of IHC detected LN micrometastases is probably not the same of H&E-only LN metastases, with the former being related to a better overall survival [56]. From a practical perspective, further studies are required to determine whether detecting micrometastases allows better staging and is indicative of prognosis.
Conclusion In CRCLM, the presence of intrahepatic lymphatic dissemination has been reported to be associated with an increased risk of intrahepatic recurrence, and poorer survival after liver resection. Thus, lymphatic invasion seems to be a key prognostic marker of tumor’s aggressiveness and risk of systemic dissemination. The frequency and the prognostic implication of hepatic pedicle LNs invasion as well as indications, extent, and therapeutic role of hilar lymphadenectomy are subjects of ongoing interest. Although pedicle LN involvement is related to worst survival rates, it does not differentiate patients who will relapse from those who will not. Moreover, the therapeutic value of systematic lymphadenectomy is not yet entirely understood, and only prospective randomized studies comparing groups with and without lymphadenectomy could fully solve this question. Thus, before advocating systematic hepatic hilar dissection, more studies are needed to establish the value of node involvement as an independent prognostic variable and the routine search for lymph node involvement should be proposed only within the frame of clinical trials. These still awaited studies might also impact in the future the strategy of adjuvant therapies after resection of CRCLM, the utility of which could vary according to the hepatic pedicle nodal status, as for primary colorectal tumors. Acknowledgments The authors thank Marcos Retzer (graphic designer) who drawned figure 1. Conflict of interest of interest.
The authors declare that they have no conflict
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REVIEW ARTICLE
Lymphatic drainage of the liver and its implications in the management of colorectal cancer liver metastases Renato Micelli Lupinacci • Franc¸ois Paye • Fabricio Ferreira Coelho • Jaime Arthur Pirolla Kruger Paulo Herman
•
Received: 11 July 2014 / Accepted: 22 August 2014 Ó Springer-Verlag Italia 2014
Abstract The liver is the most common site of distant metastases in patients with colorectal cancer. Surgery represents the mainstream for curative treatment of colorectal cancer liver metastases (CRCLM) with long-term survival up to 58 and 36 % at 5 and 10 years, respectively. Despite advances on diagnosis, staging and surgical strategies, 60–70 % of patients will develop recurrence of the disease even after R0 resection of CRCLM. Tumor staging, prognosis, and therapeutic approaches for cancer are most often based on the extent of involvement of regional lymph nodes (LNs) and, to a lesser extent, on the invasion of regional lymphatic vessels draining the primary tumor. For CRCLM, the presence of intra hepatic lymphatic and blood vascular dissemination has been associated with an increased risk of intra hepatic recurrence, poorer diseasefree and overall survival after liver resection. Also, several studies have reviewed the role of surgery in the patient with concomitant CRCLM and liver pedicle LN metastasis. Although pedicle LN involvement is related to worst survival rates, it does not differentiate patients that will
R. M. Lupinacci (&) Service de chirurgie Digestive, visce´rale et endocrinienne, Groupe Hospitalier Diaconesses Croix-Saint-Simon, 125, rue d’Avron, 75020 Paris, France e-mail: [email protected] R. M. Lupinacci F. F. Coelho J. A. P. Kruger P. Herman Department of Gastroenterology, University of Sa˜o Paulo Medical School, Sa˜o Paulo, Brazil F. Paye University Pierre et Marie Curie, Paris, France F. Paye Department of Digestive Surgery, Hoˆpital Saint Antoine, Paris, France
relapse from those that will not. This review aims to briefly describe the anatomy of the liver’s lymphatic drainage, the incidence of intrahepatic lymphatic invasion and hilar lymph node involvement, as well as their clinical impact in CRCLM. A better understanding of the role of liver lymphatic metastasis might, in the near future, impact the strategy of systemic therapies after liver resection as for primary colorectal tumors. Keywords Colorectal cancer Lymphatic metastasis Hepatectomy Lymphadenectomy
Introduction In patients with colorectal cancer, the liver is the most common site of distant metastases. Surgery represents the basis for curative treatment of colorectal cancer liver metastases (CRCLM) with long-term survival ranging from 36 to 58 % and from 23 to 36 % at 5 and 10 years, respectively [1–7]. Technical improvements and preoperative chemotherapy have improved resectability rates and allowed an expansion of indications to include patients with large, multiple, or bilobar lesions [8–13] with low postoperative morbidity and mortality rates [10, 11]. Several clinical and pathological predictive factors for survival after hepatic resection have been identified. These factors include features of the primary tumor such as pT or pN stage, preoperative level of carcino-embryonic antigen (CEA), and the interval between the diagnosis of the primary and the metastatic lesions. Characteristics of liver metastases such as number of lesions, size, and location have also been identified as prognostic factors [14–16]. However, despite advances on diagnosis, staging and surgical strategies, 60–70 % of patients will develop
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recurrence of the disease even after R0 resection of CRCLM [17, 18]. Tumor staging, prognosis, and therapeutic approaches for cancer are most often based on the extent of involvement of regional lymph nodes (LNs) and, to a lesser extent, on the invasion of regional lymphatic vessels draining the primary tumor [19–21]. Indeed, oncological surgery of most carcinomas includes therefore a concomitant performance of lymphadenectomy [22]. Recent studies support the hypothesis that blood and lymph vessels invasion are not only two different routes of metastatic cancer cells spread, but also present different biological behavior, with lymphatic metastasis playing the role of major pathway to progression into the systemic circulation and to distant organ sites [19–21]. Hereupon, this review aims to briefly describe the anatomy of the liver’s lymphatic drainage, the incidence of intrahepatic lymphatic invasion and hilar lymph node involvement, as well as their clinical impact in CRCLM.
Anatomical considerations Intrahepatic lymphatic vessels The liver produces a large amount of lymph, representing 25–50 % of all lymph flowing through the thoracic duct [23, 24]. As in other organs, lymphatic vessels in the liver work both as a tissue drainage system and an immunological control system [23]. The hepatic lymphatic vessels can be classified into three categories depending on their location: portal, sublobar, and superficial lymphatic vessels [24]. The hepatic lymph comes primarily from the hepatic sinusoids, filters out of the sinusoids into the perisinusoidal space (Disse’s space), reaching the perilobular space (Mall’s space) and at last entering the interstitial space of the portal tract. Lymph coming from the Disse’s space may also travel through channels between hepatocytes to reach sublobular and superficial lymphatic vessels and then the sublobar veins, hepatic capsule, or into lymphatic vessels running along the inferior vena cava [23, 24]. It is suggested that 80 % or more of hepatic lymph drains into portal lymphatic vessels, while the remainder drains through sublobar and capsular lymphatic vessels [24] reaching the caval venous system, or traveling directly toward the posterior mediastinal chains through the ligaments attaching the liver to the diaphragm. Extrahepatic (hilar) lymphatic drainage Liver metastases originate from dissemination of primary colorectal cells to the liver, grow in the liver, and then re-
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Fig. 1 Lymphatic hepatobiliary drainage runs through three main routes within the gastrohepatic omentum
metastasize to the (LNs) [25]. As mentioned above, much of the lymph produced in the liver drains toward the portal pedicle, the coeliac region and then to nodes located between the aorta and inferior vena cava under the renal vein, before reaching the thoracic duct [23]. According to the classification proposed by Ito and colleagues, the lymphatic hepatobiliary drainage runs through three main routes within the gastrohepatic omentum, all reaching para-aortic LNs [23, 26] (Fig. 1). First, the main and constant hepato-cholecystic-retropancreatic route courses from the right lymphatic group of the gastrohepatic omentum to the posterior surface of the head of the pancreas. It includes the LNs of the porta hepatis, cystic node, node of the omental foramen, superior retroduodenal-pancreatic node, retroportal nodes and the posterior pancreatic-duodenal and celiac retropancreatic LNs. Second, the accessory hepato-cholecystic-celiac route runs to the left of the gastrohepatic omentum reaching the common hepatic artery and celiac trunk. It is composed of the retroligamentous node, supra-and retropyloric LNs, anterior and posterior common hepatic LNs, and celiac LNs. Third, the accessory hepato-cholecystic-mesenteric route courses from the anterior and left aspect of the portal trunk to the origin of the superior mesenteric artery [23].
Intrahepatic lymphatic dissemination In primary colorectal cancer, the presence of lymph-vascular invasion has been shown as an independent adverse prognostic factor for early recurrence, disease-free survival, and overall survival after resection [27, 28]. Also, in
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stage II patients it can be used to determine if adjuvant therapy should be employed [29]. For CRCLM, the presence of intra hepatic lymphatic and blood vascular dissemination of CRCLM has been associated with an increased risk of intra hepatic recurrence, poorer disease-free and overall survival after liver resection [30–34]. Sasaki et al. [30] were the first to investigate the role of intrahepatic lymphatic invasion (IHLI) as a mechanism of metastatic spread of CRCLMs. IHLI was observed in 15.4 % of patients and was independently associated with recurrence and death after hepatectomy. Based on immunohistochemical detection of intrahepatic lymphatic vessels, Korita et al. [32] found IHLI in 12.3 % of patients, independently impairing overall and disease-free survival. We have recently confirmed these results and also demonstrated that the presence of tumoral emboli within other intra hepatic structures (blood vessels, sinusoids or biliary ducts) although frequently observed are not related to recurrence or survival [35]. Experimentally, using a murine cancer model, Hadj et al. [36] have demonstrated a concurrent development of lymphatics within CRCLM and normal liver during tumor growth, suggesting that lymphatic development is likely to play a significant role in the intrahepatic and periportal dissemination of CRCLM.
Extrahepatic lymph node involvement In a recent systematic review, the overall prevalence of positive nodes in patients with CRCLM was 16 % [37]. However, there is a wide variation of reported prevalences of lymph node involvement, from 5.4 to 50 %, probably due to differences in patient selection, adequacy of preoperative staging, exclusion of macroscopic nodal disease, number of examined nodes, number of sections per node, and use of dedicated techniques to identify microscopic involvement [22, 37–48]. Noteworthy, studies with systematic dissection of suspicious and non-suspicious hilar LNs report higher rates of nodal involvement, showing that assessment only based on palpation and macroscopic inspection is inaccurate. Regarding the extent of lymphadenectomy, some surgeons harvest only nodes along the hepatoduodenal ligament whilst others also remove nodes along the common hepatic artery, celiac artery, and retropancreatic area. In the study of Jaeck et al. [49] with an extensive lymphadenectomy, the prevalence of involved nodes along the hepatoduodenal ligament and retropancreatic area was only 5 % and an additional 5.6 % of patients had involvement of the nodes along the common hepatic artery and celiac artery.
Some authors tried to describe the main routes of dissemination in accordance to the location of liver lesions. Kokudo et al. [46] have shown a tendency toward pericholedochal nodal involvement in patients with metastases of the right hemi liver and toward the common hepatic artery for lesions of the left hemi liver. Other authors, however, did not find any relationship between involved nodes and the topography of liver metastases [40, 44, 45, 49]. Noteworthy, Elias et al. [45] found microscopic lymph node involvement in several lymphatic chains studied without a continuous progression from one chain to another (lymph node skipping metastasis). Thus, one may conclude that there is no specific lymph node group able to reflect the true overall nodal status in patients with metastatic hepatic lesions. Pre- and peroperative lymph node staging A very important issue is the accuracy of pre- and peroperative assessment of lymph node involvement. This important topic has been poorly investigated and literature shows contradictory results. Grobmeyer et al. studied 100 patients undergoing resection for primary and metastatic hepatic malignancies associated with pedicle lymph node sampling. Clinical intraoperative assessment by inspection and palpation had a high negative predictive value (NPV) = 99 % but a low positive predictive value (PPV) = 39 %. CT scan had a high NPV = 95 % and a low PPV = 30 %, whereas PET scan had a NPV of 88 % and a PPV of 100 %. When preoperative CT and PET scans were both negatives, only 1 out of 48 patients (2.1 %) had metastatic nodal disease [50]. Rau et al. [51] reported different results in a prospective study of 76 patients who underwent liver resection for CRCLM associated with systematic pedicular lymphadenectomy. NPV and PPV of preoperative CT scan were 85 and 56 %, respectively, whereas intraoperative clinical evaluation had high NPV (91 %) and low PPV (43 %). In their series, 27 % of the patients with histologically proven positive LN could not be identified by peroperative evaluation (CT and intraoperative examination). Indeed, the authors concluded that only systematic lymphadenectomy during liver resection can provide an accurate oncological nodal staging. Most authors agree that pedicular lymphadenectomy, with a minimum of 3–4 harvested LNs could be considered as the best way to reliably state lymph node status [44, 45, 52], but to date there is no consensus regarding the extent of lymphadenectomy. Moszkowickz et al. have recently described the technique of a standardized lymphadenectomy with en-bloc resection of supra- and retropyloric anterior and posterior common hepatic duct, pericholedochal, retroligamentous,
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cystic, retroportal, superior retroduodeno-pancreatic, and retropancreatic LNs [23]. At last, although some authors have shown pedicular lymph node involvement to be related to the number of liver metastases, the degree of liver involvement and to high CEA levels [49, 53–55], several studies failed to determine subgroups with high risk of pedicular lymph node involvement [44, 46, 52, 56]. Though surgeons who are reluctant for systematic lymphadenectomy argue that LN dissection increases operative time and carries potential complications, including postoperative bleeding, postoperative lymphatic leakage with ascites, and ischemic bile duct stricture [45, 49], complications of lymphadenectomy are actually uncommon and usually harmless. A lymphatic leak attributable to lymphadenectomy was noted in only 7 % of patients in the series of Elias et al. [45]. In the study from Ercolani et al. [22] only one patient over 120 exhibited a surgical complication (intra-abdominal bleeding) directly related to lymph node dissection, and in the study of Rau et al. systematic LN dissection only slightly increased the operative time by a mean of 20 ± 12.5 min, without any specific morbidity nor mortality attributed to the lymphadenectomy [51]. Sentinel lymph node evaluation The role of sentinel lymph node detection in liver tumors is poorly studied [57, 58]. Kane JM 3rd et al. [57] examined the technique of intraoperative hepatic lymphatic mapping with isosulfan blue dye in CRCLM. A blue-stained lymphatic was visualized in 11 of 13 injections and a blue lymph node was visualized in 7 of 13 injections (54 %) with no complications associated with the intrahepatic dye injections. All biopsied LNs were negative for metastatic tumor. Noteworthy, authors did not perform a systematic hilar lymphadenectomy but only a picking of suspected nodes. Although there is a potential benefit in identifying patients with nodal involvement prior to undertaking a major hepatic resection, no definite conclusion can be drawn thus far from this study.
Role of liver resection for CRCLM in the presence of hilar metastatic lymph nodes Whether hepatic resection is indicated in patients with metastatic hilar LNs remains questionable. Various studies have reviewed the role of surgery in the patient with concomitant CRCLM and extra-hepatic disease (EHD) including liver pedicle LNs. In the largest series on CRCLM resection in the presence of EHD, Carpizo et al. found that patients with a solitary site of EHD (n = 117)
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had an almost twofold difference in median survival compared with patients with multiple EHD sites. Noteworthy, patients with portal lymph node metastases had a worse survival when compared to patients with lung or ovarian metastases [59]. A recent systematic review found an overall 3- and 5-year survival rates in node-positive patients of 11.3 and 1.5 % compared to 3- and 5-year survival rates of 53.9 and 32.1 % in node-negative patients [37]. Other studies that have examined the impact of lymph node involvement on survival have also found a negative effect [44, 48, 49]. Some authors, however, have reported significant survival rates in liver metastasis and hilar lymph node disease in patients who undergo combined liver resection and lymphadenectomy [40, 46, 60, 61]. In two separate series of patients undergoing simultaneous hepatectomy and resection of EHD, Elias et al. have reported 3- and 5-year survival of 20 and 28 %, respectively [10, 62], reinforcing the statement that the presence of EHD should no longer contraindicate resection. Wakai et al. [63] showed a 29 % 5-year long-term survival rate after hilar lymphadenectomy, exactly the same survival rate found for EHD in the largest series from Carpizo et al. [59]. Recently, Adam et al. [64] reported a 18 % global 5-year survival rate in a selected group of patients with hepatic metastases and compromised hepatic hilar LNs that underwent hepatic resection and lymphadenectomy. Two other studies have found 3-year survival rates between 38 and 45 % in patients with positive liver pedicle LNs that underwent liver resection and lymphadenectomy [49, 65]. In a context where the presence of metastatic hilar lymph node should no longer preclude resection, the location of the compromised LNs seems, however, to be a major issue. Jaeck et al. [49] have shown that resection of positive LNs located in the hepatoduodenal ligament/retropancreatic area may offer long-term survival benefits; on the contrary, when positive LNs are located along the common hepatic artery/celiac axis or para-aortic, long-term survival is significantly worse and liver resection should not be recommended. Isolated micrometastatic involvement The study of micrometastases has been routinely used in several solid cancers [66, 67]. Immunohistochemistry (IHC) is particularly helpful for the detection of micrometastases because it associates a specific immunological reaction with the morphological control of immunoreactive cells. Several studies have confirmed that the association of IHC with serial sections expands the diagnostic sensibility and seems to be the best technique for evaluation of H&E negative nodes [52, 67–71]. In a prospective study on systematic hilar lymphadenectomy for non suspected LNs during hepatectomy for
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CRCLM, Viana et al. used multiple serial sections and IHC staining and detected a further 10.8 % of the patients with micrometastatic involvement of pedicle LNs [52]. The clinical impact of IHC detected LN micrometastases is probably not the same of H&E-only LN metastases, with the former being related to a better overall survival [56]. From a practical perspective, further studies are required to determine whether detecting micrometastases allows better staging and is indicative of prognosis.
Conclusion In CRCLM, the presence of intrahepatic lymphatic dissemination has been reported to be associated with an increased risk of intrahepatic recurrence, and poorer survival after liver resection. Thus, lymphatic invasion seems to be a key prognostic marker of tumor’s aggressiveness and risk of systemic dissemination. The frequency and the prognostic implication of hepatic pedicle LNs invasion as well as indications, extent, and therapeutic role of hilar lymphadenectomy are subjects of ongoing interest. Although pedicle LN involvement is related to worst survival rates, it does not differentiate patients who will relapse from those who will not. Moreover, the therapeutic value of systematic lymphadenectomy is not yet entirely understood, and only prospective randomized studies comparing groups with and without lymphadenectomy could fully solve this question. Thus, before advocating systematic hepatic hilar dissection, more studies are needed to establish the value of node involvement as an independent prognostic variable and the routine search for lymph node involvement should be proposed only within the frame of clinical trials. These still awaited studies might also impact in the future the strategy of adjuvant therapies after resection of CRCLM, the utility of which could vary according to the hepatic pedicle nodal status, as for primary colorectal tumors. Acknowledgments The authors thank Marcos Retzer (graphic designer) who drawned figure 1. Conflict of interest of interest.
The authors declare that they have no conflict
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