PHL is extremely rare, representing 0.4% of extranodal NHL  and 0.016-0.06% of NHL [11,12]. The most predominant type of PHL is DLBCL. The other histologic types described in the literature include lymphoblastic lymphoma, Burkitt lymphoma, anaplastic large cell lymphoma, follicular lymphoma and extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue, small lymphocytic lymphoma, mantle cell lymphoma and peripheral T-cell lymphoma [13-15].
Clinical manifestations for PHL were non-specific. Most of patients with PHL had abdominal pain, B-symptoms and hepatomegaly associated with hepatic tumors. PHL patients also have abnormal liver function tests, mostly elevated AST and ALT. A solitary or multiple lesions in the liver was reported [11,14,16].
The etiology of PHL still remains unclear, although viruses such as HBV, HCV, HIV and EBV have been implicated as local factors in lymphomagenesis. A French study of 31 patients with PHL including 22 patients of primary hepatic DLBCL reported that the prevalence of HCV and HBV infection was 21% and 9.5%, respectively . In a Japanese study of 20 patients with PHL, HCV infection was observed in eight of 12 patients of primary hepatic DLBCL (66.7%). The prevalence of HBV infection was 16.7% (2 of 12 primary hepatic DLBCL patients). EBER was positive in two DLBCL PHL patients . Thus, the two studies in France and Japan suggested a potential pathogenic role of HCV infection in PHL development. Persistent or chronic stimulation of the immune system by HCV may result in clonal expansion of B-cells in liver. HCV genome was detected in tumor cells of a patient with PHL . In addition, the development of PHL in HIV-positive patients has been also reported in the setting of immunosuppressive states [19,20].
RA patients have a modestly increased risk of the development of LPDs irrespective of immunosuppressive therapy for the disease. In RA treatment, the most popular immunosuppressive agent is MTX. Since the first report of a RA patient by Ellman et al. , which describes the development of lymphoma during low dose weekly MTX therapy for 33 months, the development of reversible LPDs has been recognized as a complication of immunosuppression associated with prolonged use of low dose MTX. Spontaneous regression of LPDs following discontinuation of MTX shows the interplay of immunosuppression resulted from MTX therapy with lymphoproliferation. Tumor cells of the reversible LPDs frequently express EBV [3-7].
Approximately 40-50% of MTX-associated LPDs occurred in extranodal sites [5,8,9]. Hoshida et al. reported 48 patients with MTX-associated LPDs, of whom the primary site was nodal in 22 patients, extranodal in 23 patients and undetermined in 3 patients . A Study of 37 patients with MTX-associated LPDs reported extranodal organ involvement, including lung, pleura, skin, salivary glands, kidney and pancreas .
To our knowledge, four RA patients with MTX-associated PHL have been reported in the English literature [17,21,22]. Among them, one patient reported by Tatsumi et al.  was negative for HBV, HCV and HIV, and tumor cells of the patient expressed EBER via ISH. One patient reported by Miyagawa et al.  was negative for HBV, HCV and tumor cell EBER by ISH, but no mention was made of HIV infection status. Moreover, it is interesting to note that in contrast to our patient, the two patients did not show spontaneous tumor regression after the withdrawal of MTX. On the other hand, there was no detailed description regarding the other two patients . Our patient was negative for EBV, HBV, HCV and HIV. MTX sometimes shows a significant hepatotoxicity. Persistent elevated transaminase levels were noted while receiving MTX therapy in our patient. Based upon the findings obtained from the present case, we suggest the possibility that in addition to MTX-induced immunosuppression, chronic liver injury resulted from MTX may play a causative role in PHL development. The fact that both of a drastic regression of the tumor masses and improvement of liver dysfunction were observed following discontinuation of MTX further supports our argument. However, because of the rarity of PHL, further investigation should be required.