MTX is a key drug used in the management RA worldwide. MTX–LPD is a rare, but well-known, life-threatening complication that develops in patients with RA treated with MTX [3]. Because MTX is an anti-folate metabolic agent, its action on the folate metabolic pathway may affect the risk of LPD development [4]. Approximately 60% of patients with MTX–PLD are Epstein–Barr virus (EBV) positive. Since MTX reactivates the latent EBV owing to its immunosuppressive effects, mechanism for the development of MTX–LPD via EBV reactivation has been reported [5]. MTX–LPD has a generally favorable prognostic outcome compared to lymphoma [6]. Spontaneous regression is seen in 50–70% of MTX–LPD cases after MTX withdrawal [6]. Moreover, EBER positivity was considered to be a favorable sign of regression [3].

MTX–LPD frequently involve extranodal lesions, whereas hepatic MTX–LPD is extremely rare [2]. To the best of our knowledge, only 17 cases, including ours, have been reported in the English literature (Table 1). Of this, 11 patients had multiple lesions compared to five with single lesions. Four patients had lesions outside the liver, including in the lungs, spleen, abdominal para-aortic lymph nodes, adrenal glands, and mediastinal lymph nodes. In the current case, enlargement of mediastinal lymph nodes was clue of diagnosed with MTX–LPD; however, the lymph nodes were small and round shape, and showed only little change after MTX-discontinuation. One previous report described a case with mediastinal lymphadenectomy [8]. Because the appearance of mediastinal lymph nodes and those clinical courses were different between previous case and our case, the mediastinal lymph nodes might not be a true lesion of MTX–LPD in the current case. The incidence of hepatic MTX–LPD increases with age, and 76% of patients were aged > 60 years. The median age of the patients was 64 years, and the prevalence was more in female patients (56%). The background disease was almost RA except for one adult-onset Still’s disease. The duration of MTX administration ranged from 5 months to 17 years. The median MTX administration period was 6 years. Fever, malaise, and abdominal pain were common symptoms; however, approximately 40% (7/17) of patients, including our patient, were asymptomatic.

Preoperative diagnosis is challenging due to the rarity of hepatic MTX–LPD. No specific imaging findings is not identified for this condition. Generally, hypoechoic lesions are the most common ultrasonographic imaging findings of MTX–LPD in the liver [8,9,10,11,12]. Contrast-enhanced CT generally reveals a low-density mass [8, 12], sometimes with a ring-like enhancement [13, 14]. The masses sometimes exhibit duct-penetrating signs [7, 10]. MRI shows low intensity on T1-weighted images, high intensity on T2-weighted images, and high intensity on diffuse-weighted images [10,11,12, 15,16,17]. Gd-EOB–DAPT enhancement MRI reveals that the lesion showed diminished uptake of Gd-EOB–DAPT on the hepatobiliary phase [13]. In the current case, contrast-enhanced CT showed heterogenous poorly enhanced mass, and Gd-EOB–DAPT enhancement MRI showed diminishment of Gd-EOB–DAPT on the hepatobiliary phase. These findings were similar to previous reports. 18F-fluorodeoxyglucose positron emission tomography/computed tomography (FDG–PET/CT) reveals an abnormal accumulation of FDG throughout the tumor [9, 10, 13, 18] or at the tumor edge [16, 17, 19]. And The difference in tumor enhancement or FDG accumulation seemed to reflect the difference between the variable and necrotic lesions. MTX–LPD has a strong tendency towards necrosis, which often occurs internally. MTX–LPD with necrotic changes reveals ring-like enhancement and accumulation of FDG at the tumor edge, whereas MTX–LPD without necrotic changes shows homogenous, slightly enhanced, and strong accumulated FDG in the whole tumor.

These imaging features were generally similar to primary hepatic lymphoma [12, 20]. Duct-penetration sign was known as a clue finding of hepatic lymphoma [20]. The presence of duct-penetrating sign was described in the previous report [7, 10]. We could not investigate the presence of vascular invasion due to no viable tumor cell in our resected specimen, and the other previous reports describing surgically treated cases did not mention the vascular invasion of MTX–LPD. Although the tumor characteristics which is the absence of vascular invasion did not be investigated, duct-penetration sign may be an important imaging finding of MTX–LPD as well as primary hepatic lymphomas.

Pathologic findings were consistent with diffuse large B-cell lymphoma in nine cases, B-cell lymphoma in six, T- and B-cell lymphoma in one, and lymphocytes with interstitial fibrosis in one. Hepatic MTX–LPD are generally B-cell lymphomas; however, T-cell lymphomas have also been reported. EBER was positive in nine reported cases (56%). In the present case, no atypical cells were identified. And EBER was negative. The majority of tumors were necrotic CD 20 positive cells. Our patient underwent surgical resection 3 weeks after MTX discontinuation. MTX–LPD often shows spontaneous regression after MTX withdrawal [6], and the historical findings are similar to those of rapidly necrotic lymphoma. Thus, the patient was diagnosed with MTX–LPD of the liver.

Tissue sampling is extremely important for diagnosis, and liver biopsy is relatively easy to perform. Many cases are diagnosed using biopsy specimens. Patients who have undergone hepatectomy because of the suspicion of a primary malignant tumor in the liver, as in our case, have also been reported [15, 16]. Among the patients diagnosed by biopsy specimens, seven patients showed spontaneous regression after MTX withdrawal, five patients underwent chemotherapy, and four achieved a complete response. Three patients underwent a surgical resection. Two patients underwent transhepatic arterial chemoembolization.

Of the patients with MTX–LPD regardless of the primary location, 62.5% showed at least partial regression of LPD in response to MTX withdrawal without additional antitumor therapy [21]. The association between EBV positivity and tumor remission after MTX withdrawal was known. It has been reported that approximately 60% of EBV-positive cases achieved complete remission within 1 month by discontinuing MTX alone, while approximately 30% of EBV-negative cases achieved complete remission within 1 month [1]. Regarding of hepatic MTX–LPD, among four cases who required additional chemotherapy after insufficient regression, three cases was negative for EBER. Therefore, EBV-positive hepatic MTX–LPD may also be a favorable sign of regression after MTX withdraw. In the current case, MTX–LPD were completely necrosis and spontaneously regressed after MTX discontinuation, despite ERER was negative.

When MTX–LPD is suspected, clinicians should consider tissue sampling, discontinuation of MTX, and monitoring for at least 2 weeks. If improvement is observed during this period, the patient’s progress will be followed up; however, if there is no change or worsening, chemotherapy should be considered [6]. Tissue sampling was recommended within 2 weeks after discontinuation of MTX, because approximately 70% of MTX–LPD was regress in 2 weeks [22]. 12–16. If spontaneous regression was observed after discontinuation of MTX, the tumor could be clinically diagnosed with MTX–LPD [22]. In those cases, tissue biopsy or additional treatment was not necessary except for recurrent or regrowth the disease [22]. Additional treatment for hepatic MTX–LPD has not been established. According to primary hepatic lymphoma, chemotherapy was a 1st line therapy, and it was crucial for tissue sampling [23, 24]. If the tumor was solitary without extrahepatic lesion, surgical intervention was considered [24]. However, these diseases generally show the good response for chemotherapy and all resected cases reporting hepatic MTX–LPD including our case, described that they perform hepatectomy for primary hepatic tumor, then the tumor was pathologically diagnosed with hepatic MTX–LPD postoperatively. Therefore, the significance of surgical intervention for solitary or oligo hepatic lesion was not unclear.

Patients with hepatic MTX–LPD were generally good, and no recurrent lesion was reported in this literature review; however, the follow-up period was short (median follow-up period was only 11 months, range 4–24 months). 5-year survival of all patients with MTX–LPD was 58.9% [1]. In the other words, this disease is sometimes recurrent and life threatening. Therefore, regular follow-ups are necessary for hepatic MTX–LPD each 3–6 months according to malignant lymphoma [23]. However, appropriate duration and interval of follow-up time was not established for MTX–LPD.