Review ArticleClinical Characteristics and Management of Patients With Concomitant Liver Cirrhosis and Lymphoma: A Systematic Review
Graphical Abstract
Introduction
Liver cirrhosis and malignancy represent significant public health issues due to their high incidence.1 As both diseases are quite common in the general population, there is a risk of simultaneously suffering liver cirrhosis and malignancy.2
Liver cirrhosis represents the final stage of liver disease with various underlying pathogenesis. The distinction between compensated and decompensated stages is made upon the presence of clinical signs of portal hypertension and/or liver impairment (ie, ascites, jaundice, variceal bleeding, encephalopathy). The prognosis for patients with decompensated liver disease is dismal compared to the compensated stage (median survival two years vs. 12 years).2 The prevalence of chronic disease and liver cirrhosis is estimated to be 100 (range 25-400) per 100,000 subjects, with significant variations between regions.3 The incidence rate is around 14-26 per 100,000 subjects per year.2 However, the actual incidence and prevalence in the general population are difficult to assess, as many cases with compensated liver cirrhosis are not recognized.4 The leading causes of liver disease worldwide are hepatitis C virus (HCV) and alcohol, followed by non-alcoholic fatty liver disease (NAFLD) and hepatitis B virus (HBV) infection. Other causes represent less than 2% of all causes of cirrhosis.3 Prognostication and assessment of the severity of liver cirrhosis are mainly based on 2 models. The Child-Pugh score based on prothrombin time, albumin and bilirubin levels, presence of ascites, and encephalopathy ranges from A to C, with the 5 year overall survival (OS) of 70% in Child A compared to 25% in stage C.4 The other score, MELD (Model for End-Stage Liver Disease), and its modification MELD-Na determine the priority for liver transplantation in decompensated patients.3,5
Liver cirrhosis is the major risk factor for developing hepatocellular cancer (HCC). However, the risk of developing other malignancies also increases.1 The incidence of lymphoma in patients with liver cirrhosis is uncertain due to the rarity of both diseases in one patient.
Lymphomas represent approximately 4.7% of all malignant tumors and are divided into 2 main types, namely Hodgkin and Non-Hodgkin lymphoma (NHL).1 NHLs can be divided into indolent and aggressive histology. Despite the wide variety of treatment options for lymphoma patients, treatment is often tailored according to the patient's age, comorbidity status, patient preferences, etc.6 Due to quite limited data on treating patients with lymphoma and liver cirrhosis, the management of these patients is mainly referred to the current oncology recommendations. Although current treatment protocols for lymphomas include guidance for dose reduction in patients with deranged liver function tests, there is no specific guidance for liver cirrhosis patients. Furthermore, extensive studies which report the outcome of liver cirrhosis patients treated according to these protocols are lacking as patients with diagnosed liver cirrhosis are mainly excluded from clinical trials.7 In 2016, the European Society of Medical Oncology recommended a multidisciplinary approach to evaluate the severity of cirrhosis and malignancy when choosing the best treatment approach.2
Since there are no standard guidelines on treating patients with liver cirrhosis and lymphoma, we conducted a systematic review to summarize all publications that analyzed patients with lymphoma who were previously or concomitantly diagnosed with liver cirrhosis. We focused on several aims. First, we examined the cause of liver cirrhosis and types of lymphomas. Secondly, we examined treatment options and causes of treatment reductions and modifications. Third, we sought to determine the risk of side effects and death due to chemo(immuno)therapy.
The study was done according to the Preferred Reporting Items guidelines for Systematic Reviews and Meta-analysis.8
Data were extracted with respect to PICOS (Population, Intervention, Comparison, Outcome, and study design). The target population consisted of patients with liver cirrhosis and lymphoma. The intervention was lymphoma treatment, and the comparator was standard lymphoma treatment vs. treatment used in the target population. The primary outcome measures were treatment reduction and/or modification, side effects, treatment outcome, OS, and vital status. A literature search was performed using the Medical Subject Headings (MeSH) and text words items by two authors (JJ, BA). The search was performed in two databases (PubMed and Embase) to identify articles that analyzed patients with both lymphoma and liver cirrhosis. The electronic search used the following terms: “lymphoma,” “cirrhosis,” and “liver.” The search included all the studies published between January 2000 and January 2022. Only articles written in English were considered for further analysis. Moreover, a reference list of each relevant paper was checked for additional references.
The main inclusion criteria were that the article reported a case and/or case series representing patient/patients with lymphoma and liver cirrhosis. The patients should be diagnosed with liver cirrhosis previous to or concomitantly with lymphoma. Articles that reported patients with liver cirrhosis that occurred after initial lymphoma diagnosis but before relapse were also included in the final list. Moreover, only patients diagnosed with Hodgkin lymphoma and NHL (all subtypes) were included in the analysis. All types of articles (original research, short commentaries, letters to the editor, conference papers) were considered as potential resources for the current systematic review.
Articles were excluded if they analyzed patients who developed liver cirrhosis after lymphoma diagnosis, described patients with posttransplant lymphoproliferative disease, lacked sufficient information on when lymphoma occurred compared to liver cirrhosis, or if data could not be extracted sufficiently. Articles that used only the term lymphoma without stating the type (eg, NHL, B-cell lymphoma, Hodgkin lymphoma.) were also excluded from further analysis. Papers from the author(s) that published several articles on the same and/or similar patient population with cirrhosis were also excluded from the analysis. Original articles that did not provide sufficient information on the individual patient were also excluded. Patients with cancer or other hematological malignancies (eg, acute leukemia, myeloproliferative disease, multiple myeloma) were excluded from the final list.
The 2 authors (JJ, BA) performed an independent electronic search according to inclusion and/or exclusion criteria, identifying all relevant studies. After all non-English, non-human studies and duplicates were excluded, the titles and abstracts of the remaining records were screened, and studies that met inclusion criteria were retrieved for full-text analysis. After examining the full text, only relevant studies were included in the final lists and checked for the availability of relevant data. The following data necessary for descriptive analysis were extracted: the first author's name, publication year, country, type of article, number of analyzed patients, age, cause of cirrhosis, comorbidities, histology of lymphoma, localization, stage, B symptoms, performance status, laboratory data, treatment, cause of treatment reduction and/or modification, side-effects, survival, treatment response, and vital status.
These considerations refer to laboratory findings, lymphoma staging, HBV assessment, HCV status, the severity of cirrhosis, and survival.
If an author published several articles on the same topic, then the most recent or the one that provided the most information on a patient was included in the final analysis. If the risk of including the same patients from different studies was present (eg, regions and/or countries with a high incidence of HCV and many publications on similar patient populations), then studies were not included in the final list to avoid duplicates.
The quality of the selected publication was performed independently by 2 authors (JJ, BA) according to the Methodological quality and synthesis of case series and case reports.9 According to the question of interest, four domains (selection, ascertainment, causality, and reporting) were assessed in all studies. Inconsistencies were solved by a third party.
All patients from different studies were summarized and analyzed as a group. Quantitative variables were analyzed by median and range, while categorical variables were described by counts and relative frequencies. Association between categorical variables was tested by nonparametric tests (Hi-square test). The Kaplan-Meier method was used to estimate survival curves, and differences were compared with the log-rank test. Survival was done on all patients with available variables of interest. Proportional Cox's hazard model was used for univariate and multivariate analysis. The limit of significance was defined as P ≤ .05. All statistical analyses were performed using the SPSS Statistics 22.0 software package (SPSS Inc., Chicago, IL, United States).
Section snippets
Type of articles
Figure 1 presents a flowchart of the search strategy. A total of 153 publications were included in the final list (Suppl. Table 2). Most articles were case reports (73, 48%), followed by abstracts (23, 15%), case series (17, 11%), letters to the editor (13, 8%), and short communications (10, 7%). Seventeen papers (11%) were marked as original articles, as they analyzed more than ten patients.
Baseline clinical characteristics of patients
A total of 230 patients with liver cirrhosis and lymphoma were analyzed as a group. There was a
Discussion
We conducted a systematic review to evaluate the clinical and treatment characteristics in patients with concomitant liver cirrhosis and lymphoma. We included 153 records (230 patients) that were heterogeneous regarding data availability and information on treatment and outcome.
Regarding the etiology of liver cirrhosis, we found that 62.6% of patients had HCV-related liver cirrhosis, 13.5% HBV, and 7.8% alcoholic liver disease (ALD). However, a large British population-based study found that
Conclusion
We performed a comprehensive literature search of papers analyzing lymphoma in liver cirrhosis patients. The most common cause of liver cirrhosis in analyzed patients was viral hepatitis with HCV predomination compared to HBV. Furthermore, most patients had aggressive lymphoma, particularly DLBCL. Inferior survival was found in males, patients with decompensated liver cirrhosis, aggressive lymphoma histology, and patients receiving dose and intensity-reduced therapy. Different treatment
Clinical Practice Points
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The risk of simultaneously suffering liver cirrhosis and lymphoma is increasing.
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Viral hepatitis is the most frequent cause of liver cirrhosis among patients with lymphoma
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Patients with lymphoma and decompensated liver cirrhosis tend to receive treatment modifications due to liver disease.
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Patients with Child-Pugh A could tolerate standard/more intensive lymphoma treatments.
Authors contribution
JJ and BA performed a data search. JJ participated in acquiring data, analysis, and interpretation of data. JJ wrote the first draft of the manuscript. ZB supervised the statistical analysis. BA, ZB, TSL, and ADF made substantial contributions regarding the critical revision of the article. All authors approved the final version of the article.
Disclosure
The authors have stated that they have no conflicts of interest.
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