Author Affiliations: Department of Pathology (Bai YF, Liu JM, Zhang XM and Jiang CZ), and Division of Hepatobiliary Pancreatic Surgery (Xu X and Zheng SS), the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China; Department of Pathology and Molecular Medicine, Faculty of Health Sciences, McMaster University, Hamilton L8S 4K1, Canada (Liu JM)

Corresponding Author: Shu-Sen Zheng, MD, PhD, FACS, Division of Hepatobiliary Pancreatic Surgery, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China (Tel: +86-571- 87236570; Fax: +86-571-87236466; Email: shusenzheng@zju.edu.cn)

 

© 2017, Hepatobiliary Pancreat Dis Int. All rights reserved.

doi: 10.1016/S1499-3872(16)60169-8

Published online January 5, 2017.

 

 

Acknowledgements: We thank Professor Jan Lerut from University Hospitals Saint Luc - UCL Brussels for his constructive suggestions in editing the manuscript.

Contributors: ZSS proposed the study. BYF, LJM, ZXM, JCZ and XX collected the materials and reviewed all the slides. BYF and LJM wrote the first draft. BYF, LJM and ZXM contributed equally to this manuscript. All authors contributed to the design and interpretation of the study and to further drafts. ZSS is the guarantor.

Funding: This study was supported by a grant from the major research and development plan of the National Natural Science Foundation of China (91542205).

Ethical approval: This study was approved by the Ethics Committee of the First Affiliated Hospital of Zhejiang University School of Medicine.

Competing interest: No benefits in any form have been received or will be received from a commercial party related directly or indirectly to the subject of this article.

 

 

BACKGROUND: Hepatic lymphoma (HL) is categorized as primary and secondary hepatic lymphoma (PHL and SHL). This disorder can present as hepatic mass or mass-like lesion. Chemotherapy often is the first line treatment for patients with HL. Thus, an accurate pre-management histological diagnosis is essential to potentially improve clinical outcomes. The present study was to explore the prevalence of HL in ultrasound guided liver biopsies for hepatic mass or mass-like lesions, to investigate HL associated clinicopathological features, to raise the awareness of early recognition and proper diagnosis of this entity, and to assess specimen adequacy in needle core biopsy.

 

METHODS: Twenty-one cases of HL were enrolled. Clinical and pathological characteristics were evaluated, quality of biopsies was assessed and pertinent literature was reviewed.

 

RESULTS: HL was diagnosed in 0.94% of 2242 liver biopsy cases with ambiguous clinical presentation, laboratory tests and image studies. There were two cases of PHL (0.09%), and nineteen cases of SHL (0.85%). Histopathologically, diffuse large B-cell lymphoma was the most common type, followed by B-cell lymphoma not otherwise specified, T-cell lymphoma, Hodgkin’s lymphoma, and B-cell chronic lymphocytic leukemia/small lymphocytic lymphoma. Additionally, three lymphocytic infiltration patterns were documented microscopically. The nodular infiltration was the most common type.

 

CONCLUSIONS: HL is a rare entity and histopathology along with ancillary tests remains the only way to make the diagnosis. Clinicians’ awareness of this entity and early liver biopsy are essential in patient management.

 

(Hepatobiliary Pancreat Dis Int 2017;16:58-64)

 

KEY WORDS: hepatic lymphoma; primary and secondary; percutaneous needle core biopsy

 

The incidence of hepatic lymphoma (HL), including primary (PHL) and secondary (SHL), is increasing recently.^{[1, 2]} Most of the HLs are secondary as a result of systemic spreading of the disease. PHL is a rare entity and is confined in the liver at the early stage of lymphoma without infiltration of other locations.^[3,4] The clinical presentations of HL are often nonspecific. Intrahepatic solitary/multiple lesions or diffuse infiltration are the most common radiological findings. These features resemble other intrahepatic neoplasm, i.e. metastatic cancer, hepatocellular carcinoma (HCC), etc. Since HL patients require chemotherapy instead of surgical excision, an accurate histopathological diagnosis is essential in patients with hepatic mass or mass-like lesion.

 

Several methods, including surgical biopsy (open or laparoscopic), needle core biopsy (percutaneous or transjugular) and fine needle aspiration are available in assessing histological changes. Among all the listed methods, surgical biopsy is only used when patients are having an abdominal procedure for other medical conditions. Ultrasound-guided fine needle aspiration has recently been applied in evaluating liver mass.^[3] However, cytological material alone bears its limitation and cannot be used for complete histological and sometimes immunophenotypic assessment. Ultrasound-guided percutaneous liver needle core biopsy, safe in both in- and outpatients,^[5] is a well-established method in the diagnosis of patients with medical liver diseases, mass-like lesions and liver transplant assessment. Compared to the surgical open biopsy, liver needle core biopsy is less invasive and highly effective in diagnosing HL.^[6]

 

According to the location and amount of the neoplastic lymphocytes, three basic and two additional patterns of lymphocytic infiltration have been described.^[7] In portal infiltration pattern, the neoplastic lymphocytes are confined to the portal tracts; in nodular infiltration pattern, the neoplastic lymphocytes are present in the hepatic lobules and form nodules; in sinusoidal infiltration pattern, the neoplastic lymphocytes are dispersed in the sinusoids with preserved lobular architecture. Furthermore, depending on the density of the lymphocytes, both portal and nodular infiltrating types can be divided into loose and dense infiltration. The present study was to explore the prevalence of HL in ultrasound guided liver needle biopsies for hepatic mass or mass-like lesions, to investigate HL associated clinicopathological features, to raise the awareness of this entity among the clinicians, and to assess specimen adequacy of needle core biopsy.

 

 

We reviewed 2242 consecutive percutaneous liver needle core biopsies for liver mass or mass-like lesion at the Department of Pathology, the First Affiliated Hospital, Zhejiang University School of Medicine, from January 2007 to December 2014. All liver biopsies with a diagnosis of hepatic lymphoproliferative disorder or lymphoma were included in the study. Additionally, patient demographics, clinical history, laboratory and radiology studies were retrieved from the hospital electronic medical records. This project was approved by the hospital ethics committee.

 

Twenty-four patients were diagnosed as HL; three were eliminated from the study due to insufficient clinical history and/or inadequate biopsy material. The biopsies were performed routinely by the radiologists under ultrasound guidance, using an 18 G Tru-Cut needle. The diameter and total length of the biopsy cores were measured. All routine hematoxylin and eosin (H/E) and immunohistochemical (IHC) stained slides, and other ancillary testing results were reviewed by two pathologists. Different types of lymphoma were diagnosed according to the WHO lymphoma classification.^[8]

 

 

Of the enrolled 21 patients, there were two cases of PHL and nineteen cases of SHL. The prevalence of PHL and SHL was 0.09% (2/2242) and 0.85% (19/2242), and PHL to SHL ratio was close to 1:10 (Fig. 1). Two female patients, with the diagnosis of diffuse large B-cell lymphoma (DLBCL) met the criteria of PHL. The first patient, 61 years old, presented with fatigue and fever of unknown origin (FUO), and had hepatomegaly. No discrete hepatic lesion was identified on abdominal CT scan. The second patient, 43 years old, with a long history of nephritis and Sjögren syndrome presented jaundice at an annual physical examination. Further imaging examination revealed multiple hepatic masses. Both patients had normal serum AFP and were negative for hepatitis B virus (HBV) and human immunodeficiency virus (HIV). The first patient also had negative serology for hepatitis C virus (HCV), while the second patient’s HCV status was unknown (Tables 1 and 2).

 

The mean age of the SHL patients was 53.5 years (range 33-79), and 53% (10/19) patients were female. The most common clinical presentation was fever, followed by abdominal discomfort, back pain, inguinal lump and pleural effusion. Four patients were identified by the image study incidentally during an annual physical examination. Generalized lymphadenopathy was present in most patients. Some patients also had concomitant other organ involvement, i.e. adrenal gland, stomach, pancreas, spleen, kidney, and appendix. Imaging revealed solid or multiple hepatic masses, or hepatomegaly alone. Liver enzyme tests for SHL varied from normal to up to 2 to 4 times of the upper limit of normal (ULN). Only one patient had a marked rise of ALP, 12-fold ULN. Total bilirubin and LDH were normal or mildly elevated in most patients, while one patient had a marked rise (11-fold ULN) of total bilirubin, and another patient had an elevated LDH (7-fold ULN). All patients had a normal serum AFP level. Most patients had negative tests for HBV (15/21), HCV (15/16) and HIV (21/21) infection (Tables 1 and 2).

 

Bone marrow examination was negative in both PHLs, while 5/12 SHL patients had positive findings. Bone marrow gene rearrangement was performed on all three T-cell lymphomas, and all were monoclonal.

 

On average, each case had 1-3 biopsy cores. Every core measured 1 mm in diameter. The combined length for each case was 15.5±6.9 mm (Table 1). Eighteen cases had ≥10 mm long biopsy cores and 3 cases had less than 10 mm long cores (Table 1).

 

There were nineteen non-Hodgkin’s lymphoma, and two Hodgkin’s lymphoma cases. Among the non-Hodgkin’s lymphoma, DLBCL was the most common type (9/19), followed by B-cell lymphoma not otherwise specified (NOS) (6/19), T-cell lymphoma (3/19) [T-cell lymphoma NOS, hepatosplenic T-cell lymphoma and precursor T lymphoblastic lymphoma/lymphoblastic leukemia (T-ALL/LBL)], and one case of B-cell chronic lymphocytic leukemia/small lymphocytic lymphoma (B-CLL/SLL) (1/19) (Table 3 and Fig. 1).

 

Three types of lymphocytic growth pattern, in terms of portal, nodular and sinusoidal infiltration were documented. The nodular infiltration was the most common tumor growth pattern and occurred in 16/21 (76%) cases (Fig. 2). There were eight DLBCL, six B-cell lymphoma (NOS), one Hodgkin’s lymphoma and one T-ALL/LBL. The portal infiltration was the second common type of growth pattern. It presented in 3/21 (14%) patients (Fig. 3), and included one Hodgkin’s lymphoma, one B-CLL/SLL and one T-cell lymphoma. Sinusoidal infiltration was only identified in 2/21 (10%) patients, and composed of one DLBCL and one hepatosplenic T-cell lymphoma (Fig. 4 and Table 4). Both PHL cases were DLBCL, with a nodular infiltration and sinusoidal infiltration pattern, respectively.

 

 

PHL is a hepatic lymphoproliferative disorder with no evidence of other organ or tissue involvement at the time of the initial diagnosis.^{[3, 4]} This disorder is extremely rare, and occurs only about 0.4% of all extranodal non-Hodgkin’s lymphoma and 0.016% of total non-Hodgkin’s lymphoma cases.^[2] The relationship between PHL and chronic hepatitis C infection has been reported,^[9] while the effect of chronic hepatitis B infection on PHL remains controversial.^[2] Patients with a clinical history of impaired immune surveillance, such as acquired immune deficiency syndrome (AIDS), transplant recipients and systemic lupus erythematosus seem to be linked to some PHL cases.^[10] Radiologically, in contrast to SHL presenting as multifocal masses or diffuse infiltrative pattern, a solitary hepatic mass is highly suggestive of PHL.^[11] Histopathologically, DLBCL is the most common type of PHL.^[12] In our study, two of the PHL were middle aged females. The clinical presentation and image study were nonspecific, i.e. jaundice, fatigue and FUO, as well as hepatomegaly and multiple hepatic mass lesions. Microscopically, both belonged to DLBCL as the final diagnosis. The etiology for both cases remained unknown; however, a long history of immunological disorder was noted in the second patient. Apparently, HBV was not related to the pathogenesis of this disorder.

 

In addition to bone marrow and spleen, liver is the most common site for extranodal lymphoma.^[7] Among the HLs, there were up to 90% cases of non-Hodgkin’s lymphoma and 10% cases of Hodgkin’s lymphoma.^[7] In our study, the ratio between non-Hodgkin’s lymphoma and Hodgkin’s lymphoma was 90% (19/21) to 10% (2/21) and the percentage of B-cell-derived non-Hodgkin’s lymphoma and T-cell lymphoma was 84.2% (16/19) and 15.8% (3/19). Loddenkemper et al^[7] reported the prevalence of hepatic T-cell lymphoma reaching 12% (25/205); they also pointed out that the frequency of liver involvement by T-cell lymphoma is higher than other extranodal sites except for skin and small intestine. T lymphocyte mediated immunological activity in the liver, especially in chronic viral and autoimmune hepatitis might contribute to this phenomenon.^[13]

 

In general, Hodgkin’s lymphoma is a lymph node-based disease. Hepatic involvement of Hodgkin’s lymphoma often occurs in the late stage of the disease. There are limited numbers of publication on extranodular Hodgkin’s lymphoma in Chinese population.^[14] This study revealed two cases of Hodgkin’s lymphoma involving liver. Clinically, both patients presented FUO; HBV, HCV and HIV serology was negative and liver enzymes were mildly elevated. The level of LDH at the initial diagnosis has been considered as a prognostic marker in advanced-stage Hodgkin’s lymphoma.^[15] In our study, microscopic examination revealed portal infiltration in one patient and nodular infiltration in the other patient. Since Hodgkin’s lymphoma has different morphologic subtypes, the diagnosis of this entity can be challenging. The diagnosis of hepatic Hodgkin’s lymphoma should always be suspected if the lesional tissue contains enlarged portal tracts with edema, large amount of atypical lymphocytes and neutrophilic cholangitis.^[16] A diligent search for R-S cells on routine H/E sections or IHC stains should be performed.

 

The incidence of post-transplant lymphoproliferative disorder (PTLD) after solid organ transplantation varies with the type of allograft transplanted; the highest incidence is observed in recipients of small bowel, multiorgan transplant, heart, lung, kidney and liver.^[17] The occurrence time of PTLD ranges from 2 to 158 months after transplantation, with a peak from 12 to 36 months.^[18] In our study, one liver transplant recipient, aged 46, presented FUO at month 37 post-transplant. He was diagnosed of DLBCL, a type of PTLD; Epstein-Barr virus serology was negative.

 

Unlike most malignancies, the diagnosis and treatment of HCC are not regularly established by histopathology but rather based on imaging, according to well-defined diagnostic criteria.^[19] Only in patients with cirrhosis or long-lasting liver disease, imaging can be used as a solo method for the diagnosis. However the sensitivity and specificity for the diagnosis of HCC radiologically are 100% and 60%, respectively.^[20] Based on the above calculation, 40% of radiologically suspected HCC patients still require histological diagnosis. Furthermore, in patients with radiology proven liver mass or mass-like lesion and lacking history of chronic liver disease, a liver biopsy is necessary. Since the prevalence of HL was 0.94% in our study, these patients could be easily missed preoperatively in case of no biopsy. Without histopathology assessment, patients with HL or other subtype of hepatic lesions presented as a mass-like lesion could end up with a dismal outcome. Therefore, we advocate the proper use of liver biopsy in all patients with hepatic mass and mass-like lesions. Additionally, the information obtained from biopsy could guide the management and follow-up. Percutaneous liver biopsy is an invaluable tool for the diagnosis of different types of medical liver disease, transplant liver, liver mass or mass-like lesion, and sometimes post mortem cases.^[21-24] The length and width of biopsy specimen, as well as the number of portal tracts have been used to evaluate the specimen adequacy. These numbers vary depending on different studies.^[21] Based on recent publications, the recommended length of the biopsy tissue should be 20.0-30.0 mm and the number of acceptable portal tracts should be 11 in assessing medical liver and transplant liver disorders.^[25,26] The diameter of the core is another important factor. The broader gauge needles, i.e. 16 G needle are preferable for liver biopsies.^{[25, 26]} In our study, we used an 18 G Tru-Cut needle and on average of all the specimens were 15.5±6.9 mm long, and 1.0 mm in diameter. The number of portal tracts within the biopsy cores varied significantly among the specimens. Under the hepatic neoplastic condition, the tumor cells are prone to infiltrate and destroy normal hepatic architecture. Therefore we assessed the specimen adequacy on the basis of combined specimen length alone rather than on the number of portal tracts. In our study, 18 G needle and 15.5 mm long biopsy cores were adequate in evaluating hepatic mass or mass-like lesion. Occasionally, a biopsy core, less than 10.0 mm long was also acceptable, if the tissue contained diagnostic material. Additionally, compared with other studies,^[3,6] our data were from a single referral center and all biopsies were done under ultrasound guidance by the radiologists, guaranteeing therefore reliable quality of the tissue samples.

 

In conclusion, the liver may be an anatomical site for both primary and secondary lymphoma. Similar to the systemic lymphoma, our study demonstrated that HL consists of a heterogeneous group of lymphoproliferative disorders. The clinical presentation, laboratory and radiology results of HL are often ambiguous. The awareness of this entity and early application of histopathology evaluation in patients presenting with intrahepatic mass or mass-like lesion will ultimately improve clinical outcomes.

 

 

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