World Journal of Pathology Volume No 9

Original Article Open Access

Nodular Regenerative Hyperplasia and sinusoidal hepatic lesions in oxaliplatin based chemotherapy

1 Azcue P,2 Mercado M,3Amat I, 4Galbete A, 5 5Gomez-Dorronsoro ML

  • 1 Institut de Recherches International Servier. Paris, France.
  • 2,3,5 Department of Patholog, CHNavarra. Pamplona, Spain,
  • 4 Unit of Methodology, Navarrabiomed. Pamplona, Spain
  • Submitted:Thursday, May 21, 2020
  • Accepted: Saturday, June 20, 2020
  • Published: Wednesday, July 1, 2020

This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited

Abstract

Introduction

Nodular Regenerative Hyperplasia (NRH), Sinusoidal Obstruction Syndrome (SOS) and Sinusoidal Dilatation (SD) are the most recognized patterns of drug-induced liver injury secondary to oxaliplatin based regimens in colorectal liver metastases (CRLM). The use of different combinations in chemotherapy treatments, an incidence reported for NRH that ranges between 4.8% and 15%, and a considerable variability for other vascular lesions, makes the evaluation a challenge.

Study Design

A historic prospective maintained database cohort of 160 tissue samples of CRLM.

Methods

The aim of this study is to evaluate the incidence of vascular hepatic lesions (SD, SOS and NRH) due to oxaliplatin based regimens. Additionally, it details a series of seven cases of NHR, its relationship with other vascular alterations, type of treatment and the presence or not of blue liver syndrome.

Results

Univariate analysis showed association between preoperative use of oxaliplatin with or without biological agents and developing SD (p&0.05). Notably, the use of 5-FU was also found to increase the risk of SD. Multivariate analysis confirmed the association between oxaliplatin and developing SD (p=0.021). All seven cases of NRH (incidence of 6%) were treated with FOLFOX regimen with at least 6 cycles. These cases presented severe SD and diagnosis of SOS and represented 31.8% of all patients with SOS.

Conclusions

Oxaliplatin based chemotherapies regimens are associated with SD, SOS, NRH and blue liver syndrome. These vascular alterations seem to be part of an evolutionary process. The role of 5-FU although not extensively studied, could act as a synergic factor.

Key Words

Nodular Regenerative Hyperplasia, Sinusoidal Obstruction Syndrome, Sinusoidal Dilatation, Colorectal liver metastasis, oxaliplatin

Introduction

Surgical resection remains the only treatment with a curative potential for patients suffering from colorectal liver metastasis (CRLM). Preoperative chemotherapy with or without biological agents has proven beneficial for tumour downsizing, shrinking and recurrence and has allowed surgical unresectable lesions to become resectable [1, 2]. Moreover, it has been reported a longer progression free survival and overall survival [3 4]. Preoperative chemotherapy and biological agents is also recommended for patients with resectable metastatic lesions, since it reduces relapse rate and increases the negative margin (R0) resection preserving mores liver remnant [1,5]. The addition of oxaliplatin, irinotecan and capecitabine to the classic chemotherapy regimens based on 5-fluorouracil (5-FU) remain the most recommended preoperative treatments in different combinations for CRLM [6, 7]. However, a negative effect of the addition of these drugs as histopathological liver lesions has been studied by de Leve et al., and Rubbia-Brandt et al., These studies focus on the repercussion on the remaining hepatic parenchyma by evaluating the integrity of the sinusoidal wall and its relationship with treatment [8, 9].

In this context, Vauthey et al., described these effects as steatosis, steatohepatitis and sinusoidal injury [10]. The most important vascular lesions described within chemotherapy regimens based on oxaliplatin are Sinusoidal Dilatation (SD), the presence of perisinusoidal fibrosis in the Sinusoidal Obstruction Syndrome (SOS) and Nodular Regenerative Hyperplasia (NRH) [1113]. Finally, the blue liver syndrome has been described as a macroscopic expression of advanced vascular lesions [14].

The incidence of SD, SOS and NRH varies greatly among published series. This is probably due to a lack of standardization and heterogenic histologic description of these lesions. Nevertheless, Pathology reporting protocols clearly recommends that a histological report should include the evaluation of these alterations in the non-tumoural post-treatment liver [15,16]. Furthermore, the repercussion in morbi-mortality and the effect on outcome is still unclear [17].

Longer survival rates have been published with the use of biological agents such as bevacizumab and cetuximab in addition to standard chemotherapy regimens. A potential benefit of bevacizumab, in addition to oxaliplatin based regimens, has even been published as “protector” for developing vascular hepatic lesions [1820]. In contrast, the histological effects in the liver of cetuximab have not been extensively studied.

Liver NRH and SOS are the most severe lesions within the spectrum of the vascular damage attributed to oxaliplatin based treatments. After the first reports alerting about these alterations, different series have established an incidence of NRH, varying from 4.8% to 15% [2022]. Among the liver vascular lesions mentioned previously, the NRH is the least frequent and its impact is poorly known. Likewise, there is considerable variability in the incidence published when evaluating SD and SOS due to chemotherapy.

As a result, the objective of the present manuscript is to establish the incidence of vascular hepatic lesions, namely SD, SOS and NRH, due to oxaliplatin based regimens in a cohort of 160 surgical specimens of CRLM from our hospital and to describe the occurrence of seven cases of NHR.

Patients and Methods

A historic prospective maintained database of 160 liver resections that underwent preoperative chemotherapy and surgery due to CRLM was assessed for SD, SOS and NRH. The resections, with curative intention, took place between 2007 and 2013 at the Pathology Department of the Hospital Complex of Navarra (Pamplona, Spain). All patients were revised and approved by the Multidisciplinary Committee of Digestive Tumours board.

Preoperative chemotherapy was defined as at least six cycles of any chemotherapy regimen within six months prior to surgical liver resection. Only specimens with available non-tumoural liver parenchyma >20mm away from the metastasis for histological evaluation were included. Each resection was then carefully reviewed for metastatic synchronicity or metachronicity, primary localization, type of chemotherapy regimens and biological agents, number of chemotherapy cycles and date of surgery.

Twelve (12) patients were lost either for not meeting the criteria abovementioned or insufficient pathological or clinical data during this assessment. The remaining 148 liver resections, including primary clinical characteristics, chemotherapy and type of biological agent, are described in Table 1. The series consist of 44 women and 104 men, with a median age in years of 64 (Standard Deviation 9.9). Synchronous metastases were reported in 91 cases and metachronous in 57. Thirty-two patients did not receive any preoperative treatment and acted as control group.

Table 1: Clinical and Treatment Characteristics .auto-style1 { text-align: right; }

N (%)
Age [yr]* 64 [9.9]
Gender
Female 44 (29.7)
 Male 104 (70.3)
Primary Localization
 Colon 94 (63.5)
 Rectum 54 (36.5)
Type of Metastasis  
 Synchronous 91 (61.5)
Metachronous 57 (38.5)
Chemotherapy
 Oxaliplatin based 99 (67.8)
 5-Fluorouracil 88 (59.5)
 Capecitabine 21 (14.4)
 Irinotecan 17 (11.5)
Biological agent
 Bevacizumab 39 (26.4)
 Cetuximab 23 (15.5)
No treatment 32 (21.6)
* Values are mean.

Ninety-nine (99) cases received oxaliplatin based regimens, eighty (80/99) were in combination with 5-FU with or without irinotecan/capecitabine. Seventeen (17) cases did not received oxaliplatin and were based in either irinotecan or capecitabine, of which eight (8/17) were in combination with 5-FU.

Within the oxaliplatin based group, fifty-one (51/99) received biological agent (34 bevacizumab and 17 cetuximab). In the group not receiving oxaliplatin, eleven (11/17) received biological agent (5 bevacizumab and 6 cetuximab).

All clinical decisions were made homogenously at Multidisciplinary Hepato-oncology board.

Pathological Study

All tissue was formalin-fixed and paraffin-embedded. Morphological analysis was made on haematoxylin and eosin (HE), Masson’s trichrome and reticulin stains. Histopathological review was made by two different expert pathologists blinded to the medical history or chemotherapy regimens. To evaluate and classify histologically the liver damage secondary to chemotherapy a protocol developed by Gómez Dorronsoro et al., [23] was used for our evaluation.

The slides were reviewed for histological features of SD, NRH and perisinusoidal fibrosis for SOS. These lesions were evaluated and graded according to the degree presented by Rubbia-Brandt et al., [20]. SD was graded 0, 1, 2 or 3: 0, absent; 1, mild (centrilobular involvement limited to one-third of the lobular surface); 2, moderate (centrilobular involvement in two-thirds of the lobular surface); and 3, severe (complete centrilobular involvement). As an evolution of SD, the presence of perisinusoidal fibrosis was used to determine histological SOS as present or absent, as is described by consensus [23] protocol as high grade sinusoidal lesions.

Finally, NRH was defined as a micronodular transformation of the liver on behalf of hepatocyte nodules delimited by atrophic trabecules in the absence of fibrous septa, which is evident with HIM in the majority of examined areas, and then confirmed with reticuline. NRH was evaluated as present or absent.

Further review was made for the NRH cases for clinical signs including portal hypertension, hepatic insufficiency, embolization, blue liver and type of surgery.

Statistical Analysis

For statistical analysis purposes all variables were treated as dichotomic variables except for age. SD was considered as positive if any grade 1, 2 or 3 was assessed by the expert pathologist and negative for grade 0.

Association between variables was determined using Fisher’s test and χ² test. Univariate and multivariate analysis was made using logistic regression model. The variables used were the presence or absence between dilatation any grade, presence or absence of SOS, the use of oxaliplatin based chemotherapy, other chemotherapy used, biological agent, localization, sex and synchronous or metachronous metastasis. Statistical significance was set as two tailed p-value of <0.05.

This study has been performed in accordance with the World Medical Association Declaration of Helsinki.

Results

Our series consisted of 148 liver resections, where 116 received preoperative chemotherapy and 32 received only surgery as treatment and acted as a control group.

Among the group treated with preoperative chemotherapy, SD was present in 47/116 specimens, of which 44/47 were treated with a regimen containing oxaliplatin and 16/47 in combination with bevacizumab. As an evolution of the previous lesion, SOS, as presence of fibrosis (Figure 1)., was present in 22/116 specimens, all of them with a regimen containing oxaliplatin and only 6/22 in combination with bevacizumab. NRH was found on 7/116 specimens, all of them 7/7 treated with a FOLFOX regimen (5-FU + Leucovorin + Oxaliplatin) and 3/7 in combination with bevacizumab.

 

Figure 1: Masson trichrome a)Centrilobular sinusoidal dilatation X200 b)Endothelial sinusoids disruption, hepatocellular atrophy and perisinusoidal fibrosis (SOS) X200

Notably, among the control group there were no findings of SD, SOS or NRH in any specimen.

The association analysis in Table 2 highlights the interrelationship between the vascular lesions. From the 47 specimens with SD, 22/47 presented SOS and 7/47 NRH. All cases of SOS presented along with SD and all cases of NRH had SOS and SD. Statistical significance was achieved between the three events of interest.

Table 2: Association analysis between events of interest in the preoperative treatment group .auto-style1 { text-align: right; }

SOS
Yes (%)
No (%)
  NRH
Yes (%)
No (%)
SD Yes 22 (46.8%) P<0.0011 7 (14.9%)


p=0.0011
25 (53.2%) 40 (85.1%)
No 0 (0.0%) 0 (0.0%)
69 (100%) 69 (100%)
SOS Yes -



-
7 (31.8%)



P<0.0011
15 (68.2%)
No - 0 (0.0%)
94 (100%)
1 Estimated using Fisher’s exact test method, two-tailed;SD: Sinusoidal Dilatation; SOS: Sinusoidal Obstruction Syndrome; NRH: Nodular Regenerative Hyperplasiap value considered significant when<0.05

Chemotherapy subgroup analysis

A subgroup analysis was performed by treatment group (oxaliplatin and control group), the results are presented in Table 3 Oxaliplatin based chemotherapy is associated with the development SD (p=0.059) and SOS (p=0.039) when compared to other chemotherapies in independence of biologic agent used. One case of SD was found for a patient receiving 5-FU without oxaliplatin.

Table 3: Subgroup analysis by treatment group .auto-style1 { text-align: right; }

SD
Yes (%)
No (%)
SOS
Yes (%)
No (%)

NRH
Yes (%)
No (%)
Oxaliplatin based chemotherapy
Other treatments Ox 44 (44.4%)   22 (22.2%) p=0.039² 7 (7.1%) p=0.591²
55 (55.6%)   77 (77.8%) 92 (92.9%)
Others 3 (17.6%) p=0.059² 0 (0.0%) 0 (0.0%)
14 (82.4%)   17 (100%) 17 (100%)
Bevacizumab Ox 28 (43.1%)   16 (24.6%) p=0.4281 4 (6.2%) p=0.689²
37 (56.9%)   49 (75.4%) 61 (93.8%)
Ox+ Bev 16 (47.1%) p=0.7051 6 (17.6%) 3 (8.8%)
18 (52.9%)   28 (82.4%) 31 (91.2%)
5-FU Ox 6 (31.6%)   2 (10.5%) p=0.229² 0 (0.0%) p=0.340²
13 (68.4%)   17 (89.5%) 19 (100%)
Ox+ 5-FU 38 (47.5%)   20 (25.0%) 7 (8.8%)
42 (52.5%) p=0.2091 60 (75.0%) 73 (91.3%)
No preoperative treatment group
Oxaliplatin None 0 (0.0%)   0 (0.0%) p=0.001² 0 (0.0%) p=0.193²
32 (100%)   32 (100%) 32 (100%)
Ox 44 (44.4%)   22 (22.2%) 7 (7.1%)
55 (55.6%) p<0.001² 77 (77.8%) 92 (92.9%)
5-FU None 0 (0.0%)   0 (0.0%) p=0.002² 0 (0.0%) p=0.187²
32 (100%)   32 (100%) 32 (100%)
5-FU 39 (44.3%)   20 (22.7%) 7 (8.0%)
49 (55.7%) p<0.001²
68 (77.3%) 81 (92.0%)
1 Estimated using Chi-squared method;2 Estimated using Fisher’s exact test method, two-tailed;SD: Sinusoidal Dilatation; SOS: Sinusoidal Obstruction Syndrome; NRH: Nodular Regenerative Hyperplasia; Ox: Oxaliplatin based chemotherapy; 5-FU: 5-Fluorouracil based chemotherapy; Bev: Bevacizumabp value considered significant when <0.05

When comparing oxaliplatin based chemotherapy group with the group without preoperative treatment, a statistical significant association was found on both SD and SOS (both p<0.001). Furthermore, when comparing the 5-FU with the control group, a statistical significant association was also found on both SD and SOS (p=0.001 and p=0.002 respectively).

Similarly, the univariate analysis showed association between preoperative use of oxaliplatin based chemotherapy with or without biological agents and developing SD (p<0.05). Notably, the use of 5-FU was also found to increase the risk of both liver vascular lesions, although it did not reach statistical significance (p=0.09). Additionally, our results did not confirm any protective effect of bevacizumab on SD (p=0.632), nor cetuximab (p=0.747).

Finally, the multivariate analysis confirmed a statistically significant association between oxaliplatin based chemotherapy and developing SD (p=0.021).

NRH description of cases

NRH description of casesThere were 7 cases of NRH (Figure 2) which presented morphological changes of SD and diagnosis of SOS as summarized in Table 4. These cases represent 31.8% of all patients with SOS. Notably, all NRH cases were men and were treated with FOLFOX regimens with at least 6 cycles at the moment of assessment. These patients presented a median age of 62 (range:47-83). Two underwent embolization, one presented portal hypertension, one hepatic insufficiency and blue liver was reported in 4 patients who afterwards were diagnosed of NRH. A major or complex type of hepatectomy was seen in 6 of the 7 patients.

 

Figure 2: NRH a) Fresh cut section of a liver with micronodular transformation b) Nodular regenerative Hyperplasia. Reticulin staining X100

Table 4:  Description of NRH

Age Gender Location Type of metastases Preoperative regimen Adjuvant Agent # of cycles Type of Surgery Histological findings Clinical findings
62 Male Rectum Synchronous FOLFOX Cetuximab 6 Left hepatectomy + limited X4 SD (3),
SOS
Embolization Hep insuff.
67 Male Rectum Metachronous FOLFOX Bevacizumab 6 Left hepatectomy SD (2),
SOS
Blue Liver
76 Male Rectum-Sigma Synchronous FOLFOX None 12 Left hepatectomy + seg. VIII SD (3),
SOS
Blue Liver
75 Male Rectum Synchronous FOLFOX Bevacizumab 6 Seg. V SD (2), SOS, Steatosis -
69 Male Colon Synchronous FOLFOX Cetuximab 6 Hepatectomy of seg. II-II + IV SD (2),
SOS
Blue Liver
50 Male Colon Synchronous FOLFOX Cetuximab 7 Hepatectomy of seg. II, IIIab, IVb SD (2),
SOS
Blue Liver
59 Male Rectum Synchronous FOLFOX Bevacizumab 6 Left hepatectomy + seg. V-VIII SD (2),
SOS
Embolization
Seg: segmentomy; Hep. insuff: Hepatic insufficiency; SD (x): Sinusoidal Dilatation (grade); FOLFOX: 5-FU/Leucovorin/Oxaliplatin.

In our series, nine patients were reported with blue liver macroscopic appearance (Figure 3). All of them were treated with oxaliplatin based chemotherapy and diagnosed with high grade SD and SOS. In four of them NRH was present.

 

Figure 3: Blue liver, Hepatic surface.

Discussion

The findings of this study have demonstrated an association between preoperative oxaliplatin based chemotherapy in CRLM patients and the development of histological vascular liver lesions. The use of biological agents has not proven beneficial as “protector” of the liver. Furthermore, this study has provided a detailed description of seven NRH cases and its relationship with FOLFOX chemotherapy regimen, SD, SOS and blue liver syndrome.

Oxaliplatin based chemotherapy is the gold standard treatment for colorectal cancer especially in the metastatic setting. It has been associated with vascular liver lesions, mainly with SD, SOS and, less frequently, NRH [13, 2426].

In our study the incidence of SD in oxaliplatin based regimens is consistent with what has been reported in literature. Such incidence varies depending on the grading and therefore definition of SD. If SD is considered only in severe dilatation (grade 2 or 3), the incidence in our series is of 26,7% while previously reported range is between 9,7% and 23% [27]. However, if SD is considered as part of an evolutive process, mild dilatation (grade 1) is also comprised as presence of SD, in our series the incidence is of 40,5%. This result is slightly underrepresented compared to the incidence ranged between 52% and 56% reported in literature [27, 28] and up to 79% first described by Rubbia-Brandt et al., [20].

Our study has shown oxaliplatin based chemotherapy as a predictor for developing SD. In the multivariate analysis, when SD was considered as positive when graded 1, 2 or 3, showed a statistical significant (p=0.021) association with oxaliplatin based chemotherapy. Moreover, when SD was considered as positive only when graded 2 or 3, p value was in the limit for statistical significance (p=0.057). Previous results suggest the relationship of oxaliplatin with the entity of SD despite the scoring used.

There is no standard histological classification for SOS. Histopathologic vascular liver lesions, such as SD, perisinusoidal haemorrhage, fibrosis and NRH, are included together in this broad spectrum [22], resulting also in a discordance in terminology among series [28]. Recently, a more objective assessment of sinus damage is being attempted through the immunohistochemical study with CD 31/34 AML to digitally assess the endothelization of these sinusoids and establish Indices of Sinusoidal Damage [14, 16].

The findings of this study are biologically plausible since the physiological process of sinusoidal lesion usually begins as a mild dilatation (SD). As it the dilatation progresses, the sinusoidal wall could be compromised and ruptured, sometimes peliosis can be found, and finally perisinusoidal fibrosis is formed (SOS) [29]. Besides biologic processes involved in the pathogenesis of SOS [27] oxidative stress, remodelling of the extracellular matrix and the coagulation cascade, gene expression analyses have suggested angiogenic pathways [12].

NRH can also occur within this setting of toxic liver injury previously reported by Rubbia-Brant et al., [20], in which the macroscopic examination shows a liver with a micro-macro nodular configuration often alongside blue liver [27].

Published literature reports that incidence varies between 4.8% and 15% [21, 22, 27]. In our cohort, the 7 cases diagnosed with NRH represent 6% among the treated group and 7.1% among the ones treated with oxaliplatin, therefore greater numbers are needed to study a specific correlation with primary and/or concomitant treatment. All 7 cases of NRH, presented either SD grade 2 or 3 and diagnosis of SOS, supporting the evolutionary process hypothesis. Notably, except for one exception all cases underwent a mayor or complex hepatectomy, indicative of an already fragile patient due to surgery with the additional liver damage.

SOS and other hepatic sinusoidal abnormalities may show a characteristic macroscopic aspect called the “blue liver” or “blue liver syndrome” [8, 9 26, and 30]. There is a relationship between blue liver and SOS and NRH since we found that out of the 9 (29%) patients were reported with blue liver, all presented SD grade 2 (33.3%) or 3 (66.6%) and all with were treated with oxaliplatin based chemotherapy. Furthermore, all 9 cases presented SOS and 4 presented the final stage of NRH, suggesting the macroscopical finding of blue liver might be indicative of advanced hepatic vascular lesions.

The effect on vascular alterations of 5FU in combination with oxaliplatin, irinotecan or capecitabine based regimens, has not been extensively studied. Although not the main object of this manuscript, this study found a possible correlation for 5-FU and the development of SOS in the multivariate analysis (p=0.067) in accordance to some publications [25, 26, 28] as a possible synergic effect.

These results should be further studied since from the 88 patients treated with 5-FU, 80 were in combination with oxaliplatin and 8 with either irinotecan or capecitabine. Additionally, we found a reduced incidence of SD in irinotecan based regimens (p=0.053), also in line with some publications [13]. However, the number of patients treated with irinotecan in our series is limited (17 patients).

Longer survival rates have been proven with the use of monoclonal antibodies in addition to oxaliplatin based regimens. It has been also published a potential benefit of the use of Bevacizumab as “protective factor” for developing sinusoidal lesions [19, 20, 31], and even with Cetuximab [32], however this was not evident in our analysis.

Out of the scope of this study are the clinical implications of our histological findings in morbidity and mortality to establish prognostic factors, a prospective study is needed. The main limitation of our study is the number of liver resections given the low incidence of previously discussed hepatic vascular alterations. With more events of interest, a more powerful subgroup analysis could be performed, especially for NRH.

Conclusions

In conclusion, sinusoidal lesions and NHR are not frequent; the incidence of these vascular lesions in our series is similar to others reported in literature. Oxaliplatin based chemotherapy regimens, have a relationship with the development of these sinusoidal lesions and with the appearance of NRH. The role of 5-FU although not extensively studied, seems to act as a synergic factor for vascular alterations. Preventive strategies such as the use of bevacizumab are still not clear. These vascular alterations are part of an evolutionary process that starts with a mild SD and may progress to fibrosis and SOS and finally NRH.

Learning Points

1. Systemic Oxaliplatin- based chemotherapies are associated with sinusoidal lesions in liver parenchyma.

2. Sinusoidal dilatation, sinusoidal obstruction syndrome and nodular regenerative hyperplasia are part of an evolutionary process.

 3.5-Fluorouracil seems also to have a synergic effect on these vascular lesions when in chemotherapy combined therapies.

List of abbreviations used

5-FU: 5-Fluorouracil

CRLM: Colorectal Liver Metastasis

 FOLFOX: Chemotherapy regimen based on 5-Fluorouracil + Leucovorin + Oxaliplatin

NRH: Nodular Regenerative Hyperplasia

SD: Sinusoidal Dilatation

 SOS: Sinusoidal Obstruction Syndrome

Declaration of Interest

PA works for Institut de Recherches International Servier (I.R.I.S.) however, there were no affiliation or financial involvement with this or any other organization or entity, with financial or scientific interest, with the subject matter or materials discussed in the manuscript.

All other authors reported no conflicts of interest.

Authors' Contribution

PA designed the study, contributed with data acquisition, performed data analysis and interpretation, draft writing, review and edition of final manuscript,

MGD conceptualized the study, participated in the study design, literature search, read, revised and approved the final manuscript for submission,

MM participated in the acquisition of data, methodology and interpretation the histological slides, review and edition of the final manuscript,

IA participated in the acquisition of data, interpreted the histological slides, review and edition of the final manuscript,

AG performed the analysis and interpretation of data, software management and reviewed and edit and approved the final manuscript.

All authors have read and agreed to the published version of the manuscript.

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