Acta Med. Okayama, 2024
Vol. 78, No. 1, pp. 29‑36
CopyrightⒸ 2024 by Okayama University Medical School.

Original Article

http://escholarship.lib.okayama-u.ac.jp/amo/

Regression of Necrotic Lesions after Methotrexate Withdrawal in Patientswith Methotrexate-Associated Lymphoproliferative Disorders:
A Retrospective CT Study
Takahiro Kitayamaa＊, Takashi Tanakab, Yuichiro Kaniec, Yohei Marukawad,
Katsuhide Kojimac, Takehiro Tanakae, Soshi Takaof and Takao Hirakia,gDepartments of aRadiology, ePathology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University,c
Department of Radiology, Okayama University Hospital, Departments of fEpidemiology, gRadiology, Faculty of Medicine,
Dentistry and Pharmaceutical Sciences, Okayama University, Okayama 700-8558, Japan,b
Department of Radiology, Okayama City Hospital, Okayama 700-8557, Japan,dDepartment of Radiology, Okayama Saiseikai General Hospital, Okayama 700-8511, Japan

This retrospective study investigated whether necrotic lesions detected on a computed tomography (CT) scan
are more regressive than non-necrotic lesions after methotrexate withdrawal in patients pathologically diagnosed with methotrexate-associated lymphoproliferative disorders (MTX-LPD). In total, 89 lesions extracted
from 24 patients on CT scans were included in the analysis. All patients had been evaluated for the presence of
necrosis within lesions via CT scan upon first suspicion of MTX-LPD (baseline CT scan). The percentage lesion
size reduction between the baseline and initial follow-up CT scan was calculated. The association between
necrosis within lesions and size changes was estimated via linear regression analyses using both crude andadjusted models. Necrosis was significantly more common in extranodal lesions (27 out of 30 lesions, 90%)
than in nodal lesions (9 out of 59 lesions, 15%, p < 0.001). In the crude model, the regression of necrotic lesions
was 58.5% greater than that of non-necrotic lesions; the difference was statistically significant (p < 0.001).
Additionally, the longest diameter of necrotic lesions at the baseline CT scan was significantly greater than thatof non-necrotic lesions (p < 0.001). Based on the adjusted model, necrotic lesions showed 49.3% greater regression than non-necrotic lesions (p = 0.017). Necrosis detected on a CT scan was found to be an independent predictor of regression after MTX withdrawal in patients with MTX-LPD.
Key words: methotrexate, lymphoproliferative disorder, computed tomography, necrosisMethotrexate-associated lymphoproliferative disorders (MTX-LPD) are rare benign lymphoidproliferations or malignant lymphomas that occur predominantly in patients with rheumatoid arthritis against
a background of immunodeficiency caused by treatment with MTX. The prominent clinical characteristicof MTX-LPD is regression after MTX withdrawal.
Received April 28, 2023 ; accepted August 9, 2023.
Corresponding author. Phone : +81-86-235-7313; Fax : +81-86-235-7316
E-mail : kitayama-t@s.okayama-u.ac.jp (T. Kitayama)＊

Therefore, MTX withdrawal is the initial step for managing clinically suspected MTX-LPD [1-5].
Thus far, several prognostic factors have beenreported. A clinicopathological study of MTX-LPD
showed that histological subtype and age are correlatedwith overall survival [4]. Similarly, histological subtype
has also been reported to be associated with spontaneous regression after MTX withdrawal [6]. In addiConflict of Interest Disclosures: No potential conflict of interest relevantto this article was reported.

30

Kitayama et al.

Acta Med. Okayama Vol. 78, No. 1

tion, tumor necrosis detected via pathological investigation is a favorable factor for progression-free survival
in different subtypes of MTX-LPD [7]. Using diagnostic imaging, other studies found that necrosis detectedon computed tomography (CT) scans correlates withpoor prognosis in some subtypes of de novo lymphoma[8 , 9]. In contrast, there are no reports on the predictive value of lesion necrosis detected on a CT scan in
MTX-LPD.
At present, there is no strict guideline for the management of MTX-LPD. Diagnostic imaging aims primarily to evaluate the presence and extent of MTXLPD lesions and to monitor the prevalence of lesions
after MTX withdrawal. Imaging findings may also be
used as biomarkers for predicting the regression of
MTX-LPD lesions after MTX withdrawal.
In this study, we hypothesized that lesion necrosis
detected on a CT scan was correlated with regression
after MTX withdrawal in patients with MTX-LPD. The
present study aimed primarily to investigate whether
necrotic lesions detected on CT scans are more regressive than non-necrotic lesions after MTX withdrawal inpatients pathologically diagnosed with MTX-LPD.
Moreover, the characteristics of the lesions associatedwith regression after MTX withdrawal were evaluated.

Materials and Methods
This retrospective and observational study wasapproved by our institutional review board; informed

consent was waived due to the retrospective nature of
the research (approval no. Ken2108-019).
Participants.
Using radiology information systems, we identified all patients who met a single inclusion criterion: suspected MTX-LPD on a CT scan
performed from January 2011 to December 2020. Sixty
consecutive patients met the criterion. Out of the 60
patients, 36 patients were excluded for the following
reasons: no CT scan before or after MTX withdrawal(n = 14); non-evaluable lesions due to poor image quality (n = 8); diagnosis of other pathologies (i.e., infectious lesion or malignant tumor other than lymphoma)(n = 5); no detectable lesions on CT scan (n = 3); no
MTX withdrawal (n = 3); and no pathological confirmation (n = 3). The remaining 24 patients pathologically diagnosed with MTX-LPD were analyzed (Fig. 1).
Image acquisition. CT scans were performed
using, among others, the following helical scanners:
Discovery CT750 HD (GE Healthcare, Milwaukee, WI,USA); Aquilion ONE ViSION Edition (Canon Medical
Systems, Ohtawara, Japan); SOMATOM Deﬁnition
Flash (Siemens Healthineers, Forchheim, Germany);
Aquilion 64 (Canon Medical Systems); Aquilion
MULTI (Canon Medical Systems). In total, 15 patients
underwent a contrast-enhanced CT scan. The volumeof iodinated contrast agent used with 300 mg of iodine
per milliliter was 2-2.5 ml/kg. The contrast agent wasadministered via a mechanical injector within 50 sec
with a scanning delay of 70 sec. The other 9 patients
underwent an unenhanced CT scan. Based on our

60

36

14
8
5
3
3
3

24
Fig. 1
Flow diagram for patient inclusion.
MTX-LPD, methotrexate-associated lymphoproliferative disorders; CT, computed tomography.

February 2024

standard imaging protocol, the following parameters
were used: 120 kilovolt peak, automated tube current
modulation mode, a beam pitch of 1.0, gantry rotation
time of 0.5 sec, and field of view to fit. The images werereconstructed using axial planes with a 5 mm section
thickness. To evaluate necrosis within lesions, allimages were displayed using the soft tissue window
settings (level: 30 Hounsfield units [HU]; width:
350 HU). To measure lung lesions and other lesions,the lung window settings (level: −550HU; width:
1,500 HU) and the soft tissue window settings wereused, respectively.
Image analysis and regression assessment.
Thetarget lesions were defined according to the Lugano
Response Criteria [10]. The number of target lesions
per patient was up to 6 of the largest nodal or extranodal lesions detected by the baseline CT scan performed
upon MTX-LPD suspicion. Abnormal lymph nodes
were classified as lesions with a long axis measuring> 1.5 cm, while extranodal lesions were defined as thosewith a long axis measuring > 1.0 cm. Non-mass lesions,such as splenomegaly, hepatomegaly, and bone marrow
involvement, were not considered target lesions.
We evaluated necrosis within the lesions at the baseline CT scan upon MTX-LPD suspicion, following theprotocol used in a previous study that evaluated tumor
necrosis on CT scan in malignant lymphoma [8]. In
patients who underwent unenhanced CT scan, necrosis
was defined as a visual focal area of low attenuation
within nodal or extranodal lesions with corresponding
HU measuring between 10 and 30 HU. In addition, forpatients who underwent a contrast-enhanced CT scan,a corresponding area without a significant HU increase(up to a maximum of 5 HU) between the unenhanced
and contrast-enhanced scans was required. Sizeadjustable oval region-of-interest analysis was performed, and the corresponding HU values measured at
the center of the necrotic area were investigated.
Necrosis was independently evaluated by two experienced diagnostic radiologists, neither of whom was theradiologist who assessed the target lesion size. These
readers were blinded to any additional clinical andpathological information, including images obtained
via other modalities. All lesions were evaluated as positive or negative. In this study, we defined true necrosis
based on the necrotic findings on CT scan alone. If
there was discordance between the two readers, a consensus was achieved via discussion.

MTX-LPD

31

Regression was assessed during the initial follow-up
CT scan after MTX withdrawal and the baseline CT
scan performed upon MTX-LPD suspicion. The percentage lesion size reduction was calculated according
to differences in the product of the longest and perpendicular diameters between the baseline and the follow-up CT scans, divided by the product of the diameters at baseline CT scan, in line with previous studies
that evaluated changes in tumor size on CT scans inmalignant lymphoma [10-12].
Assessment of pathologic and clinical data.
Histopathological diagnosis was determined based on
the World Health Organization classification, revised
4th edition (2017) [13]. Pathological confirmation wasachieved through hematoxylin and eosin staining,
immunohistochemical staining, flow cytometry analysis, and in situ hybridization of Epstein–Barr virus
encoding ribonucleic acid. An experienced pathologist
confirmed all histopathological diagnoses. Patient stage
was determined based on the Lugano classification system for malignant lymphoma [10]. Table 1 shows thecharacteristics of the patients in detail. There were no
significant differences in patient characteristics between
the groups of patients who had no necrotic lesions andthose who had at least one.
Statistical analysis. Descriptive data were presented as means ± standard deviation (SD) and range
for continuous variables, and as counts for categoricalvariables. Systemic target lesions were divided into
nodal or extranodal anatomic regions, which was similar to the classification used in previous region-based
analyses of lymphoproliferative disorders [14-17]. The
percentages of lesion size reduction between necrotic
and non-necrotic lesions were compared. Continuous
variables with a normal distribution were estimatedusing the t-test. Differences between categorical variables were evaluated using Fisher’s exact test (forexpected group sizes of ≤ 5). Linear regression analyses
were used to estimate beta coefficients with 95% confidence intervals of crude and adjusted models. In theadjusted model, we controlled for lesion site (nodal or
extranodal) and size (the product of the longest andperpendicular diameters at baseline CT scan). For eachanalysis, a two-tailed p < 0.05 was considered statistically significant. All statistical analyses were performed
using Stata Statistical Software Release 17.0 (Stata Corp
LLC, College Station, TX, USA).

32

Kitayama et al.

Table 1

Acta Med. Okayama Vol. 78, No. 1

Characteristics of patients with MTX-LPD (n = 24)
Necrosis status

Age, years, mean ± SD (range)
Gender, n
MaleFemaleUnderlying disease, nRA
OtherscLength of MTX, months, mean ± SD (range)
Final dose of MTX, mg/week, mean ± SD (range)
Combination with other immunosuppressive drugs , ndsIL-2R, U/ml, mean ± SD (range)
LDH, U/l, mean ± SD (range)
Histological type, nMalignant
DLBCL
FL
HL
MZL
PTCL
Benign
EBER, nPositive
Negative
N/A
Stagee, n
I
II
III
IV
Use of contrast agent at baseline CT scanf, nContrast-enhanced scan
Unenhanced scanInterval between baseline CT scanf and MTX withdrawal,
day, mean ± SD (range)
Interval between MTX withdrawal and follow-up CT scang,day, mean ± SD (range)

All patients(n = 24)

Necrosis (-)a(n = 9)Necrosis (+)b(n = 15)

P-value

69.5 ± 9.2(39-90)71.0 ± 5.2(64-80)68.5 ± 10.9
(39-90)

0.535

6
18

1
8

5
10

23
1

8
1

15
0

115.8 ± 109.4(26-396)8.5 ± 3.1
(2.5-14)
15
1,676.6 ± 1,259.3(343-4,728)
303.0 ± 106.1(183-576)

90.6 ± 125.2(26-396)6.8 ± 1.8
(4-10)
5
1,730.3 ± 1,503.2(343-4,728)
286.7 ± 128.4(192-576)

131.2 ± 100.6(47-360)
9.4 ± 3.3
(2.5-14)10
1,644.4 ± 1,145.0(476-4,511)
312.9 ± 93.8
(183-518)

23
16
2
2
2
1
1

8
4
1
1
2
0
1

15
12
1
1
0
1
0

14
7
3

4
2
3

10
5
0

3
4
5
12

2
2
3
2

1
2
2
10

15
9

5
4

10
5

9.0 ± 8.5
(0-33)
38.2 ± 28.2
(3-101)6.0 ± 3.7
(1-12)
41.3 ± 23.7
(3-67)

10.9 ± 10.1
(0-33)
36.3 ± 31.2
(3-101)

0.351
0.375

0.423
0.0502
0.678
0.876
0.570
0.100

1.00

0.182

0.678

0.182
0.684

MTX-LPD, methotrexate-associated lymphoproliferative disorders; SD, standard deviation; RA, rheumatoid arthritis; sIL-2R, soluble interleukin-2 receptor; LDH, lactate dehydrogenase; DLBCL, diﬀuse large B-cell lymphoma; FL, follicular lymphoma; HL, Hodgkin lymphoma;
MZL, marginal zone lymphoma; PTCL, peripheral T-cell lymphoma; EBER, in situ hybridisation of Epstein‒Barr virus encoding ribonucleic acid; N/A, not available; CT, computed tomography.
aPatients who have no necrotic lesions, bPatients who have at least one necrotic lesion, cOne patient with coexisting polymyositis andSjögrenʼs syndrome, dE.g., prednisolone, tacrolimus and salazosulfapyridine, eLugano classiﬁcation system, fCT scan upon MTX-LPD
suspicion, gInitial follow-up CT scan after MTX withdrawal.

MTX-LPD

February 2024

Results
Among 89 lesions, 36 with necrosis and 53 without
were included in the analysis and were followed up.
Table 2 presents the specific site of each nodal or
extranodal lesion. Necrosis was identified within 9(15%) of 59 nodal lesions and 27 (90%) of 30 extranodal lesions. Necrosis was significantly more common
in extranodal lesions than in nodal lesions (p < 0.001).
Table 3 shows the percentage lesion size reduction
based on the univariate analysis. The mean ± SD for thepercentage size reduction in lesions without necrosis
Table 2

Speciﬁc site of each nodal or extranodal lesion (n = 89)
Necrosis (-)a(n = 53)

Necrosis (+)b(n = 36)

Nodal, n
Neckc
Infraclavicular
Axillary and pectoral
Mediastinal
Hilar
SpleenParaaortic
Iliac

50
7
1
11
12
1
2
6
10

9
2
0
1
2
1
0
3
0

Extra nodal, nRenal and adrenal
Lung
Skin/subcutaneous
Liver
Othersd

3
1
1
0
0
1

27
11
9
6
1
0

CT, computed tomography; MTX-LPD, methotrexate-associatedlymphoproliferative disorders.
aLesions without necrosis on CT scan upon MTX-LPD suspicion,b
Lesions with necrosis on CT scan upon MTX-LPD suspicion,cIncluded cervical, supraclavicular, occipital, and preauricularregions, dThyroid.

Table 333

and those with necrosis were −10.5 ± 79.1% and48.0 ± 24.1%, respectively. Necrotic lesions had moresignificant regression than non-necrotic lesions(p < 0.001). In addition, the mean ± SD of the longest
diameter of non-necrotic lesions at baseline CT scan
was 25.6 ± 7.3 mm, whereas it was 39.5 ± 20.9 mm fornecrotic lesions, a significant difference (p < 0.001).
Table 4 shows the association between necrosis andthe percentage lesion size reduction based on the linear
regression analysis. In the model adjusted for lesion site(nodal or extranodal) and size (the product of the longest and perpendicular diameters at baseline CT scan),necrotic lesions regressed 49.3% (95% confidence interval : 9.0-89.6) more than non-necrotic lesions(p = 0.017); the difference was statistically significant.
Figures 2 and 3 show respective representative images ofnecrotic and non-necrotic lesions.

Discussion
This retrospective study revealed that necrotic
lesions detected on CT scans were more regressive than
non-necrotic lesions after MTX withdrawal in patientswith MTX-LPD. Lesion site and size at baseline CT
scan were correlated with the presence of necrosis.
However, multivariate analysis revealed that necrosis
was a predictor of regression independent of these factors. Previous reports have found that MTX withdrawal is the initial step for managing MTX-LPD
because some lesions regress after MTX withdrawal[1-5]. Immediate chemotherapy is not required in thesepatients, and the importance of predicting regression isunderscored by the fact that the patients with MTXLPD are usually older and immunocompromised andthus more at risk of adverse effects. This researchemphasized the role of CT scan imaging in predicting

Percentage lesion size reduction based on the univariate analysis

Longest diameter at the baseline CTc, mm, mean ± SD (range)
Longest diameter at the follow-up CTe, mm, mean ± SD (range)
Percentage lesion size reductionf, %, mean ± SD (range)

Necrosis (-)a (n = 53)

Necrosis (+)b (n = 36)

P-value25.6 ± 7.3 (16-47)
25.1 ± 12.1 (0-51)-10.5 ± 79.1 (-284-100)

39.5 ± 20.9 (16-107)
28.4 ± 18.7 (0-82)
48.0 ± 24.1 (-4-100)< 0.001d
0.318< 0.001d

CT, computed tomography; SD, standard deviation; MTX-LPD, methotrexate-associated lymphoproliferative disorders.
aLesions without necrosis on CT scan upon MTX-LPD suspicion, bLesions with necrosis on CT scan upon MTX-LPD suspicion, cCT scan
upon MTX-LPD suspicion, dStatistically signiﬁcant (p < 0.05), eInitial follow-up CT scan after MTX withdrawal, fCalculated according to
diﬀerences in the product of the longest and perpendicular diameters between the baseline and the follow-up CT scans, divided by the
product of the diameters at baseline CT scan.

34

Kitayama et al.

Acta Med. Okayama Vol. 78, No. 1

Table 4
Association between necrosis and the percentage lesion size reductiona based on the linear regression analysis
Crude model (n = 89)

Necrosis (-)c
Necrosis (+)dAdjusted modelb (n = 89)

Beta coeﬃcients (95% CI), %P-value

Beta coeﬃcients (95% CI), %P-value

58.5 (31.5-85.6)< 0.001e

49.3 (9.0-89.6)

0.017eCI, conﬁdence interval; CT, computed tomography; MTX-LPD, methotrexate-associated lymphoproliferative
disorders.
aCalculated according to diﬀerences in the product of the longest and perpendicular diameters between thebaseline and the follow- up CT scans, divided by the product of the diameters at baseline CT scan, bAdjusted
for lesion site (nodal or extranodal) and size (the product of the longest and perpendicular diameters at baseline
CT scan), cLesions without necrosis on CT scan upon MTX-LPD suspicion, dLesions with necrosis on CT scan
upon MTX-LPD suspicion, eStatistically signiﬁcant (p < 0.05).

Fig. 2
Representative images of a necrotic lesion. A, A 74-year-old man presented with diﬀuse large B-cell lymphoma and extensive
necrosis (arrow) at the center of the liver lesion (arrowhead) on a contrast-enhanced axial computed tomography scan before methotrexate
withdrawal; B, Lesion size reduction (arrowhead) on follow-up contrast-enhanced axial computed tomography scan performed 3 days after
methotrexate withdrawal.

Fig. 3
Representative images of a non-necrotic lesion. A, 65-year-old woman presented with follicular lymphoma but without a necrotic
area within the right axillary lesion (arrowhead) on a contrast-enhanced axial computed tomography scan before methotrexate withdrawal; B, No signiﬁcant change in lesion size (arrowhead) on follow-up unenhanced axial computed tomography scan 56 days after
methotrexate withdrawal.

February 2024

regression after MTX withdrawal among patients with
MTX-LPD.
Few studies have reported on diagnostic imaging
predictors after MTX withdrawal in MTX-LPD.
Takanashi et al. used the maximum standardized uptake
value on 18F-fluorodeoxyglucose positron emission
tomography/computed tomography (FDG PET/CT)
and the maximum size of MTX-LPD-associated tumors
as predictors of spontaneous regression after MTX
withdrawal [18]. Kameda et al. reported that the sumof the metabolic tumor volume and the sum of totallesion glycolysis on 18F-FDG PET/CT can be used as
predictors of spontaneous regression [19]. However,
Watanabe et al. showed that none of the 18F-FDG PET
factors before MTX withdrawal could be used to predictclinical outcomes after MTX withdrawal [17]. Thus,
predictors of regression after MTX withdrawal on diagnostic imaging remain controversial.
Previous studies have not reported on necrosis
within lesions detected on CT scans in MTX-LPD.
Only the study conducted by Kurita et al. assessed
pathologically identified necrosis within lesions in
MTX-LPD. Their results showed that necrosis was asigniﬁcant factor for better progression-free survival indiffuse large B-cell lymphoma and a subspecific subtypeof LPD lesions [7]. On the other hand, in de novo diffuse large B-cell lymphoma, patients with necrosis
within lesions detected on CT scans had signiﬁcantly
worse progression-free survival and overall survival
than those without necrosis [8]. Similarly, in de novo
peripheral T-cell lymphoma, patients with necrosis
within lesions detected on CT scans had signiﬁcantly
poorer outcomes (progression during therapy or lesion
relapse within 24 months after therapy) than those
without necrosis [9]. Thus, necrosis detected on CT
scans is correlated with a poor prognosis in some subtypes of de novo lymphoma. Our results may help clinicians prevent unnecessary chemotherapy in patientswith MTX-LPD who have necrotic lesions. Currently,
it is unclear why necrotic lesions detected on CT scans
are more regressive than non-necrotic lesions after
MTX withdrawal in patients with MTX-LPD. We speculate that necrosis might reflect potential host immunity against MTX-LPD, but further studies to elucidate
its etiology are desired.
Watanabe et al. observed extranodal involvement on
18
F-FDG PET/CT in 17 (18%) of 92 anatomic regions[17]. In our study, 30 (34%) of 89 lesions were identi-

MTX-LPD

35

fied in the extranodal regions. In several patient-based
evaluations, extranodal involvement was observed in
40-50% of patients [1 , 2 , 7 , 19]. Furthermore, in ourstudy, necrosis was identified on 36 (40%) of 89 lesions
and was significantly more common within extranodal
than within nodal lesions. In a clinicopathologicalstudy, Kurita et al. showed that 103 (48%) of 214
patients had extranodal involvement. Moreover, 56(29%) of 192 lesions presented with pathologically
identified necrosis, but the correlation between lesion
site (nodal or extranodal) and frequency of necrosis was
not reported [7]. The cause of this association is
unclear. However, in our study, necrosis within lesions
detected on CT scans was an independent predictor of
regression based on the multivariate analysis.
To the best of our knowledge, only the study by
Takanashi et al. evaluated the specific size of MTX-LPD
lesions on 18F-FDG PET/CT [18]. Their results showedthat the mean maximum diameter of the largest tumors
upon diagnosis was 30 mm (range: 10-110 mm) (n = 18).
This was similar to our results, in which the mean longest diameter of all lesions at baseline CT scan was
31 mm (range: 16-107 mm). However, Takanashi et al.
assessed the size of the largest lesion of each patientalone, and thus their results cannot be directly compared with ours. In addition, they reported that the
maximum diameters of the spontaneous regression
group were smaller than those of the nonspontaneous
regression group (n = 5, mean = 20 mm; and n = 13,
mean = 52 mm, respectively; p = 0.04). In contrast, ourresults showed that necrotic lesions were larger than
non-necrotic lesions at baseline CT scan. However, ourmultivariate analysis showed that necrotic lesions had
significantly more regression than non-necrotic lesions.
The association between lesion size and regression thus
remains unclear, and further prospective studies are
warranted.
The present study had several limitations. First, we
included various imaging modalities and protocols
because of our study’s retrospective nature. Second, thestudy cohort comprised a relatively small number ofpatients because of the rarity of this disease. Third, we
did not consider non-mass lesions, such as splenomegaly, hepatomegaly, and bone marrow involvement, astarget lesions. In clinical practice, a comprehensive
assessment of these findings is required when evaluating regression after MTX withdrawal.
In conclusion, necrosis detected on a CT scan is an

36

Kitayama et al.

Acta Med. Okayama Vol. 78, No. 1

independent predictor of spontaneous regression after
MTX withdrawal in patients with MTX-LPD. The
results of this study enhance the role of CT imaging in
MTX-LPD in predicting regression after MTX withdrawal as well as in evaluating the extent of the lesions.

10.

References

11.

1.

2.

3.

4.

5.
6.

7.

8.

Salloum E, Cooper DL, Howe G, Lacy J, Tallini G, Crouch J,
Schultz M and Murren J: Spontaneous regression of lymphoproliferative disorders in patients treated with methotrexate for rheumatoid arthritis and other rheumatic diseases. J Clin Oncol (1996) 14:
1943-1949.
Ichikawa A, Arakawa F, Kiyasu J, Sato K, Miyoshi H, Niino D,
Kimura Y, Takeuchi M, Yoshida M, Ishibashi Y, Nakashima S,
Sugita Y, Miura O and Ohshima K: Methotrexate/iatrogenic
lymphoproliferative disorders in rheumatoid arthritis: histology,
Epstein-Barr virus, and clonality are important predictors of disease progression and regression. Eur J Haematol (2013) 91: 2028.
Inui Y, Matsuoka H, Yakushijin K, Okamura A, Shimada T, Yano S,
Takeuchi M, Ito M, Murayama T, Yamamoto K, Itoh T, Aiba K
and Minami H: Methotrexate-associated lymphoproliferative disorders: management by watchful waiting and observation of early
lymphocyte recovery after methotrexate withdrawal. Leuk Lymphoma(2015) 56: 3045-3051.
Tokuhira M, Saito S, Okuyama A, Suzuki K, Higashi M, Momose
S, Shimizu T, Mori T, Anan-Nemoto T, Amano K, Okamoto S,
Takeuchi T, Tamaru JI and Kizaki M: Clinicopathologic investigation of methotrexate-induced lymphoproliferative disorders, with afocus on regression. Leuk Lymphoma (2018) 59: 1143-1152.
Tokuhira M, Tamaru JI and Kizaki M: Clinical management forother iatrogenic immunodeﬁciency-associated lymphoproliferative
disorders. J Clin Exp Hematop (2019) 59: 72-92.
Gion Y, Iwaki N, Takata K, Takeuchi M, Nishida K, Orita Y,
Tachibana T, Yoshino T and Sato Y: Clinicopathological analysisof methotrexate-associated lymphoproliferative disorders: Comparison of diﬀuse large B-cell lymphoma and classical Hodgkin lymphoma types. Cancer Sci (2017) 108: 1271-1280.
Kurita D, Miyoshi H, Ichikawa A, Kato K, Imaizumi Y, Seki R,
Sato K, Sasaki Y, Kawamoto K, Shimono J, Yamada K, Muto R,
Kizaki M, Nagafuji K, Tamaru JI, Tokuhira M and Ohshima K:
Methotrexate-associated Lymphoproliferative Disorders in Patients
With Rheumatoid Arthritis: Clinicopathologic Features andPrognostic Factors. Am J Surg Pathol (2019) 43: 869-884.
Adams HJA, de Klerk JMH, Fijnheer R, Dubois SV, Nievelstein
RAJ and Kwee TC: Prognostic value of tumor necrosis at CT in
diﬀuse large B-cell lymphoma. Eur J Radiol (2015) 84: 372-377.

9.

12.

13.

14.

15.

16.

17.

18.

19.

Yang W, Jiang S, Lin J and Li Y: CT ﬁndings predict survival ofpatients with peripheral T cell lymphoma: a preliminary study.
Radiol Oncol (2019) 53: 31-38.
Cheson BD, Fisher RI, Barrington SF, Cavalli F, Schwartz LH,
Zucca E and Lister TA: Recommendations for initial evaluation,
staging, and response assessment of Hodgkin and non-Hodgkin
lymphoma: the Lugano classiﬁcation. J Clin Oncol (2014) 32:
3059-3068.
Spira D, Vogel W, Sökler M, Löﬄer S, Sauter A, Schulze M andHorger M: Size and attenuation CT (SACT) of residual masses inpatients with follicular non-Hodgkin lymphoma: more than a statusquo? Eur J Radiol (2012) 81: 1657-1661.
Wei YC, Ding CY, Liang JH, Wang L, Zhu HY, Xia Y, Wu JZ,
Fan L, Li TN, Li JY and Xu W: Interim response in diﬀuse large B
cell lymphoma on CT: what is the optimal size reduction (ΔSPD)
for predicting outcome? Eur Radiol (2020) 30: 3094-3100.
Swerdlow S, Campo E, Harris N, Jaﬀe E, Pileri S, Stein H,
Thiele J, Arber D, Hasserjian R, Beau M, Orazi A and Siebert R:
WHO classiﬁcation of tumors of haematopoietic and lymphoid tissues, Revised 4th Ed, IARC, Lyon (2017).
Moon SH, Cho SK, Kim WS, Kim SJ, Chan Ahn Y, Choe YS,
Lee KH, Kim BT and Choi JY: The role of 18F-FDG PET/CT for
initial staging of nasal type natural killer/T-cell lymphoma: a comparison with conventional staging methods. J Nucl Med (2013) 54:
1039-1044.
London K, Cross S, Onikul E, Dalla-Pozza L and Howman-Giles R:
18F-FDG PET/CT in paediatric lymphoma: comparison with conventional imaging. Eur J Nucl Med Mol Imaging (2011) 38: 274284.
Fueger BJ, Yeom K, Czernin J, Sayre JW, Phelps ME and AllenAuerbach MS: Comparison of CT, PET, and PET/CT for stagingof patients with indolent non-Hodgkinʼs lymphoma. Mol Imaging
Biol (2009) 11: 269-274.
Watanabe S, Manabe O, Hirata K, Oyama-Manabe N, Hattori N,
Kikuchi Y, Kobayashi K, Toyonaga T and Tamaki N: The usefulness of (18)F-FDG PET/CT for assessing methotrexate-associatedlymphoproliferative disorder (MTX-LPD). BMC Cancer (2016) 16:
635.
Takanashi S, Nakazato T, Aisa Y, Ito C, Arakaki H, Osada Y,
Hirano M and Mori T: The prognostic value of positron emission
tomography/computed tomography in rheumatoid arthritis patientswith methotrexate-associated lymphoproliferative disorders. Ann
Hematol (2018) 97: 1611-1618.
Kameda T, Nakashima S, Mitamura K, Yamamoto Y, Norikane T,
Shimada H, Wakiya R, Kato M, Miyagi T, Sugihara K, Mino R,
Mizusaki M, Kadowaki N and Dobashi H: FDG-PET/CT imaging
parameters for predicting spontaneous regression of methotrexateassociated lymphoproliferative disorder in patients with rheumatoid
arthritis. Sci Rep (2022) 12: 15367.