Unusual manifestation of methotrexate-associated lymphoproliferative disorder as a palatal mass

Abstract

Methotrexate-associated lymphoproliferative disorder (MTX-LPD) can occur in the oral cavity, and only a few cases with palatal involvement have been reported. Chemotherapy may be needed if there is no remission after the withdrawal of MTX. We report a case of MTX-LPD presenting with a swelling of the palate that required chemotherapy. A woman in her 70s with rheumatoid arthritis reported a swelling on the left side of the palate. Her condition was diagnosed as Epstein-Barr virus-negative diffuse large B-cell lymphoma (MTX-LPD). Since the mass did not remit after MTX withdrawal, she underwent five courses of chemotherapy. Currently, the patient is in complete remission. In patients on MTX who develop a swelling on the palate, MTX-LPD should be included among the differential diagnostic possibilities. Diagnosis and treatment of MTX-LPD call for consultation with a haematologist. If the mass fails to regress following withdrawal of MTX, appropriate chemotherapy is indicated.

Background

Patients with rheumatoid arthritis (RA) must be treated with disease-modifying antirheumatic drugs (DMARDs), which are classified into four categories: conventional synthetic, targeted synthetic, originator biological and biosimilar biological DMARDs.¹ In recent years, biological and targeted synthetic DMARDs have been introduced in addition to conventional synthetic DMARDs such as methotrexate (MTX), and clinical remission has become a realistic therapeutic goal for the majority of patients with RA due to these drugs.² A recent study reported that monotherapy with sarilumab, an originator biological DMARD, could be a treatment alternative for patients with RA with a contraindication/intolerance to MTX.³

In most situations, MTX is still recommended as an anchor drug for RA,⁴ and several cases of MTX-associated lymphoproliferative disorder (MTX-LPD) have been reported.^{5 6} MTX-LPD is classified as ‘other iatrogenic immunodeficiency-associated LPD’ in the fourth edition of the WHO classification.^6–8 Of the LPDs reported in patients receiving MTX, 40%–50% are extranodal, occurring at sites such as the gastrointestinal tract, skin, liver, spleen, lung, kidney, adrenal gland, thyroid gland, bone marrow and central nervous system.⁷ Although MTX-LPD can occur at sites in the oral cavity, such as the gingiva, tongue and mouth floor,^{6 7} only a few cases of MTX-LPD in the palate have been reported.^{4 9}

An association between LPDs and infection with Epstein-Barr virus (EBV) has been suggested.⁴ Approximately 30%–50% of cases of LPDs have been shown to be EBV positive.^{4 10 11} Moreover, patients with spontaneous regression have a significantly higher rate of EBV positivity.¹² For the treatment of patients with MTX-LPD, observation after MTX withdrawal is recommended as the initial management.^{8 10} Approximately 60% of MTX-LPDs show spontaneous remission after MTX withdrawal.¹² However, if a patient does not experience remission even after the withdrawal of MTX, chemotherapy may be needed.^{9 13 14}

Herein, we report a relatively rare case in which swelling of the palate was the initial manifestation of MTX-LPD that required chemotherapy.

Case presentation

The patient was a woman in her 70s who visited the Department of Oral and Maxillofacial Surgery at Kyoto University Hospital in February 2019 with a swelling on the left side of the palate. She had been diagnosed with RA 7 years ago and was taking MTX (6–10 mg/week) for the last 91 months (total dose: 3278 mg) along with prednisolone. There were no remarkable findings in her systemic examination, apart from RA. Intraoral clinical examination revealed a soft and fluctuant mass on the left side of the hard palate, measuring 23×12 mm in size. The surface of the mass was reddish and smooth (figure 1). CT revealed no obvious resorption of the palatal bone surrounding the mass (figure 2).

Figure 1.

Intraoral photograph showing a non-ulcerative mass in the left side of the hard palate measuring 23×12 mm in size.

Figure 2.

CT shows no obvious resorption of the palatal bone surrounding the mass.

Investigations

Since the clinical diagnosis was palatal neoplasm, with salivary gland neoplasm and mucous cyst as the differential diagnoses, fine-needle aspiration was performed. As the specimen showed a large number of atypical lymphoid cells, an incisional biopsy was subsequently performed. Histopathologically, H&E staining showed a dense infiltration of lymphocytes in the submucosal stroma (figure 3A). In the high-power view, there was an accumulation of large lymphocytes with atypical nuclei inconsistent with an inflammatory infiltrate (figure 3B). Immunohistochemical staining demonstrated that the atypical large lymphocytes were positive for CD20 and negative for CD3, CD5, and CD10 (figure 3C). EBV-encoded small RNA in situ hybridisation was negative (figure 3D). The histopathological diagnosis was EBV-negative diffuse large B-cell lymphoma (DLBCL).

Figure 3.

Histopathological examination with H&E and immunohistochemical staining. (A) Low-power view showing diffuse, unencapsulated, cellular infiltration of the submucosal stroma (H&E ×40). (B) High-power view showing diffuse monotonous cellular lymphoid infiltrate inconsistent with an inflammatory infiltrate (H&E ×200). (C) Atypical lymphoid infiltrate showing positive immunoexpression for CD20, indicative of an exclusively B cell proliferation (immunohistochemical ×200). (D) Dense infiltrate of B cells with negative immunoexpression for EBV-encoded small RNA in situ hybridisation (×200). EBV, Epstein-Barr virus.

At this stage, fluorodeoxyglucose (FDG)-positron emission tomography/CT performed in consultation with a haematologist indicated increased FDG uptake only in the left palate (figure 4A, B). Based on the clinical course and these examinations, the patient was diagnosed with MTX-LPD localised only in the palate.

Figure 4.

Fluorodeoxyglucose (FDG)-positron emission tomography/CT showing pathological uptake of FDG only in the left palate ((A) whole body, (B) craniomaxillofacial region).

Treatment

As the mass did not reduce in size after several months of MTX withdrawal, the haematologist proactively suggested chemotherapy. However, the patient refused chemotherapy. Since the mass persisted during follow-up, chemotherapy was initiated 14 months after MTX withdrawal with the patient’s consent. One course of rituximab plus cyclophosphamide, vincristine and prednisone, and four courses of rituximab plus cyclophosphamide and prednisone were administered. She responded to five courses of chemotherapy over a period of approximately 3 months, and the mass was completely resolved. Since the completion of chemotherapy, RA has been managed by administering targeted synthetic and originator biological DMARDs including sarilumab.

Outcome and follow-up

Currently, she has had no signs of recurrence for 3 years after the initial visit, and the mass has completely disappeared intraorally (figure 5).

Figure 5.

Intraoral photograph showing disappearance of the mass.

Discussion

Important clinical issues were demonstrated in the present case. Most oral cavity MTX-LPDs present as an ulcerated mass on the gingiva; however, in relatively rare instances, MTX-LPD can present as a palatal swelling. Patients with EBV-positive MTX-LPD often respond to withdrawal of MTX with spontaneous regression of the mass. In cases where there is no evidence of remission, chemotherapy in keeping with standard care for malignant lymphoma may be required.

In a review article, Kondo et al⁴ reported that the most characteristic local findings of oral LPDs were ulceration and pain. While oral cavity cases have been reported,4 6 8 9 there were only two previously reported cases of MTX-LPD occurring in the palate.^{4 9} One was a case of MTX-LPD (EBV-positive DLBCL) complicated by bisphosphonate-related osteonecrosis of the jaw arising on the right side of the palate. The lesion, associated with ulcer formation, regressed after MTX withdrawal. The other case of MTX-LPD (EBV-negative DLBCL) initially presented as a swelling on the right side of the palate in addition to a mass at the left nasolabial sulcus. The mass resolved after MTX discontinuation. Therefore, the present case is the third reported case of MTX-LPD (EBV-negative DLBCL) arising in the palate. Furthermore, the unique aspect of our case was that the solitary LPD without ulceration and pain in the palate required chemotherapy due to a lack of regression after withdrawal of MTX.

Generally, immunodeficient/immunosuppressed patients show a higher risk of LPDs than immunocompetent individuals.⁹ As to the occurrence of MTX-LPDs, various factors such as the age of onset of RA, duration of MTX treatment, total dose of MTX, RA disease activity, EBV infection and Sjogren syndrome complications have been described in the literature.4 12 15–18 Hoshida et al¹¹ reported that patients who later developed MTX-LPD took 24–4785 mg (mean, 940 mg) of MTX over 2–131 months (mean, 54 months). Obata et al⁶ also reported that the dose of MTX administration was 7.26 mg/week (range 2.0–15.5 mg/week), and that the duration of MTX treatment was 99.0 months (range 1–360 months) in patients with MTX-LPD of the oral cavity. The patient we report here had taken a total amount of 3278 mg of MTX (6–10 mg/week) over 91 months. The risk of developing LPDs should be considered in patients with RA who receive high amounts of MTX for long term.

EBV infects >90% of the world’s population and is usually suppressed by cell-mediated immunity after the primary infection, whereas EBV activation by immune suppression, including MTX treatment, reportedly causes various diseases such as LPDs.^19–21 There is a high prevalence of EBV DNA in the saliva, gingival crevicular fluid and gingival tissue of patients with periodontal disease.⁶ Porphyromonas gingivalis, one of the major pathogens causing periodontitis, can induce EBV reactivation through epigenetic regulation.²² In the oral cavity, high EBV load in the gingival crevicular fluid of patients with periodontal disease may be associated with the frequent occurrence of gingival MTX-LPD.

In terms of treatment, MTX-LPDs may spontaneously remit after withdrawal of MTX therapy as the immune system recovers.^{4 15 16} Spontaneous regression following MTX withdrawal has been associated with EBV positivity and non-DLBCL type of LPD.⁷ In a review article, Tokuhira et al²³ reported that the rate of regressive LPD was higher in EBV-positive DLBCL than in non-specific DLBCL (65% and 32%, respectively). However, if no remission is observed following MTX withdrawal, treatment for malignant lymphoma, such as chemotherapy, should be considered.⁴ Soubrier et al²⁴ stated that a follow-up of 6–8 weeks is required before starting chemotherapy because regression of LPDs after MTX withdrawal is rapid, and that the absence of complete regression should lead to specific treatment. In the present case, although the induction of chemotherapy was postponed due to the patient’s refusal, the patient remained in complete remission after chemotherapy.

In conclusion, although intraoral occurrences of MTX-LPDs in the palate are relatively rare, those pathological entities should be included as a differential diagnosis in patients with swelling of the palate without ulceration in order to arrive at a proper diagnosis. Although the immediate withdrawal of MTX is recommended as the first choice of management, appropriate chemotherapy should be administered if the mass does not regress. We successfully managed a patient with MTX-LPD with the close cooperation of a haematologist for ensuring accurate diagnosis and treatment. Recently, Saito et al²⁵ demonstrated a decrease in the absolute lymphocyte count in peripheral blood towards the time of LPD development in patients with regressive LPD, suggesting a key role of lymphocytes in the pathogenesis of MTX-LPD. Close clinical observation at regular intervals is mandatory to intercept any signs of disease recurrence as late relapse or recurrence in another organ has been reported.²⁴ Patients aged >70 years and the DLBCL type are predictive of a shorter survival.⁷ In the future, cumulative data, including lymphocytes and other factors, from further studies are required to elucidate the pathogenesis of MTX-LPD.

Learning points.

• Methotrexate-associated lymphoproliferative disorders (MTX-LPDs) should be included as a differential diagnosis in patients with swelling of the palate without ulceration.

• Diagnosis and treatment of MTX-LPD call for consultation with a haematologist.

• In cases where there is no evidence of remission after withdrawal of MTX, chemotherapy in keeping with standard care for malignant lymphoma may be required.

Ethics statements

Patient consent for publication

Obtained.