SciELO - Scientific Electronic Library Online

vol.26 número2 índice de autoresíndice de materiabúsqueda de artículos
Home Pagelista alfabética de revistas  

Servicios Personalizados




Links relacionados

  • En proceso de indezaciónCitado por Google
  • No hay articulos similaresSimilares en SciELO
  • En proceso de indezaciónSimilares en Google


Revista Española de Cirugía Oral y Maxilofacial

versión On-line ISSN 2173-9161versión impresa ISSN 1130-0558

Rev Esp Cirug Oral y Maxilofac vol.26 no.2 Madrid mar./abr. 2004


Página del Residente

Which is the diagnosis?
¿Cuál sería su diagnóstico?


A 79 year old patient diagnosed of rheumatoid arthritis 15 years earlier and treated since then with methotrexate at a dose of 7.5 mg/week and sulfasalazine 1 g three times a day. As intercurrent diseases, she presented arterial hypertension of several years evolution treated with hydrochlorothiazide. In regards to the rest, she presented no medical-surgical background of interest and the control of her baseline disease was optimum.

The patient came to our medical unit reporting the appearance of a progressively growing ulceration in the oral vestibule and anterior upper maxillary gum together with an important and progressive mobility of the remanent upper dental pieces of several weeks evolution, with intense pain and chewing difficulty. Equally, she reported the appearance of a communication between the palate and right nasogenian area with escaping of intermittent purulent material one week earlier.

On examination, the patient presented this necrotic appearing ulceration in the areas described, with irregular outline and exposure of the upper maxillary bone with ground glass appearance as well as great mobility of all the upper remnant dental pieces, this being more accentuated in the left anterior front, with pain on palpation. In addition, the opening of a fistulous pathway was observed in the left region of the palate and its emptying into the right nasogenian area. During the examination, no escape of purulent fluid through the fistulous opening was observed. (Fig.1)

The rest of the physical examination by apparatuses was normal without any other symptoms except for cervical discomfort of years of evolution. In the plain X-ray examination, the patient presented degenerative arthropathy with posterior subluxation of C3 on C2.

In the MRI, an increase of the soft parts in the left upper labial region and a fistulous pathway that extends from the left upper maxillary to the right nasogenian sulcus was observed.

In the CT scan, bone reabsorption was observed in the third anterior portion of the left hard palate with the already mentioned cutaneous fistulous pathway associated to bone reabsorption phenomena of the alveolar apophysis in both the left and right upper maxillary.

Epstein-Barr virus serology was positive and the thoracicabdominal CT scan was completely normal.

The bone marrow study showed a gross analysis and a normal cytology study.

The biopsy reported it as a non-Hodgkin’s lymphoma of large B cells with numerous plasmoblasts and atypical plasma cells, presenting traits of angiocentricity and necrotic zones with intense cellular proliferation.(Fig. 2 y 3)

The immunohistochemical study revealed the presence of B cells with CD79a expression and occasionally CD 20 without cyotplasmic positivity for immunoglobulins and with an elevated cellular proliferation rate (ki 67). The Epstein- Barr virus serology was positive and the thoracic-abdominal CT scan was completely normal.

Non-hodgkin’s lymphoma of oral cavity associated to treatment with methotrexate
Linfoma no-Hodgkin de cavidad oral asociado a tratamiento con metotrexate


C. Navarro1, F. Riba1, H. Herencia1, J. Acero2, J.J. Verdaguer2, J. Menarguez3

1 Medico residente. HGU Gregorio Marañón.
2 Médico adjunto. HGU Gregorio Marañón.
3 Médico adjunto. Pathology Service. HGU Gregorio Marañón. Madrid. España.

Servicio de Cirugía Oral y Maxilofacial
Hospital General Universitario Gregorio Marañón.
Universidad Complutense de Madrid. Madrid. España

Carlos Navarro Cuéllar
C/María Molina 60, 7ºA
28006 Madrid. Spain.
Tel: 91-562 40 46


The patient has been diagnosed of Type B non-Hodgkin’s lymphoma associated with the use of methotrexate, so that treatment with this drug was immediately discontinued.

After, administration of chemotherapy was begun with four cycles of VLCOP-B in which 300 mg/m2 of cyclphosphamide and 10 mg/m2 of mitoxantrone were administered. It was decided to not use treatment with monoclonal antibodies given the limited expression of CD 20 in this case.

The imaging tests performed at the end of the fourth chemotherapy cycle showed a partial remission of the tumor, and the patient died months later.


Rheumatoid arthritis is a chronic and multisystemic disease characterized by permanent synovitis that bilaterally and symmetrically affects the peripheral joints. Its extra-articular manifestations are well described in the literature, but its relationship with neoplastic conditions is not well known. Different studies suggest that there is a relationship between this disease and malignant tumor diseases. In 1958, Abbatt and Lea1 observed an increase in the incidence of leukemia in patients with rheumatoid arthritis. In 1964, Lea2 described an increase of lymphomas in patients with this same disease. After, Isomaki3, Hakulinen4 and Prior5 detected an increase in the incidence of lymphoproliferative lesions, especially of lymphomas, in this same type of patients.

On the contrary to the above, there are studies in which no real relationship is found between rheumatoid arthritis and malignant hematological diseases. Katusic6 performed a revision of patients with rheumatoid arthritis seen between 1950 and 1975 without finding an increase in the incidence of malignant conditions except for multiple myeloma. In 1992, Doody7 concluded that there is no evidence that clearly associates the relationship between the musculoskeletal conditions in rheumatoid arthritis with the consequent development of lymphomas. Finally, Banks8 did not find any differences between the lymphomas in patients with rheumatoid arthritis and lymphomas of patients who do not suffer this disease.

Methotrexate is an antimetabolite that is structurally analogue to folic acid. The action mechanism of this drug consists in an alteration in the synthesis of DNA by inhibition of dihydrofolate reductase. The exact mechanism by which methotrexate acts in suppressing the activity of rheumatoid arthritis is not well known, although recent studies suggest the possibility of increased adenosine release in the affected areas9.

Since the end of the last century, we know that some lymphoproliferative disorders that appear in patients with rheumatoid arthritis treated with methotrexate are associated with colonization by the Epstein-Barr virus (EBV), their possible remission once this drug is eliminated being described10 and it is presently considered a defined clinical entity, although there is still some controversy in this regards.

Bologna11 performed a retrospective analysis investigating a possible relationship between the use of methotrexate and the development of hematological tumor conditions in patients with rheumatoid arthritis and did not establish any type of cause-effect relationship.

Moder12 performed a retrospective study of 39 patients and did not find histological differences between the lymphomas of methotrexate treated patients and lymphomas of those treated with other antirheumatic agents. He concluded by saying that if the risk of developing a lymphoma in patients treated with methotrexate exists, it is small and it is not related with the cumulative dose or with the maximum dose or with the treatment duration.

Presentation of the Cell B Non-Hodgkin’s lymphoma associated to methotrexate is an extremely rare situation, there being an extranodal location in up to 40%, especially in the digestive tract, lung, skin and kidney and, rarely, in the head and neck area. (Fig,2 y 3)

The role of methotrexate in the genesis and development of malignant conditions in patients with rheumatoid arthritis and, in general, in immunodepressed patients is, thus very controversial. Some authors suggest that the immunosuppression produced by this drug, together with the previous immunodepressed state of the patients with rheumatoid arthritis, favor colonization and proliferation of EBV in B lympocytes. In fact, this type of patients presents a very high prevalence of B lymphocytes infected by EBV with extranodal site and its remission may be possible once methotrexate is discontinued. 13,14

The last mechanisms by which methotrexate precipitates this situation and contributes in the genesis of the lymphoma are many, although they are not well known due to the rareness of this association. On the one hand, it accentuates T lymphocyte dysfunction by direct induction of its apoptosis and inhibition of the polyamines, basically for growth and cellular replication15.

On the other hand, it decreases the normal function of the cytotoxic T lymphocytes and natural killer cells, favoring the growth and development of the B lymphocytes infected by EBV, thus achieving its transformation and accumulation in the lymph nodes and synovial fluid16. (Fig.4)

Studies exist in both senses in regards to the possible relationship between withdrawal of the drug and spontaneous remission of the neoplastic condition.

In 1996, Salloum13 published a study in which he reviewed 16 cases of rheumatoid arthritis treated with methotrexate and their later development of non-Hodgkin’s lymphoma. Once this drug was withdrawn, only 37.5% of the patients achieved complete remission. Equally, Usman and Yunus17 analyzed 18 cases with the same characteristics and reported complete and spontaneous remission after withdrawal of the drug in 16%.

However, there are other studies that indicate the contrary and show spontaneous remission of non-Hodgkin’s lymphoma once methotrexate is withdrawn, thus suggesting a possible causal relationship18-20.

Thus, and in spite of the studies in one sense or another, the cause-effect relationship between the administration of methotrexate in patients with rheumatoid arthritis and the later development of non-Hodgkin’s lymphoma is well-established at present.

It is a very rare entity whose diagnosis may be suggested if a destructive condition appears suggestive of lymphoma in patients undergoing treatment with methotrexate. The fatality of the picture is high with an approximate survival rate of 50% at 5 years.

Withdrawal of this drug should be contemplated as a first therapeutic step in the management of the disease, a control period of 2-3 months being suggested to verify a possible spontaneous remission before beginning chemotherapy.


1. Abbat JD, Lea AJ. Leukaemogens. Lancet 1958;2:880-3.         [ Links ]

2. Lea AJ. Anassociation between the rheumatic diseases and the reticulotes. ANN Rheum Dis 1964;23:480-4.         [ Links ]

3. Isomäki HA, Hakulinen T, Joutsenlahti U. Excess risk of lymphomas, leukemia and myeloma in patients with rheumatoid arthritis. J Chronic Dis 1978;31:691-6.         [ Links ]

4. Hakulinen T, Isomäki HA, Knekt P. Rheumatoid arthritis and cancer studies based on linking nationwide registries in Finland. Am J Med 1984;78(suppl.1a):29-32.         [ Links ]

5. Prior P, Symmons DPM, Hawkins CF. Cancer morbidity in rheumatoid arthritis. Ann Rheum Dis 1984;43:128-31.         [ Links ]

6. Katusic S, Beard CM, Kurland LT. Occurrence of malignant neoplasms in the Rochester, Minnesota,rheumatoid arthritis cohort. Am J Med 1985;78 (suppl 1a):50-55.         [ Links ]

7. Doody MD, Linet MS, Glass AG. Leukemia, lymphoma and multiple myeloma following selected medical conditions. Cancer Causes Control 1992;3:449-56.         [ Links ]

8. Banks PM, Witrak GA, Conn DL. Lymphoid neoplasia following connective tissue disease. Mayo Clin Proc 1979; 54:104-8.         [ Links ]

9. Cronstein BN, Naime D, Olstad E. The antiinflamatory mechanism of methotrexate. Increased adenosine release at inflamed sites diminished leukocyte accumulation in an in vivo model of inflammation. J Clin Invest 1993;92: 2675-82.         [ Links ]

10. Kamel OW, Van de Rijn M, Weiss LM. Reversible lymphomas associated with Epstein-Barr virus occurring during methotrexate therapy for rheumatoid arthritis and dermatomyositis. N Engl J Med 1993;328: 1317-21.         [ Links ]

11. Bologna C, Picot MC, Jorgensen C, Viu P, Verdier R, Sany J. Study of 8 cases of cancer in 426 rheumatoid artritis patients treated with methotrexate. Ann Rheum Dis 1997;56:97-102.         [ Links ]

12. Moder KG, Teffery A, Cohen MD, Menke DM, Luthra HS. Hematologic malignancies and the use of methotrexate in rheumatoid arthritis: a retrospective study. Am J Med 1995;99:276-81.         [ Links ]

13. Salloum E, Cooper DL, Howe G, Lacy J, Tallini G, Crouch J. Spontaneous regression of lymphoproliferative disorders in patients treated with methotrexate for rheumatoid arthrties and other rheumatic diseases. J Clin Oncol 1996;14:1943-49.         [ Links ]

14. Georgescu L, Quinn G, Schwartzman S, Paget S. Lymphoma in patients with rheumatoid arthritis: association with the disease state of methotrexate treatment. Semin Arthritis Rheum 1997;26:794- 804.         [ Links ]

15. Kremer J. Is methotrexate oncogenic in patients with rheumatoid arthritis? Semin Arthritis Rheum 1997;26:785-7.         [ Links ]

16. Van deRijn M, Cleary M, Variakojis D, Warnke RA, Chang PP, Kamel O. Epstein-Barr virus clonality in lymphomas occurring in patients with rheumatoid arthritis. Arthrtis Rheum 1996;39:638-42.         [ Links ]

17. Usman AR, Yunus MB. Non-Hodgkin´s lymphoma in patients with rheumatoid arthritis treated with low-dose of methotrexate. J Rheum 1996;23:1095-7.         [ Links ]

18. Sibilia J, Liote F, Mariette X. Lymphoproliferative disorders in rheumatoid arthritis patients on low-dose metotrexate. Revue Du Rhumatisme, English Edition 1998;65: 267-273.         [ Links ]

19. Georgescu L, Paget SA. Lymphoma in patients with rheumatoid arthritis: what is the evidence of a link with methotrexate? Drug Safety 1999;20:475-87.         [ Links ]

20. Le Goff P, Chicault P, Saraux A, Baron D, Valls-Bellec I, Leroy JP. Lymphoma with regression after methotrexate withdrawal in a patient with rheumatoid arthritis. Role for the Epstein-Barr virus. Revue Du Rhumatisme, English Edition 1998;65:283-6.         [ Links ]

Creative Commons License Todo el contenido de esta revista, excepto dónde está identificado, está bajo una Licencia Creative Commons