MALT lymphoma is a low-grade B-cell lymphoma, among which HP-related gastric MALT lymphoma is the most common. At present, there are relatively recognized unified standards for the diagnosis and treatment of gastric MALT lymphoma. However, primary hepatic MALT lymphoma is extremely rare, its etiology, clinical characteristics and best treatment methods have not yet been clarified. Therefore, we summarize and study our case and combine with the reported literatures to improve the understanding of the disease and enrich clinical evidence for future diagnosis and treatment.
We searched case reports of hepatic MALT lymphoma through PubMed and performed reading analysis. When the disease was confined to the liver and there was no evidence of extrahepatic invasion, we believed that the hepatic lymphoma was primary and included in the statistics. According to statistics, we found 66 reports,5,7–71 including this case, a total of 110 cases of primary hepatic MALT lymphoma, of which 79 cases had relatively detailed clinical data (Table 1). Among them, 42 cases were male (38%), 45 cases were female (41%), with an age ranging from 30 to 89 years and a median age of 63.5 years. Most patients (57.3%) were asymptomatic, and most cases (68.2%) had a single tumor with a diameter ranging from 0.7cm to 20cm.
Table 1
Summary of clinical features of reported cases of primary hepatic MALT lymphoma (including the present case)
Characteristics
|
Total cases (n=110)
|
Age (y)
|
63.5 (30–89) median
|
Sex
Male
Female
NA
|
42 (38%)
45 (41%)
23 (21%)
|
Presenting symptoms
Asymptomatic
Pyrexia
Abdominal pain
Weight loss
Generalized weakness
|
63 (57.3%)
1 (0.9%)
7 (6.4%)
2 (1.8%)
3 (2.7%)
|
Preexisting liver disease
HBV
HCV
PBC
AIH
|
21 (19.1%)
16 (14.5%)
8 (7.3%)
2 (1.8%)
|
Tumor number
Solitary
Multiple
|
75 (68.2%)
17 (15.5%)
|
Tumor diameter (cm)
|
3.5 (0.7–20)
|
Available MRI description
Available ultrasound scan description
Available CEUS description
Available 18F-FDG PET/CT
Mean SUV max
|
35 (31.8%)
28 (25.5%)
6 (5.5%)
17 (15.5%)
4.6 (3.5-8.6)
|
Misdiagnose
Hepatocellular carcinoma
Hepatic hemangioma
Cholangiocellular carcinoma
Hepatic metastasis
Pseudolymphoma
|
24 (21.8%)
18 (16.3%)
2 (1.8%)
2 (1.8%)
1 (0.9%)
1 (0.9%)
|
Type of treatment
Chemotherapy
Radiotherapy
Chemotherapy + radiotherapy
Resection
Resection + chemotherapy
Resection + radiotherapy
Resection + rituximab
Resection + antiviral treatment
Liver transplantation
Radio frequency ablation
No treatment
|
20 (18.2%)
2 (1.8%)
1 (0.9%)
24 (21.8%)
12 (10.9%)
1 (0.9%)
8 (7.3%)
2 (1.8%)
6 (5.5%)
2 (1.8%)
6 (5.5%)
|
Follow-up time (m)
|
26.5 (1-111)
|
Outcome
Disease free survival at the last
Relapse
Death
Lost to follow-up
NA
|
56 (50.9%)
9 (8.2%)
5 (4.5%) (died of other causes)
17 (15.5%)
23 (21%)
|
The median (range) of age, tumor diameter and follow-up time is shown. NA: non available; HBV: hepatitis B virus; HCV: hepatitis C virus; PBC: primary biliary cirrhosis; AIH: autoimmune hepatitis; MRI: magnetic resonance imaging; CEUS: contrast-enhanced ultrasonography; 18F-FDG PET/CT: fluorine-18-fluorodeoxyglucose positron emission tomography/computed tomography; SUV: standardized uptake value.
|
MALT lymphoma usually develops in chronic inflammation accompanied by infectious pathogens, such as HP-related chronic gastritis and autoimmune diseases. Nevertheless, the cause of primary hepatic MALT lymphoma is not fully understood. Some studies revealed that the HCV infection rate in PHL patients was 9% to 42%,72–74 while the HBV infection rate was even as high as 60%.75 Interestingly, being infected with HBV/HCV would not affect the chemotherapy results and prognosis of PHL patients.12 Some scholars believe the continuous inflammatory stimulation may induce the occurrence of the disease.5 In previous case reports, primary hepatic MALT lymphoma was considered to be related to primary biliary cirrhosis (PBC),54 HCV,19,72,76,77 HBV,48,62 HP infection,31 and non-alcoholic steatohepatitis (NASH),27 etc. Meanwhile, some literatures indicated that it might be related to Epstein-Barr virus, which induced polyclonal B-cell proliferation to lead to lymphoma.78 However, a meta-analysis involving approximately 16,300 patients with PBC did not find a significant correlation between PBC and NHL.79 In the literature review, there were 21 cases (19.1%) of HBV infection and 16 cases (14.5%) of HCV infection, while there were 8 cases of PBC (7.3%), 2 cases of autoimmune hepatitis (1.8%), and 12 cases of HP infection (10.9%). In our case, the patient has no history of HBV, HCV, autoimmune disease, or HP infection. Due to the rarity of disease, the exact role of related risk factors in the occurrence of primary hepatic MALT lymphoma needs further investigation.
Patients with PHL usually have elevated LDH.51,78 It has been reported that LDH is a more recognized lymphoid tumor marker.80 Page et al. consider that when the elevated LDH level exceeds 10% of the normal standard, the risk of disease recurrence in such patients increases.51 The elevated level of LDH in patients with PHL is positively correlated with the degree of tumor malignancy, which can be used as an auxiliary index to judge the prognosis.81 Relevant literature shows that tumor markers in hepatic MALT lymphoma, including AFP, CA19-9, CEA, etc., are often within the normal range.50 Therefore, any patient with liver mass whose LDH is elevated, AFP and CEA are normal, should be considered whether there is the possibility of hepatic MALT lymphoma. This can be regarded as a valuable biological feature.
The signal intensity analysis of PHL lesions showed no significant difference in unenhanced or enhanced images. Some literature summarizes that PHL usually manifests as hypoechoic changes under ultrasound. In MRI, PHL usually shows low or iso-signal T1 and high-signal T2.2 After the administration of contrast medium, about 50% of the cases showed a lower density of the lesions in the arterial phase and the delayed phase.82 Meanwhile, 30% of cases showed patchy enhancement and 15% of cases were ring-like enhancement.10 All cases showed low signal during hepatobiliary phase. However, more than 90% of the PHL cases were diffuse large B-cell lymphoma (DLBCL), so far, there is still no characteristic description of hepatic MALT lymphoma imaging. Dong et al. consider that when liver tumors have no obvious space-occupying effect in CT imaging, and the blood vessels and bile ducts in the liver are running normally, the possibility of hepatic MALT lymphoma should not be excluded.20 In our literature review, there are 35 more complete MRI descriptions. Almost all cases showed T1 low signal and T2 high signal, but there was no regular performance in the arterial and portal phase. CEUS guidelines suggest that CEUS can distinguish hepatocellular carcinoma and other lesions (such as regenerative nodules), as well as benign and malignant lesions. It also helps in the differential diagnosis of rare liver tumors.83 However, due to the small number of related cases, the guidelines did not mention the imaging findings of primary hepatic MALT lymphoma. According to our statistics, 5 cases of primary hepatic MALT lymphoma were diagnosed and analyzed by CEUS (4 cases are described in detail), and 2 of them showed uneven enhancement in the arterial phase and uneven regression in the portal phase.22 Our case showed the same performance. The other 2 cases showed uniform wash-in and wash-out in the arterial and portal phase respectively, showing more prone to hepatocellular carcinoma.23,59 However, it is not very typical to see uneven enhancement in the arterial phase of hepatocellular carcinoma. Therefore, when the tumor shows uneven wash-in and wash-out in the arterial and portal phase, we should include hepatic MALT lymphoma among the diseases that require differential diagnosis. Meanwhile, Shiozawa et al. consider that the feature of no blood vessel penetrating the tumor may distinguish primary hepatic MALT lymphoma from other malignant lymphomas. Compared with dynamic CT and MRI, CEUS can evaluate intratumoral hemodynamics in real time, which is easier and more accurate to see penetrating blood vessels.59 Although there is no specific imaging of primary hepatic MALT lymphoma, the rare sharpness and irregularity of the lesion edge on ultrasound examination may be more prone to lymphoma, and it is worth performing a local biopsy to clarify the nature.22
The role of 18F-FDG PET/CT in the detection rate, diagnosis and follow-up of extragastric MALT lymphoma has been controversial. A study analyzed 227 MALT lymphomas, which indicated that the metabolic rate of 18F-FDG was related to the location and general morphological characteristics of the lesion. However, the diagnosis of primary hepatic MALT lymphoma by 18F-FDG PET/CT is not described.84 In previous reports, 17 cases of PET-CT were performed, and their hepatic MALT lymphomas all showed high metabolism of 18F-FDG.7,9,11,17,19,20,29,34,49,61,69,75 A recent study proposed that the 18-FDG metabolic rate of extragastric MALT lymphoma is significantly related to Ki-67 proliferation.85 When Ki-67>15%, the 18-FDG intake of the lesions was significantly increased, but only 4 cases of related hepatic MALT lymphoma cases were involved. This result still needs to be further studied, but it is still valuable for postoperative prognostic evaluation and follow-up. Significantly, compared with other aggressive lymphomas such as DLBCL, MALT lymphoma has a relatively low FDG uptake intensity,86,87 which has more differential significance. Regrettably, our case failed to perform 18F-FDG PET/CT before surgery. The postoperative 18F-FDG PET/CT showed no hypermetabolic lesions. This not only indicates no extrahepatic lesions, but also proves that the result of RFA was very successful. Lugano classification proposes that 18F-FDG PET/CT is officially included in the standard staging of FDG-avid lymphoma, which can improve the accuracy of staging and better evaluate the prognosis.88 Whether 18F-FDG PET/CT can also be used for early diagnosis, staging, and treatment of hepatic MALT lymphoma, it is still necessary to collect large samples for analysis. However, 18F-FDG PET/CT is still helpful in the diagnosis of primary hepatic MALT lymphoma when there are no high-uptake lesions in other parts of the body. It may become a new method for staging, follow-up and prognostic evaluation in the future.
Most masses are discovered accidentally and lack extrahepatic manifestations, which are often misdiagnosed. Among the retrieved cases, almost all cases could not be clearly diagnosed before pathological diagnosis. Some cases (21.8%) were diagnosed as other malignant tumors or even benign tumors before surgery or biopsy. In our case, we initially diagnosed it as hepatocellular carcinoma before surgery. Therefore, the diagnosis of primary hepatic MALT lymphoma still needs pathological biopsy to confirm. Pathological biopsy of primary hepatic MALT lymphoma shows the presence of reactive follicles. The marginal zone cells infiltrate the epithelium, which can cause the formation of lymphoepithelial lesions and lead to the destruction of part of the bile duct structure. Lymphoepithelial lesions of the bile duct are typical manifestations of primary hepatic MALT lymphoma,89 which are consistent with our case. Marginal zone B-cell lymphomas are usually positive for CD20 and CD79a, but lack CD5, CD10, CD23, and CD43, and usually express IgM and Bcl-2. Ki67, p53 and Bcl-6 may help distinguish liver marginal zone B-cell lymphoma from DLBCL. Typical liver marginal zone B-cell lymphoma grows inertly, if these markers are diffusely expressed, the mass is closer to DLBCL.89 Therefore, proper immunohistochemistry and molecular research are also essential. It is not only to help distinguish lymphoma from other malignant tumors, but also to judge the immunophenotype of lymphoma.
To our knowledge, there is no consensus on the optimal treatment for non-gastric MALT lymphomas. The recommendations of the United States National Comprehensive Cancer Network for non-gastric MALT lymphomas include radiotherapy, surgery, chemotherapy and comprehensive treatment. Because cases of primary hepatic MALT lymphoma are extremely rare, we are unable to design prospective randomized clinical trials to determine the optimal treatment. According to literature statistics, most of the patients (48.2%) underwent surgical resection or liver transplantation after diagnosis, accompanied by chemotherapy adjuvant therapy, and the postoperative effect was well, and most of them could be cured. However, there were still 2 cases of tumor recurrence during long-term follow-up after surgical resection,25,35 suggesting the importance of close follow-up after treatment. Obiorah et al. reported a case of primary hepatic MALT lymphoma that developed pulmonary MALT lymphoma 1 year after surgical resection, and parotid MALT lymphoma occurred 7 years later.49 Chen et al. reported the surgical patient of primary hepatic MALT lymphoma developed pulmonary MALT lymphoma 8 years later.16 Both cases provide us with the possibility of future progression of primary hepatic MALT lymphoma. Although the course of the disease usually progresses slowly,90 it may relapse after many years and involve other common external nodes. Therefore, we should be alert to the possibility of distant metastasis, and regular follow-up is recommended even after 5 years of surgery.
As far as we know, only one primary hepatic MALT lymphoma Japanese received RFA treatment before.28 In our case, RFA was performed after confirmation of liver malignant tumor. Postoperative imaging results showed that the surgical scope was well. The patient was regularly followed up one year after surgery and no signs of recurrence. Our case indicates that RFA is safe and effective in the treatment of primary hepatic MALT lymphoma in the short run while avoiding unnecessary liver resection. However, long-term follow-up and more relevant cases are still needed to observe the effect of RFA on long-term survival of this disease. As can be seen from our case, when the tumor is confirmed by pathological biopsy, non-resection therapy, such as RFA, can also be selected. Our case provides a new option for the treatment of hepatic MALT lymphoma.