Abstract Hepatic hemangiomas are the most common benign tumor of the liver and the second most common tumor following metastases. The diagnosis and management of hepatic hemangiomas has improved signifi cantly for the past decade. The decision to treat this tumors surgically should be based mostly on symptomatology, inability to exclude malignancy, documented growth and less on feasibility for resection or patient anxiety. The decision for observation should be based on a thorough examination of asymptomatic tumors with benign characteristics on imaging. The surgical treatment of choice has evolved from formal hepatectomies to selected enucleation with improvement in outcomes regardless of the size of the lesion. Minimal invasive techniques have similar results as open surgery in appropriately selected patients with no difference in morbidity and mortality. Keywords Hepatic hemangioma • Liver tumors • Enucleation Introduction Hepatic hemangiomas are the most frequent benign tumors of the liver with a frequency of 0.4–7.3 % in adults with a higher incidence in woman [ 1 – 3 ]. The accurate diagnosis of hemangiomas is a key component given the current high frequency of incidental fi ndings on CT scans that lead to further workup to differentiate malignant neoplasms from benign tumors. The most sensitive studies are MRI (100 %), CT scan (98.3) and US (96.9 %) [ 4 ]. The most common indications for the treatment of hemangiomas are abdominal pain , diagnostic uncertainty, enlargement, occupations and hobbies that may entail abdominal trauma and the extremely rare Kasabach-Merrit syndrome. The defi nition of “ giant hemangioma s” in the majority of the studies is a tumor with more than 4 cm in diameter [ 5 , 6 ]. J. M. Millis (*) • D. C. Molina Department of Surgery , University of Chicago Hospitals , MC 5027 , Chicago , IL 60637 , USA e-mail: [email protected] 26 There are four classic surgical methods of treatment for hepatic hemangiomas: liver resection , enucleation , hepatic artery ligation and liver transplant ation [ 7 ]. Enucleation refers to the creation of a plane between the normal liver parenchyma and the hemangioma without (or minimal) removal of normal hepatic parenchyma and it’s though to decrease blood loss, bile leak and preservation of parenchyma [ 8 ]. Newer adjuvants in the surgical treatment had emerged in the past decade including laparoscopic ultrasonic resection and supraselective arterial embolization , those techniques are used to increase safety of surgery [ 9 , 10 ]. Other non surgical treatments like radiotherapy , chemotherapy and transarterial embolization (TAE) had been proposed as successful alternatives when surgical resection is not indicated or feasible [ 11 – 13 ]. The resection can be achieved via an open or laparoscopic technique and new technology like RFA has been used as part of the surgical minimal invasive category. Search Strategy An online literature search on English Language of publications from 2000 to 2014 was used to identify and select published data on the surgical management of hepatic hemangiomas using the PICO outline (Table 3.1 ). The Databases used for the search were PubMed, Cochrane Evidence Based Medicine , MEDLINE-MEDLINE plus/OVID, Science Citation Index Expanded (SCI-EXPANDED). The terms used for the search were: “liver/hepatic hemangioma treatment” “surgical treatment of liver/hepatic hemangioma” “ management of liver/hepatic hemangioma” “ resection of/for hepatic hemangioma”, “treatment of liver/hepatic hemangioma”. The search was expanded to use articles that included or addressed hepatic hemangiomas as part of benign tumors of the liver since hemangiomas tend to be clustered in that group as well, those terms include: “benign liver tumor s” “treatment of benign liver tumors” and “management of benign liver tumors”. The studies showed were: Randomized controlled trials: 0, Retrospective cohort: 26. Table 3.1 PICO table for surgical management of hepatic hemangiomas P (Patients) I (Intervention) C (Comparator group) Outcomes (Outcomes measured Patients with diagnosed liver hemangioma (symptomatic or asymptomatic) Surgical intervention (Open, Laparoscopic, mixed interventions with adjuvant treatment) No surgical intervention ( observation) vs Surgical intervention ( enucleation vs hepatectomy, open vs Laparoscopic) Perioperative complications J.M. Millis and D.C. Molina 27 Results Observation vs Surgical Treatment with Hepatectomy The decision to treat hepatic hemangiomas surgically can be challenging when the indications are not well established and up to date guidelines are not encountered in the literature. Resection is indicated for symptoms and questionable diagnosis and the most widely methods studied are resection and enucleation [ 14 – 16 ]. A study from the University of Cincinnati from 2003 proposed an algorithm where the initial step is a triple phase CT , if there was any uncertainty of the diagnosis of hemangioma a tagged RBC/MRI scan was obtained, if the lesion was asymptomatic observation would be granted and surgery was indicated in symptomatic patients or increase in size along with large size hemangiomas. Ninety two percent of the entire series was properly diagnosed with this algorithm. Hemangiomas were 29 % of the cohort [ 17 ]. In 2001 Terkivatan et al. study aimed to prove that surgical treatment may not be justifi ed during long term follow up of patient with benign tumors of the liver. This study involved other benign liver tumor s and a total of 208 patients were analyzed of which 49.5 % (103) were hemagiomas and 24.2 % (25) of those patients underwent surgical resection . The main indication for resection in this subset of patients was abdominal pain (60 %) followed by suspected metastases. Non-anatomic resection (40 %) and segmental resections (28 %) were the most common procedures utilized. In terms of postoperative morbidity 24 % (6) had a reportable complication. The mean follow up for this group was 39 months. Of the conservative arm (non operative) a mean follow up of 45 months showed no mortality or coagulation, although there’s no mention on growth or increased pain in the follow up [ 18 ]. In a retrospective cohort at the University of Miami including benign and solid tumors of the liver seen over 14 years a total of 130 cases where treated, 55 % were hemangiomas (71 patients). Surgical excision was performed in 49 %. The morbidity was 5 %. No rupture or progression of symptoms was observed in the asymptomatic group, although the follow up details are not specifi ed in the study they concluded that resection in asymptomatic patients is not justifi ed no matter the size [ 3 ]. In 2003 Yoon et al . at MSKCC published a large series where only hemangiomas where included. A total of 115 patients in the 8 year cohort were analyzed, 45.3 % (52 patients) presented with symptoms (abdominal pain ) and underwent surgical resection , whereas 54.7 % (63) where observed. Inability to exclude malignancy was the indication in 29 %. The median size of the resected group was 11 cm vs 4 cm unresected group, and of those more than half (58 %) had tumors larger than 10 cm. Enucleation was the treatment of choice in 60 %. Their complication rate was 25 %. In the observation arm only four patients had persistent symptoms without major complications [ 5 ]. In 2005 a paper from a group at the University of São Paolo presented a retrospective series of 249 patients over 14 years. In this series 31.7 % patient were 3 What Is the Best Surgical Method of Addressing Hepatic Hemangiomas? 28 symptomatic. The paper made emphasis in conservative treatment, only 3.2 % (n = 8) were treated with surgery , the main indication was pain . Giant hemangiomas (>4 cm) were present in 27.4 % of the cohort. The mean follow up was 78 months without any complications in the observation arm [ 19 ]. In the Amsterdam experience a cohort of 34 patients were identifi ed and surgical resection was undertaken in 14 (41 %) after a mean follow up of 36.5 months due to progressive abdominal pain and suspected malignancy. Fifty eight percent of a group of tumors >5 cm underwent surgical treatment whereas in the group of smaller hemangiomas (<5 cm) only 20 %. The observation arm did not show any complications with a mean follow-up of 19.6 month [ 20 ]. A retrospective cohort from the Mayo Clinic in 2010 evaluated the rate of hemangioma- associated complications in patients with giant hemangioma s after clinical observation and after operative management to identify the optimal treatment algorithm. This series was based in a survey examination. A total of 233 patient (80.6 %) fell in the nonoperative group and 56 (19.4 %). Only 11 % of the nonoperative group had symptoms whereas 52 % on the operative group had abdominal pain . Nine percent of patient in the observation group developed symptoms or complications after diagnosis . Of the operative arm 34 patients had partial hepatectomy (60.7 %), 22 patients underwent enucleation (1 laparoscopic ). The survey revealed that 93 % of patients undergoing surgery had good or better health status and there was no statistical signifi cant difference in the overall rate of adverse events between the two groups. The long term risk of adverse events associated with non operative management is similar to the short term risk of operative intervention. Based on this study, prophylactic intervention independent of the size without any clinical indication is not recommended due to the potential life-threatening event (2 % nonoperative vs 7 % operative) [ 6 ]. Yedibela et al. in 2013 published a large series of patients undergoing observation or surgical treatment of hemangiomas larger than >4 cm. A total of 103 patients underwent surgical resection mainly for abdominal pain (60 %). The indication for surgery in 51 % of asymptomatic patients was anxiety. There was resolution of symptoms in 88 % of patients. There was no statistical difference in the overall rate of adverse events between the surgical and observation group [ 21 ]. Enucleation vs Hepatectomy In the year 2000 Özden published a study including 172 patients of which 42 underwent a surgical procedure for the treatment of hepatic hemangioma. Patients were evaluated to assess the effect of surgery ( enucleation using Pringle maneuver). Abdominal pain was the major indication for elective surgery, 78.5 % underwent enucleation followed by formal hepatectomy Early morbidity occurred in 12 % (5 patients) bleeding being the most common. A total of 33 patients (78 %) were followed for a median interval of 53 months, of those patients 96 % (32) were symptomatic prior the intervention. Complete resolution of pain was achieved in J.M. Millis and D.C. Molina 29 88 % (24) of patients and US revealed no recurrences. The evaluation method was not well standardized and enucleation was favored as a safer technique by the authors [ 22 ]. At the University of Chicago a cohort of benign tumors of the liver included 28 patients with benign tumors 35.7 % being hemangiomas (10 patients) the most common presenting symptom was pain and enucleation was performed in 64 % of patients. The complication rate was 10.7 % for the total cohort with no mention on hemangioma related complications [ 23 ]. A series from 2001 illustrated the changing indications for resection when patients are analyzed in a large cohort when indications changed (sixe, symptoms etc). This series included 57 patients undergoing resection for abdominal pain or size >4 cm, (criteria until 1996, cohort 1995–1999 after that only hemangiomas larger than 10 cm and pain were indications for surgery ). Sixty six percent their cases were enucleation as it was favored over the course of the cohort. Their complication rate was 10.4 % without any mortality . A recurrence occurred in 5.2 % of their patients (3 patients) [ 24 ]. Another series of 2001 demonstrated the relationship between tumor size and presence of symptoms, this series included 155 patient with benign liver tumor s, of which 63 % (97 patients) had been diagnosed with hemangiomas, 40 % of those patients underwent resection with the main indication being persistent symptoms (23 %). The majority (53 %) underwent enucleation , followed by segmentectomy (20 %). The median follow-up was 16 months and the series complication rate was 21 % [ 25 ]. A case series for giant cavernous hemangioma s including 52 patients was published to compare the outcomes on patients undergoing enucleation vs lobectomy. The series showed a higher complication rate with lobectomy (44 % vs 11 %), right lobe lesions more often treated with enucleation. Pringle fl ow occlusion was used far more frequently for enucleations (78 % vs 16 %). There was no statistical difference in operative times and transfusions, although there was a trend towards improvement with enucleation [ 26 ]. The second study to compare enucleation versus hepatic resection was published in 2005. A cohort of 22 symptomatic patients underwent enucleation (n = 10) or formal liver resection (n = 12). The operative time was longer in the resection group and blood loss along with need for transfusion was also greater in the resection group with no effect in length of stay. The complication rate was 14.2 %. In this study tumor localization and number of hemangiomas were the factors for the selection of surgery , being multiple and deep/central masses likely o have a formal resection [ 27 ]. A small cohort of 21 patients published in the 2007 showed that patients undergoing enucleation had less operative time (170 vs 230 min), blood loss (400 vs 1329 cc) and no morbidity with decreased length of hospital stay (5.6 vs 9.9 days) compared to liver resection . In this series the major indication were symptoms followed by uncertain diagnosis [ 28 ]. The approach for the surgical treatment with enucleation was addressed by the largest study available by Xiao-Hui regarding centrally of peripherally lesions and 3 What Is the Best Surgical Method of Addressing Hepatic Hemangiomas? 30 their respective outcomes , with the assumption that centrally located lesions (defi ned Couinaud’s segments I, IV, V and VII) are more challenging to resect. A total of 172 patients underwent enucleation with Pringle maneuver for pain , lesions larger than 10 cm or enlarging tumors. A total of 76 (44.2 %) were centrally located and 96 (55.8 %) were peripherally located. Enucleation of centrally located hemangiomas required signifi cantly longer vascular infl ow occlusion time (45.3 vs 32.6 min)longer operating time (124.5 vs 89 min), higher volume of blood loss (800 vs 500 cc), greater blood transfusion (51 vs 42 pts, at least one unit of blood) and longer hospital stay (10.2 vs 9.1). The morbidity was 2.9 % for the entire series with no difference in the two groups, no mortality was registered. The median follow-up was 27 months and complete resolution of pain was achieved in 39.8 % and amelioration in 49.4 %. This study is the only one to compare a crucial factor when deciding on resection of hemangiomas, the location of the hemangioma. As seen on previous papers, peripherally located lesions are more amenable for laparoscopic resection [ 8 ]. In 2011 a cohort of 74 patients was analyzed and were divided in two groups, for their management , operative (54.1 %) and nonoperative (45.9 %) with a median follow-up of 77.3 months. Abdominal pain was present in 37.8 % of the total cohort and in 62 % of the patients undergoing resection compared to 8.8 % in the nonoperative group. The mean size of the lesions was larger in the operative group (11.9 vs 6 cm). A total of 28 formal liver resection s were made and 12 enucleations. This cohort includes a change after year 2000 when 50 % were resected by enucleations, size not being any different for enucleation vs formal resection. The decision was based on the location and the relationship with major vascular and biliary structures. The resection group had more pedicle clamping time than the enucleation subset, the rest of the intraoperative parameter did not show any statistical difference [ 29 ]. Minimal Invasive Approach Minimal invasive techniques include laparoscopic and robotic resection with adjuvant technical instruments that facilitate the procedure [ 30 ]. One of the fi rst laparoscopic liver resection series of benign tumors was published in 2003 to asses the feasibility, safety and outcomes in a multicenter setting in 18 centers in Europe. In this series of 87 patients only 13 patients (15 %) corresponded to hemangiomas. The main indication for resection was pain an undetermined nature of atypical features. In the overall series 95 % of the tumors were located in the left lobe or anterior segments. For the hemangiomas almost 60 % of the lesions where localized in segments II and II with a median size of 6 cm with a 10 % conversion to open procedures (bleeding being the major cause, 45 %). The main procedures were wedge resection followed by segmentectomy and major hepatectomy in three patients. Only one conversion was documented for a 13 cm hemangioma [ 31 ]. J.M. Millis and D.C. Molina 31 The fi rst paper to describe a series a laparoscopic radiofrequency ablation of hepatic hemangiomas consisted of 27 patients with symptomatic and rapid-growth lesions. A total of 50 liver lesions were treated successfully. There was a median follow up of 21 months without any complications. An intraoperative laparoscopic ultrasound was used prior and at completion of the ablation. An abdominal US and CT were performed 7 days and a moth after RFA . Follow up CT scans were obtained 3–6 months achieving 100 % necrosis and relieve of symptoms in about 85 % of patients [ 32 ]. The use of other technology as adjuvant in surgical treatment has been addressed in paper utilizing ultrasonically activated device in 12 patients (8 formal resections, 4 enucleations) was published with no mortality or morbidity [ 33 ]. A most recent study from Ho et al. addressed factors determining surgical outcomes . The series includes 61 patients undergoing resection for giant hemangioma s (>4 cm), postoperative complications were associated with larger tumors, symptomatic presentation, increased blood loss and operative time and greater use of intraoperative infl ow control. A Pringle maneuver was used in 50.8 %. The patients who had complications the majority had central tumors and required lobectomy. The complication rate was 4 % for enucleation and 19.4 % for resection [ 34 ]. A study by Yang et al. aimed to compare an important technical aspect of the surgical resection of hemangiomas, selective hepatic vascular exclusion (SHVE). A total of 273 patients had a hemangioma at least compressing one of the major hepatic veins from. Either SHVE (n = 120) or Pringle maneuver (n = 153) was used. No protocol was used for the selection. There was a signifi cant difference favoring SHVE in the following intraoperative data: Blood loss (600 vs 1,000), blood transfusion units (2 vs 4). Major blood loss of 2000 L only happened in the Pringle group and 85 % in this group did not undergo a blood transfusion compared to 76 % in the Pringle group, also there was no air embolism and no conversion to total hepatic vascular exclusion (7.2 % in the Pringle group). The operative time was longer in the SHVE group (139.8 vs 124.2) The overall complication rate was higher in the Pringle group (30.7 % vs 20.8 %) [ 35 ]. More recently Miura et al. described a retrospective review from six major liver centers in the US. A total of 241 patients underwent open surgery (mainly hepatectomy or segmentectomy) but 17 % had a laparoscopic approach, showing the tendency to adopt this technique. A total of 63.2 % of the patient undergoing surgery for symptoms had improvement. Complication rate was 14 % with improvement of symptoms in 63.2 % [ 36 ]. A summary of the major published reports describing the various surgical options for hepatic hemangiomas is provided in Table 3.2 . 3 What Is the Best Surgical Method of Addressing Hepatic Hemangiomas? 32 Table 3.2 Hepatic hemangioma treatment Author (year) N Age Size (cm) Operation Complication rate Other Study type (QOE a ) Özden et al. (2000) [ 22 ] 42 50 10 Enucleation 12 % Retrospective cohort-low Terkivatan et al. (2001) [ 18 ] Total cohort: 208 48 9.0 Segmentectomy, Lobectomy, wedge resection 24 % Includes other benign liver tumors Retrospective cohort-low 103: Hemangiomas (25 operative, 78 observation) Kammula et al. (2001) [ 23 ] Total: 28 35 7 Enucleation 10.7 % Includes other benign liver tumors Retrospective cohort-low Hemangiomas: 10 Reddy et al. (2001) [ 3 ] Total: 130 49 6.9 Segmentectomy, Lobectomy trisegmentectomy 5 % Includes other benign liver tumors Retrospective cohort-low Hemangiomas: 71 (35 operative, 36 observation) 1.2 % mortality (pt with FNH) One unresectable hemangioma Charny et al. (2001) [ 25 ] Total: 155 52 12.1 Enucleation. Segmentectomy, lobectomy 21 % (whole series) Includes other benign liver tumors Retrospective cohort-low Hemangioma :97 (39 operative) Popescu et al. (2001) [ 24 ] 57 44.2 9 Enucleation, segmentectomy and hepatectomy 10.3 Retrospective cohort-low Yoon et al. (2003) [ 5 ] 115 (52 operative, 63 observation) 52 6 Enucleation, Segmentectomy 25 % 96 % symptom resolution Retrospective cohort-low Median ebl 400 cc Descottes et al. (2003) [ 31 ] Total: 87 41 6 Laparoscopic resection 5 % (whole series) Includes other benign liver tumors . One conversion to open Retrospective cohort-low Hemangiomas: 13 Tsai et al. (2003) [ 14 ] 43 Symptomatic vs suspicious diagnosis Retrospective cohort. Low J.M. Millis and D.C. Molina 33 Author (year) N Age Size (cm) Operation Complication rate Other Study type (QOE a ) Liu et al. (2004) [ 37 ] Total : 107 43 2.8 (whole series) Lobectomy,Segmentectomy, wedge 16 % Includes benign and malignant pathology Retrospective cohort-low Hemangiomas: 12 Kim et al. (2004) [ 17 ] Total: 71 41 NA Lobectomy, wedge segementectomy 27 % (whole series) Retrospective cohort-low Hemangioma: 21 Lerner et al. (2004) [ 31 ] 52 (27 lobectomy, 25 enucleation) 48 10.9 Enucleation vs Lobectomy 27 % Only giant hemangiomas , compared resection vs enucleation Case series Hamaloglu et al. (2005) [ 27 ] 22 46 9 Hepatectomy vs enucleation 14.2 Only giant hemangiomas compared enucleation vs resection Herman et al. (2005) [ 19 ] 249 (only 8 underwent surgery) 49 3.7 Lobectomy, segmentectomy None Surgical treatment granted to lesions >14 cm Retrospective cohort-low Fan (2005) 27 41 5.5 Laparoscopic RFA (50 lesions treated) None Complete necrosis achieved in 100 % Retrospective cohort-low Ibrahim et al. (2007) [ 38 ] Total: 84 43.6 8.2 Lobectomy, segmentectomy, wedge 8.3 (whole series) Included patients with Hep-B Retrospective cohort-low Hemangiomas: 46 Erdogan et al. et al. (2007) [ 20 ] 34 (14 operative) 48.5 12.9 Bisegmentectomy, lobectomy, segmentectomy 21 % Retrospective cohort-low Singh et al. (2007) [ 28 ] 21 42.5 9.5 Enucleation vs Hepatectomy 23 % (all in the resected group Belli et al. (2009) [ 33 ] 180 (12 surgical treatment NA NA Enucleation Enucleation using ultrasonically activated device in 4 cases Retrospective cohort-low (continued) 3 What Is the Best Surgical Method of Addressing Hepatic Hemangiomas? 34Table 3.2 (continued) Author (year) N Age Size (cm) Operation Complication rate Other Study type (QOE a ) Fu Xiao-Hui et al. (2009) [ 8 ] 172 (96 peripheral, 76 central) 46/42 10/11 Enucleation 2.6 Centrally vs peripherally, impact of location Retrospective cohort-low Schnelldorfer et al. (2010) [ 6 ] 289 (233 nonoperative, 56-operative) 51 8.4 Partial hepatectomy/ enucleation/ RFA 7.1 % Retrospective cohort-low Giuliante et al. (2011) [ 29 ] 74 (34 nonoperative, 40 op 46.3 6/ 11.9 Partial hepatectomy/ enucleation 10 % Retrospective cohort-low Ho et al (2012) [ 34 ] 61 47.3 10 Enucleation/lobectomy 13.1 % Only giant hemangiomas Retrospective cohort-low Yedibela et al. (2013) [ 21 ] 246 (103 operative, 143 non operative) 52 9.1 hepatectomy, segmentectomy 17 % Yang Y et al. (2014) [ 35 ] 273 45/41 14.2/12.9 Lobectomy/Segmentectomy 26 %, 1.3 % mortality Compares selective vascular exclusion vs Pringle maneuver Retrospective cohort-low Miura et al. (2014) [ 36 ] 241 46 8.5 Enucleation/ hepatectomy/ seg mentectomy- 5.7 %, 0.8 % mortality Retrospective cohort-low a Quality of evidence J.M. Millis and D.C. Molina 35 Recommendations • The indication for the resection of hepatic hemangiomas has to be based on symptoms, suspicion of malignancy or growth, although no size increment or specifi c time interval is known (Evidence quality Moderate, strong recommendation) • When feasible, enucleation is the method of choice to allow preservation of parenchyma, decreased blood loss and need for outfl ow control (Evidence quality Moderate, strong recommendation) • Laparoscopic resection of hemangiomas is a safe procedure when patients are appropriately selected and the procedure is performed by an experienced surgeon. (Evidence quality low: weak recommendation) • Alternative procedures like Radiation, Chemotherapy and TAE should be used as second line agents or for palliation purposes (Evidence quality low: weak recommendation) References 1. Iwatzuki S, Starzl TE. Personal experience with 411 hepatic resections. Ann Surg. 1988;208:421–34. 2. Mortele KJ, Ros PR. Benign liver neoplasms. 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Best Surgical Method of Addressing Hepatic Hemangiomas?
