Introduction

Lymphoproliferative disorders (LPDs) arise in patients who have been treated with immunosuppressants, and diffuse large B-cell lymphoma (DLBCL) is the most common type. One such immunosuppressant, methotrexate (MTX), is the first choice for patients with rheumatoid arthritis (RA) [1, 2]. EBV reactivation associated with reduced immunocompetence is known to be responsible for the development of MTX-LPD. As MTX administration for RA tends to be prolonged, development of MTX-LPD is known to be a severe complication [3]. Here we report our experience with a RA patient who developed MTX-LPD, DLBCL type, in the liver and colon.

Case presentation

A 66 year-old woman was admitted to our hospital with a 3 day history of tarry stools. She had RA and had been treated with salazosulfapyridine, iguratimod and MTX for 2 years. Her RA symptoms were well controlled. Her abdomen was flat, soft, and not tender. Severe anemia (hemoglobin 7.6 g/dL) was evident, and the serum levels of C-reactive protein and soluble interleukin-2 receptor were 9.19 mg/dL and 2,630 U/mL, respectively. Epstein–Barr virus (EBV) DNA was detected in the peripheral blood at 3.60 log IU/ml (Table 1). Contrast-enhanced CT revealed a mass with enhancement in the ileocecal region (Fig. 1A), and multiple nodular masses without enhancement in the liver and para-aortic region (Fig. 1B and C). Contrast-enhanced magnetic resonance imaging (MRI) with gadolinium-ethoxybenzyl diethylenetriamine-pentaacetic acid (Gd-EOB-DTPA) showed multiple tumors in the liver with central necrosis (Fig. 1D-G). Lower gastrointestinal endoscopy revealed a mass in the ileocecal region which was suspected malignant tumor (Fig. 2). Liver metastasis of ileocecal cancer or malignant lymphoma was suspected, and ultrasound-guided biopsy of the liver tumors was performed. Histological examination of the liver and colon specimens revealed proliferation of CD20-positive large lymphoid cells with necrosis and in situ hybridization (ISH) demonstrated Epstein-Barr encoding region (EBER)-1 positivity. Histological examination showed diffuse proliferation of mostly large lymphoid cells with necrosis in the liver (Fig. 3A and B) and colon, although there was no atypia in the epithelium of the surface mucosa of colon. Immunohistochemically, these large lymphoid cells were CD20 ( +) (Fig. 3C), CD30 ( +) (Fig. 3D), CD10 ( +) (Fig. 3E), CD 23 (−) (Fig. 3F), BCL2 (−) (Fig. 3G), BCL6 (−) (Fig. 3H), and MUM1 (−) (Fig. 3I). The Ki-67 labeling index was 80% (Fig. 3J). EBER positivity was detected by ISH (Fig. 3K). Immunostaining of biopsies from the colon yielded similar findings (Fig. 3L and M). The final diagnosis was Oi-DLBCL based on the WHO classification revised fourth edition, as the multiple tumors began to shrink after MTX withdrawal.

Table 1 Laboratory data of the present case at the time of hospitalization
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Fig. 1
figure 1

Abdominal imaging modalities. Contrast-enhanced computed tomography (CT) showed a mass with enhancement in the ileocecal region (A, arrow), and multiple nodular masses without enhancement in the liver (B) and para-aortic region (C, arrow). Penetrating vessels running through the tumor were detected in the liver (B, arrow). Contrast-enhanced magnetic resonance imaging (MRI) with gadolinium-ethoxybenzyl diethylenetriamine-penta-acetic acid (Gd-EOB-DTPA) showed that multiple tumors in the liver were lower contrast than the liver parenchyma in portal phase (D). T1-weighted images showed low signal in all lesions (E). The coarse lesion was centrally high signal on T2-weighted images (F) and low signal on DWI images (G)

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Fig. 2
figure 2

Lower gastrointestinal endoscopy. Lower gastrointestinal endoscopy revealed a mass in the ileocecal region which was suspected malignant tumor

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Fig. 3
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Histological findings in the liver and colon specimens. Histological examination showed diffuse proliferation of mostly large lymphoid cells with necrosis (A, B). Immunohistochemically, the liver specimens revealed CD20 ( +) (C), CD30 ( +) (D), CD10 ( +) (E), CD 23 (−) (F), BCL2 (−) (G), BCL6 (−) (H), MUM1 (−) (I), and Ki-67 labeling index 80% (J). EBV encoding RNA (EBER) positivity was detected by in situ hybridization (ISH) (K). Similarly, histology of the colon specimens also revealed CD20 ( +) (L) and EBER-ISH positivity (M)

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Observation was continued, and CT of the abdomen four months later revealed spontaneous shrinkage of most of the tumors (Fig. 4A). The serum level of sIL-2R improved spontaneously (312 IU/ml), and EBV DNA in the peripheral blood decreased to less than the standard value. After the withdrawal of MTX, the patient experienced no deterioration in her joints. There has been no sign of recurrence for 8 months (Fig. 4B and 5).

Fig. 4
figure 4

Imaging of the abdomen after methotrexate withdrawal. CT of the abdomen four months later revealed spontaneous shrinkage of most of the tumors (A). There has been no sign of recurrence for eight months (B)

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Fig. 5
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Lower gastrointestinal endoscopy after methotrexate withdrawal. The tumor in the ileocecal region disappeared 8 months later

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Discussion

RA patients are known to have a 2- to 4-fold higher incidence of malignant lymphoma as a complication than the general population [4]. Although MTX is used as a first-line treatment for patients with RA, it carries a risk of LPD [2]. When LPD occurs, biologics are often used in the RA patients as an alternative to MTX [5]. LPD, including malignant lymphoma, has been found to occur in RA patients receiving MTX, and this is termed MTX-LPD. The WHO classifies it as immunodeficiency-associated LPD. EBV infection is said to be a complication in about half of MTX-LPD cases, and EBV reactivation has been implicated [6,7,8]. It is thought that the EBV gene releases factors similar to growth factors, transcription factors, and apoptosis inhibitors, causing B lymphocytes to transform into lymphoblasts, exhibiting tumor-like growth [9]. The most common sites of MTX-LPD are lymph nodes [10] and tonsils [11], but thyroid [12], lung [13], liver [14], and colon lesions [15] have also been reported.

Imaging modalities, such as US and CT, can aid the diagnosis of hepatic lymphoma/MTX-LPD. A previous report has indicated that penetrating vessels running through the tumor visualized by US was helpful for diagnosis of hepatic lymphoma [16]. In the present case, penetrating vessels running through the tumor were detected by CT scan. The evidence suggests that MTX-LPD should be considered in RA patients who are receiving MTX medications when CT or US shows a hepatic mass with signs of penetrating vessels.

A search of PubMed using the terms “MTX-LPD” and “hepatic”, or “MTX-LPD” and “liver”, yielded 12 available studies published in English between 2000 and 2022 [10, 14, 17,18,19,20,21,22,23,24,25,26]. In all cases the patients had been treated with immunosuppressants such as MTX, steroids, infliximab, and tacrolimus. All had taken MTX for more than 24 months, and the median total dose of MTX was 1932 mg (960–6000 mg). Ten patients showed reactivation of EBV. The present patient had taken MTX for 24 months (total dose, 960 mg) and also showed reactivation of EBV. MTX-LPD involving the liver along with other parenchymal organs must be differentiated from cancer metastasis. As shown in Table 2, five patients with hepatic MTX-LPD accompanied by other parenchymal organ lesions involvement of the adrenal gland (n = 2), multiple lymph nodes (n = 1), spleen (n = 1), and colon (n = 1, this case).

Table 2 Reported cases of rheumatoid arthritis patients with methotrexate-related lymphoproliferative disease in the liver
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In the listed MTX-LPD, DLBCL type cases (n = 8), MTX was discontinued and three of the patients achieved complete remission. Three additional patients achieved complete remission with chemotherapy. Two patients were treated by partial hepatectomy and had no recurrence. Two patients with MTX-LPD, Hodgkin lymphoma type, also stopped using MTX. One of them suffered relapse even after withdrawal of MTX, and the other underwent partial hepatectomy and had no recurrence. Our present patient achieved complete remission after MTX had been withdrawn. These findings suggest that immediate withdrawal of MTX is recommended for patients with hepatic MTX-LPD, DLBCL type. Our patient had two lesions; these may have been concurrent, or one may have been due to metastasis from the colon to the liver. Because of the multiple lymph node metastases and the histological similarities of the lesions, the possibility that the colon lesion had metastasized to the liver could not be ruled out. To our knowledge, this is the first case of MTX-LPD involving both the liver and colon to have been reported in English.

Conclusion

We have experienced a case of MTX-LPD, DLBCL type, in which multiple liver masses and colon lesions were concurrent. Multiple systemic masses in RA patients receiving MTX are suggestive of MTX-LPD, and early discontinuation of MTX should be considered.