The Spontaneous Regression of Grade 3 Methotrexate-related Lymphomatoid Granulomatosis: A Case Report and Literature Review.

Lymphomatoid granulomatosis (LYG) is a rare lung disorder diagnosed by radiological imaging of multiple pulmonary nodules and occasionally induced by methotrexate (MTX) use. To date, the treatment of LYG has not been standardized. We herein report the case of a patient with grade 3 MTX-related LYG who presented a bulky lung mass. Importantly, the disease condition only improved after the discontinuation of MTX and remained stable for more than 1 year. Chest physicians should be aware that LYG can develop as a single lung mass and spontaneously regress, even without aggressive chemotherapy, following the cessation of MTX.

Introduction

Lymphomatoid granulomatosis (LYG) is a rare disorder characterized by multiple nodular lesions with lymphocytic invasion of the vascular walls (1-3). The development of LYG is associated with the reactivation of Epstein-Barr (EB) virus under an immunosuppressive state (4,5). Several previous studies have reported that long-term methotrexate (MTX) use induced an immunosuppressive state in patients with rheumatoid arthritis (RA) that resulted in the development of LYG (6). We report the case of a patient with grade 3 MTX-related LYG with a single bulky lung mass, which improved following the cessation of MTX.

Case Report

A 79-year-old man visited our hospital due to cough which had persisted for 5 months. He was an ex-smoker (20 pack-year; however, he had not smoked since he was 40 years of age) and had hemiplegia due to cerebral infarction. He also had a 29 year-history of RA, which had been treated with MTX (6 mg/week), prednisolone (2.5 mg/day), and clopidogrel (75 mg/day). A chest X-ray and contrast-enhanced whole body computed tomography (CT) revealed a single cavitary mass surrounded by ground glass attenuation in the left lower lobe, and a small amount of bilateral pleural effusion (Fig. 1a, b) without mediastinal or hilar lymphadenopathy. The patient did not present any B symptoms (10% weight loss, fever, night sweat), and a physical examination showed no abnormalities (including skin rash and abnormal breath sounds). The patient’s laboratory data were as follows: white blood cell count (WBC), 8,400/μL; neutrophils, 83%; lymphocytes, 6.1%; monocytes, 9.6%; eosinophils, 0.3%; lactate dehydrogenase (LDH), 220 U/L; C-reactive protein (CRP), 9.96 mg/dL; rheumatoid factor, 28 IU/mL; anti-cyclic citrullinated peptide antibody, 227.4 mg/dL. The tumor marker levels [including soluble interleukin (IL)-2 receptor] were within the normal ranges. We administered antibiotics (ampicillin and sulbactam) empirically in consideration of the lung abscess. The CRP level decreased slightly from 9.96 mg/dL to 6.71 mg/dL; however, the chest X-ray findings showed no improvement. The pathological analysis of a CT-guided pulmonary biopsy specimen demonstrated vascular infiltration of large atypical lymphoid cells surrounded by small lymphocytes and plasma cells (Fig. 2a). The immunohistological findings showed that the large atypical lymphoid cells were positive for CD20 (Fig. 2b) and EB-encoded small RNA (EBER) (Fig. 2c), whereas the small lymphocytes surrounding the areas of dense infiltration of large atypical lymphoid cells were positive for CD3 (Fig. 2d). There were 70 EBER-positive lymphocytes per high power field. Serum antibody tests were positive for EB virus nuclear IgG (1 : 320) and negative for EB virus capsid IgM, which is consistent with a prior non-acute EBV infection. The EBV capsid IgG ratio and the early antigen-DR component IgG ratio were abnormally high (1:640 and 1:160, respectively). EB virus DNA was found at 2,000 copies/mL. These results confirmed the reactivation of EBV. Based on these findings, the patient was diagnosed with grade 3 LYG. Because his performance status was 3 at the diagnosis of LYG, MTX was discontinued with careful observation. One month later, the symptoms of LYG disappeared and the lung mass apparently shrunk with the improvement of the high CRP level, which remained stable for 15 months (Fig. 1c, d).

Figure 1.

(a) Chest X-ray and (b) chest computed tomography (CT) revealed single pulmonary cavitary mass in the left lower lobe. (c), (d) The pulmonary mass improved and remained stable at 9 months from the day of MTX discontinuation.

Figure 2.

(a) Elastica van Gieson staining image of an infiltrated blood vessel showing predominantly small lymphoid cells with a few large cells. (b) Large lymphoid cells were stained with CD20. (c) Small lymphoid cells around large lymphoid cells were stained with CD3. (d) Epstein-Barr virus encoded RNAs (EBER) were visible following in situ hybridization. The number of EBER positive cells was 70 per high power field.

Discussion

LYG is a rare, EBV-associated, extranodal B-cell lymphoproliferative disease. The lung is the most common site of involvement (>90%) with or without skin (25-50%), renal (32%), liver (29%), and central nerve (32%) involvement (1). The diagnosis of LYG requires the histological demonstration of angiocentric and angiodestructive lesions consisting of populations of small lymphocytes, plasma cells, histiocytes, and large atypical lymphoid cells. An immunohistological investigation to identify the B-cell subset, and to demonstrate EBV infection by EBER, is helpful in confirming the diagnosis. The severity of LYG is graded as 1 to 3 according to the number of EBER-positive large B cells.

Our report describes the case of a patient with MTX-related LYG who presented with a bulky mass, which shrunk after the cessation of MTX. The results of our case study indicated the following three clinical implications. First, the discontinuation of MTX without aggressive chemotherapy is an important option for MTX-related LYG patients, even those with high-grade LYG. In fact, in our case of grade 3 LYG, the patient’s symptoms, bulky lung mass, and high CRP level improved within one month after the cessation of MTX. To date, the treatment of LYG has not been standardized. Aggressive combined chemotherapy is often selected for the treatment of high-grade LYG, because grade 3 LYG shows a prognosis that is somewhat similar to that of diffuse large B-cell lymphoma (DLBCL) (1,7,8). To the best of our knowledge, there are 14 case reports of MTX-related LYG patients with RA (Table). Nine case reports, including one case of grade 3 LYG (9) described the improvement of the LYG patient’s condition after the withdrawal of MTX, as occurred in our study. A previous study of rituximab, cyclophosphamide, doxorubicin hydrochloride, oncovin, and prednisone (R-CHOP) therapy, which is often administered for high-grade LYG and DLBCL patients, reported that grade 3-4 adverse events occurred in 14% of elderly patients (10). Thus, chemotherapy would not always be the first choice, particularly for elderly LYG patients (such as our patient). These results suggest that the physician should discontinue the administration of MTX first with close observation, then chose R-CHOP therapy if the tumor does not regress.

Table.

Reports of MTX Related LYG Patient with RA.

Age /Sex	History of RA	Duration of MTX	Grade	Organ involvement	Regression following withdrawal of MTX	Response duration	Ref no.
54 F	24 y	10 y	ND	Pulmonary (multiple), Liver, Spleen	Yes	ND	15
65 F	27 y	17 y	3	Pulmonary (multiple), Skin, Brain	Yes	over 2 y	9
70 F	41 y	5 y	2	Pulmonary (multiple), Kidney, Brain	Yes*	over 6 m	16
71 M	6 y	5 y	1	Pulmonary (multiple), Liver, Spleen, Ileum	Yes	over 8 m	17
73 F	20 y	14 m	2	Pulmonary (multiple), Liver	Yes	over 6 m	18
75 M	12 y	12 y	ND	Pulmonary (multiple)	Yes	over 6 y	19
76 M	18 y	9 y	2	Pulmonary (multiple), Liver	Yes	ND	20
76 F	18 y	18 y	1	Pulmonary (multiple), Liver	Yes	over 20 m	21
76 F	ND	5.5 y	2	Pulmonary (single)	Yes	over 1 y	13
79 F	39 y	18 y	3	Pulmonary (single)	Yes	over 15 m	Our case
60 F	ND	ND	ND	Pulmonary (multiple)	No**	-	22
64 F	ND	10 y	3	Pulmonary (multiple)	No	-	23
70 F	13 y	5 y	2-3	Pulmonary (multiple)	No	-	24
71 M	6 y	29 m	ND	Systemic lymph node (complicated by MTX related interstitial pneumonia)	No	-	25
74 F	28 y	21 m	ND	Skin	No	-	26

* The patient received radiotherapy for brain involvement.

** The patient received chemotherapy immediately after diagnosis.

Second, MTX-related LYG can present as a single mass mimicking lung cancer or abscess. In fact, the patient described in our report developed a bulky mass; thus, lung cancer was suspected before a lung biopsy. Generally, chest radiography typically reveals multiple poorly-defined nodules in the mid and lower lung zones with possible diffuse reticular abnormalities in LYG patients (11,12). Similarly, patients with MTX-related LYG commonly present multiple masses (Table). Only one case report described a patient who developed grade 2 LYG as a single lung mass (13). These reports suggest that although LYG is a rare disorder, chest physicians should carefully investigate the possibility regardless of the number of pulmonary lesions.

Third, the withdrawal of MTX can be effective-particularly for LYG patients who have undergone long-term MTX treatment. A previous report noted that the incidence of lymph proliferative disorder (LPD) in RA patients was 2.0-5.5 times higher than that in patients without RA, and the interval between RA and the diagnosis of LPD in RA patients treated with MTX was significantly shorter in comparison to patients treated without MTX (14). These results suggest that both RA and MTX can induce the development of LPD. As shown in Table, the duration of MTX treatment was described in 14 of 15 case reports, including our case. Of note, in patients with the spontaneous improvement of LYG after the withdrawal of MTX, the duration of MTX treatment was longer in comparison to those without (median: 10.0 years vs. 3.7 years; Mann-Whitney U test, p=0.038). On the other hand, the duration of RA treatment was described in 10 case reports. There was no significant difference in the disease duration of the patients with the spontaneous improvement of LYG after the withdrawal of MTX and those without spontaneous improvement (median: 19.0 years vs. 13.0 years; Mann-Whitney U test, p=0.55). Although it is difficult to distinguish whether LYG is induced by RA or MTX in clinical practice, LYG patients who have undergone long-term MTX treatment would be more affected by MTX than by RA. Thus, the withdrawal of MTX could be effective for such patients.

In conclusion, we reported the case of a patient with a bulky mass caused by LYG, which only improved after the cessation of MTX. Chest physicians should be aware that LYG can develop as a single lung mass, and that the discontinuation of MTX without aggressive chemotherapy represents an important treatment choice for LYG. Further studies are necessary to confirm our results.

The authors state that they have no Conflict of Interest (COI).