Case Report
Epstein-Barr virus-related diffuse large B-cell lymphoma type methotrexate-associated lymphoproliferative disorders presenting in the adrenal gland
Kazuki Doi,1 (D Mototsugu Muramaki,1 Tetsuro Yamamoto,2 Daiki Katsura,1 Hiroyuki Fukunaga,1 D Kosuke Takahashi,1 Minori Matsumoto1 and Yuji Yamada1
Departments of 1Urology and 2Pathology, Hyogo Prefectural Amagasaki General Medical Center, Amagasaki-shi, Hyogo, Japan
Abbreviations & Acronyms
DLBCL = diffuse large B-cell lymphoma EBER = EBV-encoded RNA transcript EBV = Epstein-Barr virus IVC = inferior vena cava LPD = lymphoproliferative disorder MRI = magnetic resonance imaging MTX = methotrexate PET-CT = positron emission tomography and computed tomography RA = rheumatoid arthritis sIL2-R = soluble interleukin-2 receptor VCA = viral capsid antigen
Correspondence: Mototsugu Muramaki M.D., Ph.D., Department of Urology, Hyogo Prefectural Amagasaki General Medical Center, 2- 17-77 Higashinaniwa-cho, Amagasaki- shi, 660-8550, Japan. Email: mmuramaki@gmail.com
How to cite this article: Doi K,
Muramaki M, Yamamoto T, et al. Epstein-Barr virus-related diffuse large B-cell lymphoma type methotrexate- associated lymphoproliferative disorders presenting in the adrenal gland. IJU Case Rep. 2022; 5: 172- 174.
This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribu- tion in any medium, provided the original work is properly cited, the use is non- commercial and no modifications or adaptations are made.
Received 12 November 2021; accepted 19 February 2022. Online publication 8 March 2022
Introduction: Methotrexate-associated lymphoproliferative disorders appear during treatment with methotrexate as an immunosuppressive drug. However, the mechanism and frequency are still unknown, and the treatment is undefined.
Case presentation: A 76-year-old woman was admitted to the hospital with back pain, and magnetic resonance imaging showed a tumor in the right adrenal region. She had received methotrexate for rheumatoid arthritis. Enhanced computed tomography showed a tumor of 90 mm in diameter on the dorsal side of the liver abutting to the inferior vena cava. The preoperative diagnosis was a hepatic invasion of right adrenocortical carcinoma and right adrenalectomy was performed. The histopathological diagnosis was diffuse large B-cell lymphoma. The final diagnosis was methotrexate- associated lymphoproliferative disorders.
Conclusion: It is important to consider methotrexate-associated lymphoproliferative disorders before surgery when neoplastic lesions are found in patients taking methotrexate.
Key words: DLBCL, EBV, methotrexate, MTX-LPD, primary adrenal lymphoma.
Keynote message
MTX-LPD is a tumor that occurs in patients taking MTX, which rarely involves adrenal glands. We should be aware of MTX-LPD as a differential diagnosis when neoplastic lesions are found in patients taking MTX.
Introduction
MTX-LPD is a lymphoproliferative disease that appears during treatment with methotrexate as an immunosuppressive drug. It is particularly common in patients with rheumatoid arthri- tis.1-4 Kawano et al. recently reported 2 out of 23 Japanese patients with primary adrenal DLBCL had the treatment history with MTX for RA.5 There are a few other cases of primary adrenal MTX-LPD, but reports are very few.6,7
MTX-LPD is usually treated by discontinuing or reducing the MTX. However, the mecha- nism and frequency of MTX-LPD is still unknown, and the treatment of MTX-LPD is unde- fined. This case report provides important insights into the pathogenesis and treatment of MTX-LPD.
Case presentation
A 76-year-old woman was admitted to our hospital with back pain. MRI revealed a tumor in the adrenal region. She had been diagnosed with RA in 1992 and had received MTX (14 mg/ week) since 2006. Her family history was not remarkable. A physical examination showed no specific abdominal findings.
The results of routine blood tests were normal, and her serum tumor marker levels (CEA, CA19-9, NSE) were within the normal limits. Her serum cortisol level was 13.3 µg/dL (normal range : 3.7-19.4 µg/dL), and her ACTH level was 43.5 pg/mL (normal range : 7.2-63.3 pg/
(a)
(b)
(c)
0
mL). Her other serum hormone values were as follows: epi- nephrine, <0.01 ng/ml (normal range: < 0.1 ng/ml); nore- pinephrine, 0.38 ng/ml (normal range: 0.1-0.50 ng/ml); dopamine, <0.01 ng/ml (normal range: < 0.03 ng/ml); testos- terone, 17.8 ng/mL (normal range: 10.8-56.9 ng/ml); DHEA- S, 203 ng/ml (normal range: 7-177 ng/ml), and renin activity was 0.9 ng/ml/hr (normal range : 0.2-3.9 ng/ml/hr). The 24- h urinary level of norepinephrine was within the reference ranges. Enhanced computed tomography revealed a 90 mm mass at the right adrenal area extending from the S7 region of the right lobe of liver to the right renal head. The hepatic vein to IVC was compressed and displaced by the tumor (Fig. 1a). MRI revealed the mass showing a low-signal intensity on T1 and a high-signal on T2, with a low-signal region in the center (Fig. 1b). PET-CT showed accumulation in the tumor area (Fig. 1c). The preoperative differential diagnosis included intrahepatic cholangiocarcinoma, adrenal tumor, and hepatic malignant lymphoma, but did not reach a definitive diagnosis. We discussed biopsy to make a defini- tive diagnosis; however, it was determined that complete
resection of the tumor was possible. Under the preoperative diagnosis of adrenal carcinoma (cT4N0M0), we performed resection of the right adrenal tumor, extended resection of the posterior lobe of liver and blood vessel prosthesis implantation. The tumor was hard and adhered tightly to the IVC. Histologically, there was diffuse growth of med- ium to large round atypical cells (Fig. 2a). Immunohisto- chemistry was positive for CD20, EBER, and MUM-1 (Fig. 2b-d) and negative for bcl-6, CD30, CD5, CD10, and Cyclin D1. The Ki-67 labeling index was 50% (Fig. 2c).
Given these findings, we finally diagnose EBV-positive DLBCL-type primary adrenal MTX-LPD. Serum anti-EBV VCA IgG antibody and anti-EBNA antibody were positive, and anti-EBV VCA IgM antibody was negative, and the sIL- 2R level was 1320 U/mL (normal range: 122-496 U/mL) in additional blood tests. Postoperatively, PET-CT was per- formed, but no hot spot was found. We withdraw MTX, and the patient was followed up periodically. The patient has remained free from recurrence for 22 months.
(a)
HE
(b)
CD20
(c)
EBER
50 um
50 um
50 um
(d)
MUM-1
(e)
Ki-67
50 um
50 um
Discussion
MTX-LPD is a lymphoproliferative disease that appears during treatment with methotrexate as an immunosuppressive drug. It is particularly common in patients with RA. The mechanism and frequency of the disease are still unknown; however, RA, the use of MTX, and EB virus infection are thought to be the three main causes. The probability of developing LPD is 2.0- 5.5 times higher in patients with RA, than that in the general population.8-10 Disease activity in RA is associated with a higher risk on the development of lymphoma; exposure to sys- temic inflammation may result in the developing lymphoma. In addition IL-10 (which is a cytokine known to be increased in RA) may function as autocrine growth factors in B-cell lym- phoma.11 EBV is thought to have a mechanism for causing lymphoma.12 RA patients treated with MTX have higher EBV loads in their blood than those treated without MTX. Thus, RA and use of MTX promote the activation of EBV, leading to the development of LPD.
There is no comprehensive report on the imaging findings of MTX-LPD. It is known that most EBV-associated LPD is associated with internal necrosis, whereas normal LPD is rarely associated with internal necrosis. In this case, the patient only complained of back pain. Although the imaging findings were consistent with LPDs, this could not be distin- guished from adrenal carcinoma. Thus, we should pay atten- tion to MTX-LPD as a differential diagnosis when neoplastic lesions are observed in patients undergoing MTX therapy.
Rashidi and Fisher define primary adrenal lymphoma as a histologically proven lymphoma that involves one or both adrenal glands and has both of the following features at pre- sentation: (i) there is no prior history of lymphoma else- where; (ii) if lymph nodes or other organs are involved, adrenal lesions are unequivocally dominant.13 In this case, PET-CT showed no other lesions, and the adrenal lesions with hepatic invasion were clearly dominant; thus, it can be regarded as primary adrenal malignant lymphoma. Primary adrenal MTX-LPD is rare, with only about a few cases docu- mented in the literature before this.5-7
MTX-LPD regresses in 70% of patients who discontinue MTX.14 The duration from the withdrawal of MTX to relapse is reported 27.2 months14; thus, long-term follow-up is neces- sary, even after the regression of lesions.
Conclusion
Urologists should pay attention MTX-LPD as a differential diagnosis when neoplastic lesions are observed in patients undergoing MTX therapy. In such cases, discussion with immunologists is encouraged in order to determine the treat- ment strategy.
Author Contributions
Kazuki Doi: Conceptualization; Data curation; Formal analy- sis; Investigation; Methodology; Resources; Writing - origi- nal draft; Writing - review & editing. Mototsugu Muramaki: Formal analysis; Investigation; Project administration; Super- vision. Tetsuro Yamamoto: Data curation. Daiki Katsura:
Data curation. Hiroyuki Fukunaga: Data curation. Kosuke Takahashi: Data curation. Minori Matsumoto: Data curation. Yuji Yamada: Methodology; Project administration; Supervi- sion.
Conflict of interest
The authors declare no conflict of interest.
Approval of the research protocol by an Institutional Reviewer Board
Not applicable.
Informed consent
Not applicable.
Registry and the Registration No. of the study/trial
Not applicable.
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