Ann Surg Oncol DOI 10.1245/s10434-015-4533-0
ORIGINAL ARTICLE – HEPATOBILIARY TUMORS
Nodular Regenerative Hyperplasia in Patients Undergoing Liver Resection for Colorectal Metastases After Chemotherapy: Risk Factors, Preoperative Assessment and Clinical Impact Luca Vigano`, MD1,2, Laura Rubbia-Brandt, MD3,6, Giovanni De Rosa, MD4, Pietro Majno, MD5,6, Serena Langella, MD2, Christian Toso, MD, PhD5,6, Gilles Mentha, MD5,6, and Lorenzo Capussotti, MD2 1
Department of Hepatobiliary and General Surgery, Humanitas Research Hospital, Humanitas University, Rozzano, MI, Italy; 2Department of HPB and Digestive Surgery, Ospedale Mauriziano Umberto I, Turin, Italy; 3Department of Clinical Pathology, University Hospitals, Geneva, Switzerland; 4Department of Pathology, Ospedale Mauriziano Umberto I, Turin, Italy; 5Department of Visceral and Transplantation Surgery, University Hospitals, Geneva, Switzerland; 6HepatoPancreato-Biliary Centre, University Hospitals, Geneva, Switzerland
ABSTRACT Background. Nodular regenerative hyperplasia (NRH) is a severe form of chemotherapy-related liver injury (CALI) that may worsen the short-term outcome of liver resection (LR) for colorectal metastases (CRLM). The present study aimed to clarify the incidence, risk factors, preoperative assessment, and clinical impact of NRH. Methods. Overall, 406 patients undergoing 478 LRs for CRLM after chemotherapy between 2000 and 2012 were studied. All resection specimens were reviewed. After Gomori staining, NRH was graded according to the Wanless score. Results. NRH was diagnosed in 87 (18.2 %) patients, grades 2–3 in 14 (2.9 %) patients. At multivariate analysis, the prevalence of NRH was increased after oxaliplatin administration (21.4 vs. 8.4 %; p = 0.003), and reduced by the addition of bevacizumab (11.7 vs. 19.8 %; p = 0.020). Two parameters predicted the presence of NRH: the APRI score (AST to platelet ratio index: 25.5 % if [0.36 vs. 9.8 % if B0.36; p = 0.004), and the platelet count (63.6 % if \100 9 103/mm3 vs. 25.3 % if 100–200 9 103/mm3 vs. 11.9 % if [200 9 103/mm3; p = 0.032). Ninety-day mortality and liver failure rates were 0.6 and 3.6 %. NRH was an independent predictor of postoperative liver failure (9.2 % if present vs. 2.3 % if not present; p = 0.021). In
Ó Society of Surgical Oncology 2015 First Received: 10 October 2014 L. Vigano`, MD e-mail: [email protected]
patients with grades 2–3 NRH, the rate of liver failure was 14.3 %, 25.0 % after major hepatectomy. No other forms of CALI impacted short-term outcomes. Conclusions. NRH was the most relevant form of CALI, increasing the risk of postoperative liver failure. Oxaliplatin increased the incidence of NRH, while bevacizumab decreased it. The APRI score and platelet count were useful tools for predicting NRH.
During the last decades, liver surgery has become safer, with mortality rates below 1 % in patients operated of liver resection (LR) for colorectal metastases (CRLM).1–6 However, in these patients, new risk factors have been identified, particularly chemotherapy-related liver injuries (CALI). Three main forms of CALI have been described: steatosis, steatohepatitis, and sinusoidal obstruction syndrome (SOS).7–10 SOS has been associated with increased postoperative morbidity, and steatohepatitis has even been associated with higher 90-day mortality rates.7,9,11–14 The term SOS deserves further clarification. SOS is associated with different types of histological lesions, e.g. sinusoidal dilatation (the most common change and the object of the large majority of studies), centrilobular vein fibrosis, perisinusoidal fibrosis, peliosis, and nodular regenerative hyperplasia (NRH).10 The clinical impact of SOS-associated lesions other than sinusoidal dilatation has so far been neglected in the literature. Theoretically, NRH is the most dangerous form of CALI because it may compromise liver function and lead to portal hypertension,15–18 but this has not yet been confirmed in clinical series. To date, only one paper by the Paul Brousse group
L. Vigano` et al.
FIG. 1 Low-power examination of the liver parenchyma. Nodular regenerative hyperplasia is difficult to diagnose on hematoxilin and eosin staining (a), but is highlighted on reticulin staining (b), i.e. grade 1 nodular regenerative hyperplasia
suggested a higher rate of postoperative bile leak in patients with NRH.12 The present study aimed to investigate the clinical impact of NRH in patients undergoing LR for CRLM after modern preoperative chemotherapy, with special attention paid to (1) the prevalence of NRH; (2) the factors associated with its occurrence; (3) the possibility of a preoperative diagnosis; and (4) the impact on postoperative clinical outcomes. METHODS All consecutive patients undergoing LR for CRLM at the Mauriziano Umberto I Hospital of Turin and the University Hospitals of Geneva between January 2000 and December 2012 were considered for the present study. Inclusion criteria comprised preoperative oxaliplatin- and/ or irinotecan-based chemotherapy, chemotherapy duration C2 months, and resectability at laparotomy. Both first LR and redo-LR were considered, provided that chemotherapy before LR had been given. Specimens of all eligible patients were reviewed. Patients for whom a specimen was not available for review (n = 41) were excluded from the study. Pathology Data All specimens were reviewed by two experienced hepatic pathologists (GDR and LRB) to assess CALI in the non-tumoral liver. These two pathologists agreed on the criteria for pathological review at the beginning of the study, and both were blinded to the clinical informations, treatment regimen, and outcome of each patient. The tissue was fixed in formalin, paraffin-embedded, and stained with hematoxylin and eosin, Masson’s trichrome, and Gomori staining.
The following histological features were analyzed in the non-tumoral hepatic parenchyma: steatosis, lobular inflammation, hepatocellular ballooning, sinusoidal dilatation, centrilobular and perisinusoidal fibrosis, NRH, hemorrhagic centrilobular necrosis, and peliosis. The standard scores for the evaluation of steatosis, steatohepatitis, and sinusoidal dilatation were adopted.8,19,20 NRH is a histological alteration of the liver architecture presenting as nodularity in the absence of significant fibrosis. A specific staining for NRH was adopted (Gomori), i.e. a silver reticulin staining that allows assessment of both collagen and liver architecture. NRH was graded according to the Wanless scoring system,21 as follows: 0, absent; 1, mild (focal occasionally distinct nodular hyperplasia on reticulin staining but indistinct on hematoxylin and eosin staining); 2, moderate (focal distinct nodular hyperplasia apparent on hematoxylin and eosin staining, clearly highlighted on reticulin staining); 3, severe (diffuse nodular hyperplasia, distinct in most areas on hematoxylin and eosin staining and highlighted on reticulin staining) (Fig. 1). Details of the Analysis Both centers prospectively entered the data into an institutionally approved database (since 1991 in Geneva and 1998 in Turin). Both databases were merged and analyzed retrospectively. Patient management in the two centers has been previously reported.19,22,23 Major hepatectomy was defined as the resection of three or more Couinaud’s segments, while extended hepatectomy was defined as the resection of more than four Couinaud’s segments. Operative mortality was defined as death within 90 days after surgery or before discharge from the hospital. Morbidity included all postoperative complications, and was graded according to the Dindo–Clavien classification.24 Postoperative liver failure was defined as serum bilirubin [3 mg/
Nodular Regenerative Hyperplasia and Resection
dL and/or prothrombin time \ 50 % on postoperative day 5 or thereafter.25 Bile leakage was defined as the drainage of C50 mL of bile from the surgical drain, or from drainage of an abdominal collection, for 3 or more days.26 Aspartate aminotransferase (AST) to platelet ratio index (APRI) score was calculated according to the following formula: [(AST value/upper limit of the normal range of AST value)/platelet count] 9 100. The APRI score was first used for hepatitis C virus-related liver disease, but has been recently proposed to predict sinusoidal dilatation in patients receiving chemotherapy for CRLM.27 Statistical Analysis The Gaussian distribution of continuous variables was assessed graphically (histogram). Continuous variables were then compared between groups using the unpaired t test or Mann–Whitney U test, as appropriate. Categorical variables were compared using the v2 test or Fisher exact test, as appropriate. A multivariate analysis was performed using a logistic regression model to identify independent predictive factors of NRH and of postoperative liver failure. Multivariate analysis was completed for factors with a p value B0.10 in the univariate analysis. Receiver operating characteristic (ROC) curves were plotted to assess the area under the curve (AUC) of every single liver function test for NRH prediction and to identify the best cut-off value. A p value \0.05 was considered significant for all tests. RESULTS Between January 2000 and December 2012, a total of 478 LRs performed in 406 patients after C2 months of oxaliplatin- and/or irinotecan-based chemotherapy were included in the present analysis. Patient Characteristics and Chemotherapy Details The study included 294 (61.5 %) male patients and the median age was 62 years (range 31–84). CRLM were synchronous to the primary tumor in 355 (74.3 %) patients, the number of metastases was [3 in 161 (33.7 %) patients, and the size was [50 mm in 108 (22.6 %) patients. A total of 164 (34.3 %) patients required a major hepatectomy, including 32 (6.7 %) requiring an extended LR. The proportion of major LR was similar between patients with and without NRH. The preoperative chemotherapy regimen was oxaliplatin in 243 (50.8 %) patients, irinotecan in 119 (24.9 %) patients, and both in 116 (24.3 %) patients. A total of 214 (44.8 %) patients had seven or more cycles of
chemotherapy and 63 (13.2 %) had two or more chemotherapy lines. Targeted therapies were associated in 204 (42.7 %) patients—bevacizumab in 152 patients and cetuximab in 52 patients. Chemotherapy-Related Liver Injuries Pathology results are summarized in Table 1. A total of 286 (59.8 %) patients had at least one relevant form of CALI (i.e. grades 2–3 sinusoidal dilatation, NRH, grades 2– 3 steatosis, or steatohepatitis). The most common injury was sinusoidal dilatation [n = 326 (68.2 %) patients, grades 2–3 in 185 patients], followed by grades 2–3 steatosis [n = 117 (24.5 %)], and steatohepatitis [n = 48 (10.0 %)]. NRH was observed in 87 (18.2 %) patients, grade 1 NRH in 83.9 % of cases (n = 73). NRH diagnosis was significantly associated with the diagnosis of grades 2–3 sinusoidal dilatation (p \ 0.0001), perisinusoidal fibrosis (p = 0.0001), peliosis (p = 0.014) and hemorrhagic centrilobular necrosis (p \ 0.0001). NRH diagnosis was not associated with the presence of grades 2–3 steatosis and steatohepatitis. Predictive and Risk Factors of Nodular Regenerative Hyperplasia Four independent risk factors of NRH were identified (Table 2): arterial hypertension (p = 0.005), APRI score (p = 0.004), platelet count (p = 0.032), and preoperative oxaliplatin (p = 0.003). One independent protective factor was identified, i.e. the association of bevacizumab to chemotherapy (p = 0.020). No correlation was demonstrated between NRH and the number of chemotherapy cycles, the liver function tests, or the indocyanine green retention test (available in 263 patients). The cut-off of APRI score was identified on the basis of the ROC curve analysis (AUC = 0.670; p \ 0.0001): an APRI score of 0.36 had 75.9 % sensitivity, 50.0 % specificity, and 90.3 % negative predictive value (NPV) in NRH prediction. The ROC curve analysis for the platelet count was significant (AUC = 0.623; p \ 0.0001) but did not allow the identification of a single adequate cut-off value. Two platelet count cut-off values stratified patients having different NRH prevalence: if the platelet count was \100 9 103/mm3, the NRH prevalence was 63.6 %; if 100–200 9 103/mm3, it was 25.3 %; and if [200 9 103/ mm3, it was 11.9 %. The combination of the APRI score with the platelet count optimized NRH prediction: in patients with a platelet count \200 9 103/mm3, the APRI score achieved a 94 % sensitivity and a 91 % NPV (of note, all patients with a platelet count\100 9 103/mm3 had an APRI score[0.36).
L. Vigano` et al. TABLE 1 Chemotherapy-related liver injuries N (%) [N = 478] NRH
87 (18.2)
Grade 1
73 (15.3)
Grade 2
8 (1.7)
Grade 3
6 (1.3) N (%)
Among NRH? [N = 87] (%)
Among NRH[N = 391] (%)
p value \0.0001
Grade 2–3 sinusoidal dilatation
185 (38.7)
53 (60.9)
132 (33.8)
Perisinusoidal fibrosis
263 (55.0)
64 (73.6)
199 (50.9)
0.0001
Centrilobular fibrosis
164 (34.3)
37 (42.5)
127 (32.5)
0.074
Peliosis
40 (8.4)
13 (14.9)
27 (6.9)
0.014
Hemorrhagic centrilobular necrosis
68 (14.2)
24 (27.6)
44 (11.3)
\0.0001
117 (24.5)
18 (20.7)
99 (25.3)
NS
48 (10.0)
9 (10.3)
39 (10.0)
NS
Grade 2–3 steatosis Steatohepatitis
NRH nodular regenerative hyperplasia, NS not significant
In patients with a platelet count [200 9 103/mm3, the APRI score was less effective (sensitivity 48 %) but the high NPV persisted (90 %).
was observed: liver failure risk 4.8 % if APRI score [0.36 vs. 1.9 % if B0.36; liver failure risk 10.0 % if platelet count \100 9 103/mm3 vs. 5.1 % if 100–200 9 103/mm3 vs. 2.2 % if[200 9 103/mm3 (p [ 0.05 for both).
Postoperative Outcomes DISCUSSION Overall, the mortality rate was 0.6 % (n = 3). Two patients died because of liver dysfunction (one with grade 1 NRH) and one because of bile leak-related sepsis (grade 0 NRH). A total of 139 (29.1 %) patients had postoperative complications, including 54 (11.3 %) with grades III–V morbidities. Postoperative outcomes are summarized in Table 3. Patients with and without NRH had similar mortality, overall morbidity, and severe morbidity rates, but patients with NRH had higher liver failure rates (9.2 vs. 2.3 %; p = 0.002). Considering patients with grades 2–3 NRH, the liver failure rate rose to 14 %. Of note, two (2.3 %) patients with NRH developed severe ascites after a minor wedge resection without changes in the liver function tests; this complication did not occur in patients without NRH. Bile leak rates were similar between the two groups. The remaining CALI had no impact on postoperative outcomes. Patients with grades 2–3 sinusoidal dilatation without NRH had the same outcomes as patients with normal liver parenchyma. At multivariate analysis (Table 4), two independent risk factors of postoperative liver failure were identified: major hepatectomy (p = 0.043) and NRH (p = 0.021). Patients with NRH undergoing major hepatectomy had a liver failure risk of 14 %. If grades 2–3 NRH was diagnosed, the risk of liver failure after major hepatectomy was 25 %. The APRI score and platelet count (independent NRH predictors) were not predictors of postoperative liver failure, even if a trend
Recently, the impact of CALI on outcomes of LR for CRLM has been the object of several studies.7–16,19,27–30 Patients with CALI have been reported to have worse short-term outcomes in comparison to patients with normal liver parenchyma.7,9,11–14 SOS is the most common lesion, present in up to 60–80 % of patients receiving modern chemotherapy, especially oxaliplatin.10,13,19 However, SOS is associated with different types of lesions, e.g. sinusoidal dilatation, NRH, peliosis, and centrilobular fibrosis.10 Almost all studies focused on sinusoidal dilatation, and the impact on postoperative outcomes of SOS lesions other than sinusoidal dilatation remains unknown. Special attention should be paid to NRH. This condition has been reported after azathioprine therapy and bone marrow transplantation,31,32 but poorly analyzed in patients receiving chemotherapy for CRLM. Preliminary data reported a prevalence of NRH after chemotherapy of approximately 15–20 %,10,12,33 confirmed by the present series (18 %). A specific staining (Gomori) was used to accurately diagnose NRH. Standard specimen preparation may lead to NRH underestimation, as recently occurred.29 Silver reticulin stainings, such as Gomori or Gordon–Sweet staining, are needed because both collagen and liver architecture have to be assessed. The authors also analyzed the severity of NRH according to the Wanless score.29 Only a minority of patients developed grades 2–3 NRH
Nodular Regenerative Hyperplasia and Resection TABLE 2 Univariate and multivariate analysis of predictive and risk factors of NRH NRH prevalence (%)
Univariate
Multivariate analysis
p value
p value
NS
–
NS
–
NS
–
NS
–
0.006
0.005
HR (95 % CI)
Age [70 years Y
17.0
N
18.5
Sex M
19.0
F
16.8
BMI (kg/m2)a \25
17.8
25–30
13.0
[30
22.6
Diabetes Y
20.3
N
17.6
Arterial hypertension Y
25.3
N
14.9
2.138 (1.264–3.617) 1
Dyslipidemia Y
16.3
N
18.4
NS
–
NS
–
NS
–
\0.0001
0.004
Aspirin intake Y N Oral anticoagulant therapy
23.3 17.9
Y
23.5
N
18.0
APRI score [0.36
25.5
B0.36
9.8
2.510 (1.338–4.706) 1
Total bilirubin [2 mg/dL Y
30.0
N
17.3
NS
–
0.001
NS
0.045
NS
0.006
NS
\0.0001
0.032
AST [35 UI/L Y
27.6
N
14.4
ALT [40 UI/L Y
24.7
N
16.0
GGT [50 UI/L Y N
22.2 12.6
Platelet count (103/mm3) \100
63.6
100–200
25.3
0.267 (0.066–1.082)
[200
11.9
0.168 (0.040–0.707)
b
ICG-R15 [10 % Y
22.4
N
17.1
NS
–
1
L. Vigano` et al. TABLE 2 continued NRH prevalence (%)
Univariate
Multivariate analysis
p value
p value
HR (95 % CI)
0.002
0.003
3.053 (1.470–6.342)
Oxaliplatin Y
21.4
N
8.4
1
Irinotecan Y
14.9
N
21.4
0.065
NS
0.068
0.020
Associated bevacizumab Y N Associated cetuximab
11.7 19.8
Y
16.1
N
18.5
0.424 (0.206–0.872) 1
NS
–
NS
–
NS
–
NS
–
Response to chemotherapy CR
23.8
PR
18.4
SD
18.2
PD
11.5
Chemotherapy lines 1
17.3
C2
23.8
Chemotherapy cycles 1–6
17.4
7–12
19.4
13–18 C19
16.2 25.0
M male, F female, Y yes, N no, BMI body mass index, ICG-R15 indocyanine green retention test at 15 min, CR complete response, PR partial response, SD stable disease, PD disease progression, HR hazard ratio, CI confidence interval, NS not significant, NRH nodular regenerative hyperplasia, AST aspartate aminotransferase, ALT alanine aminotransferase, GGT c-glutamyltransferase, APRI AST to platelet ratio index a b
Available in 424 patients Available in 263 patients
(\5 % of the whole population; approximately one-fifth of patients with NRH). Finally, the correlation among the different types of CALI was analyzed. As expected, the diagnosis of NRH was often associated with the diagnosis of other SOS lesions, especially sinusoidal dilatation and peliosis. On the contrary, steatosis and steatohepatitis had no relationship with NRH, confirming different etiologies and onset pathways. The risk and predictive factors of NRH have been poorly investigated. As observed for other SOS lesions,8,19 the prevalence of NRH increases after oxaliplatin administration. On the contrary, patients receiving bevacizumab in association with chemotherapy had a lower prevalence of NRH. Similar findings were previously reported for SOS lesions by the MD Anderson group and by RubbiaBrandt et al.10,28 No correlation was demonstrated between the diagnosis of NRH and the number of cycles of
chemotherapy. Nevertheless, short and effective chemotherapy is always recommended to limit NRH, as any other CALI.34 Wicherts et al. observed a correlation between both c-glutamyltransferase and total bilirubin with NRH.12 This was not confirmed in the present study but other parameters correlated with the presence of NRH. First, the APRI score, recently proposed by Soubrane et al. to predict sinusoidal dilatation,27 was predictive of NRH with good sensitivity (76 %) and NPV (90 %). Of note, the present analysis identified exactly the same cut-off proposed by Soubrane et al. (APRI = 0.36), supporting the reliability of this threshold value. Second, we found that the lower the platelet count, the higher the prevalence of NRH. This correlation between NRH and platelet count suggests NRH as a possible cause of portal hypertension,15–18 even if the measurement of portal pressure is needed to confirm this hypothesis, and factors other than
Nodular Regenerative Hyperplasia and Resection TABLE 3 Short-term outcomes Overall (N = 478) (%)
NRH
p value
Yes (N = 87) (%) Mortality Overall morbidity Severe complications (grade III–V)
No (N = 391) (%)
3 (0.6)
1 (1.1)
2 (0.5)
NS
139 (29.1)
27 (31.0)
112 (28.6)
NS
54 (11.3)
11 (12.6)
43 (11.0)
NS
Liver dysfunction
17 (3.6)
8 (9.2)
9 (2.3)
Bile leak
33 (6.9)
5 (5.7)
28 (7.2)
Abdominal collection
29 (6.1)
5 (5.7)
24 (6.1)
NS
Renal dysfunction Pulmonary morbidity
8 (1.7) 53 (11.1)
3 (3.4) 12 (13.8)
5 (1.3) 41 (10.5)
NS NS
13 (14.9)
42 (10.7)
Blood transfusions Hospital stay
55 (11.5) 9 (4–114)
10 (5–68)
9 (4–114)
0.002 NS
NS NS
Hospital stay (continuous variable) is reported as median value (range) NRH nodular regenerative hyperplasia, NS not significant
TABLE 4 Univariate and multivariate analysis of predictive factors of postoperative liver failure
Age [70 years BMI [30 kg/m2
a
Univariate analysis
Multivariate analysis
p value
p value
NS
–
HR (95 % CI)
0.056
NS
ASA score III–IV
NS
–
Diabetes
0.030
NS
Arterial hypertension
NS
–
CTx regimen (oxaliplatin/irinotecan/both)
NS
–
CTx cycles C7 Total bilirubin [2 mg/dL
NS NS
– –
AST [35 UI/L
0.062
NS
ALT [40 UI/L
NS
–
GGT [50 UI/L
NS
–
Platelet count, 103/mm3 (\100/100 to 200/[200)
NS
–
APRI score [0.36
0.097
NS
b
NS
–
Major hepatectomy
0.007
0.043
2.954 (1.037–8.415)
NRH
0.002
0.021
3.391 (1.204–9.551)
ICG-R15 [10
BMI body mass index, CTx chemotherapy, ICG-R15 indocyanine green retention test at 15 min, HR hazard ratio, CI confidence interval, NS not significant, NRH nodular regenerative hyperplasia, AST aspartate aminotransferase, ALT alanine aminotransferase, GGT c-glutamyltransferase, APRI AST to platelet ratio index a
Available in 424 patients
b
Available in 263 patients
portal hypertension may impact platelet count in chemotherapy-treated patients (e.g. bone marrow toxicity or immune response). Finally, the prevalence of NRH was increased in patients with arterial hypertension (one-quarter of patients). An intrahepatic negative impact of high arterial pressure can be hypothesized but experimental studies are needed to confirm and elucidate this correlation. The combination of different laboratory data (APRI
score and platelet count) with clinical data may allow good NRH prediction. The last and most relevant issue concerns the clinical impact of NRH. To date, only one study by the Paul Brousse group analyzed this question in a small series (22 patients with NRH) and reported higher bile leak rates in the presence of NRH (27 vs. 0 %).12 The present large series (87 NRH patients of 478) did not confirm that
L. Vigano` et al.
finding: the bile leak rate was low (7 %) and similar between the two groups. A more relevant impact was observed: NRH was an independent predictive factor of postoperative liver failure. Liver failure risk increased from 2 % in patients without NRH to 9 % in patients with NRH. Outcomes worsened in relation to the severity of NRH: the incidence of liver failure was as high as 14 % in the presence of grades 2–3 NRH, reaching 25 % in case of major hepatectomy. No other form of CALI impacted the risk of liver failure. According to the present data, NRH, and not sinusoidal dilatation, is the true determinant of short-term outcomes in patients undergoing LR after chemotherapy: patients with sinusoidal dilatation without NRH had the same outcomes as patients with normal liver. The strict association between NRH and sinusoidal dilatation could explain the link between sinusoidal dilatation and poorer surgical outcomes in previous publications. NRH not only compromises liver function but can also cause portal hypertension.15–18 The negative impact of portal hypertension on postoperative outcomes is wellknown.35 In the present study, two patients in the NRH group developed severe postoperative ascites despite minor hepatectomies. In our series, portal pressure was not systematically measured, neither preoperatively nor intraoperatively, but the correlation observed between the platelet count and the prevalence of NRH suggests a causal link. Furthermore, the lower the platelet count the higher the risk of liver failure. Prospective studies with systematic portal pressure measurement are needed to fully ascertain the correlation among NRH, portal hypertension, and operative outcomes. The present study has a relevant clinical impact. First, any future study regarding CALI should include NRH. Silver reticulin stainings are recommended to avoid underestimating the prevalence of NRH, and the Wanless score to assess the severity of the lesions. Second, the impact of NRH on postoperative outcomes underlines the importance of diagnosing it preoperatively. To diagnose NRH, radiological investigations offer a limited contribution, while the APRI score and platelet count, together with clinical data (oxaliplatin or bevacizumab administration), may be helpful. The diagnostic value of preoperative biopsy has been denied for steatohepatitis and sinusoidal dilatation because of their heterogeneous distribution in the liver.13 Theoretically, NRH has a more homogeneous distribution and is ubiquitary in moderate to severe (grades 2–3) forms. Preoperative biopsy could be considered in selected high-risk patients (for instance, patients with high APRI score/low platelet count candidates for major hepatectomies) and its usefulness should be investigated. Finally, the potential association between NRH and portal hypertension should be explored. Spleen
size could be taken into account (data not available in the present series). Theoretically, a transjugular liver biopsy could allow both the diagnosis of NRH and the evaluation of the presence and severity of portal hypertension, but at present it cannot be recommended on a routine basis. Even if the present study is a non-intention-to-treat retrospective analysis, the large cohort size, the inclusion of all consecutive resected patients, and the systematic review of the specimens by two experienced pathologists guarantee a high reliability of data. CONCLUSIONS NRH is a clinically relevant CALI; it may cause portal hypertension and increases the risk of postoperative liver failure. Oxaliplatin increases the incidence of NRH, while bevacizumab seems to attenuate it. The APRI score and platelet count suggest the presence of NRH. Patients scheduled for major hepatectomy who are suspected of having NRH on the basis of clinical and laboratory data may need more liberal access to portal vein embolization, both as a preparation and also as a stress test for postoperative liver failure. ACKNOWLEDGMENT Lorenzo Capussotti, MD, and Gilles Mentha, MD, passed away unexpectedly during the final stages of manuscript preparation. They both contributed greatly to the improvement and progress of hepato-biliary-pancreatic surgery, and will be greatly missed by all of us. CONFLICT OF INTEREST Luca Vigano`, Laura Rubbia-Brandt, Giovanni De Rosa, Pietro Majno, Serena Langella, Christian Toso, Gilles Mentha, and Lorenzo Capussotti have no conflict of interest to declare.
REFERENCES 1. Imamura H, Seyama Y, Kokudo N, et al. One thousand fifty-six hepatectomies without mortality in 8 years. Arch Surg. 2003; 138:1198–206. 2. Jarnagin WR, Gonen M, Fong Y, et al. Improvement in perioperative outcome after hepatic resection: analysis of 1803 consecutive cases over the past decade. Ann Surg. 2002;236:397–406. 3. Andres A, Toso C, Moldovan B, et al. Complications of elective liver resections in a center with low mortality: a simple score to predict morbidity. Arch Surg. 2011;146(11):1246–52. 4. Pawlik TM, Choti MA. Surgical therapy for colorectal metastases to the liver. J Gastrointest Surg. 2007;11(8):1057–77. 5. Simmonds PC, Primrose JN, Colquitt JL, Garden OJ, Poston GJ, Rees M. Surgical resection of hepatic metastases from colorectal cancer: a systematic review of published studies. Br J Cancer. 2006;94(7):982–99. 6. Vigano` L, Russolillo N, Ferrero A, Langella S, Sperti E, Capussotti L. Evolution of long-term outcome of liver resection for colorectal metastases: analysis of actual 5-year survival rates over two decades. Ann Surg Oncol. 2012;19(6):2035–44.
Nodular Regenerative Hyperplasia and Resection 7. Vauthey JN, Pawlik TM, Ribero D, et al. Chemotherapy regimen predicts steatohepatitis and an increase in 90-day mortality after surgery for hepatic colorectal metastases. J Clin Oncol. 2006; 24(13):2065–72. 8. Rubbia-Brandt L, Audard V, Sartoretti P, et al. Severe hepatic sinusoidal obstruction associated with oxaliplatin-based chemotherapy in patients with metastatic colorectal cancer. Ann Oncol. 2004;15(3):460–6. 9. de Meijer VE, Kalish BT, Puder M, Ijzermans JNM. Systematic review and meta-analysis of steatosis as a risk factor in major hepatic resection. Br J Surg. 2010;97(9):1331–39. 10. Rubbia-Brandt L, Lauwers GY, Wang H, et al. Sinusoidal obstruction syndrome and nodular regenerative hyperplasia are frequent oxaliplatin-associated liver lesions and partially prevented by bevacizumab in patients with hepatic colorectal metastasis. Histopathology. 2010;56(4):430–39. 11. Nakano H, Oussoultzoglou E, Rosso E, et al. Sinusoidal injury increases morbidity after major hepatectomy in patients with colorectal liver metastases receiving preoperative chemotherapy. Ann Surg. 2008;247(1):118–24. 12. Wicherts DA, de Haas RJ, Sebagh M, et al. Regenerative nodular hyperplasia of the liver related to chemotherapy: impact on outcome of liver surgery for colorectal metastases. Ann Surg Oncol. 2011;18(3):659–69. 13. Vigano` L, Ravarino N, Ferrero A, Motta M, Torchio B, Capussotti L. Prospective evaluation of accuracy of liver biopsy findings in the identification of chemotherapy-associated liver injuries. Arch Surg. 2012;147(12):1085–91. 14. Aloia T, Sebagh M, Plasse M, et al. Liver histology and surgical outcomes after preoperative chemotherapy with fluorouracil plus oxaliplatin in colorectal cancer liver metastases. J Clin Oncol. 2006;24(31):4983–90. 15. Hubert C, Sempoux C, Horsmans Y, et al. Nodular regenerative hyperplasia: a deleterious consequence of chemotherapy for colorectal liver metastases? Liver Int. 2007;27(7):938–43. 16. Schwarz L, Faitot F, Soubrane O, Scatton O. Splenic artery ligation for severe oxaliplatin induced portal hypertension: A way to improve postoperative course and allow adjuvant chemotherapy for colorectal liver metastases. Eur J Surg Oncol .2014; 40(6):787–88. 17. Al-Mukhaizeem KA, Rosenberg A, Sherker AH. Nodular regenerative hyperplasia of the liver: an under-recognized cause of portal hypertension in hematological disorders. Am J Hematol. 2004;75(4):225–30. 18. Sarin SK, Khanna R. Non-cirrhotic portal hypertension. Clin Liver Dis. 2014;18(2):451–76. 19. Vigano` L, Capussotti L, De Rosa G, De Saussure WO, Mentha G, Rubbia-Brandt L. Liver resection for colorectal metastases after chemotherapy: impact of chemotherapy-related liver injuries, pathological tumor response, and micrometastases on long-term survival. Ann Surg. 2013;258(5):731–40. 20. Kleiner DE, Brunt EM, Van Natta M, et al. Design and validation of a histological scoring system for nonalcoholic fatty liver disease. Hepatology. 2005;41(6):1313–21.
21. Wanless IR. Micronodular transformation (nodular regenerative hyperplasia) of the liver: a report of 64 cases among 2,500 autopsies and a new classification of benign hepatocellular nodules. Hepatology. 1990;11(5):787–97. 22. Vigano` L, Langella S, Ferrero A, Russolillo N, Sperti E, Capussotti L. Colorectal cancer with synchronous resectable liver metastases: monocentric management in a hepatobiliary referral center improves survival outcomes. Ann Surg Oncol. 2013;20(3): 938–45. 23. Mentha G, Roth AD, Terraz S, et al. ‘Liver first’ approach in the treatment of colorectal cancer with synchronous liver metastases. Dig Surg. 2008;25(6):430–35. 24. Dindo D, Demartines N, Clavien PA. Classification of surgical complications: a new proposal with evaluation in a cohort of 6336 patients and results of a survey. Ann Surg. 2004;240(2): 205–13. 25. Capussotti L, Vigano` L, Giuliante F, Ferrero A, Giovannini I, Nuzzo G. Liver dysfunction and sepsis determine operative mortality after liver resection. Br J Surg. 2009;96(1):88–94. 26. Capussotti L, Ferrero A, Vigano` L, Sgotto E, Muratore A, Polastri R. Bile leakage and liver resection: Where is the risk? Arch Surg. 2006;141(7):690–94. 27. Soubrane O, Brouquet A, Zalinski S, et al. Predicting high grade lesions of sinusoidal obstruction syndrome related to oxaliplatin-based chemotherapy for colorectal liver metastases: correlation with post-hepatectomy outcome. Ann Surg. 2010; 251(3):454–60. 28. Ribero D, Wang H, Donadon M, et al. Bevacizumab improves pathologic response and protects against hepatic injury in patients treated with oxaliplatin-based chemotherapy for colorectal liver metastases. Cancer. 2007;110(12):2761–7. 29. Morris-Stiff G, White AD, Gomez D, et al. Nodular regenerative hyperplasia (NRH) complicating oxaliplatin chemotherapy in patients undergoing resection of colorectal liver metastases. Eur J Surg Oncol. 2014;40(8):1016–20. 30. Aloia TA, Vauthey JN. Management of colorectal liver metastases: past, present, and future. Updates Surg. 2011;63(1):1–3. 31. Snover DC, Weisdorf S, Bloomer J, McGlave P, Weisdorf D. Nodular regenerative hyperplasia of the liver following bone marrow transplantation. Hepatology. 1989;9(3):443–8. 32. Duvoux C, Kracht M, Lang P, Vernant JP, Zafrani ES, Dhumeaux D. Nodular regenerative hyperplasia of the liver associated with azathioprine therapy. Gastroenterol Clin Biol. 1991;15(12):968– 73. 33. Washington K, Lane KL, Meyers WC. Nodular regenerative hyperplasia in partial hepatectomy specimens. Am J Surg Pathol. 1993;17(11):1151–8. 34. Mentha G, Terraz S, Andres A, Toso C, Rubbia-Brandt L, Majno P. Operative management of colorectal liver metastases. Semin Liver Dis Management of colorectal liver metastases: past, present, and future 2013;33(3):262–72. 35. Allard MA, Adam R, Bucur PO, et al. Posthepatectomy portal vein pressure predicts liver failure and mortality after major liver resection on noncirrhotic liver. Ann Surg. 2013;258(5):822–9.
ORIGINAL ARTICLE – HEPATOBILIARY TUMORS
Nodular Regenerative Hyperplasia in Patients Undergoing Liver Resection for Colorectal Metastases After Chemotherapy: Risk Factors, Preoperative Assessment and Clinical Impact Luca Vigano`, MD1,2, Laura Rubbia-Brandt, MD3,6, Giovanni De Rosa, MD4, Pietro Majno, MD5,6, Serena Langella, MD2, Christian Toso, MD, PhD5,6, Gilles Mentha, MD5,6, and Lorenzo Capussotti, MD2 1
Department of Hepatobiliary and General Surgery, Humanitas Research Hospital, Humanitas University, Rozzano, MI, Italy; 2Department of HPB and Digestive Surgery, Ospedale Mauriziano Umberto I, Turin, Italy; 3Department of Clinical Pathology, University Hospitals, Geneva, Switzerland; 4Department of Pathology, Ospedale Mauriziano Umberto I, Turin, Italy; 5Department of Visceral and Transplantation Surgery, University Hospitals, Geneva, Switzerland; 6HepatoPancreato-Biliary Centre, University Hospitals, Geneva, Switzerland
ABSTRACT Background. Nodular regenerative hyperplasia (NRH) is a severe form of chemotherapy-related liver injury (CALI) that may worsen the short-term outcome of liver resection (LR) for colorectal metastases (CRLM). The present study aimed to clarify the incidence, risk factors, preoperative assessment, and clinical impact of NRH. Methods. Overall, 406 patients undergoing 478 LRs for CRLM after chemotherapy between 2000 and 2012 were studied. All resection specimens were reviewed. After Gomori staining, NRH was graded according to the Wanless score. Results. NRH was diagnosed in 87 (18.2 %) patients, grades 2–3 in 14 (2.9 %) patients. At multivariate analysis, the prevalence of NRH was increased after oxaliplatin administration (21.4 vs. 8.4 %; p = 0.003), and reduced by the addition of bevacizumab (11.7 vs. 19.8 %; p = 0.020). Two parameters predicted the presence of NRH: the APRI score (AST to platelet ratio index: 25.5 % if [0.36 vs. 9.8 % if B0.36; p = 0.004), and the platelet count (63.6 % if \100 9 103/mm3 vs. 25.3 % if 100–200 9 103/mm3 vs. 11.9 % if [200 9 103/mm3; p = 0.032). Ninety-day mortality and liver failure rates were 0.6 and 3.6 %. NRH was an independent predictor of postoperative liver failure (9.2 % if present vs. 2.3 % if not present; p = 0.021). In
Ó Society of Surgical Oncology 2015 First Received: 10 October 2014 L. Vigano`, MD e-mail: [email protected]
patients with grades 2–3 NRH, the rate of liver failure was 14.3 %, 25.0 % after major hepatectomy. No other forms of CALI impacted short-term outcomes. Conclusions. NRH was the most relevant form of CALI, increasing the risk of postoperative liver failure. Oxaliplatin increased the incidence of NRH, while bevacizumab decreased it. The APRI score and platelet count were useful tools for predicting NRH.
During the last decades, liver surgery has become safer, with mortality rates below 1 % in patients operated of liver resection (LR) for colorectal metastases (CRLM).1–6 However, in these patients, new risk factors have been identified, particularly chemotherapy-related liver injuries (CALI). Three main forms of CALI have been described: steatosis, steatohepatitis, and sinusoidal obstruction syndrome (SOS).7–10 SOS has been associated with increased postoperative morbidity, and steatohepatitis has even been associated with higher 90-day mortality rates.7,9,11–14 The term SOS deserves further clarification. SOS is associated with different types of histological lesions, e.g. sinusoidal dilatation (the most common change and the object of the large majority of studies), centrilobular vein fibrosis, perisinusoidal fibrosis, peliosis, and nodular regenerative hyperplasia (NRH).10 The clinical impact of SOS-associated lesions other than sinusoidal dilatation has so far been neglected in the literature. Theoretically, NRH is the most dangerous form of CALI because it may compromise liver function and lead to portal hypertension,15–18 but this has not yet been confirmed in clinical series. To date, only one paper by the Paul Brousse group
L. Vigano` et al.
FIG. 1 Low-power examination of the liver parenchyma. Nodular regenerative hyperplasia is difficult to diagnose on hematoxilin and eosin staining (a), but is highlighted on reticulin staining (b), i.e. grade 1 nodular regenerative hyperplasia
suggested a higher rate of postoperative bile leak in patients with NRH.12 The present study aimed to investigate the clinical impact of NRH in patients undergoing LR for CRLM after modern preoperative chemotherapy, with special attention paid to (1) the prevalence of NRH; (2) the factors associated with its occurrence; (3) the possibility of a preoperative diagnosis; and (4) the impact on postoperative clinical outcomes. METHODS All consecutive patients undergoing LR for CRLM at the Mauriziano Umberto I Hospital of Turin and the University Hospitals of Geneva between January 2000 and December 2012 were considered for the present study. Inclusion criteria comprised preoperative oxaliplatin- and/ or irinotecan-based chemotherapy, chemotherapy duration C2 months, and resectability at laparotomy. Both first LR and redo-LR were considered, provided that chemotherapy before LR had been given. Specimens of all eligible patients were reviewed. Patients for whom a specimen was not available for review (n = 41) were excluded from the study. Pathology Data All specimens were reviewed by two experienced hepatic pathologists (GDR and LRB) to assess CALI in the non-tumoral liver. These two pathologists agreed on the criteria for pathological review at the beginning of the study, and both were blinded to the clinical informations, treatment regimen, and outcome of each patient. The tissue was fixed in formalin, paraffin-embedded, and stained with hematoxylin and eosin, Masson’s trichrome, and Gomori staining.
The following histological features were analyzed in the non-tumoral hepatic parenchyma: steatosis, lobular inflammation, hepatocellular ballooning, sinusoidal dilatation, centrilobular and perisinusoidal fibrosis, NRH, hemorrhagic centrilobular necrosis, and peliosis. The standard scores for the evaluation of steatosis, steatohepatitis, and sinusoidal dilatation were adopted.8,19,20 NRH is a histological alteration of the liver architecture presenting as nodularity in the absence of significant fibrosis. A specific staining for NRH was adopted (Gomori), i.e. a silver reticulin staining that allows assessment of both collagen and liver architecture. NRH was graded according to the Wanless scoring system,21 as follows: 0, absent; 1, mild (focal occasionally distinct nodular hyperplasia on reticulin staining but indistinct on hematoxylin and eosin staining); 2, moderate (focal distinct nodular hyperplasia apparent on hematoxylin and eosin staining, clearly highlighted on reticulin staining); 3, severe (diffuse nodular hyperplasia, distinct in most areas on hematoxylin and eosin staining and highlighted on reticulin staining) (Fig. 1). Details of the Analysis Both centers prospectively entered the data into an institutionally approved database (since 1991 in Geneva and 1998 in Turin). Both databases were merged and analyzed retrospectively. Patient management in the two centers has been previously reported.19,22,23 Major hepatectomy was defined as the resection of three or more Couinaud’s segments, while extended hepatectomy was defined as the resection of more than four Couinaud’s segments. Operative mortality was defined as death within 90 days after surgery or before discharge from the hospital. Morbidity included all postoperative complications, and was graded according to the Dindo–Clavien classification.24 Postoperative liver failure was defined as serum bilirubin [3 mg/
Nodular Regenerative Hyperplasia and Resection
dL and/or prothrombin time \ 50 % on postoperative day 5 or thereafter.25 Bile leakage was defined as the drainage of C50 mL of bile from the surgical drain, or from drainage of an abdominal collection, for 3 or more days.26 Aspartate aminotransferase (AST) to platelet ratio index (APRI) score was calculated according to the following formula: [(AST value/upper limit of the normal range of AST value)/platelet count] 9 100. The APRI score was first used for hepatitis C virus-related liver disease, but has been recently proposed to predict sinusoidal dilatation in patients receiving chemotherapy for CRLM.27 Statistical Analysis The Gaussian distribution of continuous variables was assessed graphically (histogram). Continuous variables were then compared between groups using the unpaired t test or Mann–Whitney U test, as appropriate. Categorical variables were compared using the v2 test or Fisher exact test, as appropriate. A multivariate analysis was performed using a logistic regression model to identify independent predictive factors of NRH and of postoperative liver failure. Multivariate analysis was completed for factors with a p value B0.10 in the univariate analysis. Receiver operating characteristic (ROC) curves were plotted to assess the area under the curve (AUC) of every single liver function test for NRH prediction and to identify the best cut-off value. A p value \0.05 was considered significant for all tests. RESULTS Between January 2000 and December 2012, a total of 478 LRs performed in 406 patients after C2 months of oxaliplatin- and/or irinotecan-based chemotherapy were included in the present analysis. Patient Characteristics and Chemotherapy Details The study included 294 (61.5 %) male patients and the median age was 62 years (range 31–84). CRLM were synchronous to the primary tumor in 355 (74.3 %) patients, the number of metastases was [3 in 161 (33.7 %) patients, and the size was [50 mm in 108 (22.6 %) patients. A total of 164 (34.3 %) patients required a major hepatectomy, including 32 (6.7 %) requiring an extended LR. The proportion of major LR was similar between patients with and without NRH. The preoperative chemotherapy regimen was oxaliplatin in 243 (50.8 %) patients, irinotecan in 119 (24.9 %) patients, and both in 116 (24.3 %) patients. A total of 214 (44.8 %) patients had seven or more cycles of
chemotherapy and 63 (13.2 %) had two or more chemotherapy lines. Targeted therapies were associated in 204 (42.7 %) patients—bevacizumab in 152 patients and cetuximab in 52 patients. Chemotherapy-Related Liver Injuries Pathology results are summarized in Table 1. A total of 286 (59.8 %) patients had at least one relevant form of CALI (i.e. grades 2–3 sinusoidal dilatation, NRH, grades 2– 3 steatosis, or steatohepatitis). The most common injury was sinusoidal dilatation [n = 326 (68.2 %) patients, grades 2–3 in 185 patients], followed by grades 2–3 steatosis [n = 117 (24.5 %)], and steatohepatitis [n = 48 (10.0 %)]. NRH was observed in 87 (18.2 %) patients, grade 1 NRH in 83.9 % of cases (n = 73). NRH diagnosis was significantly associated with the diagnosis of grades 2–3 sinusoidal dilatation (p \ 0.0001), perisinusoidal fibrosis (p = 0.0001), peliosis (p = 0.014) and hemorrhagic centrilobular necrosis (p \ 0.0001). NRH diagnosis was not associated with the presence of grades 2–3 steatosis and steatohepatitis. Predictive and Risk Factors of Nodular Regenerative Hyperplasia Four independent risk factors of NRH were identified (Table 2): arterial hypertension (p = 0.005), APRI score (p = 0.004), platelet count (p = 0.032), and preoperative oxaliplatin (p = 0.003). One independent protective factor was identified, i.e. the association of bevacizumab to chemotherapy (p = 0.020). No correlation was demonstrated between NRH and the number of chemotherapy cycles, the liver function tests, or the indocyanine green retention test (available in 263 patients). The cut-off of APRI score was identified on the basis of the ROC curve analysis (AUC = 0.670; p \ 0.0001): an APRI score of 0.36 had 75.9 % sensitivity, 50.0 % specificity, and 90.3 % negative predictive value (NPV) in NRH prediction. The ROC curve analysis for the platelet count was significant (AUC = 0.623; p \ 0.0001) but did not allow the identification of a single adequate cut-off value. Two platelet count cut-off values stratified patients having different NRH prevalence: if the platelet count was \100 9 103/mm3, the NRH prevalence was 63.6 %; if 100–200 9 103/mm3, it was 25.3 %; and if [200 9 103/ mm3, it was 11.9 %. The combination of the APRI score with the platelet count optimized NRH prediction: in patients with a platelet count \200 9 103/mm3, the APRI score achieved a 94 % sensitivity and a 91 % NPV (of note, all patients with a platelet count\100 9 103/mm3 had an APRI score[0.36).
L. Vigano` et al. TABLE 1 Chemotherapy-related liver injuries N (%) [N = 478] NRH
87 (18.2)
Grade 1
73 (15.3)
Grade 2
8 (1.7)
Grade 3
6 (1.3) N (%)
Among NRH? [N = 87] (%)
Among NRH[N = 391] (%)
p value \0.0001
Grade 2–3 sinusoidal dilatation
185 (38.7)
53 (60.9)
132 (33.8)
Perisinusoidal fibrosis
263 (55.0)
64 (73.6)
199 (50.9)
0.0001
Centrilobular fibrosis
164 (34.3)
37 (42.5)
127 (32.5)
0.074
Peliosis
40 (8.4)
13 (14.9)
27 (6.9)
0.014
Hemorrhagic centrilobular necrosis
68 (14.2)
24 (27.6)
44 (11.3)
\0.0001
117 (24.5)
18 (20.7)
99 (25.3)
NS
48 (10.0)
9 (10.3)
39 (10.0)
NS
Grade 2–3 steatosis Steatohepatitis
NRH nodular regenerative hyperplasia, NS not significant
In patients with a platelet count [200 9 103/mm3, the APRI score was less effective (sensitivity 48 %) but the high NPV persisted (90 %).
was observed: liver failure risk 4.8 % if APRI score [0.36 vs. 1.9 % if B0.36; liver failure risk 10.0 % if platelet count \100 9 103/mm3 vs. 5.1 % if 100–200 9 103/mm3 vs. 2.2 % if[200 9 103/mm3 (p [ 0.05 for both).
Postoperative Outcomes DISCUSSION Overall, the mortality rate was 0.6 % (n = 3). Two patients died because of liver dysfunction (one with grade 1 NRH) and one because of bile leak-related sepsis (grade 0 NRH). A total of 139 (29.1 %) patients had postoperative complications, including 54 (11.3 %) with grades III–V morbidities. Postoperative outcomes are summarized in Table 3. Patients with and without NRH had similar mortality, overall morbidity, and severe morbidity rates, but patients with NRH had higher liver failure rates (9.2 vs. 2.3 %; p = 0.002). Considering patients with grades 2–3 NRH, the liver failure rate rose to 14 %. Of note, two (2.3 %) patients with NRH developed severe ascites after a minor wedge resection without changes in the liver function tests; this complication did not occur in patients without NRH. Bile leak rates were similar between the two groups. The remaining CALI had no impact on postoperative outcomes. Patients with grades 2–3 sinusoidal dilatation without NRH had the same outcomes as patients with normal liver parenchyma. At multivariate analysis (Table 4), two independent risk factors of postoperative liver failure were identified: major hepatectomy (p = 0.043) and NRH (p = 0.021). Patients with NRH undergoing major hepatectomy had a liver failure risk of 14 %. If grades 2–3 NRH was diagnosed, the risk of liver failure after major hepatectomy was 25 %. The APRI score and platelet count (independent NRH predictors) were not predictors of postoperative liver failure, even if a trend
Recently, the impact of CALI on outcomes of LR for CRLM has been the object of several studies.7–16,19,27–30 Patients with CALI have been reported to have worse short-term outcomes in comparison to patients with normal liver parenchyma.7,9,11–14 SOS is the most common lesion, present in up to 60–80 % of patients receiving modern chemotherapy, especially oxaliplatin.10,13,19 However, SOS is associated with different types of lesions, e.g. sinusoidal dilatation, NRH, peliosis, and centrilobular fibrosis.10 Almost all studies focused on sinusoidal dilatation, and the impact on postoperative outcomes of SOS lesions other than sinusoidal dilatation remains unknown. Special attention should be paid to NRH. This condition has been reported after azathioprine therapy and bone marrow transplantation,31,32 but poorly analyzed in patients receiving chemotherapy for CRLM. Preliminary data reported a prevalence of NRH after chemotherapy of approximately 15–20 %,10,12,33 confirmed by the present series (18 %). A specific staining (Gomori) was used to accurately diagnose NRH. Standard specimen preparation may lead to NRH underestimation, as recently occurred.29 Silver reticulin stainings, such as Gomori or Gordon–Sweet staining, are needed because both collagen and liver architecture have to be assessed. The authors also analyzed the severity of NRH according to the Wanless score.29 Only a minority of patients developed grades 2–3 NRH
Nodular Regenerative Hyperplasia and Resection TABLE 2 Univariate and multivariate analysis of predictive and risk factors of NRH NRH prevalence (%)
Univariate
Multivariate analysis
p value
p value
NS
–
NS
–
NS
–
NS
–
0.006
0.005
HR (95 % CI)
Age [70 years Y
17.0
N
18.5
Sex M
19.0
F
16.8
BMI (kg/m2)a \25
17.8
25–30
13.0
[30
22.6
Diabetes Y
20.3
N
17.6
Arterial hypertension Y
25.3
N
14.9
2.138 (1.264–3.617) 1
Dyslipidemia Y
16.3
N
18.4
NS
–
NS
–
NS
–
\0.0001
0.004
Aspirin intake Y N Oral anticoagulant therapy
23.3 17.9
Y
23.5
N
18.0
APRI score [0.36
25.5
B0.36
9.8
2.510 (1.338–4.706) 1
Total bilirubin [2 mg/dL Y
30.0
N
17.3
NS
–
0.001
NS
0.045
NS
0.006
NS
\0.0001
0.032
AST [35 UI/L Y
27.6
N
14.4
ALT [40 UI/L Y
24.7
N
16.0
GGT [50 UI/L Y N
22.2 12.6
Platelet count (103/mm3) \100
63.6
100–200
25.3
0.267 (0.066–1.082)
[200
11.9
0.168 (0.040–0.707)
b
ICG-R15 [10 % Y
22.4
N
17.1
NS
–
1
L. Vigano` et al. TABLE 2 continued NRH prevalence (%)
Univariate
Multivariate analysis
p value
p value
HR (95 % CI)
0.002
0.003
3.053 (1.470–6.342)
Oxaliplatin Y
21.4
N
8.4
1
Irinotecan Y
14.9
N
21.4
0.065
NS
0.068
0.020
Associated bevacizumab Y N Associated cetuximab
11.7 19.8
Y
16.1
N
18.5
0.424 (0.206–0.872) 1
NS
–
NS
–
NS
–
NS
–
Response to chemotherapy CR
23.8
PR
18.4
SD
18.2
PD
11.5
Chemotherapy lines 1
17.3
C2
23.8
Chemotherapy cycles 1–6
17.4
7–12
19.4
13–18 C19
16.2 25.0
M male, F female, Y yes, N no, BMI body mass index, ICG-R15 indocyanine green retention test at 15 min, CR complete response, PR partial response, SD stable disease, PD disease progression, HR hazard ratio, CI confidence interval, NS not significant, NRH nodular regenerative hyperplasia, AST aspartate aminotransferase, ALT alanine aminotransferase, GGT c-glutamyltransferase, APRI AST to platelet ratio index a b
Available in 424 patients Available in 263 patients
(\5 % of the whole population; approximately one-fifth of patients with NRH). Finally, the correlation among the different types of CALI was analyzed. As expected, the diagnosis of NRH was often associated with the diagnosis of other SOS lesions, especially sinusoidal dilatation and peliosis. On the contrary, steatosis and steatohepatitis had no relationship with NRH, confirming different etiologies and onset pathways. The risk and predictive factors of NRH have been poorly investigated. As observed for other SOS lesions,8,19 the prevalence of NRH increases after oxaliplatin administration. On the contrary, patients receiving bevacizumab in association with chemotherapy had a lower prevalence of NRH. Similar findings were previously reported for SOS lesions by the MD Anderson group and by RubbiaBrandt et al.10,28 No correlation was demonstrated between the diagnosis of NRH and the number of cycles of
chemotherapy. Nevertheless, short and effective chemotherapy is always recommended to limit NRH, as any other CALI.34 Wicherts et al. observed a correlation between both c-glutamyltransferase and total bilirubin with NRH.12 This was not confirmed in the present study but other parameters correlated with the presence of NRH. First, the APRI score, recently proposed by Soubrane et al. to predict sinusoidal dilatation,27 was predictive of NRH with good sensitivity (76 %) and NPV (90 %). Of note, the present analysis identified exactly the same cut-off proposed by Soubrane et al. (APRI = 0.36), supporting the reliability of this threshold value. Second, we found that the lower the platelet count, the higher the prevalence of NRH. This correlation between NRH and platelet count suggests NRH as a possible cause of portal hypertension,15–18 even if the measurement of portal pressure is needed to confirm this hypothesis, and factors other than
Nodular Regenerative Hyperplasia and Resection TABLE 3 Short-term outcomes Overall (N = 478) (%)
NRH
p value
Yes (N = 87) (%) Mortality Overall morbidity Severe complications (grade III–V)
No (N = 391) (%)
3 (0.6)
1 (1.1)
2 (0.5)
NS
139 (29.1)
27 (31.0)
112 (28.6)
NS
54 (11.3)
11 (12.6)
43 (11.0)
NS
Liver dysfunction
17 (3.6)
8 (9.2)
9 (2.3)
Bile leak
33 (6.9)
5 (5.7)
28 (7.2)
Abdominal collection
29 (6.1)
5 (5.7)
24 (6.1)
NS
Renal dysfunction Pulmonary morbidity
8 (1.7) 53 (11.1)
3 (3.4) 12 (13.8)
5 (1.3) 41 (10.5)
NS NS
13 (14.9)
42 (10.7)
Blood transfusions Hospital stay
55 (11.5) 9 (4–114)
10 (5–68)
9 (4–114)
0.002 NS
NS NS
Hospital stay (continuous variable) is reported as median value (range) NRH nodular regenerative hyperplasia, NS not significant
TABLE 4 Univariate and multivariate analysis of predictive factors of postoperative liver failure
Age [70 years BMI [30 kg/m2
a
Univariate analysis
Multivariate analysis
p value
p value
NS
–
HR (95 % CI)
0.056
NS
ASA score III–IV
NS
–
Diabetes
0.030
NS
Arterial hypertension
NS
–
CTx regimen (oxaliplatin/irinotecan/both)
NS
–
CTx cycles C7 Total bilirubin [2 mg/dL
NS NS
– –
AST [35 UI/L
0.062
NS
ALT [40 UI/L
NS
–
GGT [50 UI/L
NS
–
Platelet count, 103/mm3 (\100/100 to 200/[200)
NS
–
APRI score [0.36
0.097
NS
b
NS
–
Major hepatectomy
0.007
0.043
2.954 (1.037–8.415)
NRH
0.002
0.021
3.391 (1.204–9.551)
ICG-R15 [10
BMI body mass index, CTx chemotherapy, ICG-R15 indocyanine green retention test at 15 min, HR hazard ratio, CI confidence interval, NS not significant, NRH nodular regenerative hyperplasia, AST aspartate aminotransferase, ALT alanine aminotransferase, GGT c-glutamyltransferase, APRI AST to platelet ratio index a
Available in 424 patients
b
Available in 263 patients
portal hypertension may impact platelet count in chemotherapy-treated patients (e.g. bone marrow toxicity or immune response). Finally, the prevalence of NRH was increased in patients with arterial hypertension (one-quarter of patients). An intrahepatic negative impact of high arterial pressure can be hypothesized but experimental studies are needed to confirm and elucidate this correlation. The combination of different laboratory data (APRI
score and platelet count) with clinical data may allow good NRH prediction. The last and most relevant issue concerns the clinical impact of NRH. To date, only one study by the Paul Brousse group analyzed this question in a small series (22 patients with NRH) and reported higher bile leak rates in the presence of NRH (27 vs. 0 %).12 The present large series (87 NRH patients of 478) did not confirm that
L. Vigano` et al.
finding: the bile leak rate was low (7 %) and similar between the two groups. A more relevant impact was observed: NRH was an independent predictive factor of postoperative liver failure. Liver failure risk increased from 2 % in patients without NRH to 9 % in patients with NRH. Outcomes worsened in relation to the severity of NRH: the incidence of liver failure was as high as 14 % in the presence of grades 2–3 NRH, reaching 25 % in case of major hepatectomy. No other form of CALI impacted the risk of liver failure. According to the present data, NRH, and not sinusoidal dilatation, is the true determinant of short-term outcomes in patients undergoing LR after chemotherapy: patients with sinusoidal dilatation without NRH had the same outcomes as patients with normal liver. The strict association between NRH and sinusoidal dilatation could explain the link between sinusoidal dilatation and poorer surgical outcomes in previous publications. NRH not only compromises liver function but can also cause portal hypertension.15–18 The negative impact of portal hypertension on postoperative outcomes is wellknown.35 In the present study, two patients in the NRH group developed severe postoperative ascites despite minor hepatectomies. In our series, portal pressure was not systematically measured, neither preoperatively nor intraoperatively, but the correlation observed between the platelet count and the prevalence of NRH suggests a causal link. Furthermore, the lower the platelet count the higher the risk of liver failure. Prospective studies with systematic portal pressure measurement are needed to fully ascertain the correlation among NRH, portal hypertension, and operative outcomes. The present study has a relevant clinical impact. First, any future study regarding CALI should include NRH. Silver reticulin stainings are recommended to avoid underestimating the prevalence of NRH, and the Wanless score to assess the severity of the lesions. Second, the impact of NRH on postoperative outcomes underlines the importance of diagnosing it preoperatively. To diagnose NRH, radiological investigations offer a limited contribution, while the APRI score and platelet count, together with clinical data (oxaliplatin or bevacizumab administration), may be helpful. The diagnostic value of preoperative biopsy has been denied for steatohepatitis and sinusoidal dilatation because of their heterogeneous distribution in the liver.13 Theoretically, NRH has a more homogeneous distribution and is ubiquitary in moderate to severe (grades 2–3) forms. Preoperative biopsy could be considered in selected high-risk patients (for instance, patients with high APRI score/low platelet count candidates for major hepatectomies) and its usefulness should be investigated. Finally, the potential association between NRH and portal hypertension should be explored. Spleen
size could be taken into account (data not available in the present series). Theoretically, a transjugular liver biopsy could allow both the diagnosis of NRH and the evaluation of the presence and severity of portal hypertension, but at present it cannot be recommended on a routine basis. Even if the present study is a non-intention-to-treat retrospective analysis, the large cohort size, the inclusion of all consecutive resected patients, and the systematic review of the specimens by two experienced pathologists guarantee a high reliability of data. CONCLUSIONS NRH is a clinically relevant CALI; it may cause portal hypertension and increases the risk of postoperative liver failure. Oxaliplatin increases the incidence of NRH, while bevacizumab seems to attenuate it. The APRI score and platelet count suggest the presence of NRH. Patients scheduled for major hepatectomy who are suspected of having NRH on the basis of clinical and laboratory data may need more liberal access to portal vein embolization, both as a preparation and also as a stress test for postoperative liver failure. ACKNOWLEDGMENT Lorenzo Capussotti, MD, and Gilles Mentha, MD, passed away unexpectedly during the final stages of manuscript preparation. They both contributed greatly to the improvement and progress of hepato-biliary-pancreatic surgery, and will be greatly missed by all of us. CONFLICT OF INTEREST Luca Vigano`, Laura Rubbia-Brandt, Giovanni De Rosa, Pietro Majno, Serena Langella, Christian Toso, Gilles Mentha, and Lorenzo Capussotti have no conflict of interest to declare.
REFERENCES 1. Imamura H, Seyama Y, Kokudo N, et al. One thousand fifty-six hepatectomies without mortality in 8 years. Arch Surg. 2003; 138:1198–206. 2. Jarnagin WR, Gonen M, Fong Y, et al. Improvement in perioperative outcome after hepatic resection: analysis of 1803 consecutive cases over the past decade. Ann Surg. 2002;236:397–406. 3. Andres A, Toso C, Moldovan B, et al. Complications of elective liver resections in a center with low mortality: a simple score to predict morbidity. Arch Surg. 2011;146(11):1246–52. 4. Pawlik TM, Choti MA. Surgical therapy for colorectal metastases to the liver. J Gastrointest Surg. 2007;11(8):1057–77. 5. Simmonds PC, Primrose JN, Colquitt JL, Garden OJ, Poston GJ, Rees M. Surgical resection of hepatic metastases from colorectal cancer: a systematic review of published studies. Br J Cancer. 2006;94(7):982–99. 6. Vigano` L, Russolillo N, Ferrero A, Langella S, Sperti E, Capussotti L. Evolution of long-term outcome of liver resection for colorectal metastases: analysis of actual 5-year survival rates over two decades. Ann Surg Oncol. 2012;19(6):2035–44.
Nodular Regenerative Hyperplasia and Resection 7. Vauthey JN, Pawlik TM, Ribero D, et al. Chemotherapy regimen predicts steatohepatitis and an increase in 90-day mortality after surgery for hepatic colorectal metastases. J Clin Oncol. 2006; 24(13):2065–72. 8. Rubbia-Brandt L, Audard V, Sartoretti P, et al. Severe hepatic sinusoidal obstruction associated with oxaliplatin-based chemotherapy in patients with metastatic colorectal cancer. Ann Oncol. 2004;15(3):460–6. 9. de Meijer VE, Kalish BT, Puder M, Ijzermans JNM. Systematic review and meta-analysis of steatosis as a risk factor in major hepatic resection. Br J Surg. 2010;97(9):1331–39. 10. Rubbia-Brandt L, Lauwers GY, Wang H, et al. Sinusoidal obstruction syndrome and nodular regenerative hyperplasia are frequent oxaliplatin-associated liver lesions and partially prevented by bevacizumab in patients with hepatic colorectal metastasis. Histopathology. 2010;56(4):430–39. 11. Nakano H, Oussoultzoglou E, Rosso E, et al. Sinusoidal injury increases morbidity after major hepatectomy in patients with colorectal liver metastases receiving preoperative chemotherapy. Ann Surg. 2008;247(1):118–24. 12. Wicherts DA, de Haas RJ, Sebagh M, et al. Regenerative nodular hyperplasia of the liver related to chemotherapy: impact on outcome of liver surgery for colorectal metastases. Ann Surg Oncol. 2011;18(3):659–69. 13. Vigano` L, Ravarino N, Ferrero A, Motta M, Torchio B, Capussotti L. Prospective evaluation of accuracy of liver biopsy findings in the identification of chemotherapy-associated liver injuries. Arch Surg. 2012;147(12):1085–91. 14. Aloia T, Sebagh M, Plasse M, et al. Liver histology and surgical outcomes after preoperative chemotherapy with fluorouracil plus oxaliplatin in colorectal cancer liver metastases. J Clin Oncol. 2006;24(31):4983–90. 15. Hubert C, Sempoux C, Horsmans Y, et al. Nodular regenerative hyperplasia: a deleterious consequence of chemotherapy for colorectal liver metastases? Liver Int. 2007;27(7):938–43. 16. Schwarz L, Faitot F, Soubrane O, Scatton O. Splenic artery ligation for severe oxaliplatin induced portal hypertension: A way to improve postoperative course and allow adjuvant chemotherapy for colorectal liver metastases. Eur J Surg Oncol .2014; 40(6):787–88. 17. Al-Mukhaizeem KA, Rosenberg A, Sherker AH. Nodular regenerative hyperplasia of the liver: an under-recognized cause of portal hypertension in hematological disorders. Am J Hematol. 2004;75(4):225–30. 18. Sarin SK, Khanna R. Non-cirrhotic portal hypertension. Clin Liver Dis. 2014;18(2):451–76. 19. Vigano` L, Capussotti L, De Rosa G, De Saussure WO, Mentha G, Rubbia-Brandt L. Liver resection for colorectal metastases after chemotherapy: impact of chemotherapy-related liver injuries, pathological tumor response, and micrometastases on long-term survival. Ann Surg. 2013;258(5):731–40. 20. Kleiner DE, Brunt EM, Van Natta M, et al. Design and validation of a histological scoring system for nonalcoholic fatty liver disease. Hepatology. 2005;41(6):1313–21.
21. Wanless IR. Micronodular transformation (nodular regenerative hyperplasia) of the liver: a report of 64 cases among 2,500 autopsies and a new classification of benign hepatocellular nodules. Hepatology. 1990;11(5):787–97. 22. Vigano` L, Langella S, Ferrero A, Russolillo N, Sperti E, Capussotti L. Colorectal cancer with synchronous resectable liver metastases: monocentric management in a hepatobiliary referral center improves survival outcomes. Ann Surg Oncol. 2013;20(3): 938–45. 23. Mentha G, Roth AD, Terraz S, et al. ‘Liver first’ approach in the treatment of colorectal cancer with synchronous liver metastases. Dig Surg. 2008;25(6):430–35. 24. Dindo D, Demartines N, Clavien PA. Classification of surgical complications: a new proposal with evaluation in a cohort of 6336 patients and results of a survey. Ann Surg. 2004;240(2): 205–13. 25. Capussotti L, Vigano` L, Giuliante F, Ferrero A, Giovannini I, Nuzzo G. Liver dysfunction and sepsis determine operative mortality after liver resection. Br J Surg. 2009;96(1):88–94. 26. Capussotti L, Ferrero A, Vigano` L, Sgotto E, Muratore A, Polastri R. Bile leakage and liver resection: Where is the risk? Arch Surg. 2006;141(7):690–94. 27. Soubrane O, Brouquet A, Zalinski S, et al. Predicting high grade lesions of sinusoidal obstruction syndrome related to oxaliplatin-based chemotherapy for colorectal liver metastases: correlation with post-hepatectomy outcome. Ann Surg. 2010; 251(3):454–60. 28. Ribero D, Wang H, Donadon M, et al. Bevacizumab improves pathologic response and protects against hepatic injury in patients treated with oxaliplatin-based chemotherapy for colorectal liver metastases. Cancer. 2007;110(12):2761–7. 29. Morris-Stiff G, White AD, Gomez D, et al. Nodular regenerative hyperplasia (NRH) complicating oxaliplatin chemotherapy in patients undergoing resection of colorectal liver metastases. Eur J Surg Oncol. 2014;40(8):1016–20. 30. Aloia TA, Vauthey JN. Management of colorectal liver metastases: past, present, and future. Updates Surg. 2011;63(1):1–3. 31. Snover DC, Weisdorf S, Bloomer J, McGlave P, Weisdorf D. Nodular regenerative hyperplasia of the liver following bone marrow transplantation. Hepatology. 1989;9(3):443–8. 32. Duvoux C, Kracht M, Lang P, Vernant JP, Zafrani ES, Dhumeaux D. Nodular regenerative hyperplasia of the liver associated with azathioprine therapy. Gastroenterol Clin Biol. 1991;15(12):968– 73. 33. Washington K, Lane KL, Meyers WC. Nodular regenerative hyperplasia in partial hepatectomy specimens. Am J Surg Pathol. 1993;17(11):1151–8. 34. Mentha G, Terraz S, Andres A, Toso C, Rubbia-Brandt L, Majno P. Operative management of colorectal liver metastases. Semin Liver Dis Management of colorectal liver metastases: past, present, and future 2013;33(3):262–72. 35. Allard MA, Adam R, Bucur PO, et al. Posthepatectomy portal vein pressure predicts liver failure and mortality after major liver resection on noncirrhotic liver. Ann Surg. 2013;258(5):822–9.
