Methotrexate-related Epstein-Barr Virus (EBV)-associated lymphoproliferative disorder--so-called "Hodgkin-like lesion"--of the oral cavity in a patient with rheumatoid arthritis

Abstract

Patients affected by autoimmune diseases (rheumatoid arthritis, psoriasis, dermatomyositis) who are treated with methotrexate (MTX) sometimes develop lymphoproliferative disorders (LPDs). In approximately 40% of reported cases, the affected sites have been extranodal, and have included the gastrointestinal tract, skin, lung, kidney, and soft tissues. However, MTX-associated LPD (MTX-LPD) is extremely rare in the oral cavity. Here we report a 69-year-old Japanese woman with rheumatoid arthritis (RA) who developed MTX-LPD resembling Hodgkin's disease--so-called "Hodgkin-like lesion"--in the left upper jaw. Histopathologically, large atypical lymphoid cells including Hodgkin or Reed-Sternberg-like cells were found to have infiltrated into granulation tissue in the ulcerative oral mucosa. Immunohistochemistry showed that the large atypical cells were positive for CD20, CD30 and Epstein-Barr virus (EBV)-latent infection membrane protein-1 (LMP-1) and negative for CD15. EBV was detected by in situ hybridization (ISH) with EBV-encoded small RNA (EBER), and polymerase chain reaction (PCR) for LMP-1 and EBNA-2 in material taken from the formalin-fixed, paraffin-embedded specimen. To our knowledge, this is the first reported case of MTX-related EBV-associated LPD (MTX-EBVLPD), "Hodgkin-like lesion", of the oral cavity in a patient with RA.

Fig. 1

Intra-oral findings, and radiologic and gross features of the tumor. a Intraoral view showing swollen ulcerative mucosa in the upper jaw buccal gingiva from the first premolar to molar. b Panoramic radiograph showing absence of neoplastic osteolysis in the area surrounding the lesion

Fig. 2

Microscopic features of the biopsy specimen. a Granulomatous tissue is evident in the submucosal stroma with lymphocyte-based area of severe inflammation (HE, original magnification × 100). b Palisade-like arrangement of epithelioid cells with caseous-like necrosis found in the granulomatous lesion (HE, original magnification × 200)

Fig. 3

Microscopic features of the re-biopsy specimen. a Ulcer and severe inflammatory cell infiltration is evident in the submucosa (HE, original magnification × 20). b Inflammation of atypical large round cells is evident around the ulcer (HE, original magnification × 200). c Atypical round large cells are evident in the edematous submucosal stroma (inset; atypical cells with large nuclei), (HE, original magnification × 200). d Atypical large cells (inset; Reed-Sternberg like cells) are evident the epithelioid granulomatous tissue with a background of morphologically unremarkable inflammatory cells (HE, original magnification × 100)

Fig. 4

Immunohistochemical features of the re-biopsy specimen. a, c, e, g, showing an edematous submcosal stroma (original magnification × 400). b, d, f, h Granuloma formation (original magnification × 400). a HE staining of the edematous submcosal stroma. b HE staining of the granulomatous area. c, d Atypical large cells show positivity for CD20. e, f An atypical large cell positive for CD30. f Reed-Sternberg (R-S)-like cells show positivity for CD30. g, h Similarity, nuclei of large round atypical cells are markedly positive for Ki-67 (labeling index exceeding 60–70%)

Fig. 5

Detection of Epstein-Barr virus (EBV) in the re-biopsy specimen. a Immunohistochemically, EBV-LMP-1-positive cells are present in small foci of granuloma (original magnification × 400). b In situ hybridization for EBV shows strong staining in the nuclei (original magnification × 400)

Fig. 6

PCR analysis of the Epstein-Barr virus (EBV) gene using formalin-fixed, paraffin-embedded tissue. LMP-1 (129 bp) and EBNA-2 (186 bp) were detected in each of the specimens (biopsy, re-biopsy and surgical), and these bands showed the same levels in the Raji cells used as a positive control