J Med Cases

Journal of Medical Cases, ISSN 1923-4155 print, 1923-4163 online, Open Access

Article copyright, the authors; Journal compilation copyright, J Med Cases and Elmer Press Inc

Journal website https://www.journalmc.org

Case Report

Volume 14, Number 8, August 2023, pages 282-288

Primary Hepatic Other Iatrogenic Immunodeficiency-Associated Lymphoproliferative Disorders After Methotrexate Therapy

Figure 1. Enhanced computed tomography (CT) images performed at the time of detection and 87 and 132 days after the initial detection. (a) Precontrast phase; (b) arterial phase; (c) portal phase; (d) 18F-fluorodeoxyglucose positron emission tomography (PET)/CT performed at 139 days after the initial detection. The tumor is indicated by arrowheads.

Figure 2. Pathological findings of the liver biopsy. Hematoxylin and eosin (H&E) staining revealed lymphocyte proliferation and a wide variety of forms. The tumor cells were positive for CD20 and CD3 and negative for CD5 and CD10. In situ hybridization revealed partial positivity for EBV-encoded small RNAs (EBERs). (a) H&E staining, × 400; (b) anti-CD3 staining, × 100; (c) anti-CD5 staining, × 100; (d) anti-CD10 staining, × 100; (e) anti-CD20 staining, × 100; (f) in situ hybridization EBERs, × 100 (arrows denote cells positive for EBERs on in situ hybridization).

**Table 1.** Laboratory Data on First Visit to Our Hospital
	Results	Reference values
WBCs: white blood cells; RBCs: red blood cells; AST: aspartate aminotransferase; ALT: alanine aminotransferase; LDH: lactic dehydrogenase; ALP: alkaline phosphatase; γ-GTP: γ-glutamyl transpeptidase; BUN: blood urea nitrogen; CRP: C-reactive protein; sIL-2R: soluble interleukin-2 receptor; HBsAg: hepatitis B s antigen; HBeAg: hepatitis B e antigen; HBeAb: hepatitis B e antibody; HBV-DNA: hepatitis B virus DNA; HCVAb: hepatitis C virus antibody; CEA: carcinoembryonic antigen; CA19-9: carbohydrate antigen 19-9; AFP: α-fetoprotein; PIVKA-II: protein induced by vitamin K absence or antagonist-II.
Peripheral blood
WBC	4,530/µL	4,000 - 8,600
Eosinophil	6.2%	0 - 6
Lymphocyte	13.7%	27 - 47
Monocyte	10.2%	2 - 8
Neutrophil	68.4%	45 - 74
RBC	421 × 10⁴/µL	380 - 480
Hemoglobin	13.6 g/dL	12 - 16
Platelet	20.6 × 10⁴/µL	15 - 35
Biochemistry
Total protein	7.7 g/dL	6.5 - 8.2
Albumin	4.7 g/dL	3.8 - 5.1
Total bilirubin	0.6 mg/dL	0.1 - 1.0
AST	28 IU/L	13 - 33
ALT	24 IU/L	6 - 30
LDH	401 IU/L	119 - 229
γ-GTP	56 IU/L	6 - 46
BUN	12.1 mg/dL	8 - 20
Creatinine	0.82 mg/dL	0.48 - 0.79
Serology
CRP	< 0.03 mg/dL	0 - 0.33
Immunology
sIL-2R	1,060 U/mL	121 - 613
Viral marker
HBsAg	3.4 IU/mL	(-)
HBeAg	(-)	(-)
HBeAb	(+)	(-)
HBV-DNA	(-) LogIU/mL	(-)
HCVAb	(-)	(-)
Tumor marker
CEA	3.4 ng/mL	0 - 5
CA19-9	143 U/mL	0 - 37
AFP	1.5 ng/mL	0 - 10
PIVKA-II	20 mAU/mL	-40

Table 1. Laboratory Data on First Visit to Our Hospital

Results

Reference values

WBCs: white blood cells; RBCs: red blood cells; AST: aspartate aminotransferase; ALT: alanine aminotransferase; LDH: lactic dehydrogenase; ALP: alkaline phosphatase; γ-GTP: γ-glutamyl transpeptidase; BUN: blood urea nitrogen; CRP: C-reactive protein; sIL-2R: soluble interleukin-2 receptor; HBsAg: hepatitis B s antigen; HBeAg: hepatitis B e antigen; HBeAb: hepatitis B e antibody; HBV-DNA: hepatitis B virus DNA; HCVAb: hepatitis C virus antibody; CEA: carcinoembryonic antigen; CA19-9: carbohydrate antigen 19-9; AFP: α-fetoprotein; PIVKA-II: protein induced by vitamin K absence or antagonist-II.

Peripheral blood

WBC

4,530/µL

4,000 - 8,600

Eosinophil

6.2%

0 - 6

Lymphocyte

13.7%

27 - 47

Monocyte

10.2%

2 - 8

Neutrophil

68.4%

45 - 74

RBC

421 × 10⁴/µL

380 - 480

Hemoglobin

13.6 g/dL

12 - 16

Platelet

20.6 × 10⁴/µL

15 - 35

Biochemistry

Total protein

7.7 g/dL

6.5 - 8.2

Albumin

4.7 g/dL

3.8 - 5.1

Total bilirubin

0.6 mg/dL

0.1 - 1.0

AST

28 IU/L

13 - 33

ALT

24 IU/L

6 - 30

LDH

401 IU/L

119 - 229

γ-GTP

56 IU/L

6 - 46

BUN

12.1 mg/dL

8 - 20

Creatinine

0.82 mg/dL

0.48 - 0.79

Serology

CRP

< 0.03 mg/dL

0 - 0.33

Immunology

sIL-2R

1,060 U/mL

121 - 613

Viral marker

HBsAg

3.4 IU/mL

(-)

HBeAg

(-)

HBeAb

(+)

(-)

HBV-DNA

(-) LogIU/mL

(-)

HCVAb

(-)

Tumor marker

CEA

3.4 ng/mL

0 - 5

CA19-9

143 U/mL

0 - 37

AFP

1.5 ng/mL

0 - 10

PIVKA-II

20 mAU/mL

-40

**Table 2.** Summary of 11 Reported Cases of Hepatic Methotrexate-Associated Lymphoproliferative Disorders
Case	Reference	Years	Age	Gender	Primary disease	Liver disease	Solitary or multiple	Duration of MTX (years)	Other immunosuppressants and immunomodulators	Tissue collection	Pathological diagnosis	EBV-encoded small RNAs (EBER) in situ hybridization	Treatment
RA: rheumatoid arthritis; MTX: methotrexate; DLBCL: diffuse lymphocyte B-cell lymphoma; PSL: prednisolone; TACE: transcatheter arterial chemoembolization; AOSD: adult-onset Still’s disease; R-THP-COP: rituximab, tetrahydropyranyl adriamycin, cyclophosphamide, vincristine, and prednisolone; R-CHOP: rituximab, adriamycin, cyclophosphamide, vincristine, and prednisolone; ABVD: adriamycin, bleomycin, vinblastine, and dacarbazine; EBV: Epstein-Barr virus.
1	[5]	2006	48	F	RA	(-)	Solitary	3.25	Unknown	Biopsy	Large B-cell lymphoma	Positive	Withdrawal of MTX
2	[6]	2013	69	M	RA	(-)	Solitary	7	Unknown	Biopsy	Lymphocytic infiltration	Positive	Withdrawal of MTX
3	[7]	2014	67	F	RA	(-)	Multiple	6	PSL	Biopsy	DLBCL	Positive	R-THP-COP
4	[8]	2015	56	F	RA	(-)	Multiple	7	Unknown	Biopsy	DLBCL	Negative	R-CHOP
5	[9]	2015	64	M	RA, sarcoidosis	(-)	Multiple	2	Infliximab	Biopsy	DLBCL	Negative	Withdrawal of MTX
6	[10]	2016	63	M	RA	(-)	Multiple	10	Unknown	Biopsy	DLBCL	Positive	Withdrawal of MTX
7	[11]	2017	65	F	RA	HBV	Solitary	7	Unknown	Surgery	Malignant lymphoma	Positive	Surgery/Withdrawal of MTX
8	[12]	2017	88	F	RA	(-)	Diffuse	6	Infliximab	Biopsy	Hodgkin lymphoma	Positive	ABVD
9	[13]	2019	82	M	RA	(-)	Multiple	9.5	PSL, bucillamine	Biopsy	B-cell lymphoma	Negative	Withdrawal of MTX
10	[14]	2019	70	F	RA	(-)	Multiple	5	PSL, golimumab	Biopsy	Lymphocyte proliferation	Negative	Withdrawal of MTX
11	[15]	2020	70	F	RA	LC AIH	Multiple	17	PSL, salazosulfapyridine	Biopsy	DLBCL	Positive	TACE/Withdrawal of MTX
Ours		2023	71	F	AOSD	HBV	Solitary	5 months	PSL, tocilizumab	Biopsy	Lymphocyte proliferation	Positive	R-CHOP

Table 2. Summary of 11 Reported Cases of Hepatic Methotrexate-Associated Lymphoproliferative Disorders

Case

Reference

Years

Age

Gender

Primary disease

Liver disease

Solitary or multiple

Duration of MTX (years)

Other immunosuppressants and immunomodulators

Tissue collection

Pathological diagnosis

EBV-encoded small RNAs (EBER) in situ hybridization

Treatment

RA: rheumatoid arthritis; MTX: methotrexate; DLBCL: diffuse lymphocyte B-cell lymphoma; PSL: prednisolone; TACE: transcatheter arterial chemoembolization; AOSD: adult-onset Still’s disease; R-THP-COP: rituximab, tetrahydropyranyl adriamycin, cyclophosphamide, vincristine, and prednisolone; R-CHOP: rituximab, adriamycin, cyclophosphamide, vincristine, and prednisolone; ABVD: adriamycin, bleomycin, vinblastine, and dacarbazine; EBV: Epstein-Barr virus.

[5]

2006

(-)

Solitary

3.25

Unknown

Biopsy

Large B-cell lymphoma

Positive

Withdrawal of MTX

[6]

2013

(-)

Solitary

Unknown

Biopsy

Lymphocytic infiltration

Positive

Withdrawal of MTX

[7]

2014

(-)

Multiple

PSL

Biopsy

DLBCL

Positive

R-THP-COP

[8]

2015

(-)

Multiple

Unknown

Biopsy

DLBCL

Negative

R-CHOP

[9]

2015

RA, sarcoidosis

(-)

Multiple

Infliximab

Biopsy

DLBCL

Negative

Withdrawal of MTX

[10]

2016

(-)

Multiple

Unknown

Biopsy

DLBCL

Positive

Withdrawal of MTX

[11]

2017

HBV

Solitary

Unknown

Surgery

Malignant lymphoma

Positive

Surgery/Withdrawal of MTX

[12]

2017

(-)

Diffuse

Infliximab

Biopsy

Hodgkin lymphoma

Positive

ABVD

[13]

2019

(-)

Multiple

9.5

PSL, bucillamine

Biopsy

B-cell lymphoma

Negative

Withdrawal of MTX

[14]

2019

(-)

Multiple

PSL, golimumab

Biopsy

Lymphocyte proliferation

Negative

Withdrawal of MTX

[15]

2020

LC AIH

Multiple

PSL, salazosulfapyridine

Biopsy

DLBCL

Positive

TACE/Withdrawal of MTX

Ours

2023

AOSD

HBV

Solitary

5 months

PSL, tocilizumab

Biopsy

Lymphocyte proliferation

Positive

R-CHOP